Headache as a symptom of COVID-19 could help predict survival for inpatients with the disease, according to recent research published in the journal Headache.

In the systematic review and meta-analysis, Víctor J. Gallardo, MSc, of the headache and neurologic pain research group, Vall d’Hebron Research Institute at the Universitat Autònoma de Barcelona, and colleagues performed a search of studies in PubMed involving headache symptoms, disease survival, and inpatient COVID-19 cases published between December 2019 and December 2020. Overall, 48 studies were identified, consisting of 43,169 inpatients with COVID-19. Using random-effects pooling models, Mr. Gallardo and colleagues estimated the prevalence of headache for inpatients who survived COVID-19, compared with those who did not survive.

Within those studies, 35,132 inpatients (81.4%) survived, while 8,037 inpatients (18.6%) died from COVID-19. The researchers found that inpatients with COVID-19 and headache symptoms had a significantly higher survival rate compared with inpatients with COVID-19 without headache symptoms (risk ratio, 1.90; 95% confidence interval, 1.46-2.47; P < .0001). There was an overall pooled prevalence of headache as a COVID-19 symptom in 10.4% of inpatients, which was reduced to an estimated pooled prevalence of 9.7% after the researchers removed outlier studies in a sensitivity analysis.

Other COVID-19 symptoms that led to improved rates of survival among inpatients were anosmia (RR, 2.94; 95% CI, 1.94-4.45) and myalgia (RR, 1.57; 95% CI, 1.34-1.83) as well as nausea or vomiting (RR, 1.41; 95% CI, 1.08-1.82), while symptoms such as dyspnea, diabetes, chronic liver diseases, chronic respiratory diseases, and chronic kidney diseases were more likely to increase the risk of dying from COVID-19.

The researchers noted several limitations in their meta-analysis that may make their findings less generalizable to future SARS-CoV-2 variants, such as including only studies that were published before COVID-19 vaccines were available and before more infectious SARS-CoV-2 variants like the B.1.617.2 (Delta) variant emerged. They also included studies where inpatients were not tested for COVID-19 because access to testing was not widely available.

“Our meta-analysis points toward a novel possibility: Headache arising secondary to an infection is not a ‘nonspecific’ symptom, but rather it may be a marker of enhanced likelihood of survival. That is, we find that patients reporting headache in the setting of COVID-19 are at reduced risk of death,” Mr. Gallardo and colleagues wrote.
 

More data needed on association between headache and COVID-19

While headache appeared to affect a small proportion of overall inpatients with COVID-19, the researchers noted this might be because individuals with COVID-19 and headache symptoms are less likely to require hospitalization or a visit to the ED. Another potential explanation is that “people with primary headache disorders, including migraine, may be more likely to report symptoms of COVID-19, but they also may be relatively less likely to experience a life-threatening COVID-19 disease course.”

The researchers said this potential association should be explored in future studies as well as in other viral infections or postviral syndromes such as long COVID. “Defining specific headache mechanisms that could enhance survival from viral infections represents an opportunity for the potential discovery of improved viral therapeutics, as well as for understanding whether, and how, primary headache disorders may be adaptive.”

In a comment, Morris Levin, MD, director of the University of California San Francisco Headache Center, said the findings “of this very thought-provoking review suggest that reporting a headache during a COVID-19 infection seems to be associated with better recovery in hospitalized patients.”

Dr. Levin, who was not involved with the study, acknowledged the researchers’ explanation for the overall low rate of headache in these inpatients as one possible explanation.

“Another could be that sick COVID patients were much more troubled by other symptoms like respiratory distress, which overshadowed their headache symptoms, particularly if they were very ill or if the headache pain was of only mild to moderate severity,” he said. “That could also be an alternate explanation for why less dangerously ill hospitalized patients seemed to have more headaches.”

One limitation he saw in the meta-analysis was how clearly the clinicians characterized headache symptoms in each reviewed study. Dr. Levin suggested a retrospective assessment of premorbid migraine history in hospitalized patients with COVID-19, including survivors and fatalities, might have helped clarify this issue. “The headaches themselves were not characterized so drawing conclusions regarding migraine is challenging.”

Dr. Levin noted it is still not well understood how acute and persistent headaches and other neurological symptoms like mental fog occur in patients with COVID-19. We also do not fully understand the natural history of post-COVID headaches and other neurologic sequelae and the management options for acute and persistent neurological sequelae.

Three authors reported personal and institutional relationships in the form of grants, consultancies, speaker’s bureau positions, guidelines committee member appointments, and editorial board positions for a variety of pharmaceutical companies, agencies, societies, and other organizations. Mr. Gallardo reported no relevant financial disclosures. Dr. Levin reported no relevant financial disclosures.

Headache as a symptom of COVID-19 could help predict survival for inpatients with the disease, according to recent research published in the journal Headache.

In the systematic review and meta-analysis, Víctor J. Gallardo, MSc, of the headache and neurologic pain research group, Vall d’Hebron Research Institute at the Universitat Autònoma de Barcelona, and colleagues performed a search of studies in PubMed involving headache symptoms, disease survival, and inpatient COVID-19 cases published between December 2019 and December 2020. Overall, 48 studies were identified, consisting of 43,169 inpatients with COVID-19. Using random-effects pooling models, Mr. Gallardo and colleagues estimated the prevalence of headache for inpatients who survived COVID-19, compared with those who did not survive.

Within those studies, 35,132 inpatients (81.4%) survived, while 8,037 inpatients (18.6%) died from COVID-19. The researchers found that inpatients with COVID-19 and headache symptoms had a significantly higher survival rate compared with inpatients with COVID-19 without headache symptoms (risk ratio, 1.90; 95% confidence interval, 1.46-2.47; P < .0001). There was an overall pooled prevalence of headache as a COVID-19 symptom in 10.4% of inpatients, which was reduced to an estimated pooled prevalence of 9.7% after the researchers removed outlier studies in a sensitivity analysis.

Other COVID-19 symptoms that led to improved rates of survival among inpatients were anosmia (RR, 2.94; 95% CI, 1.94-4.45) and myalgia (RR, 1.57; 95% CI, 1.34-1.83) as well as nausea or vomiting (RR, 1.41; 95% CI, 1.08-1.82), while symptoms such as dyspnea, diabetes, chronic liver diseases, chronic respiratory diseases, and chronic kidney diseases were more likely to increase the risk of dying from COVID-19.

The researchers noted several limitations in their meta-analysis that may make their findings less generalizable to future SARS-CoV-2 variants, such as including only studies that were published before COVID-19 vaccines were available and before more infectious SARS-CoV-2 variants like the B.1.617.2 (Delta) variant emerged. They also included studies where inpatients were not tested for COVID-19 because access to testing was not widely available.

“Our meta-analysis points toward a novel possibility: Headache arising secondary to an infection is not a ‘nonspecific’ symptom, but rather it may be a marker of enhanced likelihood of survival. That is, we find that patients reporting headache in the setting of COVID-19 are at reduced risk of death,” Mr. Gallardo and colleagues wrote.
 

More data needed on association between headache and COVID-19

While headache appeared to affect a small proportion of overall inpatients with COVID-19, the researchers noted this might be because individuals with COVID-19 and headache symptoms are less likely to require hospitalization or a visit to the ED. Another potential explanation is that “people with primary headache disorders, including migraine, may be more likely to report symptoms of COVID-19, but they also may be relatively less likely to experience a life-threatening COVID-19 disease course.”

The researchers said this potential association should be explored in future studies as well as in other viral infections or postviral syndromes such as long COVID. “Defining specific headache mechanisms that could enhance survival from viral infections represents an opportunity for the potential discovery of improved viral therapeutics, as well as for understanding whether, and how, primary headache disorders may be adaptive.”

In a comment, Morris Levin, MD, director of the University of California San Francisco Headache Center, said the findings “of this very thought-provoking review suggest that reporting a headache during a COVID-19 infection seems to be associated with better recovery in hospitalized patients.”

Dr. Levin, who was not involved with the study, acknowledged the researchers’ explanation for the overall low rate of headache in these inpatients as one possible explanation.

“Another could be that sick COVID patients were much more troubled by other symptoms like respiratory distress, which overshadowed their headache symptoms, particularly if they were very ill or if the headache pain was of only mild to moderate severity,” he said. “That could also be an alternate explanation for why less dangerously ill hospitalized patients seemed to have more headaches.”

One limitation he saw in the meta-analysis was how clearly the clinicians characterized headache symptoms in each reviewed study. Dr. Levin suggested a retrospective assessment of premorbid migraine history in hospitalized patients with COVID-19, including survivors and fatalities, might have helped clarify this issue. “The headaches themselves were not characterized so drawing conclusions regarding migraine is challenging.”

Dr. Levin noted it is still not well understood how acute and persistent headaches and other neurological symptoms like mental fog occur in patients with COVID-19. We also do not fully understand the natural history of post-COVID headaches and other neurologic sequelae and the management options for acute and persistent neurological sequelae.

Three authors reported personal and institutional relationships in the form of grants, consultancies, speaker’s bureau positions, guidelines committee member appointments, and editorial board positions for a variety of pharmaceutical companies, agencies, societies, and other organizations. Mr. Gallardo reported no relevant financial disclosures. Dr. Levin reported no relevant financial disclosures.

Headache as a symptom of COVID-19 could help predict survival for inpatients with the disease, according to recent research published in the journal Headache.

In the systematic review and meta-analysis, Víctor J. Gallardo, MSc, of the headache and neurologic pain research group, Vall d’Hebron Research Institute at the Universitat Autònoma de Barcelona, and colleagues performed a search of studies in PubMed involving headache symptoms, disease survival, and inpatient COVID-19 cases published between December 2019 and December 2020. Overall, 48 studies were identified, consisting of 43,169 inpatients with COVID-19. Using random-effects pooling models, Mr. Gallardo and colleagues estimated the prevalence of headache for inpatients who survived COVID-19, compared with those who did not survive.

Within those studies, 35,132 inpatients (81.4%) survived, while 8,037 inpatients (18.6%) died from COVID-19. The researchers found that inpatients with COVID-19 and headache symptoms had a significantly higher survival rate compared with inpatients with COVID-19 without headache symptoms (risk ratio, 1.90; 95% confidence interval, 1.46-2.47; P < .0001). There was an overall pooled prevalence of headache as a COVID-19 symptom in 10.4% of inpatients, which was reduced to an estimated pooled prevalence of 9.7% after the researchers removed outlier studies in a sensitivity analysis.

Other COVID-19 symptoms that led to improved rates of survival among inpatients were anosmia (RR, 2.94; 95% CI, 1.94-4.45) and myalgia (RR, 1.57; 95% CI, 1.34-1.83) as well as nausea or vomiting (RR, 1.41; 95% CI, 1.08-1.82), while symptoms such as dyspnea, diabetes, chronic liver diseases, chronic respiratory diseases, and chronic kidney diseases were more likely to increase the risk of dying from COVID-19.

The researchers noted several limitations in their meta-analysis that may make their findings less generalizable to future SARS-CoV-2 variants, such as including only studies that were published before COVID-19 vaccines were available and before more infectious SARS-CoV-2 variants like the B.1.617.2 (Delta) variant emerged. They also included studies where inpatients were not tested for COVID-19 because access to testing was not widely available.

“Our meta-analysis points toward a novel possibility: Headache arising secondary to an infection is not a ‘nonspecific’ symptom, but rather it may be a marker of enhanced likelihood of survival. That is, we find that patients reporting headache in the setting of COVID-19 are at reduced risk of death,” Mr. Gallardo and colleagues wrote.
 

More data needed on association between headache and COVID-19

While headache appeared to affect a small proportion of overall inpatients with COVID-19, the researchers noted this might be because individuals with COVID-19 and headache symptoms are less likely to require hospitalization or a visit to the ED. Another potential explanation is that “people with primary headache disorders, including migraine, may be more likely to report symptoms of COVID-19, but they also may be relatively less likely to experience a life-threatening COVID-19 disease course.”

The researchers said this potential association should be explored in future studies as well as in other viral infections or postviral syndromes such as long COVID. “Defining specific headache mechanisms that could enhance survival from viral infections represents an opportunity for the potential discovery of improved viral therapeutics, as well as for understanding whether, and how, primary headache disorders may be adaptive.”

In a comment, Morris Levin, MD, director of the University of California San Francisco Headache Center, said the findings “of this very thought-provoking review suggest that reporting a headache during a COVID-19 infection seems to be associated with better recovery in hospitalized patients.”

Dr. Levin, who was not involved with the study, acknowledged the researchers’ explanation for the overall low rate of headache in these inpatients as one possible explanation.

“Another could be that sick COVID patients were much more troubled by other symptoms like respiratory distress, which overshadowed their headache symptoms, particularly if they were very ill or if the headache pain was of only mild to moderate severity,” he said. “That could also be an alternate explanation for why less dangerously ill hospitalized patients seemed to have more headaches.”

