Denyse Lutchmansingh, MBBS

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms