Long COVID-19
Long COVID is a form of COVID-19 involving a wide range of health conditions that can last for months or years. This form of COVID creates unique challenges in treatment options for patients as their symptoms persist beyond the acute COVID-19 infection. Here are some important resources to understand and combat long COVID.
In 2023, 6.4% (95% CI = 6.3–6.6%) of the noninstitutionalized U.S. adults nationwide were experiencing Long COVID when surveyed. Among adults with current Long COVID, age- and sex-standardized prevalences of reporting significant Long COVID–associated activity limitation ranged from 12.8% in the District of Columbia to 29.4% in Puerto Rico. - December 19, 2024
A randomized clinical trial in Norway found that a brief outpatient rehabilitation program based on cognitive and behavioral approach was effective in reducing physical function limitations in patients with Long COVID. - December 19, 2024
This review, co-authored by someone with lived experience of severe Long COVID discusses the epidemiology, pathophysiology, clinical manifestations, and clinical investigation and management of Long COVID. - July 31, 2024
Lithium Aspartate ineffective for fatigue and cognitive dysfunction. This small (52 patients) randomized clinical trial of lithium aspartate 10-15 mg per day for 3 weeks provided no significant improvement in symptoms. Lithium Aspartate for Long COVID Fatigue and Cognitive Dysfunction: A Randomized Clinical Trial | Infectious Diseases | JAMA Network Open | JAMA Network - October 2, 2024
Persistent exertional dyspnea may be due to diaphragm muscle weakness, and amendable to inspiratory muscle training. This study only 30 individuals 2 years after hospitalization with persistent dyspnea, 18 of whom demonstrated persistent diaphragm muscle weakness. Compared to a sham control, inspiratory muscle training improved muscle function and dyspnea. Potential Diaphragm Muscle Weakness-related Dyspnea Persists 2 Years after COVID-19 and Could Be Improved by Inspiratory Muscle Training: Results of an Observational and an Interventional Clinical Trial | American Journal of Respiratory and Critical Care Medicine – September 7, 2024
Risk for autoimmune sequelae low with Omicron in vaccinated patients. This case-control cohort study in Singapore involving over 480,000 cases of highly vaccinated patients noted that there was no significantly elevated risk of 12 prespecified autoimmune sequelae noted during the Omicron and Delta periods. There was an increased risk of inflammatory bowel disease (1-2 fold) and bullous skin disease (2-9 fold) only in the subset of cases requiring hospitalization during Omicron. Autoimmune Sequelae After Delta or Omicron Variant SARS-CoV-2 Infection in a Highly Vaccinated Cohort | Infectious Diseases | JAMA Network Open | JAMA Network - August 30, 2024
This study in 5367 participants in the RECOVER-Pediatrics cohort study found that symptoms in those with a SARS-C0V-2 infection history were similar in school-age children and adolescents, but there were distinct symptoms that differentiated the groups. Long COVID symptoms unique to school-aged children included neurocognitive, pain and GI symptoms whereas those unique to adolescents included loss in smell, taste, and fatigue/malaise-related symptoms. Characterizing Long COVID in Children and Adolescents | JAMA | JAMA Network - August 21, 2024
Study confirms absence of laboratory markers for Long COVID. The RECOVER-Adult cohort study involving over 8700 participants with prior COVID-19 infection, compared to 1348 without prior infection, did not find any differences in laboratory measurements between those with Long COVID and those without. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort | Annals of Internal Medicine - August 13, 2024
No evidence was found that any of 25 routine clinical laboratory values could serve as a clinically useful biomarker of Long COVID. Over 10,000 patients from the RECOVER cohort with or without a history of COVID were evaluated 6 months after enrollment. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort | Annals of Internal Medicine (acpjournals.org) – August 13, 2024
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome not more likely after COVID-19 compared to non-COVID infections. A prospective, multisite, longitudinal cohort study (INSPIRE) involving 4378 adults under age 65 who had symptoms of a COVID-19-like illness and a positive or negative molecular or antigen SARS-CoV-2 test were enrolled and followed for up to 12 months. There was no difference in the number of ME/CFS-like illness in those with a positive SARS-CoV-2 test vs. a negative test. One limitation: tests were self-administered and the subject could choose the type of test. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection | Public Health | JAMA Network Open | JAMA Network – July 24, 2024
At three years, patients show continued improvement in CT abnormalities and pulmonary function, but more than a third continued to have abnormal findings in DLCO and CT in this Chinese longitudinal study of 728 COVID-19 survivors and 792 controls. Long-term radiological and pulmonary function abnormalities at 3 years after COVID-19 hospitalisation: a longitudinal cohort study | European Respiratory Society (ersjournals.com) – 2024
The National Academies of Science, Engineering and Medicine (NASEM) has released their Consensus Study Report on Long-term Health Effects of COVID-19. Disability and Function Following SARS-CoV-2 Infection. The report can be read for free at this link or downloaded for free. Long-Term Health Effects of COVID-19: Disability and Function Following SARS-CoV-2 Infection | The National Academies Press – 2024