One limitation he saw in the meta-analysis was how clearly the clinicians characterized headache symptoms in each reviewed study. Dr. Levin suggested a retrospective assessment of premorbid migraine history in hospitalized patients with COVID-19, including survivors and fatalities, might have helped clarify this issue. “The headaches themselves were not characterized so drawing conclusions regarding migraine is challenging.”

Dr. Levin noted it is still not well understood how acute and persistent headaches and other neurological symptoms like mental fog occur in patients with COVID-19. We also do not fully understand the natural history of post-COVID headaches and other neurologic sequelae and the management options for acute and persistent neurological sequelae.

Three authors reported personal and institutional relationships in the form of grants, consultancies, speaker’s bureau positions, guidelines committee member appointments, and editorial board positions for a variety of pharmaceutical companies, agencies, societies, and other organizations. Mr. Gallardo reported no relevant financial disclosures. Dr. Levin reported no relevant financial disclosures.

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

A version of this article first appeared on WebMD.com.

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

A version of this article first appeared on WebMD.com.

About 1 in 20 people with long COVID continue to live with symptoms at 18 months, and another 42% reported only some improvement in their health and wellbeing in the same time frame, a large study out of Scotland found.

Multiple studies are evaluating people with long COVID in the hopes of figuring out why some people experience debilitating symptoms long after their primary infection ends and others either do not or recover more quickly. 

This current study is notable for its large size – 96,238 people. Researchers checked in with participants at 6, 12, and 18 months, and included a group of people never infected with the coronavirus to help investigators make a stronger case.

“A lot of the symptoms of long COVID are nonspecific and therefore can occur in people never infected,” says senior study author Jill P. Pell, MD, head of the School of Health and Wellbeing at the University of Glasgow in Scotland. 
 

Ruling out coincidence

This study shows that people experienced a wide range of symptoms after becoming infected with COVID-19 at a significantly higher rate than those who were never infected, “thereby confirming that they were genuinely associated with COVID and not merely a coincidence,” she said. 

Among 21,525 people who had COVID-19 and had symptoms, tiredness, headache and muscle aches or muscle weakness were the most common ongoing symptoms. 

Loss of smell was almost nine times more likely in this group compared to the never-infected group in one analysis where researchers controlled for other possible factors. The risk for loss of taste was almost six times greater, followed by risk of breathlessness at three times higher. 

Long COVID risk was highest after a severe original infection and among older people, women, Black, and South Asian populations, people with socioeconomic disadvantages, and those with more than one underlying health condition.

Adding up the 6% with no recovery after 18 months and 42% with partial recovery means that between 6 and 18 months following symptomatic coronavirus infection, almost half of those infected still experience persistent symptoms.
 

Vaccination validated

On the plus side, people vaccinated against COVID-19 before getting infected had a lower risk for some persistent symptoms. In addition, Dr. Pell and colleagues found no evidence that people who experienced asymptomatic infection were likely to experience long COVID symptoms or challenges with activities of daily living. 

The findings of the Long-COVID in Scotland Study (Long-CISS) were published in the journal Nature Communications.
 

‘More long COVID than ever before’

“Unfortunately, these long COVID symptoms are not getting better as the cases of COVID get milder,” said Thomas Gut, DO, medical director for the post-COVID recovery program at Staten Island (N.Y.) University Hospital. “Quite the opposite – this infection has become so common in a community because it’s so mild and spreading so rapidly that we’re seeing more long COVID symptoms than ever before.” 

Although most patients he sees with long COVID resolve their symptoms within 3-6 months, “We do see some patients who require short-term disability because their symptoms continue past 6 months and out to 2 years,” said Dr. Gut, a hospitalist at Staten Island University Hospital, a member hospital of Northwell Health.

Patients with fatigue and neurocognitive symptoms “have a very tough time going back to work. Short-term disability gives them the time and finances to pursue specialty care with cardiology, pulmonary, and neurocognitive testing,” he said.
 

Support the whole person

The burden of living with long COVID goes beyond the persistent symptoms. “Long COVID can have wide-ranging impacts – not only on health but also quality of life and activities of daily living [including] work, mobility, self-care and more,” Dr. Pell said. “So, people with long COVID need support relevant to their individual needs and this may extend beyond the health care sector, for example including social services, school or workplace.”

Still,  Lisa Penziner, RN, founder of the COVID Long Haulers Support Group in Westchester and Long Island, N.Y., said while people with the most severe cases of COVID-19 tended to have the worst long COVID symptoms, they’re not the only ones. 

“We saw many post-COVID members who had mild cases and their long-haul symptoms were worse weeks later than the virus itself,” said Md. Penziner. 

She estimates that 80%-90% of her support group members recover within 6 months. “However, there are others who were experiencing symptoms for much longer.”

Respiratory treatment, physical therapy, and other follow-up doctor visits are common after 6 months, for example. 

“Additionally, there is a mental health component to recovery as well, meaning that the patient must learn to live while experiencing lingering, long-haul COVID symptoms in work and daily life,” said Ms. Penziner, director of special projects at North Westchester Restorative Therapy & Nursing. 

In addition to ongoing medical care, people with long COVID need understanding, she said.

“While long-haul symptoms do not happen to everyone, it is proven that many do experience long-haul symptoms, and the support of the community in understanding is important.”
 

Limitations of the study

Dr. Pell and colleagues noted some strengths and weaknesses to their study. For example, “as a general population study, our findings provide a better indication of the overall risk and burden of long COVID than hospitalized cohorts,” they noted. 

Also, the Scottish population is 96% White, so other long COVID studies with more diverse participants are warranted. 

Another potential weakness is the response rate of 16% among those invited to participate in the study, which Dr. Pell and colleagues addressed: “Our cohort included a large sample (33,281) of people previously infected and the response rate of 16% overall and 20% among people who had symptomatic infection was consistent with previous studies that have used SMS text invitations as the sole method of recruitment.”

“We tell patients this should last 3-6 months, but some patients have longer recovery periods,” Dr. Gut said. “We’re here for them. We have a lot of services available to help get them through the recovery process, and we have a lot of options to help support them.”

“What we found most helpful is when there is peer-to-peer support, reaffirming to the member that they are not alone in the long-haul battle, which has been a major benefit of the support group,” Ms. Penziner said.

A version of this article first appeared on WebMD.com.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

Foods for thought: Menstrual cramp prevention

For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.

Carlo107/Getty Images

About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?

Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.

In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.

The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
 

Stage 1 of the robot apocalypse is already upon us

The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.

Inderpreet/Pixahive

Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.

