Pulmonology

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

In less than a year, COVID-19 has infected nearly 100 million people worldwide and caused more than 2 million deaths and counting. Although the infection fatality rate is estimated to be 1% and the case fatality rate between 2% and 3%, COVID-19 has had a disproportionate effect on the older population and those with comorbidities. Some of these findings are mirrored in the US Department of Veterans Affairs (VA) population, which has seen a higher case fatality rate.^1-4

As a respiratory tract infection, the most dreaded presentation is severe pneumonia with acute hypoxemia, which may rapidly deteriorate to acute respiratory distress syndrome (ARDS) and respiratory failure.^5-7 This possibility has led to early intubation strategies aimed at preempting this rapid deterioration and minimizing viral exposure to health care workers. Intubation rates have varied widely with extremes of 6 to 88%.^8,9

However, this early intubation strategy has waned as some of the rationale behind its endorsement has been called into question. Early intubation bypasses alternatives to intubation; high-flow nasal cannula oxygen, noninvasive ventilation, and awake proning are all effective maneuvers in the appropriate patient.^10,11 The use of first-line high-flow nasal cannula oxygen and noninvasive ventilation has been widely reported. Reports of first-line use of high-flow nasal cannula oxygen has not demonstrated inferior outcomes, nor has the timing of intubation, suggesting a significant portion of patients could benefit from a trial of therapy and eventually avoid intubation.^11-14 Other therapies, such as systemic corticosteroids, confer a mortality benefit in those patients with COVID-19 who require oxygen or mechanical ventilation, but their impact on the progression of respiratory failure and need for intubation are undetermined.

There also are reports of patients who report no signs of respiratory distress or dyspnea with their COVID-19 pneumonia despite profound hypoxemia or high oxygen requirements. Various terms, including silent hypoxemia or happy hypoxia, are descriptive of the demeanor of these patients, and treatment has invariably included oxygen.^15,16 Nevertheless, low oxygen measurements have generally prompted higher levels of supplemental oxygen or more invasive therapies.

Treatment rendered may obscure the trajectory of response, which is important to understand to better position options for invasive therapies and other therapeutics. We recently encountered a patient with a course of illness that represented the natural history of COVID-19 pneumonia with low oxygen levels (referred to as hypoxemia for consistency) that highlighted several issues of management.

Case Presentation

A 62-year-old undomiciled woman with morbid obesity, prediabetes mellitus, long-standing schizophrenia, and bipolar disorder presented to our facility for evaluation of dry cough and need for tuberculosis clearance for admittance to a shelter. She appeared comfortable and was afebrile with blood pressure 111/74 mm Hg, heart rate 82 beats per minute. Her respiratory rate was 18 breaths per minute, but the pulse oximetry showed oxygen saturation of 70 to 75% on room air at rest. A chest X-ray showed bibasilar infiltrates (Figure 1), and a rapid COVID-19 nasopharyngeal polymerase chain reaction (PCR) test returned positive, confirmed by a second PCR test. Baseline inflammatory markers were elevated (Figure 2). In addition, the serum interleukin-6 also was elevated to 66.1 pg/mL (normal < 5.0), erythrocyte sedimentation rate elevated to 69 mm/h, but serum procalcitonin was essentially normal (0.22 ng/mL; normal < 20 ng/mL) as was the serum lactate (1.4 mmol/L).

The patient was admitted to the intensive care unit (ICU) for close monitoring in anticipation of the possibility of decompensation based on her age, hypoxia, and elevated inflammatory markers.¹⁷ Besides a subsequent low-grade fever (100.4 oF) and lymphopenia (manual count 550/uL), she remained clinically unchanged. Throughout her hospitalization, she maintained a persistent psychotic delusion that she did not have COVID-19, refusing all medical interventions, including a peripheral IV line and supplemental oxygen for the entire duration. Extensive efforts to identify family or a surrogate decision maker were unsuccessful. After consultation with Psychiatry, Bio-Ethics, and hospital leadership, the patient was deemed to lack decision-making capacity regarding treatment or disposition and was placed on a psychiatric hold. However, since any interventions against her will would require sedation, IV access, and potentially increase the risk of nosocomial COVID-19 transmission, she was allowed to remain untreated and was closely monitored for symptoms of worsening respiratory failure.

Discussion

The initial reports of COVID-19 pneumonia focused on ARDS and respiratory failure requiring mechanical ventilation with less emphasis on those with lower severity of illness. This was heightened by health care systems that were overwhelmed with large number of patients while faced with limited supplies and equipment. Given the risk to patients and providers of crash intubations, some recommended early intubation strategies.³ However, the natural history of COVID-19 pneumonia and the threshold for intubation of these patients remain poorly defined despite the creation of prognostic tools.¹⁷ This patient’s persistent hypoxemia and elevated inflammatory markers certainly met markers of disease associated with a high risk of progression.

The greatest concern would have been her level of hypoxemia. Acceptable thresholds of hypoxemia vary, but general consensus would classify pulse oximetry < 90% as hypoxemia and a threshold for administering supplemental oxygen. It is important to recognize how pulse oximetry readings translate to partial pressure of oxygen (PaO₂) measurements (Table 1). Pulse oximetry readings of 90% corresponds to a PaO₂ readings of 60 mm Hg in ideal conditions without the influence of acidosis, PaCO₂, or temperature. While lower readings are of concern, these do not represent absolute indications for assisted ventilatory support as lower levels are well tolerated in a variety of conditions. A common example are patients with chronic obstructive pulmonary disease. Long-term mortality benefits of continuous supplemental oxygen are well established in specific populations, but the threshold for correction in the acute setting remains a case-by-case decision. This decision is complex and is based on more than an absolute number or the amount of oxygen required to achieve a threshold level of oxygenation.

The severity of hypoxemia manifested by this patient may have elicited additional findings of respiratory distress, such as dyspnea and tachypnea. However, in patients with severe COVID-19 pneumonia, dyspnea was not a universal finding, reported in the 20 to 60% range of cohorts, higher in those with ARDS and mechanical ventilation, although some report near universal dyspnea in their series.^1,4,8,22,23 Tachypnea is another symptom of interest. Using a threshold of > 24 breaths/min, tachypnea was noted in 16 to 29% of patients with a much greater proportion (63%) in nonsurvivors.^6,24 Several explanations have been proposed for the discordance between the presence and severity of hypoxemia and lack of symptoms of dyspnea and tachypnea. It is important to recognize that misclassification of the severity of hypoxemia can occur due to technical issues and potential errors involving pulse oximetry measurement and shifts in the oxyhemoglobin dissociation curve. However, this is more pertinent for those with mild disease as the severity of hypoxemia in severe pneumonia is beyond what can be attributed to technical issues.

More important, the ventilatory response curve to hypoxemia may not be normal for some patients, blunted by as much as 50% in older patients, especially in those with diabetes mellitus.^7,25,26 In addition, the ventilatory response varies widely even among normal individuals. This would translate to lower levels of minute ventilation (less tachypnea or respiratory effort) with hypoxemia. Hypocapnic hypoxemia also blunts the ventilatory response to hypoxemia. Subjects do not increase their minute ventilation if the PaCO₂ remains low despite oxygen desaturation to < 70%, especially if PaCO₂ < 30 mm Hg or alternatively, increases in minute ventilation are not seen until the PaCO₂ exceeds 39 mm Hg.²⁷ Both scenarios occur in those with COVID-19 pneumonia and provide another explanation for the absence of respiratory symptoms or signs of respiratory distress in some patients.

The observation of more compliant lungs may help in the understanding of the variable presentation of these patients. Compliant lungs do not require the increased pressure needed to achieve a specific tidal volume that, in turn, may increase the work of breathing. This may add to the explanation of seemingly paradoxical silent hypoxemia in those patients where the combination of a blunted ventilatory response, hypocapnia, shunt physiology, and normal respiratory system compliance is represented by the absence of increased breathing effort despite severe hypoxemia.