This large patient cohort study (EHR cohort of over 3 million patients) found that the severity of reinfection appears to be associated with the severity of the initial infection and the Long COVID diagnoses appear to occur more often following initial infection than reinfection. Insights from an N3C RECOVER EHR-based cohort study characterizing SARS-CoV-2 reinfections and Long COVID | Communications Medicine (nature.com) – July 11, 2024
NASEM has also proposed a new definition of Long-COVID that they recommend be used by all federal agencies involved in research on the topic, and that definition should be re-evaluated in no more than three years. The proposed definition for LONG-COVID: an infection-associated chronic condition that occurs after COVID-19 infection and is present for at least three months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems. Federal Government, Clinicians, Employers, and Others Should Adopt New Definition for Long COVID to Aid in Consistent Diagnosis, Documentation, and Treatment | National Academies – June 11, 2024
Although confounded by a lack of a consistent definition of Long COVID (until recently – see below) new data from the Medical Expenditure Panel Survey Household Component support prior findings that about 7% of US adults (17.8 million people) had ever had long COVID as of early 2023. Females were more likely to have Long COVID, as midlife adults (perhaps a reflection of lower vaccination rates compared to older adults). Evidence Mounts That About 7% of US Adults Have Had Long COVID | Coronavirus (COVID-19) | JAMA | JAMA Network - June 7, 2024
A 15-day course of Paxlovid was ineffective in amelioration of Long-COVID symptoms in this study of 155 individuals with Long-COVID symptoms. Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial | Coronavirus (COVID-19) | JAMA Internal Medicine | JAMA Network – June 7, 2024
This large cohort study of US Veterans, involving 135,161 with a history of COVID-19 and over 5 million controls, followed for three years found that disabilities remain to some extent after three years, more so in those who had been hospitalized with the infection. A significant elevation in risk of death also was still present after 3 years in those who had been hospitalized. Since this study involved an older population, the findings may not be generally applicable. Three-year outcomes of post-acute sequelae of COVID-19 | Nature Medicine – May 30, 2024
Lung abnormalities can persist for up to 24 months after hospitalization. This study was done in Brazil, with 237 patients who had abnormal lung findings during hospitalization for COVID-19. The most common abnormality was CT findings of ground glass opacities and reticulations in 58%, but 33% had fibrotic-like lesions. 25% of patients had worsened compared to their findings at 6-12 months versus 5% who improved. Pulmonary function abnormalities included a restrictive pattern and reduced diffusing capacity in 44%. Post-COVID-19 respiratory sequelae two years after hospitalization: an ambidirectional study - The Lancet Regional Health – Americas – May 2024
The NIH has opened clinical trials to study four potential treatments for long-term symptoms including sleep disturbance, exercise intolerance, and post-exertional malaise as part of the RECOVER program. Drugs being tested for hypersomnia include modafinil and solriamfetol, melatonin and light therapy for complex sleep disturbances, personalized cardiopulmonary rehabilitation for those with exercise intolerance, and structured pacing for post-exertional malaise. NIH to open long COVID clinical trials to study sleep disturbances, exercise intolerance, and post exertional malaise | National Institutes of Health (NIH) – May 8, 2024
For those members in research who might be interested, secure data from more than 14,000 adults who participate in National Institutes of Health observational research on long COVID are now available to authorized researchers through BioData Catalyst (BDC). BDC is a cloud-based ecosystem developed by the National Heart, Lung, and Blood Institute (NHLBI), part of NIH, to accelerate research on heart, lung, blood, and sleep disorders. The research on long COVID — broadly defined as signs, symptoms, or conditions that persist or develop for at least four weeks after an infection from the virus that causes COVID-19 is provided through the NIH Researching COVID to Enhance Recovery (NIH RECOVER) Initiative. Authorized researchers can now request access to a subset of data from adults in the observational RECOVER cohort. These data include information from more than 92,000 study visits collected between Oct. 29, 2021-Sept. 15, 2023 at 79 locations throughout the United States. New RECOVER data, including data from other studies, will be added to BDC at regular intervals. NIH RECOVER makes long COVID data easier to access | National Institutes of Health (NIH) - April 25, 2024
The gut microbiome composition associated with the heterogeneity of Long_COVID symptoms and gut enterotypes associate with distinct phenotypic manifestations of the symptoms. The gut microbiome associates with phenotypic manifestations of post-acute COVID-19 syndrome: Cell Host & Microbe – April 23, 2024
This study examined plasma proteins in 466 patients with at least one Long COVID symptom compared to 233 patients who symptoms had completely resolved and found that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials. Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease | Nature Immunology – April 8, 2024