The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.

In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.

It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”

Oops. Our bad.
 

Apocalypse, stage 2: Leaping oral superorganisms

The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.

Penn Dental Medicine

Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.

While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.

Did he say “mobility”? He did, didn’t he?

To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.

“Incubated in human saliva.” There’s a phrase you don’t see every day.

It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”

So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.

Foods for thought: Menstrual cramp prevention

For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.

Carlo107/Getty Images

About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?

Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.

In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.

The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
 

Stage 1 of the robot apocalypse is already upon us

The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.

Inderpreet/Pixahive

Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.

The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.

In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.

It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”

Oops. Our bad.
 

Apocalypse, stage 2: Leaping oral superorganisms

The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.

Penn Dental Medicine

Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.

While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.

Did he say “mobility”? He did, didn’t he?

To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.

“Incubated in human saliva.” There’s a phrase you don’t see every day.

It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”

So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.

Foods for thought: Menstrual cramp prevention

For those who menstruate, it’s typical for that time of the month to bring cravings for things that may give a serotonin boost that eases the rise in stress hormones. Chocolate and other foods high in sugar fall into that category, but they could actually be adding to the problem.

Carlo107/Getty Images

About 90% of adolescent girls have menstrual pain, and it’s the leading cause of school absences for the demographic. Muscle relaxers and PMS pills are usually the recommended solution to alleviating menstrual cramps, but what if the patient doesn’t want to take any medicine?

Serah Sannoh of Rutgers University wanted to find another way to relieve her menstrual pains. The literature review she presented at the annual meeting of the North American Menopause Society found multiple studies that examined dietary patterns that resulted in menstrual pain.

In Ms. Sannoh’s analysis, she looked at how certain foods have an effect on cramps. Do they contribute to the pain or reduce it? Diets high in processed foods, oils, sugars, salt, and omega-6 fatty acids promote inflammation in the muscles around the uterus. Thus, cramps.

The answer, sometimes, is not to add a medicine but to change our daily practices, she suggested. Foods high in omega-3 fatty acids helped reduce pain, and those who practiced a vegan diet had the lowest muscle inflammation rates. So more salmon and fewer Swedish Fish.
 

Stage 1 of the robot apocalypse is already upon us

The mere mention of a robot apocalypse is enough to conjure images of terrifying robot soldiers with Austrian accents harvesting and killing humanity while the survivors live blissfully in a simulation and do low-gravity kung fu with high-profile Hollywood actors. They’ll even take over the navy.

Inderpreet/Pixahive

Reality is often less exciting than the movies, but rest assured, the robots will not be denied their dominion of Earth. Our future robot overlords are simply taking a more subtle, less dramatic route toward their ultimate subjugation of mankind: They’re making us all sad and burned out.

The research pulls from work conducted in multiple countries to paint a picture of a humanity filled with anxiety about jobs as robotic automation grows more common. In India, a survey of automobile manufacturing works showed that working alongside industrial robots was linked with greater reports of burnout and workplace incivility. In Singapore, a group of college students randomly assigned to read one of three articles – one about the use of robots in business, a generic article about robots, or an article unrelated to robots – were then surveyed about their job security concerns. Three guesses as to which group was most worried.

In addition, the researchers analyzed 185 U.S. metropolitan areas for robot prevalence alongside use of job-recruiting websites and found that the more robots a city used, the more common job searches were. Unemployment rates weren’t affected, suggesting people had job insecurity because of robots. Sure, there could be other, nonrobotic reasons for this, but that’s no fun. We’re here because we fear our future android rulers.

It’s not all doom and gloom, fortunately. In an online experiment, the study authors found that self-affirmation exercises, such as writing down characteristics or values important to us, can overcome the existential fears and lessen concern about robots in the workplace. One of the authors noted that, while some fear is justified, “media reports on new technologies like robots and algorithms tend to be apocalyptic in nature, so people may develop an irrational fear about them.”

Oops. Our bad.
 

Apocalypse, stage 2: Leaping oral superorganisms

The terms of our secret agreement with the shadowy-but-powerful dental-industrial complex stipulate that LOTME can only cover tooth-related news once a year. This is that once a year.

Penn Dental Medicine

Since we’ve already dealt with a robot apocalypse, how about a sci-fi horror story? A story with a “cross-kingdom partnership” in which assemblages of bacteria and fungi perform feats greater than either could achieve on its own. A story in which new microscopy technologies allow “scientists to visualize the behavior of living microbes in real time,” according to a statement from the University of Pennsylvania, Philadelphia.

While looking at saliva samples from toddlers with severe tooth decay, lead author Zhi Ren and associates “noticed the bacteria and fungi forming these assemblages and developing motions we never thought they would possess: a ‘walking-like’ and ‘leaping-like’ mobility. … It’s almost like a new organism – a superorganism – with new functions,” said senior author Hyun Koo, DDS, PhD, of Penn Dental Medicine.

Did he say “mobility”? He did, didn’t he?

To study these alleged superorganisms, they set up a laboratory system “using the bacteria, fungi, and a tooth-like material, all incubated in human saliva,” the university explained.

“Incubated in human saliva.” There’s a phrase you don’t see every day.

It only took a few hours for the investigators to observe the bacterial/fungal assemblages making leaps of more than 100 microns across the tooth-like material. “That is more than 200 times their own body length,” Dr. Ren said, “making them even better than most vertebrates, relative to body size. For example, tree frogs and grasshoppers can leap forward about 50 times and 20 times their own body length, respectively.”

So, will it be the robots or the evil superorganisms? Let us give you a word of advice: Always bet on bacteria.

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.