If not for the patient’s refusal of medical services, this patient quite possibly would have been intubated due to hypoxemia and health care providers’ concern for her risk of deterioration. Reported intubation and mechanical ventilation rates have varied widely from extremes of from < 5 to 88% in severely ill patients.^9,22 About 75% will need oxygen, but many can be treated and recover without the need for intubation and mechanical ventilation.

As previously mentioned, options for treatment include standard and high-flow oxygen delivery, noninvasive ventilation, and awake prone ventilation. Their role in patient management has been recently outlined, and instead of an early intubation strategy, represents gradual escalation of support that may be sufficient to treat hypoxemia and avoid the need for intubation and mechanical ventilation (Table 2).

Conclusions

Since the emergence of the COVID-19, evidence has accumulated for the benefit of several adjunctive therapies in the treatment of this type of pneumonia, with corticosteroids providing a mortality benefit. Although unknown whether this patient’s experience can be generalized to others or whether it represents her unique response, this case provides another perspective for comparison of treatments and reinforces the need for prospective, randomized clinical trials to establish treatment efficacy. The exact nature of silent hypoxemia of COVID-19 remains incompletely understood; however, this case highlights the importance of treating the individual instead of clinical markers and provides a time course for recovery from pneumonia and severe hypoxemia that occurs without oxygen or any other treatment over about 2 weeks.

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

THE CASE

A 37-year-old man with a history of asthma, schizoaffective disorder, and tobacco use (36 packs per year) presented to the clinic after 5 days of worsening cough, reproducible left-sided chest pain, and increasing shortness of breath. He also experienced chills, fatigue, nausea, and vomiting but was afebrile. The patient had not travelled recently nor had direct contact with anyone sick. He also denied intravenous (IV) drug use, alcohol use, and bloody sputum. Recently, he had intentionally lost weight, as recommended by his psychiatrist.

Medication review revealed that he was taking many central-acting agents for schizoaffective disorder, including alprazolam, aripiprazole, desvenlafaxine, and quetiapine. Due to his intermittent asthma since childhood, he used an albuterol inhaler as needed, which currently offered only minimal relief. He denied any history of hospitalization or intubation for asthma.

During the clinic visit, his blood pressure was 90/60 mm Hg and his heart rate was normal. His pulse oximetry was 92% on room air. On physical examination, he had normal-appearing dentition. Auscultation revealed bilateral expiratory wheezes with decreased breath sounds at the left lower lobe.

A plain chest radiograph (CXR) performed in the clinic (FIGURE 1) showed a large, thick-walled cavitary lesion with an air-fluid level in the left lower lobe. The patient was directly admitted to the Family Medicine Inpatient Service. Computed tomography (CT) of the chest with contrast was ordered to rule out empyema or malignancy. The chest CT confirmed the previous findings while also revealing a surrounding satellite nodularity in the left lower lobe (FIGURE 2). QuantiFERON-TB Gold and HIV tests were both negative.

THE DIAGNOSIS

The patient was given a diagnosis of a lung abscess based on symptoms and imaging. An extensive smoking history, as well as multiple sedating medications, increased his likelihood of aspiration.

DISCUSSION

Lung abscess is the probable diagnosis in a patient with indolent infectious symptoms (cough, fever, night sweats) developing over days to weeks and a CXR finding of pulmonary opacity, often with an air-fluid level.^1-4 A lung abscess is a circumscribed collection of pus in the lung parenchyma that develops as a result of microbial infection.⁴

Primary vs secondary abscess. Lung abscesses can be divided into 2 groups: primary and secondary abscesses. Primary abscesses (60%) occur without any other medical condition or in patients prone to aspiration.⁵ Secondary abscesses occur in the setting of a comorbid medical condition, such as lung disease, heart disease, bronchogenic neoplasm, or immunocompromised status.⁵

Continue to: With a primary lung abscess...

With a primary lung abscess, oropharyngeal contents are aspirated (generally while the patient is unconscious) and contain mixed flora.² The aspirate typically migrates to the posterior segments of the upper lobes and to the superior segments of the lower lobes. These abscesses are usually singular and have an air-fluid level.^1,2

Secondary lung abscesses occur in bronchial obstruction (by tumor, foreign body, or enlarged lymph nodes), with coexisting lung diseases (bronchiectasis, cystic fibrosis, infected pulmonary infarcts, lung contusion) or by direct spread (broncho-esophageal fistula, subphrenic abscess).⁶ Secondary abscesses are associated with a poorer prognosis, dependent on the patient’s general condition and underlying disease.⁷

What to rule out

The differential diagnosis of cavitary lung lesion includes tuberculosis, necrotizing pneumonia, bronchial carcinoma, pulmonary embolism, vasculitis (eg, Churg-Strauss syndrome), and localized pleural empyema.^1,4 A CT scan is helpful to differentiate between a parenchymal lesion and pleural collection, which may not be as clear on CXR.^1,4

Tuberculosis manifests with fatigue, weight loss, and night sweats; a chest CT will reveal a cavitating lesion (usually upper lobe) with a characteristic “rim sign” that includes caseous necrosis surrounded by a peripheral enhancing rim.⁸

Necrotizing pneumonia manifests as acute, fulminant infection. The most common causative organisms on sputum culture are Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas species. Plain radiography will reveal multiple cavities and often associated pleural effusion and empyema.⁹

Continue to: Excavating bronchogenic carcinomas

Excavating bronchogenic carcinomas differ from a lung abscess in that a patient with the latter is typically, but not always, febrile and has purulent sputum. On imaging, a bronchogenic carcinoma has a thicker and more irregular wall than a lung abscess.¹⁰

Treatment

When antibiotics first became available, penicillin was used to treat lung abscess.¹¹ Then IV clindamycin became the drug of choice after 2 trials demonstrated its superiority to IV penicillin.^12,13 More recently, clindamycin alone has fallen out of favor due to growing anaerobic resistance.¹⁴

Current therapy includes beta-lactam with beta-lactamase inhibitors.¹⁴ Lung abscesses are typically polymicrobial and thus carry different degrees of antibiotic resistance.^15,16 If culture data are available, targeted therapy is preferred, especially for secondary abscesses.⁷ Antibiotic therapy is usually continued until a CXR reveals a small lesion or is clear, which may require several months of outpatient oral antibiotic therapy.⁴

Our patient was treated with IV clindamycin for 3 days in the hospital. Clindamycin was chosen due to his penicillin allergy and started empirically without any culture data. He was transitioned to oral clindamycin and completed a total 3-week course as his CXR continued to show improvement (FIGURE 3). He did not undergo bronchoscopy. A follow-up CXR showed resolution of lung abscess at 9 months. (FIGURE 4).

THE TAKEAWAY

All patients with lung abscesses should have sputum culture with gram stain done—­ideally prior to starting antibiotics.^3,4 Bronchoscopy should be considered for patients with atypical presentations or those who fail standard therapy, but may be used in other cases, as well.³

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

Although recent months have seen the arrival of several promising vaccines to combat COVID-19, many researchers have been concerned about the shortage of Black and Latinx volunteers in their pivotal trials.

Sean Warren/iStockphoto.com

Minority groups have long been underrepresented in clinical research. The pandemic’s inequitable fallout has heightened the need for more inclusive COVID-19 trials. By one estimate, Black Americans are three times more likely to become infected with SARS-Cov-2 and twice as likely to die from it, compared with their White counterparts.

It was therefore welcome news this past November when the Maryland-based biotech company Novavax unveiled their plans to boost participation among specific minority groups during the phase 3 trial of their COVID-19 vaccine candidate NVX-CoV2373. To help them in their efforts, the company tapped Howard University, in Washington, D.C., to be a clinical test site. The goal was to enroll 300 Black and Latinx volunteers through a recruitment registry at the Coronavirus Prevention Network.

“We have seen quite a good number of participants in the registry, and many are African American, who are the ones we are trying to reach in the trial,” explained Siham Mahgoub, MD, medical director of the Center of Infectious Diseases Management and Research and principal investigator for the Novavax trial at Howard University, Washington. “It’s very important for people of color to participate in the trial because we want to make sure these vaccines work in people of color,” Dr. Mahgoub said.