This small study compared patients with Post COVID Condition (PCC) with matched controls and varying intensity levels of exercise and found that there were no profound symptom exacerbation among those with PCC but they did have more muscle pain after high-intensity interval training and more concentration problems after moderate intensity continuous training. Those with PCC also had lower aerobic capacity and less muscle strength. The authors concluded that cautious exercise training should be recommended for PCC patients to prevent further deconditioning. Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial | Physical Medicine and Rehabilitation | JAMA Network Open | JAMA Network – April 4, 2024
A large retrospective cohort study showed that SARS-CoV-2 vaccination was 35.4% effective against probable Long COVID and 4.7% against diagnosed Long COVID. Vaccination was more effective in adolescents (50.3%) compared to 5-11 year olds (23.8%). Vaccine Effectiveness Against Long COVID in Children | Pediatrics | American Academy of Pediatrics (aap.org) - March 8, 2024
This study from England involved 112,964 adults who completed an online assessment of cognitive function. Those whose symptoms from COVID-19 had resolved by 12 weeks had small deficits in global cognition compared to the no-COVID group. Larger deficits were seen in participants with unresolved persistent symptoms (lasting greater than 12 weeks). The degree of deficit was related to the circulating variant at the time of infection. Memory, reasoning and executive function were associated with the largest deficits. Cognition and Memory after Covid-19 in a Large Community Sample | NEJM – February 29, 2024
A study on a small number of acutely infected adults with COVID-19, some of which were studied post-infection, revealed that sustained systemic inflammation and persistent localized blood-brain barrier dysfunction is a key feature of Long COVID -associated brain fog. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment | Nature Neuroscience – February 22, 2024
This longitudinal population-based cohort study involving 112,311 individuals with a history of COVID-19 compared to two control groups found a higher risk for respiratory disease in the COVID-19 group compared to controls for asthma, COPD, bronchiectasis, interstitial lung disease, pulmonary vascular disease and lung cancer. The hazard ratio for asthma was 1.49 (95% CI, 1.28-1.74) and for COPD 1.59 (95% CI, 1.41-1.81). The risk increased with the severity of the infection, and reinfection. Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study - eClinicalMedicine (thelancet.com) - February 17, 2024
The CDC analyzed data from noninstitutionalized U.S. adults aged ≥18 years participating in the 2022 Behavioral Risk Factor Surveillance System (BRFSS), a population-based cross-sectional survey (4). Respondents were sampled using random digit dialing of both landline and cellular telephones. Individuals from all 50 states and US Territories were interviewed. The overall prevalence was 6.4% and was noted to vary from 1.9% in the US Virgin Islands to 10.6% in West Virginia. Prevalence tended to be lower in New England and the Pacific and higher in the South, Midwest and West. Notes from the Field: Long COVID Prevalence Among Adults — United States, 2022 | MMWR (cdc.gov) – February 15, 2024
A survey study of 14,767 individuals with post-COVID condition (PCC) found that 57% reported experiencing cognitive symptoms daily, compared to 27% who did not develop PCC. Cognitive Symptoms of Post–COVID-19 Condition and Daily Functioning | Infectious Diseases | JAMA Network Open | JAMA Network - February 14, 2024
This state-of-the-art narrative review provides a summary of our current knowledge about PASC in children, including prevalence, epidemiology, risk factors, clinical characteristics, underlying mechanisms, and functional outcomes. Postacute Sequelae of SARS-CoV-2 in Children | Pediatrics | American Academy of Pediatrics (aap.org) – February 7, 2024
In this study, 270 patients diagnosed with Post COVID Condition (PCC) from two different clinics in the UK and Germany were compared to two control groups: individuals who had contracted COVID-19 but did not develop PCC and uninfected individuals. Using short web-based cognitive tasks the authors found pronounced cognitive slowing in 53.5% of the patients with PCC compared to the control groups. Long COVID is associated with severe cognitive slowing: a multicentre cross-sectional study - eClinicalMedicine (thelancet.com) - January 24, 2024
This study in a small number of patients with symptoms consistent with Long COVID suggests evidence of persistent complement dysregulation and thromboinflammation. This might suggest clinical trials of complement modulation for treatment. Persistent complement dysregulation with signs of thromboinflammation in active Long COVID | Science - January 19, 2024
This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Keep in mind that Long COVID is declining among infected children, but this study compared vaccinated to unvaccinated. Vaccine Effectiveness Against Long COVID in Children | Pediatrics | American Academy of Pediatrics (aap.org) - January 16 2024