About 700,000 US military personnel were deployed in Operation Desert Storm (August 1990 to March 1991).¹ Almost 30 years since the war, a large number of these veterans continue to experience a complex of symptoms of unknown etiology called Gulf War illness (GWI), which significantly affects health and quality of life (QOL). The lack of clear etiology of the illness has impaired research to find specific treatments and has further exacerbated the stress among veterans. GWI typically includes a mixture of chronic headache, cognitive difficulties, widespread pain, unexplained fatigue, memory and concentration problems, as well as chronic respiratory and gastrointestinal (GI) symptoms.² Abdominal pain and alteration of bowel habits are also symptoms typical of irritable bowel syndrome (IBS). It has been estimated that IBS occurs in up to 30% of Gulf War veterans.³

The etiology of IBS is unknown. Possible mechanisms include visceral hypersensitivity, altered gut motor function, aberrant brain-gut interaction, and psychological factors, perhaps with a genetic predisposition.⁴ Gastroenteritis has been reported as a triggering mechanism in up to one-third of patients with IBS.⁵ Gastroenteritis can alter the gut microbiota and has been reported to be a significant risk factor for the development of IBS.⁶ In one study of Operation Desert Shield soldiers, > 50% of military personnel developed acute gastroenteritis while on duty.⁷ A high prevalence of extra-intestinal symptoms also has been reported, including fatigue, headache, joint pains, and anxiety, in Gulf War veterans with IBS. These extra-intestinal symptoms of IBS are consistent with the reported GWI symptoms. Change in gut microbiota also has been associated with many of the extra-intestinal symptoms of IBS, especially fatigue.^8,9 Gut microbiota are known to change with travel, stress, and a change in diet, all potential factors that are relevant to Gulf War veterans. This would suggest that an imbalance in the gut microbiota, ie, dysbiosis, may play a role in the pathogenesis of both IBS and GWI. Dysbiosis could be a risk factor for or alternatively a consequence of GWI.

A systematic review highlighted the heterogeneity of the gut microbiota in patients with IBS.¹⁰ Overall, Enterobacteriaceae, Lactobacillaceae, and Bacteroides were increased, whereas Clostridiales, Faecalibacterium, and Bifidobacterium were decreased in patients with IBS compared with controls. Gut microbiota also has been associated with cognitive changes, anxiety, and depression—symptoms associated with IBS and are part of the GWI.

If altered gut microbiota contributes to the etiopathogenesis of IBS, its restoration of with probiotics should help. Probiotics are live organisms that when ingested may improve health by promoting the growth of naturally occurring flora and establishing a healthy gut flora. Probiotics have several mechanisms of actions. Probiotics work in the lumen of the gut by producing antibacterial molecules and enhancing the mucosal barrier.¹¹ Probiotics also may produce metabolic compounds that alter the intestinal microbiota and improve intestinal barrier function.¹² Probiotics also have been shown to activate receptors in the enteric nervous system with the potential to promote pain relief in the setting of visceral hyperalgesia.^13,14 The anti-inflammatory properties of probiotics potentially could modulate the basic pathophysiology of IBS and improve motility, visceral hypersensitivity, and brain-gut interaction.¹⁵ Furthermore, significant gut dysbiosis has been shown with GWI; suggesting that probiotics may have a role in its management.^16,17

Probiotics have not been studied in Gulf War veterans with IBS. We performed a prospective, double-blind placebo-controlled study to determine the efficacy of a commercially available probiotic containing 8 strains of bacteria (De Simone Formulation; formally known as VSL#3 and Visbiome) on symptoms of IBS and GWI. This probiotic was selected as the overall literature suggested benefit of combination probiotics in IBS, and VSL#3 has been shown to be efficacious in ulcerative colitis and microscopic colitis.^18-20

Methods

Veterans who served in Operation Desert Storm (August 1990 to March 1991) and enrolled at the George E. Wahlen Veterans Affairs (VA) Medical Center (GEWVAMC), Salt Lake City, Utah, were eligible for the study. The inclusion criteria were: veterans aged ≥ 35 years; ≥ 2 nonintestinal GWI symptoms (eg, fatigue, joint pains, insomnia, general stiffness, and headache); IBS diagnosis based on the Rome III criteria; IBS symptoms > 6 months; normal gross appearance of the colonic mucosa; negative markers for celiac disease and inflammatory bowel disease (IBD); normal thyroid function; and serum calcium levels.²¹ Those who had a clinically significant cardiac, pulmonary, hepatic or renal dysfunction; history of/or presence of systemic malignancy; current evidence of celiac disease or IBD; unstable/significant psychiatric disease; recent change in GI medications; current pregnancy; or use of antibiotics or probiotics within the past 1 month were excluded. Subjects were enrolled from a list of veterans with GWI from the GEWVAMC Gulf War registry; referrals to gastroenterology clinics for IBS from internal medicine clinics; and posted advertisements.

Protocol

After written informed consent was obtained, each veteran was verified to have IBS and ≥ 2 GWI symptoms. All veterans had the following tests and panels: complete blood count, erythrocyte sedimentation rate, serum comprehensive metabolic panel, thyroid-stimulating hormone, tissue transglutaminase, stool test for ova and parasite, giardia antigen, and clostridia toxins to exclude organic cause of GI symptoms. Colonoscopy was performed in all veterans to exclude IBD, and to rule out microscopic or lymphocytic colitis.

Randomization was computer generated and maintained by the study pharmacist so that study personnel and patients were blinded to the trial groups. All investigators were blinded and allocation was concealed. The medication was supplied in a numbered container by the pharmacist after patient enrollment. After a 2-week run-in period, veterans were randomized (1:1) to receive either 1 sachet of probiotic (De Simone Formulation; formally known as VSL#3 and Visbiome) or placebo once daily for 8 weeks.

Each probiotic packet contains 900 billion probiotic bacteria per sachet.¹¹ This formulation contained 8 viable strains of bacteria: 4 strains of Lactobacillus (L acidophilus, L plantarum, L paracasei, L delbrueckii subsp. bulgaricus); 3 strains of Bifidobacteria (Bifidobacterium breve, B lactis, B infantis); and 1 strain of Streptococcus thermophilus. This formulation had been commercialized and studied as VSL#3 and is currently available in the United States under the Visbiome trade name. While branding changed during the study, the formulation did not. The investigational medicine (VSL#3, Visbiome, and placebo) were shipped from the manufacturer Dupont/Danisco in Madison, Wisconsin. The subjects received placebo or probiotic (VSL#3/Visbiome) and both were identical in appearance. The medication was supplied in a numbered container by the pharmacist after patient enrollment.