Over the years, Howard University has hosted several important clinical trials and studies, and its participation in the multi-institutional Georgetown–Howard Universities Center for Clinical and Translational Science consortium brings crucial infrastructural value. By bringing this vaccine trial to one of the most esteemed historically Black colleges or universities (HBCUs), researchers hoped to address a sense of hesitancy among possible participants that is prompted in part by the tragic history of medical testing in the Black community.

“The community trusts Howard,” said Dr. Mahgoub. “I think it’s great having Howard and an HBCU host this trial, because these are people who look like them.”

Novavax deliberately sought an HBCU to work with on this trial to help people of color feel more at ease and increase minority participation. Lisa M. Dunkle, MD, vice president and global medical lead for coronavirus vaccine at Novavax, explained that, in addition to Howard being located close to the company’s headquarters, the university seemed like a great fit for the overall mission.

“As part of our goal to achieve a representative trial population that includes communities who are disproportionately impacted by the pandemic, we sought out some of the HBCUs to include in our trial sites. We hoped that this might encourage people of color to enroll and to increase their comfort level with vaccines in general,” Dr. Dunkle said.
 

Building more representative clinical trials

For decades, research on some of the most groundbreaking vaccines and treatments have been based on the results of studies conducted with predominately White participants, despite the fact that a much more demographically varied general population would ultimately receive them. This has led to calls to include people of different races and ethnic backgrounds in trials.

Homogeneity in clinical trials is discouraged, but trials are not heavily regulated in this regard. In 1993, Congress passed the Revitalization Act, which requires that trials that are conducted by the National Institutes of Health include women and members of minority groups among their cohorts. However, the number or proportion of such participants is not specified.

Underrepresentation in clinical trials also reflects a general unwillingness by members of ethnic minorities to volunteer because of the deeply unsettling history of such trials in minority communities. Among some Black persons, it is not uncommon for names like Tuskegee, Henrietta Lacks, and J. Marion Simms to be mentioned when giving reasons for not participating.

“There is certainly some dark history in how minorities have been treated by our health care system, and it’s not surprising that there is some fear and distrust,” said Dr. Dunkle. “By recruiting people of color into clinical trials that are governed with strict standards, we can begin to change perceptions and attitudes.”

Vaccine hesitancy is not only rooted in the past. The current state of medical care also has some potential trial participants worried. Misinformation, inequity in health care access, and low health literacy contribute to the current fears of scientific development.
 

A trial designed to engender trust

Having information about the vaccine come from trusted voices in the community is a key means of overcoming hesitancy. Howard University President Wayne Frederick, MD, reached out to a pastor of a local Black church to have more participants enroll in the trial. One who answered the call to action was Stephanie Williams, an elementary school teacher in Montgomery County, Maryland. When she saw that her pastor was participating in the Novavax trial and when she considered the devastation she had seen from COVID-19, she was on board.

“We had about three sessions where he shared his experiences. He also shared some links to read about it more,” Ms. Williams said. “When I saw that he took it, that gave me a lot of confidence. Since I’m going be going into the classroom, I wanted to be sure that I was well protected.”

Transparency is key to gaining more participation, explained Dr. Maghoub. Webinar-based information sessions have proven particularly important in achieving this.

“We do a lot of explaining in very simple language to make sure everyone understands about the vaccine. The participants have time to ask questions during the webinar, and at any time [during the trial], if a participant feels that it is not right for them, they can stop. They have time to learn about the trial and give consent. People often think they are like guinea pigs in trials, but they are not. They must give consent.”

There are signs that the approach has been successful. Over a period of 4-5 weeks, the Howard site enrolled 150 participants, of whom 30% were Black and 20% were Latinx.

Novavax has been in business for more than 3 decades but hasn’t seen the booming success that their competitors have. The company has noted progress in developing vaccines against Middle East respiratory syndrome and severe acute respiratory syndrome. However, they missed the mark in clinical trials, failing twice in 3 years to develop a respiratory syncytial virus vaccine administered through maternal immunizations.

From being on the verge of closing, Novavax has since made a dramatic turnaround after former President Trump awarded the company $1.6 billion dollars in July 2020 as part of Operation Warp Speed. If trial results are promising, the Novavax vaccine could enter the market in a few months, representing not only a new therapeutic option but perhaps a new model for building inclusivity in clinical trials.

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

Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.

©moodboard/thinkstockphotos.com

Clinically important deterioration was a significant predictor of worsening disease and all-cause mortality in chronic obstructive pulmonary disease, a study based on data from more than 10,000 patients has shown.

For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.

The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.

In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).

The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.

Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.

Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).

Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.

In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.

In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.

The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
 

Data may help drive tailored treatments

“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.

Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.

“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.

As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.

Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.

Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.

©moodboard/thinkstockphotos.com

Clinically important deterioration was a significant predictor of worsening disease and all-cause mortality in chronic obstructive pulmonary disease, a study based on data from more than 10,000 patients has shown.

For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.

The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.

In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).

The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.

Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.

Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).

Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.

In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.

In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.

The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
 

Data may help drive tailored treatments

“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.

Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.

“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.

As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.

Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.

Patients with COPD may benefit from stepped-up treatment of short-term disease progression with triple therapy to stave off longer-term exacerbations and all-cause mortality.

©moodboard/thinkstockphotos.com

Clinically important deterioration was a significant predictor of worsening disease and all-cause mortality in chronic obstructive pulmonary disease, a study based on data from more than 10,000 patients has shown.

For this study, clinically important deterioration (CID) as a measure of COPD is defined as a combination of change in lung function and/or health status, or a first acute moderate to severe COPD exacerbation, wrote MeiLan K. Han, MD, of the University of Michigan, Ann Arbor, and colleagues.

The study was published in ERJ Open Research The investigators analyzed data from the IMPACT trial, a phase III, double-blind, multicenter, 52-week study of symptomatic COPD patients aged 40 years and older.

In the intent-to-treat population, patients with symptomatic COPD and at least one moderate or severe exacerbation in the past year were randomized to a once-daily dose of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg (4,151 patients); FF/VI 100/25 mcg (4,134 patients); or UMEC/VI 62.5/25 mcg using a single dry-power inhaler (2,070 patients).

The researchers explored both the prognostic value of a CID event on future clinical outcomes and the impact of single-inhaler triple versus dual therapy on reducing CID risk. CID was defined as any of the following: moderate/severe exacerbation; deterioration in lung function (defined as a decrease of 100 mL or more from baseline in trough forced expiratory volume per second); or deterioration in health status based on increases of 4.0 units or more on the St George’s Respiratory Questionnaire (SGRQ) total score or 2.0 units or more on the COPD Assessment Test (CAT) score.

Overall, patients with a CID by 28 weeks had significantly increased exacerbation rates after week 28, as well as smaller improvements in lung function and health status at week 52 (P < .001 for all). In addition, CID patients had an increased risk of all-cause mortality after 28 weeks, compared with patients without CID. However, FF/UMEC/VI significantly reduced CID risk, compared with dual therapies, the researchers noted.

Based on the CID SGRQ definition, patients with CID had a 75% increase in moderate to severe exacerbations by week 28 and a 96% in severe exacerbations over weeks 29-52. The increases were similar using the CID CAT definition (72% and 91%, respectively).

Patients with CID also showed significantly reduced improvements in both lung function and health status after 1 year, and a significantly increased risk of all-cause mortality compared to patients without CID.

In comparing triple vs. double therapies, FF/UMEC/VI patients showed significant reductions in CID risk by 52 weeks, compared with patients treated with FF/VI and UMEC/VI. This difference was true across all subgroups, except for the subgroup of patients who were on long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy prior to screening, the researchers said.

In addition, “treatment effect was greater at higher blood eosinophil counts for FF/UMEC/VI versus UMEC/VI,” the researchers noted.

The study findings were limited by several factors including the lack of CID as a primary endpoint, the relatively short 5-month follow-up period, and the use of a symptomatic patient population with an established risk of exacerbation, which could limit generalizability, the researchers noted. However, the findings support the value of preventing short-term CID and adding inhaled corticosteroids (ICS) or bronchodilation for patients in this study population, they said.
 

