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Post COVID Conditions (e.g. Long COVID)

Last reviewed: February 16, 2022 

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview

Some patients experience new, recurring or ongoing symptoms related to COVID-19 several weeks after the acute phase of infection (Datta, November 2020; Greenhalgh, August 2020 Shah, January 2021). The U.S. Centers for Disease Control and Prevention recommends using the umbrella term “post-COVID conditions” for a wide range of signs and symptoms that occur 4 or more weeks after acute COVID-19 infection. Standardized case definitions are still being developed. In general, post-COVID conditions are characterized by a lack of return to a usual state of health following acute COVID-19 infection.

Post-COVID conditions are referred to by a wide range of names, including “long COVID,” “post-COVID syndrome,” “post-acute COVID-19 syndrome,” as well as the research term “post-acute sequelae of SARS-CoV-2 infection.” Among the lay public, the phrase “” is also used.

The mechanism of post-COVID conditions is not well understood but is hypothesized to be secondary to virus-specific pathophysiologic changes, prolonged inflammatory response to the acute infection and sequelae of post-intensive care illness (Hosey, July 2020; Inoue, April 2019). Recent research highlights four risk factors for post-COVID conditions including early SARS-COV-2 COVID-19 RNA serum level, certain autoantibodies, Epstein-Barr virus reactivation and type 2 diabetes mellitus (Su, January 2022).

Definitions

The World Health Organization has developed a working clinical case definition of post-COVID conditions: "Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID-19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children."

Post-COVID conditions can involve different combinations of health problems for varied lengths of time. Different types of post-COVID conditions are described below:

New or Ongoing Symptoms  

Some people experience a range of new or ongoing symptoms that last several weeks or months (e.g., shortness of breath, cough, palpitations, changes in smell or taste, headaches, joint pain, difficulty thinking or concentrating, dizziness, post-exertional malaise). Unlike some other types of post-COVID conditions, these symptoms can occur even if the initial infection was mild or asymptomatic. This category is heterogeneous and will likely be modified in the future.  

Multiple Organ System Effects of COVID-19 

Some people develop multisystem inflammatory syndrome and autoimmune conditions after COVID-19 illness. We describe MIS-A and MIS-C elsewhere.

Effects of COVID-19 Illness or Hospitalization 

Effects of hospitalization or illness include tracheal stenosis from prolonged intubation, severe weakness, deconditioning, post-intensive care syndrome and post-traumatic stress disorder.

 

Post-COVID Conditions in Children 

Post-COVID conditions (i.e., long COVID and PASC) were first described in adults. But several studies now report a similar phenomenon in children, with persistent symptoms after acute COVID infection such as headache, fatigue and heart palpitations (Ludvigsson, November 2020). Even children with an asymptomatic or mildly symptomatic COVID-19 infection can develop chronic, persisting symptoms (Buonsenso, April 2021).

The exact burden and long-term consequences of post-COVID conditions in children vary widely and are a priority for further research. Data from the U.K. Health Security Agency related to lingering symptoms in children are also concerning. Almost 10% of children aged 2-11 years and 13% aged 12-16 years reported one or more lingering symptoms 5 weeks after COVID-19 infection (UKHSA COVID-19 Evidence Team, February 2022). Another study found that almost 25% of hospitalized children surveyed after discharge reported symptoms more than 5 months later. A national survey in the Netherlands showed that among 89 children suspected of having long COVID, 18% were admitted to the hospital due to their long-term symptoms (Brackel, June 2021; Osmanov, June 2022).

Di Sante and colleagues looked at immunological changes that occur in people with long COVID to see whether there are biological markers that could lead to treatments. In a small study posted as a preprint in May 2021, only the children with long COVID showed signs of chronic inflammation (Di Sante, May 2021 - preprint, not peer-reviewed).

Additional Pediatric Literature

Risk Factors for Long COVID in Previously Hospitalized Children Using the ISARIC Global Follow-Up Protocol: A Prospective Cohort Study (Osmanov, July 2021).

Post-Acute COVID-19 Outcomes in Children with Mild and Asymptomatic Disease (Say, April 2021).