Measures

Veterans completed the bowel disease questionnaire to record baseline bowel habits.²² All veterans recorded daily bowel symptoms to confirm the presence of IBS during the 2-week pretreatment period, at baseline, and at the end of the 8-week treatment. The symptoms assessed included severity of abdominal pain (0, none to 100, severe); severity of bloating (0, none to 100, severe); stool frequency; Bristol stool scale (1, very hard to 7, watery); severity of diarrhea (0, none to 100, severe); severity of constipation (0, none to 100, severe); satisfaction with bowel habits (0, none to 100, severe); and IBS affecting or interfering with life (0, none to 100, severe). The bowel symptom score is the sum of the 5 symptom scores.^23,24

IBS-specific QOL (IBS-QOL) was recorded at baseline and at the end of treatment.²⁵ The IBS-QOL consists of a 34-item validated disease-specific questionnaire that measures 8 domains relevant to subjects with IBS: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual life, and relationships. We used the Somatic Symptom Checklist to detect the following extra-intestinal symptoms that are common among veterans with GWI: headache, backache, wheeziness, insomnia, bad breath, fatigue, general stiffness, dizziness, weakness, sensitivity to hot and cold, palpitation, and tightness in chest. Subjects rated symptoms on a scale of 1 to 5: how often (1, none; 2, monthly; 3, once weekly; 4, several times weekly; 5, daily), and how bothersome (1, not at all to 5, extremely).²⁶

Subjects completed the Posttraumatic Stress Disorder (PTSD) Checklist–Military, which is specific to military experience with 17 items on a 1 to 5 scale (1, not at all to 5, extremely). Scores were summed to produce a total symptom severity score (range, 17-85).²⁷ Subjects also completed the Brief Symptom Inventory 18 (BSI-18) during the baseline evaluation.²⁸ BSI-18 measures subjects’ reported overall psychological distress. It assesses 3 symptoms dimensions (somatization, depression, and anxiety) and a global severity index. The raw scores were transferred to normative T scores based on samples of nonpatient normal men and women.

Statistical Methods

Comparisons of the probiotic vs placebo groups for demographic variable were analyzed using a 2-sample t test for continuous variables, and with a χ² test or Fisher exact test for categorical variables. The primary and secondary outcome variables were recorded daily for 2 weeks as pretreatment baseline and for 2 weeks at the end of treatment. These symptoms were recorded as ordered categorical variables, which were then averaged across the week to produce a continuous measurement for statistical analysis. For the primary outcome of GI symptoms, posttreatment comparisons were made between the study groups using a 2-sample t test of the baseline vs posttreatment values. All P values were calculated for 2-sided comparisons. The planned sample size in our study protocol was to recruit 40 individuals per group in order to achieve 80% power to detect a 30% improvement between baseline and end of treatment in the primary bowel symptom score. This study recruited 53 subjects. With this sample size, the study had 80% power to detect a 0.8 SD in any of the outcomes.

Results

We screened 101 veterans with IBS and GWI; 39 veterans did not fulfill the inclusion/exclusion criteria, 22 declined to participate or did not complete the screening questionnaires and tests, and 9 were lost to follow-up. Sixty-two participants were randomized in a double-blind placebo-controlled study design; 9 dropped out before the end of the study. Data were analyzed from 53 veterans who completed the study, 29 in the placebo group and 24 in the probiotic group (Figure 1). The cohort was primarily male with a mean (SD) age of 55 (8) years (range, 42-73) (Table 1).

Overall, the treatment was well tolerated. All subjects were contacted every 2 weeks during the study to check for adverse effects, but no serious events were reported. There were no differences at baseline in any of the BSI-18 subscale scores in veterans between the groups. There was a greater mean (SEM) improvement of diarrhea severity in the probiotic group compared with the placebo group: 18 (6), a 31% improvement, vs 6 (5), a 13% improvement, respectively; however, the difference was not statistically significance (P = .13) (Table 2). There also was a greater mean (SEM) improvement in satisfaction of bowel habits in the probiotic group compared with the placebo group: 16 (7), a 35% improvement vs 4 (9), an 8% worsening; this also was not statistically significant (P = .09). There was no difference in the change of IBS-QOL before and after treatment in either group (Figure 2). There was no improvement in any of the symptoms of GWI (all P ≥ .06) (Appendix).

Discussion

GWI is a complex multisystem illness of unknown etiology. There was high prevalence of diarrhea during deployment, and veterans were exposed to several physical, environmental, and mental stresses of the war.³ A change in gut microbiota can occur during deployment due to diet changes, environmental and physical stress, and GI infections.²⁹ These changes would suggest that manipulation of gut microbiota might offer a new modality of treatment of IBS and GWI. We evaluated the effect of a high-potency multistrain probiotic in veterans with IBS and GWI. We did not detect any statistically significant differences between the probiotic and placebo groups on bowel symptom score and individual symptoms of IBS and on QOL. Also, there was no improvement for the other symptoms of GWI. To our knowledge, this is the first study evaluating the effect of probiotics in veterans with IBS and GWI. Our results are consistent with the literature on probiotics and IBS.

The probiotic formulation used in our study has been evaluated in patients with IBS previously. Kim and colleagues found that after 8 weeks of treatment of patients with diarrhea-predominant IBS with VSL#3, there was improvement in bloating, but no effect was found on abdominal pain, gas, or urgency.³⁰ A subsequent study by the same investigators on patients with all types of IBS found that VSL#3 showed no effect on abdominal pain, stool frequency and consistency, or on bloating, but there was improvement in flatulence.³¹ Another study that evaluated the effect of VSL#3 on symptoms of diarrhea-predominant IBS and QOL found improvement in IBS symptoms from baseline in both the probiotic and the placebo groups, but the difference between the 2 groups was not statistically significant.³² Similarly, Wong and colleagues performed a double-blind, placebo-controlled mechanistic study to evaluate the effect of VSL#3. They found improvement in bowel symptom score, abdominal pain intensity, and satisfaction with bowel habits with both the VSL#3 and placebo group but similar to our study, the differences were not statistically significant.

Several reviews have evaluated the efficacy of probiotics for IBS. A 2010 review found evidence that probiotics trended toward improved IBS symptoms compared with placebo.³³ The 2014 follow-up by the same authors demonstrated that overall, probiotics improved global symptoms of IBS and multistrain probiotics were more effective.²⁰ A third meta-analysis from the same group found evidence that multistrain probiotics seemed to have a beneficial effect but could not definitively conclude that probiotics are efficacious in improving IBS symptoms.³⁴ Other authors also have seen inconsistent effects of probiotics compared with placebo on global symptoms, abdominal pain, and bloating after performing systematic reviews of the literature.^35-38 Although several reviews support that multistrain probiotics are more effective, they fail to conclude which combinations are more efficacious.

The effect of probiotics on QOL has not been investigated by many studies.³⁷ In our study, we did not find significant improvement in QOL in the probiotic group, which is in line with 2 previous studies that showed no effect on IBS QOL of VSL#3 vs placebo.^32,39 Most of the research reports that multistrain probiotics are more effective than using a single strain.^34,35,40Bifidobacterium and Lactobacillus are the most commonly used bacteria in the multistrain probiotics that have shown their positive effect on IBS.^35,41 The probiotic used in our study contained other species along with these 2 microorganisms.

The dose and duration of treatment of probiotics also has been debated. In one meta-analysis, the investigators found that studies of ≥ 8 weeks were more likely to show a positive effect; 4 of the 7 studies with statistically significant improvement in IBS symptoms were longer than 8 weeks.³⁵ However, another meta-analysis based on 35 randomized controlled trials found that there was not a statistically significant difference between groups treated for > 4 weeks vs < 4 weeks.⁴² In addition, another meta-analysis of VSL#3 on IBS in children and adults also found no difference in results based on the duration of treatment of probiotics.⁴³ Similar to our study, 3 other studies of VSL#3 treated patients for 8 weeks and found no statistically significant effect.^30-32 In the past, VSL#3 has been used at dosages of 450 or 900 billion bacteria per day.

An individual’s response to probiotics may depend on the subtype of IBS. However, most of the studies, like ours, included groups of all subtypes. It may be that probiotics are more effective in patients with moderate-to-severe symptoms. Most of our patients had milder symptoms, and we cannot discount how subjects with more severe disease may have responded to the drug. Interestingly, one study demonstrated that Lactobacillus was more effective in patients with moderately severe abdominal pain compared with mild symptoms.⁴⁴

In our study, the probiotic did not improve PTSD symptoms or other extra-intestinal symptoms common in IBS and GWI. Similar to our study, Wong and colleagues did not find significant improvement of psychological and sleep scores after treatment with VSL#3.⁶ Similarly, there is evidence that alteration in gut microbiota is associated with health and diseases, but what specific alterations occur and whether they can be improved with probiotics remains unknown.⁴⁵

Limitations

The inconsistent response to probiotics in various studies may be due to IBS heterogeneity. Furthermore, there are demographic differences between Gulf War veterans and patients enrolled in other studies: Gulf War veterans are predominantly male, many were deployed abroad and had a history of gastroenteritis during deployment, and were exposed to stressful situations.⁴⁶ These factors may be involved in triggering or maintaining IBS in Gulf War veterans. A further limitation of our randomized trial is the relatively small sample size.

Conclusions

This study did not demonstrate statistically significant improvement in symptoms of IBS or improvement in QOL after treatment with a multistrain probiotic. We also did not find any improvement in symptoms of GWI or PTSD. There was no difference in psychological scores between the placebo and treatment groups, and it is unlikely that psychological factors confounded the response to treatment in this study.

The effectiveness of a probiotic may depend on the baseline gut microbiome of the individual and depend on the strain, amount, and frequency of bacteria used. A lack of response of the probiotics does not exclude gut viruses and fungi having a role in exacerbating GWI symptoms. It is also possible that the bacteria present or the dose of the probiotic used was not sufficient to improve symptoms. So far, the definitive benefit of probiotics has been demonstrated for only a few preparations, and none are approved by the US Food and Drug Administration for any disease. More research is needed to determine whether probiotics have any role in the treatment of IBS and GWI.

Acknowledgments

AKT received grant support from the US Department of Veterans Affairs and the US Department of Defense (W81XWH-10-1-0593, W81XWH-15-1-0636). We thank Keith G. Tolman, MD, for assistance in editing the initial proposal and for periodic consultation. We thank the manufacturer of the probiotic for supplying the active drug and the placebo. The manufacture of the probiotic had no role in the design and conduct of the study, analysis and interpretation of the data, and in the preparation of the manuscript.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

Counting calories should not be the focus of weight-loss strategies for children with obesity, according to an expert who said pediatricians need to change the way they discuss weight with their patients.

During a plenary session of the American Academy of Pediatrics National Conference, Joseph A. Skelton, MD, professor of pediatrics at Wake Forest University School of Medicine, Winston-Salem, N.C., said pediatricians should recognize the behavioral, physical, environmental, and genetic factors that contribute to obesity. For instance, food deserts are on the rise, and they undermine the ability of parents to feed their children healthy meals. In addition, more children are less physically active.

“Obesity is a lot more complex than calories in, calories out,” Dr. Skelton said. “We choose to treat issues of obesity as personal responsibility – ‘you did this to yourself’ – but when you look at how we move around and live our lives, our food systems, our policies, the social and environmental changes have caused shifts in our behavior.”

According to Dr. Skelton, bias against children with obesity can harm their self-image and weaken their motivations for losing weight. In addition, doctors may change how they deliver care on the basis of stereotypes regarding obese children. These stereotypes are often reinforced in media portrayals, Dr. Skelton said.

“When children or when adults who have excess weight or obesity are portrayed, they are portrayed typically in a negative fashion,” Dr. Skelton said. “There’s increasing evidence that weight bias and weight discrimination are increasing the morbidity we see in patients who develop obesity.”

For many children with obesity, visits to the pediatrician often center on weight, regardless of the reason for the appointment. Weight stigma and bias on the part of health care providers can increase stress, as well as adverse health outcomes in children, according to a 2019 study (Curr Opin Endocrinol Diabetes Obes. 2019 Feb 1. doi: 10.1097/MED.0000000000000453). Dr. Skelton recommended that pediatricians listen to their patients’ concerns and make a personalized care plan.

Dr. Skelton said doctors can pull from projects such as Health at Every Size, which offers templates for personalized health plans for children with obesity. It has a heavy focus on a weight-neutral approach to pediatric health.

“There are various ways to manage weight in a healthy and safe way,” Dr. Skelton said.

Evidence-based methods of treating obesity include focusing on health and healthy behaviors rather than weight and using the body mass index as a screening tool for further conversations about overall health, rather than as an indicator of health based on weight.

Dr. Skelton also encouraged pediatricians to be on the alert for indicators of disordered eating, which can include dieting, teasing, or talking excessively about weight at home and can involve reading misinformation about dieting online.

“Your job is to educate people on the dangers of following unscientific information online,” Dr. Skelton said. “We can address issues of weight health in a way that is patient centered and is very safe, without unintended consequences.” Brooke Sweeney, MD, professor of internal medicine and pediatrics at University of Missouri–Kansas City, said problems with weight bias in society and in clinical practice can lead to false assumptions about people who have obesity.

“It’s normal to gain adipose, or fat tissue, at different times in life, during puberty or pregnancy, and some people normally gain more weight than others,” Dr. Sweeney said.

The body will try to maintain a weight set point. That set point is influenced by many factors, such as genetics, environment, and lifestyle.

“When you lose weight, your body tries to get you back to the set point, decreasing energy expenditure and increasing hunger and reward pathways,” she said. “We have gained so much knowledge through research to better understand the pathophysiology of obesity, and we are making good progress on improving advanced treatments for increased weight in children.”