Data may help drive tailored treatments

“This study is a post hoc analysis of data from the IMPACT trial, an RCT examining triple therapy vs ICS/LABA vs LABA/LAMA,” Dr. Han, lead and corresponding author, said in an interview. “In this particular paper, we conducted a treatment independent analysis examining individuals who experienced clinically important deteriorations at week 28 and then compared outcomes at week 52 based on CID status at week 28. Patients with a CID by week 28 had significantly increased exacerbation rates after week 28, smaller improvements in lung function and health status at week 52, and increased risk of all-cause mortality after week 28 versus patients who were CID free,” she emphasized. “We also saw that FF/UMEC/VI significantly reduced CID risk versus dual therapies.” These data suggest that shorter-term changes are associated with longer term outcomes, and provide important information both for the purposes of clinical trials design as well as patient clinical assessments, she added.

Dr. Han said she was not surprised by the findings. “I think these results are consistent with prior analyses but suggest that short-term outcomes relate to longer-term ones,” she said. However, she stressed the need for individualized treatment.

“While there are relationships between symptoms, lung function, and exacerbations as demonstrated by these analyses, in any individual patient sometimes these three disease axes do not perfectly align,” she explained. Dr. Han’s main message for clinicians in practice is that optimization of triple therapy in patients with severe disease and high risk for exacerbations was associated not only with short-term improvements in symptoms and lung function, but also with longer-term reductions in exacerbations and mortality.

As for additional research, prospective studies using CID as a primary or secondary outcome would help validate the composite outcome in this study, as regulatory agencies have been slow to adopt composite outcomes, Dr. Han said.

Dr. Han disclosed relationships with GlaxoSmithKline, which funded the study, as well as AstraZeneca, Boehringer Ingelheim, Novartis, Sunovion, Mylan, Merck, and Verona.

The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.

Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.

Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.

Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.

They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.

They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.

At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”

A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”

But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
 

VIPIT study

In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.

The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.

The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.

Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.

The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.

They said that their current findings have several important clinical implications.

“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.

They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.

Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.

They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
 

EMA data to date

Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.

Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.

He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.

The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.

These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.

For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”

Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
 

Concerns put in perspective

Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.

“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.

“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.

Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.

“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.

She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.

Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.

“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.

Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.

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

The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.

Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.

Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.

Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.

They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.

They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.

At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”

A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”

But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
 

VIPIT study

In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.

The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.

The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.

Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.

The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.

They said that their current findings have several important clinical implications.

“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.

They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.

Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.

They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
 

EMA data to date

Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.

Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.

He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.

The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.

These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.

For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”

Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
 

Concerns put in perspective

Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.

“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.

“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.

Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.

“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.

She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.

Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.

“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.

Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.

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

The European Medicines Agency continues to reassure the public about the safety of the AstraZeneca COVID-19 vaccine, although several countries have imposed new restrictions on the product, owing to its link to a rare clotting disorder.

Use of the vaccine has been suspended for individuals younger than 55 or 60 years in several European countries and in Canada after reports of a prothrombotic disorder and thrombocytopenia, mainly in younger individuals.

Now, more information on the prothrombotic disorder has become available. The vaccine appears to be linked to a condition that clinically resembles heparin-induced thrombocytopenia (HIT) and that occurs mainly in younger women.

Researchers have described clinical and laboratory details of nine patients from Germany and Austria who developed this condition 4-16 days after receiving the AstraZeneca vaccine in a preprint article published March 28, 2021, on Research Square.

They found that serum from four patients who were tested showed platelet-activating antibodies directed against platelet factor 4 (PF4), similar to what is seen in HIT.

They are proposing naming the condition “vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)” to avoid confusion with HIT.

At a press conference March 31, the EMA said its ongoing review of the situation “has not identified any specific risk factors, such as age, gender, or a previous medical history of clotting disorders, for these very rare events. A causal link with the vaccine is not proven but is possible, and further analysis is continuing.”

A statement from the agency noted: “EMA is of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalization and death, outweigh the risks of side effects.”

But it added: “Vaccinated people should be aware of the remote possibility of these very rare types of blood clots occurring. If they have symptoms suggestive of clotting problems as described in the product information, they should seek immediate medical attention and inform health care professionals of their recent vaccination.”
 

VIPIT study

In the Research Square preprint article, a group led by Andreas Greinacher, MD, professor of transfusion medicine at the Greifswald (Germany) University Clinic, reported on clinical and laboratory features of nine patients (eight of whom were women) in Germany and Austria who developed thrombosis and thrombocytopenia after they received the AstraZeneca vaccine.

The researchers explained that they investigated whether these patients could have a prothrombotic disorder caused by platelet-activating antibodies directed against PF4, which is known to be caused by heparin and sometimes environmental triggers.

The nine patients were aged 22-49 years and presented with thrombosis beginning 4-16 days post vaccination. Seven patients had cerebral venous thrombosis (CVT), one had pulmonary embolism, and one had splanchnic vein thrombosis and CVT. Four patients died. None had received heparin prior to symptom onset.

Serum from four patients was tested for anti-PF4/heparin antibodies, and all four tested strongly positive. All four also tested strongly positive on platelet activation assay for the presence of PF4 independently of heparin.

The authors noted that it has been recognized that triggers other than heparin, including some infections, can rarely cause a disorder that strongly resembles HIT. These cases have been referred to as spontaneous HIT syndrome.

They said that their current findings have several important clinical implications.

“Clinicians should be aware that onset of (venous or arterial) thrombosis particularly at unusual sites such as in the brain or abdomen and thrombocytopenia beginning approximately 5-14 days after vaccination can represent a rare adverse effect of preceding COVID-19 vaccination,” they wrote. To date, this has only been reported with the AstraZeneca vaccine.

They pointed out that enzyme immunoassays for HIT are widely available and can be used to investigate for potential postvaccination anti-PF4 antibody–associated thrombocytopenia/thrombosis. For such patients, referral should be made to a laboratory that performs platelet-activation assays.

Although this syndrome differs from typical HIT, the researchers noted that at least one patient showed strong platelet activation in the presence of heparin. They thus recommended therapy with nonheparin anticoagulants, such as the direct oral anticoagulants.

They also wrote that high-dose intravenous immunoglobulin has been shown to be effective for treating severe HIT and could also be an important treatment adjunct for patients who develop life-threatening thrombotic events, such as cerebral vein sinus thrombosis (CVST), after being vaccinated.
 

EMA data to date

Updated data, reported at the EMA press briefing on March 31, indicate that 62 cases of CVST have been reported worldwide (44 from the European Union). These data may not yet include all the German cases.

Peter Arlett, MD, head of pharmacovigilance and epidemiology at the EMA, said there were more cases than expected in the 2-week window after vaccination among patients younger than 60 and that health care professionals should be alert to features of this condition, including headache and blurred vision.

He suggested that the higher rate of the condition among younger women may reflect the population that received this vaccine, because initially, the vaccine was not recommended for older people in many countries and was targeted toward younger health care workers, who were mainly women.

The German regulatory agency, the Paul Ehrlich Institute, reported this week that it has now registered 31 cases of CVST among nearly 2.7 million people who had received the vaccine in Germany. Of these patients, 19 also were found to have a deficiency of blood platelets or thrombocytopenia. Nine of the affected patients died. All but two of the cases occurred in women aged 20-63 years. The two men were aged 36 and 57 years.

These data have prompted the German authorities to limit use of the AstraZeneca vaccine to those aged 60 years and older. Even before this decision, senior clinicians in Germany had been urging a change in the vaccination recommendations.

For example, Bernd Salzberger, MD, head of infectious diseases, University Hospital Regensburg (Germany), told the Science Media Center: “In women, a complicated course of COVID disease is less common from the start and is so rare in younger women that the chance of avoiding a fatal course through vaccination in women without comorbidities is of the same order of magnitude as the risk of this rare side effect.”

Sandra Ciesek, MD, a virologist at Goethe University, Frankfurt, Germany, told the journal Science: “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So, restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”
 

Concerns put in perspective

Commenting of the latest developments, thrombosis expert Saskia Middeldorp, MD, head of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands, said it was vitally important that these concerns be put in perspective and that the vaccination program with the AstraZeneca product continue.