This study used ‘omic” assays and serology to deeply characterize the global and SARS-CoV-2-specific immunity in the blood of individuals with clear LC and non-LC clinical trajectories, 8 months postinfection. 25% had been hospitalized for COVID-19. 27 patients had clear-cut Long COVID. These individuals exhibited evidence of systemic inflammation and immune dysregulation, manifested by global differences in T cell subset distribution as well as be sex-specific perturbations in cytolytic subsets. LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells, higher levels of SARS-CoV-2 antibodies and a mis-coordination between their SARS-CoV-2-specific T and B cell responses. The analysis suggested improper cross-talk between the cellular and humoral adaptive immunity in Long COVID. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2 | Nature Immunology - January 11, 2024
SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases and also targeted plaque macrophages. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels | Nature Cardiovascular Research - September 28, 2023
Immune profiling and biological features identified through machine learning revealed marked differences in circulating myeloid and lymphoid populations, exaggerated humoral responses against SAR-CoV-2 as well as other viruses. Distinguishing features of Long COVID identified through immune profiling | Nature - September 25, 2023
Multicenter MRI study in the UK found multiorgan abnormalities were found in 61% of adults hospitalized with COVID-19 compared to 27% of controls at a median of 5 months after discharge. Lung, brain and kidney were the most frequent involved organs. Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study - The Lancet Respiratory Medicine - September 22, 2023
Review of the immunology of Long COVID. The immunology of long COVID | Nature Reviews Immunology - September 18, 2023
This prospective study from Canada included 1026 8-13 year-old children who provided reports of symptoms every two weeks during the study period between August 2020 and March 2021. The rate of long-COVID symptoms as defined by the WHO was 0.4% and noted that pre-existing symptoms prior to COVID-19 were factors in post COVID symptoms. The study period preceded the delta and omicron, and may not apply to delta, but omicron has been reported to be associated with less long-COVID. Post–COVID-19 Condition in Children | Infectious Diseases | JAMA Pediatrics | JAMA Network - September 18, 2023
Review of studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir. Mechanisms by which these reservoirs may contribute to Long-COVID pathology are delineated. SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC) | Nature Immunology - September 4, 2023
Data from the National Health Interview Survey on Long COVID in adults is presented in this NCHS Data brief: db480.pdf (cdc.gov) - September 2023
This study from the CDC discussed the long lasting significant activity limitations among adults after the Omicron surge. Long COVID and Significant Activity Limitation Among Adults, by Age — United States, June 1–13, 2022, to June 7–19, 2023 | MMWR (cdc.gov) - August 11, 2023
This multicenter study of adults with COVID-like illness showed that symptoms can persist, emerge, reemerge or resolve after a COVID-like illness and are not unique to COVID-19 or to post-COVID conditions. Prevalence of Symptoms ≤12 Months After Acute Illness, by COVID-19 Testing Status Among Adults — United States, December 2020–March 2023 | MMWR (cdc.gov) - August 11, 2023
A systematic review of persistent clinical features following COVID-19 in pediatrics: A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population | Pediatrics | American Academy of Pediatrics (aap.org) (free access) - July 21 2023
CDC archived webinar: Evaluating and Supporting Patients with Long COVID in Returning to Work: Webinar Thursday, June 15, 2023 - Evaluating and Supporting Patients with Long COVID in Returning to Work (cdc.gov)
In this study of 1106 adults who were not vaccinated before infection compared to 628 who were not infected, up to 18% had post-COIVD 19 condition up to two years after infection, with little change from 1-2 years. Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study | The BMJ - May 31, 2023
In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score. In addition, this study noted that 30% of those with symptoms at 6 months were symptom-free at 9 months. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection | Neurology | JAMA | JAMA Network - May 25, 2023
Here is a review of the proposed neurobiology behind the cognitive impairment in humans. The neurobiology of long COVID: Neuron (cell.com) – October 6, 2022
Analysis of data on almost 10,000 patients from the RECOVER adult prospective cohort trial revealed key symptoms that could be used to identify patients with long COVID. They were, in decreasing order of frequency: post-exertional malaise, fatigue, brain fog, dizziness, GI symptoms, palpitations, loss of libido, loss of smell or taste, thirst, hair loss, chronic cough, chest pain, and abnormal movements. Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection | Infectious Diseases | JAMA | JAMA Network
VA Guidebook on Long COVID
The Department of Veterans Affairs published a new guidebook on caring for veterans with long COVID. Titled the Whole Health System Approach to Long COVID, the guidebook provides information about signs, symptoms and treatments for the illness. The guidebook also includes metrics, such as surveys, to assess autonomic symptoms. This is an excellent resource when confronted with a patient with potential long COVID. (11/7/22)
Additional Resources
Long COVID or Post-COVID Conditions | CDC (for patients) and Post-COVID Conditions: Information for Healthcare Providers (cdc.gov) for providers and the NIH website Long COVID | NIH COVID-19 Research