Dr. Skelton reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Counting calories should not be the focus of weight-loss strategies for children with obesity, according to an expert who said pediatricians need to change the way they discuss weight with their patients.

During a plenary session of the American Academy of Pediatrics National Conference, Joseph A. Skelton, MD, professor of pediatrics at Wake Forest University School of Medicine, Winston-Salem, N.C., said pediatricians should recognize the behavioral, physical, environmental, and genetic factors that contribute to obesity. For instance, food deserts are on the rise, and they undermine the ability of parents to feed their children healthy meals. In addition, more children are less physically active.

“Obesity is a lot more complex than calories in, calories out,” Dr. Skelton said. “We choose to treat issues of obesity as personal responsibility – ‘you did this to yourself’ – but when you look at how we move around and live our lives, our food systems, our policies, the social and environmental changes have caused shifts in our behavior.”

According to Dr. Skelton, bias against children with obesity can harm their self-image and weaken their motivations for losing weight. In addition, doctors may change how they deliver care on the basis of stereotypes regarding obese children. These stereotypes are often reinforced in media portrayals, Dr. Skelton said.

“When children or when adults who have excess weight or obesity are portrayed, they are portrayed typically in a negative fashion,” Dr. Skelton said. “There’s increasing evidence that weight bias and weight discrimination are increasing the morbidity we see in patients who develop obesity.”

For many children with obesity, visits to the pediatrician often center on weight, regardless of the reason for the appointment. Weight stigma and bias on the part of health care providers can increase stress, as well as adverse health outcomes in children, according to a 2019 study (Curr Opin Endocrinol Diabetes Obes. 2019 Feb 1. doi: 10.1097/MED.0000000000000453). Dr. Skelton recommended that pediatricians listen to their patients’ concerns and make a personalized care plan.

Dr. Skelton said doctors can pull from projects such as Health at Every Size, which offers templates for personalized health plans for children with obesity. It has a heavy focus on a weight-neutral approach to pediatric health.

“There are various ways to manage weight in a healthy and safe way,” Dr. Skelton said.

Evidence-based methods of treating obesity include focusing on health and healthy behaviors rather than weight and using the body mass index as a screening tool for further conversations about overall health, rather than as an indicator of health based on weight.

Dr. Skelton also encouraged pediatricians to be on the alert for indicators of disordered eating, which can include dieting, teasing, or talking excessively about weight at home and can involve reading misinformation about dieting online.

“Your job is to educate people on the dangers of following unscientific information online,” Dr. Skelton said. “We can address issues of weight health in a way that is patient centered and is very safe, without unintended consequences.” Brooke Sweeney, MD, professor of internal medicine and pediatrics at University of Missouri–Kansas City, said problems with weight bias in society and in clinical practice can lead to false assumptions about people who have obesity.

“It’s normal to gain adipose, or fat tissue, at different times in life, during puberty or pregnancy, and some people normally gain more weight than others,” Dr. Sweeney said.

The body will try to maintain a weight set point. That set point is influenced by many factors, such as genetics, environment, and lifestyle.

“When you lose weight, your body tries to get you back to the set point, decreasing energy expenditure and increasing hunger and reward pathways,” she said. “We have gained so much knowledge through research to better understand the pathophysiology of obesity, and we are making good progress on improving advanced treatments for increased weight in children.”

Dr. Skelton reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Counting calories should not be the focus of weight-loss strategies for children with obesity, according to an expert who said pediatricians need to change the way they discuss weight with their patients.

During a plenary session of the American Academy of Pediatrics National Conference, Joseph A. Skelton, MD, professor of pediatrics at Wake Forest University School of Medicine, Winston-Salem, N.C., said pediatricians should recognize the behavioral, physical, environmental, and genetic factors that contribute to obesity. For instance, food deserts are on the rise, and they undermine the ability of parents to feed their children healthy meals. In addition, more children are less physically active.

“Obesity is a lot more complex than calories in, calories out,” Dr. Skelton said. “We choose to treat issues of obesity as personal responsibility – ‘you did this to yourself’ – but when you look at how we move around and live our lives, our food systems, our policies, the social and environmental changes have caused shifts in our behavior.”

According to Dr. Skelton, bias against children with obesity can harm their self-image and weaken their motivations for losing weight. In addition, doctors may change how they deliver care on the basis of stereotypes regarding obese children. These stereotypes are often reinforced in media portrayals, Dr. Skelton said.

“When children or when adults who have excess weight or obesity are portrayed, they are portrayed typically in a negative fashion,” Dr. Skelton said. “There’s increasing evidence that weight bias and weight discrimination are increasing the morbidity we see in patients who develop obesity.”

For many children with obesity, visits to the pediatrician often center on weight, regardless of the reason for the appointment. Weight stigma and bias on the part of health care providers can increase stress, as well as adverse health outcomes in children, according to a 2019 study (Curr Opin Endocrinol Diabetes Obes. 2019 Feb 1. doi: 10.1097/MED.0000000000000453). Dr. Skelton recommended that pediatricians listen to their patients’ concerns and make a personalized care plan.

Dr. Skelton said doctors can pull from projects such as Health at Every Size, which offers templates for personalized health plans for children with obesity. It has a heavy focus on a weight-neutral approach to pediatric health.

“There are various ways to manage weight in a healthy and safe way,” Dr. Skelton said.

Evidence-based methods of treating obesity include focusing on health and healthy behaviors rather than weight and using the body mass index as a screening tool for further conversations about overall health, rather than as an indicator of health based on weight.

Dr. Skelton also encouraged pediatricians to be on the alert for indicators of disordered eating, which can include dieting, teasing, or talking excessively about weight at home and can involve reading misinformation about dieting online.

“Your job is to educate people on the dangers of following unscientific information online,” Dr. Skelton said. “We can address issues of weight health in a way that is patient centered and is very safe, without unintended consequences.” Brooke Sweeney, MD, professor of internal medicine and pediatrics at University of Missouri–Kansas City, said problems with weight bias in society and in clinical practice can lead to false assumptions about people who have obesity.

“It’s normal to gain adipose, or fat tissue, at different times in life, during puberty or pregnancy, and some people normally gain more weight than others,” Dr. Sweeney said.

The body will try to maintain a weight set point. That set point is influenced by many factors, such as genetics, environment, and lifestyle.

“When you lose weight, your body tries to get you back to the set point, decreasing energy expenditure and increasing hunger and reward pathways,” she said. “We have gained so much knowledge through research to better understand the pathophysiology of obesity, and we are making good progress on improving advanced treatments for increased weight in children.”

Dr. Skelton reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]