“There are some concerning reports about very rare blood clotting disorders and low platelet counts possibly associated with the AstraZeneca vaccine. Groups from Germany and Norway have identified a syndrome similar to HIT, which seems to explain the cause of this very rare side effect,” Dr. Middeldorp noted.

“But with such a high pressure from the virus and many countries now going into a third wave of infection, anything that might slow down vaccination rates will cause much more harm than good,” she warned.

Dr. Middeldorp believes the incidence of this HIT-type syndrome linked to the vaccine is about 1-2 per million. “These are estimates based on the number of reports of this side effect and denominators from the U.K. and EU populations,” she explained. However, Germany has restricted the vaccine on the basis of German data, which appear to show higher rates of the condition. It is not known why the rates are higher in Germany.

“The European Medicines Agency is looking at this very closely. Their statement is quite clear. There is no foundation for changing policy on vaccination,” Dr. Middeldorp stated.

She cautioned that these reports were reducing confidence in the AstraZeneca vaccine, particularly among young people, which she said was causing “a major setback” for the vaccination program.

Noting that everything must be viewed in the context of this severe pandemic, Dr. Middeldorp emphasized that the benefit of the vaccine outweighed any risk, even among young people.

“To those who may be hesitating to have the vaccine as they don’t think they are at high risk of severe COVID infection, I would say there are a lot of young people in the ICU at present with COVID, and your chance of a severe COVID illness is far higher than the 1 or 2 in a million risk of a severe reaction to the vaccine,” she stated.

Dr. Greinacher has received grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Paringenix, Bayer Healthcare, Gore, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck Sharp & Dohme, Macopharma, Bristol-Myers Squibb, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH outside the submitted work.

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

Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.

Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.

Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.

Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.

Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.

Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.

Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.

Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.

Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.

Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.

Background: More than a decade has passed since the last CAP guidelines. Since then there have been new trials and epidemiological studies. There have also been changes to the process for guideline development. This guideline has moved away from the narrative style of guidelines to the GRADE format and PICO framework with hopes of answering specific questions by looking at the quality of evidence.

Other recommendations include not routinely testing for urine pneumococcal or legionella antigens in nonsevere CAP; using PSI over CURB-65, in addition to clinical judgment, to determine need for inpatient care; using severe CAP criteria and clinical judgment for determining ICU need; not adding anaerobic coverage for aspiration pneumonia; and treating most cases of CAP that are clinically stable and uncomplicated for 5-7 days.

Bottom line: Given new data, updated recommendations have been made to help optimize CAP therapy.

Citation: Metlay JP et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-67.

Dr. Horton is a hospitalist and clinical instructor of medicine at the University of Utah, Salt Lake City.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.

Background: Beta-blockers are underutilized in patients with both COPD and established cardiovascular indications for beta-blocker therapy, despite evidence suggesting overall benefit. Prior observational studies have associated beta-blockers with improved outcomes in COPD in the absence of cardiovascular indications; however, this has not been previously evaluated in a randomized trial.

Importantly, this trial excluded patients with established indications for beta-blocker therapy, and study findings should not be applied to this population.

Bottom line: Metoprolol is not associated with increased risk of COPD exacerbations, but is associated with increased severity of COPD exacerbations in patients with moderate to severe COPD who have no established indications for beta-blockers.

Citation: Dransfield MT et al. Metoprolol for the prevention of acute exacerbations of COPD. N Engl J Med. 2019 Oct 20. doi: 10.1056/NEJMoa1908142.

Dr. Gerstenberger is a hospitalist and clinical assistant professor of medicine at the University of Utah, Salt Lake City.

Médecins Sans Frontières (MSF/Doctors Without Borders) announced early closure of its phase 2/3 trial of a 6-month multidrug regimen for multidrug-resistant tuberculosis (MDR-TB) because an independent data safety and monitoring board (DSMB) determined that the drug combination in the study regimen was superior to current therapy, according to a press release.

The trial, called TB PRACTECAL, compared the current local standard of care with a 6-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin. The interim analysis included 242 patients and the randomized, controlled trial was conducted in sites in Belarus, South Africa, and Uzbekistan.

The preliminary data will be shared with the World Health Organization soon and will also be submitted to a peer-reviewed journal. If it withstands further reviews, as is anticipated, the trial would support the first solely oral regimen for MDR-TB.

In 2019, an estimated 465,000 people developed MDR-TB and 182,000 died. The global burden of TB at that time was about 10 million new cases, many with coexisting HIV.

Current treatment for MDR-TB lasts 9-20 months and is complicated by the need for painful shots and toxic antibiotics. Side effects can include psychiatric problems from quinolones, isoniazid, ethambutol, or cycloserine; deafness from aminoglycosides; and bone marrow suppression from linezolid, among other toxicities.

It’s hoped that the shorter regimen will reduce toxicity and improve patient compliance. Poor adherence to treatment is a major driver of further drug resistance. Current regimens require up to 20 pills per day as well as daily injections.

In a prepared statement from MSF, David Moore, MD, MSc, London School of Hygiene and Tropical Medicine, a member of the TB-PRACTECAL trial’s steering committee, concluded: “The findings could transform the way we treat patients with drug-resistant forms of TB worldwide, who have been neglected for too long.”

This good news is particularly welcome as, in the time of COVID-19, “an estimated 1.4 million fewer people received care for tuberculosis in 2020 than in 2019,” according to the WHO. The drop, an overall 21% reduction in patients beginning treatment, ranged as high as 42% in Indonesia.

Although awaiting complete data, Madhukar Pai, MD, PhD, associate director of the McGill International TB Centre, McGill University, Montreal, shares Dr. Moore’s enthusiasm. In an interview, Dr. Pai compared MDR-TB with extensively drug-resistant TB (XDR-TB).

“I’m excited about the possibility that these trial results might help shorten MDR-TB treatment to 6 months,” said Dr. Pai. “That will be a huge relief to all patients battling drug-resistant disease. The 6-month BPaL regimen (bedaquiline, pretomanid, and linezolid) regimen works well in XDR-TB. So, I would expect the TB PRACTECAL regimen with one added drug (moxifloxacin) to work well in MDR-TB, which is less severe than XDR-TB. Between these two regimens, if we can bring down MDR and XDR treatment to 6 months, all oral, that would be a huge advance.”

The expense of bedaquiline has been a long-standing concern in the global health community. Janssen, a subsidiary of Johnson & Johnson, has reduced the price to $340 per 6-month treatment course for more than 135 eligible low- and middle-income countries.

Previously, the tiered pricing structure was different for low-, middle-, and high-income countries (U.S. $900, $3,000, and $30,000, respectively). “The global TB community has asked Janssen to drop the price of bedaquiline to a level no higher than $32 per month – double the price at which researchers estimated bedaquiline could be sold for a profit,” according to the Treatment Action Group A major source of contention over pricing has been that there has been considerable public investment in the drug›s development.

Dr. Pai concluded: “Bedaquiline is likely the most important drug in both 6-month regimens. We need to work harder to make bedaquiline, an excellent drug, more affordable and accessible.”

While the full data is not yet publicly available, TB PRACTECAL was a randomized, controlled, multicenter study. The fact that enrollment was discontinued early by the DSMB suggests the efficacy data was compelling and that this completely oral regimen will become the standard of care.

Dr. Stone is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. A version of this article first appeared on Medscape.com.

Médecins Sans Frontières (MSF/Doctors Without Borders) announced early closure of its phase 2/3 trial of a 6-month multidrug regimen for multidrug-resistant tuberculosis (MDR-TB) because an independent data safety and monitoring board (DSMB) determined that the drug combination in the study regimen was superior to current therapy, according to a press release.

The trial, called TB PRACTECAL, compared the current local standard of care with a 6-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin. The interim analysis included 242 patients and the randomized, controlled trial was conducted in sites in Belarus, South Africa, and Uzbekistan.

The preliminary data will be shared with the World Health Organization soon and will also be submitted to a peer-reviewed journal. If it withstands further reviews, as is anticipated, the trial would support the first solely oral regimen for MDR-TB.

In 2019, an estimated 465,000 people developed MDR-TB and 182,000 died. The global burden of TB at that time was about 10 million new cases, many with coexisting HIV.

Current treatment for MDR-TB lasts 9-20 months and is complicated by the need for painful shots and toxic antibiotics. Side effects can include psychiatric problems from quinolones, isoniazid, ethambutol, or cycloserine; deafness from aminoglycosides; and bone marrow suppression from linezolid, among other toxicities.

It’s hoped that the shorter regimen will reduce toxicity and improve patient compliance. Poor adherence to treatment is a major driver of further drug resistance. Current regimens require up to 20 pills per day as well as daily injections.

In a prepared statement from MSF, David Moore, MD, MSc, London School of Hygiene and Tropical Medicine, a member of the TB-PRACTECAL trial’s steering committee, concluded: “The findings could transform the way we treat patients with drug-resistant forms of TB worldwide, who have been neglected for too long.”

This good news is particularly welcome as, in the time of COVID-19, “an estimated 1.4 million fewer people received care for tuberculosis in 2020 than in 2019,” according to the WHO. The drop, an overall 21% reduction in patients beginning treatment, ranged as high as 42% in Indonesia.

Although awaiting complete data, Madhukar Pai, MD, PhD, associate director of the McGill International TB Centre, McGill University, Montreal, shares Dr. Moore’s enthusiasm. In an interview, Dr. Pai compared MDR-TB with extensively drug-resistant TB (XDR-TB).

“I’m excited about the possibility that these trial results might help shorten MDR-TB treatment to 6 months,” said Dr. Pai. “That will be a huge relief to all patients battling drug-resistant disease. The 6-month BPaL regimen (bedaquiline, pretomanid, and linezolid) regimen works well in XDR-TB. So, I would expect the TB PRACTECAL regimen with one added drug (moxifloxacin) to work well in MDR-TB, which is less severe than XDR-TB. Between these two regimens, if we can bring down MDR and XDR treatment to 6 months, all oral, that would be a huge advance.”

The expense of bedaquiline has been a long-standing concern in the global health community. Janssen, a subsidiary of Johnson & Johnson, has reduced the price to $340 per 6-month treatment course for more than 135 eligible low- and middle-income countries.

Previously, the tiered pricing structure was different for low-, middle-, and high-income countries (U.S. $900, $3,000, and $30,000, respectively). “The global TB community has asked Janssen to drop the price of bedaquiline to a level no higher than $32 per month – double the price at which researchers estimated bedaquiline could be sold for a profit,” according to the Treatment Action Group A major source of contention over pricing has been that there has been considerable public investment in the drug›s development.

Dr. Pai concluded: “Bedaquiline is likely the most important drug in both 6-month regimens. We need to work harder to make bedaquiline, an excellent drug, more affordable and accessible.”

While the full data is not yet publicly available, TB PRACTECAL was a randomized, controlled, multicenter study. The fact that enrollment was discontinued early by the DSMB suggests the efficacy data was compelling and that this completely oral regimen will become the standard of care.

Dr. Stone is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. A version of this article first appeared on Medscape.com.

Médecins Sans Frontières (MSF/Doctors Without Borders) announced early closure of its phase 2/3 trial of a 6-month multidrug regimen for multidrug-resistant tuberculosis (MDR-TB) because an independent data safety and monitoring board (DSMB) determined that the drug combination in the study regimen was superior to current therapy, according to a press release.

The trial, called TB PRACTECAL, compared the current local standard of care with a 6-month regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin. The interim analysis included 242 patients and the randomized, controlled trial was conducted in sites in Belarus, South Africa, and Uzbekistan.

The preliminary data will be shared with the World Health Organization soon and will also be submitted to a peer-reviewed journal. If it withstands further reviews, as is anticipated, the trial would support the first solely oral regimen for MDR-TB.

In 2019, an estimated 465,000 people developed MDR-TB and 182,000 died. The global burden of TB at that time was about 10 million new cases, many with coexisting HIV.

Current treatment for MDR-TB lasts 9-20 months and is complicated by the need for painful shots and toxic antibiotics. Side effects can include psychiatric problems from quinolones, isoniazid, ethambutol, or cycloserine; deafness from aminoglycosides; and bone marrow suppression from linezolid, among other toxicities.

It’s hoped that the shorter regimen will reduce toxicity and improve patient compliance. Poor adherence to treatment is a major driver of further drug resistance. Current regimens require up to 20 pills per day as well as daily injections.

In a prepared statement from MSF, David Moore, MD, MSc, London School of Hygiene and Tropical Medicine, a member of the TB-PRACTECAL trial’s steering committee, concluded: “The findings could transform the way we treat patients with drug-resistant forms of TB worldwide, who have been neglected for too long.”

This good news is particularly welcome as, in the time of COVID-19, “an estimated 1.4 million fewer people received care for tuberculosis in 2020 than in 2019,” according to the WHO. The drop, an overall 21% reduction in patients beginning treatment, ranged as high as 42% in Indonesia.

Although awaiting complete data, Madhukar Pai, MD, PhD, associate director of the McGill International TB Centre, McGill University, Montreal, shares Dr. Moore’s enthusiasm. In an interview, Dr. Pai compared MDR-TB with extensively drug-resistant TB (XDR-TB).

“I’m excited about the possibility that these trial results might help shorten MDR-TB treatment to 6 months,” said Dr. Pai. “That will be a huge relief to all patients battling drug-resistant disease. The 6-month BPaL regimen (bedaquiline, pretomanid, and linezolid) regimen works well in XDR-TB. So, I would expect the TB PRACTECAL regimen with one added drug (moxifloxacin) to work well in MDR-TB, which is less severe than XDR-TB. Between these two regimens, if we can bring down MDR and XDR treatment to 6 months, all oral, that would be a huge advance.”

The expense of bedaquiline has been a long-standing concern in the global health community. Janssen, a subsidiary of Johnson & Johnson, has reduced the price to $340 per 6-month treatment course for more than 135 eligible low- and middle-income countries.

Previously, the tiered pricing structure was different for low-, middle-, and high-income countries (U.S. $900, $3,000, and $30,000, respectively). “The global TB community has asked Janssen to drop the price of bedaquiline to a level no higher than $32 per month – double the price at which researchers estimated bedaquiline could be sold for a profit,” according to the Treatment Action Group A major source of contention over pricing has been that there has been considerable public investment in the drug›s development.

Dr. Pai concluded: “Bedaquiline is likely the most important drug in both 6-month regimens. We need to work harder to make bedaquiline, an excellent drug, more affordable and accessible.”

While the full data is not yet publicly available, TB PRACTECAL was a randomized, controlled, multicenter study. The fact that enrollment was discontinued early by the DSMB suggests the efficacy data was compelling and that this completely oral regimen will become the standard of care.

Dr. Stone is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. A version of this article first appeared on Medscape.com.

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

The COVID-19 pandemic has stressed all aspects of the world’s health care systems. The sheer volume of pandemic-related research produced over the past year has been challenging to process. This is as it should be, given its unprecedented spread and related morbidity and mortality. However, such rapid production and application leaves little time for proper vetting. Large numbers of providers adopted suggested, but largely unproven, practices that deviated from pre–COVID-19 guidelines. These “early adopters” theorized that COVID-19–related disease processes were different, necessitating a modification to existing practices.

While many unproven approaches were suggested and implemented, I’ll focus on two approaches. First, throughout the pandemic, many have argued that COVID-19 causes a novel acute respiratory distress syndrome (ARDS) phenotype. Early on, a group of prominent Italian ARDS researchers made a compelling case for physiological differences, concluding that early intubation was required to avoid large transpulmonary pressure swings. The logic was that COVID-19 causes significant gas-exchange abnormality without the typical effect on elastance. The resulting increase in respiratory drive would generate vigorous inspiratory effort, overstretch a relatively compliant lung, and lead to further injury.

Other equally prominent researchers countered this argument. Martin Tobin drew on physiology, while Arthur Slutsky and Niall Ferguson used emerging data to make their case. Tobin and colleagues cautioned against early intubation for anyone who could be maintained using noninvasive support. In August 2020 (well into the pandemic and after more data were available), Slutsky and colleagues argued that ARDS caused by COVID-19 wasn’t much different from lung injury due to other causes.

Two more recent studies published online recently are relevant to the debate over COVID-19 ARDS. One was a prospective study and the other a retrospective study; both had comparison groups, and both came to the same conclusions. Overall, COVID-19 ARDS isn’t much different from ARDS due to other causes. These studies were comprehensive in their comparisons and measures of outcomes, but they were both rather small and included patients from one and two hospitals, respectively. The discussions of both provide a nice review of the existing literature on COVID-19 ARDS.

A second controversial, but unproven, COVID-19 practice is aggressive anticoagulation. Early reports of a high prevalence of venous thromboembolism (VTE) in patients with COVID-19 pushed many to recommend empirically increasing prophylaxis. Most of the data guiding this approach were from retrospective, observational studies that suffered from selection bias. Early on, many of the studies were from China, where baseline VTE prophylaxis rates were low. Despite these limitations, many physicians acted on the basis of these data. An arbitrarily defined “intermediate” or treatment dose for prophylaxis was used, with some measuring D-dimer to guide their approach. An evidence-based argument against this practice, published in the New England Journal of Medicine, failed to sway readers. (Look at the poll at the end of the article and you’ll see how readers answered.)

Two articles recently published online in CHEST attempted to bring clarity to the debate over COVID-19 and VTE prophylaxis. The first study evaluated critically ill patients in France, and researchers found that higher doses of anticoagulation reduced thrombotic complications without an associated increase in bleeding events. The study is well done but certainly has its flaws. It is observational and retrospective, and it essentially uses a before-after comparison technique. Such an approach is particularly prone to bias during COVID-19, given that practice patterns change quickly.

The second paper is a systematic review looking at VTE and bleeding rates among patients hospitalized with COVID-19. The authors found high rates of VTE (17.0% overall), with screening, admission to the ICU, and the prospective study design all being associated with increased rates. Of importance, unlike the retrospective trial cited in the previous paragraph, the authors of the systematic review found treatment-dose anticoagulation was associated with higher bleeding rates.

I admit, the title of this piece is a bit of a misnomer. The “late adopters” would truly have their revenge if deviation from guidelines for COVID-19–related ARDS and VTE prophylaxis proves to be harmful. It’s not clear that’s the case, and at least for VTE prophylaxis, results from several randomized, controlled trials (REMAP-CAP, ATTACC, and ACTIV-4a) will be released soon. These are sure to provide more definitive answers. If nothing else, the COVID-19–related ARDS and VTE data reinforce how difficult it is to obtain high-quality data that yield clear results. Until something more definitive is published and released, I will remain a “late adopter.” Standard non–COVID-19 guidelines for ARDS and VTE prophylaxis are good enough for me.

Dr. Holley is program director of the Pulmonary and Critical Care Medical Fellowship at Walter Reed National Military Medical Center, Bethesda, Md.

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

Despite 30+ years of antismoking public policies and dramatic overall decline in secondhand smoke (SHS) exposure, nonsmoking low-income and non-Hispanic Black people remain at high risk for exposure to smoke.

No risk-free SHS exposure

Surendranath S. Shastri, MD, of MD Anderson Cancer Center, Houston, and colleagues underscored the U.S. Surgeon General’s determination that there is no risk-free level of SHS exposure in a recent JAMA Internal Medicine Research Letter.

“With the outbreak of the coronavirus disease 2019, which affects lung function, improving smoke-free policies to enhance air quality should be a growing priority,”they wrote.

Dr. Shastri and colleagues looked at 2011-2018 data from the National Health and Nutrition Examination Survey (NHANES), which detailed prevalence of SHS exposure in the U.S. population aged 3 years and older using interviews and biological specimens to test for cotinine levels. For the survey, nonsmokers having serum cotinine levels of 0.05 to 10 ng/mL were considered to have SHS exposure.

Disparities in SHS exposure

A second report from NHANES data for 2015-2018, published in a National Center for Health Statistics Data Brief (No. 396, February 2021) showed that 20.8% of nonsmoking U.S. adults had SHS exposure, again with greater prevalence among non-Hispanic Black adults (39.7%), than for non-Hispanic White (18.4%), non-Hispanic Asian (20.9%), and Hispanic (17.2%) adults. Exposure was also greater in the younger age groups, with SHS rates for adults aged 18-39 years, 40-59 years, and ≥60 years at 25.6%, 19.1%, and 17.6%, respectively. Lower education (high school or less vs. some college education) and lower income levels were also associated with higher levels of SHS exposure. The investigators noted that among households with smokers, non-Hispanic Black adults are less likely to have complete smoking bans in homes, and among Medicaid or uninsured parents of any race or ethnicity, bans on smoking in family vehicles are less likely.

Overall, the prevalence of SHS exposure declined from 27.7% to 20.7% from 2009 to 2018, but the decreases were mediated by race and income.

SHS exposure in private spaces

A research brief from the Centers for Disease Control and Prevention on SHS exposure in homes and vehicles in the U.S. among middle and high school students also found a general decline in SHS exposure over 2011-2018 in homes (26.8%-20.9%; P < .001) and vehicles (30.2%-19.8%; P < .001). The findings, derived from the National Youth Tobacco Survey for 2011-2019, showed that no reduction occurred in homes among non-Hispanic Black students. Overall, a significant difference in home SHS exposure was observed by race/ethnicity: non-Hispanic Black (28.4%) and non-Hispanic White (27.4%) students both had a higher prevalence compared with Hispanic (20.0%) and non-Hispanic other (20.2%) students (P < .001).

Progress in reducing SHS exposure in public spaces has been made over the last 2 decades, with 27 states and more than 1,000 municipalities implementing comprehensive smoke-free laws that prohibit smoking in indoor public places, including workplaces, restaurants, and bars. While the prevalence of voluntary smoke-free home (83.7%) and vehicle (78.1%) rules has increased over time, private settings remain major sources of SHS exposure for many people, including youths. “Although SHS exposures have declined,” the authors wrote, “more than 6 million young people remain exposed to SHS in these private settings.”

In reviewing the data, Mary Cataletto, MD, FCCP, clinical professor of pediatrics at NYU Long Island School of Medicine, stated that these studies “highlight the need for implementation of smoke-free policies to reduce exposure to secondhand smoke, especially in homes and cars and with focused advocacy efforts in highly affected communities.”

Panagis Galiatsatos, MD, MHS, assistant professor of medicine at Johns Hopkins University, Baltimore, emphasized implementation of smoke-free policies but also treatment for smokers. “I’m not at all surprised by these statistics,” he noted in an interview. “Public health policies have helped us to get to where we are now, but there’s a reason that we have plateaued over the last decade. It’s hard to mitigate secondhand smoke exposure because the ones who are smoking now are the most refractory, challenging cases. ... You need good clinical interventions with counseling supported by pharmacological agents to help them if you want to stop secondhand smoke exposure.” He added, “You have to look at current smokers no differently than you look at patients with stage IV cancer – a group that requires a lot of resources to help them get through. Remember, all of them want to quit, but the promise of well-designed, precision-medicine strategies to help them quit has not been kept. Public health policy isn’t going to do it. We need to manage these patients clinically.”

The investigators had no conflict disclosures.

Despite 30+ years of antismoking public policies and dramatic overall decline in secondhand smoke (SHS) exposure, nonsmoking low-income and non-Hispanic Black people remain at high risk for exposure to smoke.

No risk-free SHS exposure

Surendranath S. Shastri, MD, of MD Anderson Cancer Center, Houston, and colleagues underscored the U.S. Surgeon General’s determination that there is no risk-free level of SHS exposure in a recent JAMA Internal Medicine Research Letter.

“With the outbreak of the coronavirus disease 2019, which affects lung function, improving smoke-free policies to enhance air quality should be a growing priority,”they wrote.

Dr. Shastri and colleagues looked at 2011-2018 data from the National Health and Nutrition Examination Survey (NHANES), which detailed prevalence of SHS exposure in the U.S. population aged 3 years and older using interviews and biological specimens to test for cotinine levels. For the survey, nonsmokers having serum cotinine levels of 0.05 to 10 ng/mL were considered to have SHS exposure.

Disparities in SHS exposure

A second report from NHANES data for 2015-2018, published in a National Center for Health Statistics Data Brief (No. 396, February 2021) showed that 20.8% of nonsmoking U.S. adults had SHS exposure, again with greater prevalence among non-Hispanic Black adults (39.7%), than for non-Hispanic White (18.4%), non-Hispanic Asian (20.9%), and Hispanic (17.2%) adults. Exposure was also greater in the younger age groups, with SHS rates for adults aged 18-39 years, 40-59 years, and ≥60 years at 25.6%, 19.1%, and 17.6%, respectively. Lower education (high school or less vs. some college education) and lower income levels were also associated with higher levels of SHS exposure. The investigators noted that among households with smokers, non-Hispanic Black adults are less likely to have complete smoking bans in homes, and among Medicaid or uninsured parents of any race or ethnicity, bans on smoking in family vehicles are less likely.

Overall, the prevalence of SHS exposure declined from 27.7% to 20.7% from 2009 to 2018, but the decreases were mediated by race and income.

SHS exposure in private spaces

A research brief from the Centers for Disease Control and Prevention on SHS exposure in homes and vehicles in the U.S. among middle and high school students also found a general decline in SHS exposure over 2011-2018 in homes (26.8%-20.9%; P < .001) and vehicles (30.2%-19.8%; P < .001). The findings, derived from the National Youth Tobacco Survey for 2011-2019, showed that no reduction occurred in homes among non-Hispanic Black students. Overall, a significant difference in home SHS exposure was observed by race/ethnicity: non-Hispanic Black (28.4%) and non-Hispanic White (27.4%) students both had a higher prevalence compared with Hispanic (20.0%) and non-Hispanic other (20.2%) students (P < .001).

Progress in reducing SHS exposure in public spaces has been made over the last 2 decades, with 27 states and more than 1,000 municipalities implementing comprehensive smoke-free laws that prohibit smoking in indoor public places, including workplaces, restaurants, and bars. While the prevalence of voluntary smoke-free home (83.7%) and vehicle (78.1%) rules has increased over time, private settings remain major sources of SHS exposure for many people, including youths. “Although SHS exposures have declined,” the authors wrote, “more than 6 million young people remain exposed to SHS in these private settings.”

In reviewing the data, Mary Cataletto, MD, FCCP, clinical professor of pediatrics at NYU Long Island School of Medicine, stated that these studies “highlight the need for implementation of smoke-free policies to reduce exposure to secondhand smoke, especially in homes and cars and with focused advocacy efforts in highly affected communities.”

Panagis Galiatsatos, MD, MHS, assistant professor of medicine at Johns Hopkins University, Baltimore, emphasized implementation of smoke-free policies but also treatment for smokers. “I’m not at all surprised by these statistics,” he noted in an interview. “Public health policies have helped us to get to where we are now, but there’s a reason that we have plateaued over the last decade. It’s hard to mitigate secondhand smoke exposure because the ones who are smoking now are the most refractory, challenging cases. ... You need good clinical interventions with counseling supported by pharmacological agents to help them if you want to stop secondhand smoke exposure.” He added, “You have to look at current smokers no differently than you look at patients with stage IV cancer – a group that requires a lot of resources to help them get through. Remember, all of them want to quit, but the promise of well-designed, precision-medicine strategies to help them quit has not been kept. Public health policy isn’t going to do it. We need to manage these patients clinically.”

The investigators had no conflict disclosures.

Despite 30+ years of antismoking public policies and dramatic overall decline in secondhand smoke (SHS) exposure, nonsmoking low-income and non-Hispanic Black people remain at high risk for exposure to smoke.

No risk-free SHS exposure

Surendranath S. Shastri, MD, of MD Anderson Cancer Center, Houston, and colleagues underscored the U.S. Surgeon General’s determination that there is no risk-free level of SHS exposure in a recent JAMA Internal Medicine Research Letter.

“With the outbreak of the coronavirus disease 2019, which affects lung function, improving smoke-free policies to enhance air quality should be a growing priority,”they wrote.

Dr. Shastri and colleagues looked at 2011-2018 data from the National Health and Nutrition Examination Survey (NHANES), which detailed prevalence of SHS exposure in the U.S. population aged 3 years and older using interviews and biological specimens to test for cotinine levels. For the survey, nonsmokers having serum cotinine levels of 0.05 to 10 ng/mL were considered to have SHS exposure.

Disparities in SHS exposure

A second report from NHANES data for 2015-2018, published in a National Center for Health Statistics Data Brief (No. 396, February 2021) showed that 20.8% of nonsmoking U.S. adults had SHS exposure, again with greater prevalence among non-Hispanic Black adults (39.7%), than for non-Hispanic White (18.4%), non-Hispanic Asian (20.9%), and Hispanic (17.2%) adults. Exposure was also greater in the younger age groups, with SHS rates for adults aged 18-39 years, 40-59 years, and ≥60 years at 25.6%, 19.1%, and 17.6%, respectively. Lower education (high school or less vs. some college education) and lower income levels were also associated with higher levels of SHS exposure. The investigators noted that among households with smokers, non-Hispanic Black adults are less likely to have complete smoking bans in homes, and among Medicaid or uninsured parents of any race or ethnicity, bans on smoking in family vehicles are less likely.

Overall, the prevalence of SHS exposure declined from 27.7% to 20.7% from 2009 to 2018, but the decreases were mediated by race and income.

SHS exposure in private spaces

A research brief from the Centers for Disease Control and Prevention on SHS exposure in homes and vehicles in the U.S. among middle and high school students also found a general decline in SHS exposure over 2011-2018 in homes (26.8%-20.9%; P < .001) and vehicles (30.2%-19.8%; P < .001). The findings, derived from the National Youth Tobacco Survey for 2011-2019, showed that no reduction occurred in homes among non-Hispanic Black students. Overall, a significant difference in home SHS exposure was observed by race/ethnicity: non-Hispanic Black (28.4%) and non-Hispanic White (27.4%) students both had a higher prevalence compared with Hispanic (20.0%) and non-Hispanic other (20.2%) students (P < .001).

Progress in reducing SHS exposure in public spaces has been made over the last 2 decades, with 27 states and more than 1,000 municipalities implementing comprehensive smoke-free laws that prohibit smoking in indoor public places, including workplaces, restaurants, and bars. While the prevalence of voluntary smoke-free home (83.7%) and vehicle (78.1%) rules has increased over time, private settings remain major sources of SHS exposure for many people, including youths. “Although SHS exposures have declined,” the authors wrote, “more than 6 million young people remain exposed to SHS in these private settings.”

In reviewing the data, Mary Cataletto, MD, FCCP, clinical professor of pediatrics at NYU Long Island School of Medicine, stated that these studies “highlight the need for implementation of smoke-free policies to reduce exposure to secondhand smoke, especially in homes and cars and with focused advocacy efforts in highly affected communities.”

Panagis Galiatsatos, MD, MHS, assistant professor of medicine at Johns Hopkins University, Baltimore, emphasized implementation of smoke-free policies but also treatment for smokers. “I’m not at all surprised by these statistics,” he noted in an interview. “Public health policies have helped us to get to where we are now, but there’s a reason that we have plateaued over the last decade. It’s hard to mitigate secondhand smoke exposure because the ones who are smoking now are the most refractory, challenging cases. ... You need good clinical interventions with counseling supported by pharmacological agents to help them if you want to stop secondhand smoke exposure.” He added, “You have to look at current smokers no differently than you look at patients with stage IV cancer – a group that requires a lot of resources to help them get through. Remember, all of them want to quit, but the promise of well-designed, precision-medicine strategies to help them quit has not been kept. Public health policy isn’t going to do it. We need to manage these patients clinically.”

The investigators had no conflict disclosures.