Clustering and Longitudinal Change in SARS-CoV-2 Seroprevalence in School Children in the Canton of Zurich, Switzerland: Prospective Cohort Study of 55 Schools (Ulyte, March 2021).

Clinical Characteristics, Activity Levels and Mental Health Problems in Children with Long COVID: A Survey of 510 Children (Buonsenso, March 2021 - preprint, not peer-reviewed).

 

Guidelines

CDC interim guidance addresses evaluating and caring for patients with post-COVID conditions. Based on current information, many post-COVID conditions can be managed by primary care providers. As new evidence arises, guidance for health care professionals managing post-COVID conditions will likely change over time.

World Health Organization guidelines include a good practice statement on caring for COVID-19 patients after acute illness.

In the U.K., guidelines for managing the long-term effects of COVID-19
have been jointly developed by the National Institute for Health and Care Excellence, Scottish Intercollegiate Guidelines Network and Royal College of General Practitioners.

Prevention

Newer data highlight that people who have received one or more doses of a COVID-19 vaccine are less likely to develop long COVID than those who remain unvaccinated (Antonelli, September, 2021;  Kuodi, January 2022).

The studies included a recent U.K. Health Security Agency review suggesting that:

  • People who received two doses of the Pfizer, AstraZeneca, or Moderna vaccines or one dose of the Janssen vaccine and then developed COVID-19 were about half as likely as people who were unvaccinated or received only one dose of mRNA vaccine to develop post-COVID conditions lasting beyond 28 days.
  • Vaccine effectiveness against most post-COVID conditions in adults was highest in people over 60 years of age.

 

Key Literature

In summary: Reports indicate some patients may develop post-acute COVID-19 syndrome in which they experience persistent symptoms after recovering from their initial illness. The syndrome appears to affect those with mild as well as moderate-to-severe disease. The incidence, natural history and etiology of these symptoms is currently unknown.
 

Burden of Post-COVID-19 Syndrome and Implications for Health Care Service Planning: A Population-Based Cohort Study (Menges, July 2021).

Overall, in this large population-based prospective cohort study, a significant proportion of patients with COVID-19 developed long-term health consequences after the acute infection.

  • Population-based prospective cohort of 431 patients in Switzerland.  
  • Eligibility criteria included a positive RT-PCR test result and age of 18 years or older.  
  • Positive RT-PCR test result between Oct. 6, 2020 and Jan. 26, 2021, at a median of 7.2 months after their diagnosis. 

Primary endpoint:  

  • Self-reported presence of the following outcomes: fatigue, long-term respiratory complications, depression, anxiety and stress symptoms, health-related quality of life and healthcare service utilization. 

Key findings:  

  • 26% of participants reported that they had not fully recovered at 6 to 8 months after initial COVID-19 diagnosis.  
  • 55% of participants experienced fatigue, 25% reported shortness of breath and 26% had symptoms of depression.  
  • 40% of participants reported at least one general practitioner visit related to COVID-19 after their acute illness.  
  • Post-COVID symptoms were more often reported by females and hospitalized patients. 

Limitations: 

  • Most participants included in the study were enrolled early in the pandemic, which likely selected for a sicker population due to testing capacity constraints. 
  • Self-selection bias may have also occurred. 
  • Sensitivity analysis by time periods was limited. 
  • Baseline (pre-COVID-19) assessment was not performed, so it is unclear if symptoms reported are new or attributable to COVID-19.

 

Post-COVID Syndrome in Non-hospitalized Patients With COVID-19: A Longitudinal Prospective Cohort Study (Augustin, May 2021).

Overall, in this longitudinal study, post-acute COVID-19 syndrome was more frequently associated with female sex, lower-serum IgG titers, anosmia and diarrhea at disease onset. 

Study population: 

  • Longitudinal, prospective analysis of health consequences in 958 patients in Germany with confirmed mild or asymptomatic COVID-19. 
  • 97.1% of study participants did not require hospitalization. 
  • Median age was 43 years; 46.5% of participants were male.  

Primary endpoint: 

  • Presence of one of four symptoms (anosmia, ageusia, fatigue or shortness of breath) at month 4 and 7 after acute COVID-19 diagnosis.  

Key findings:  

  • 27.8% of participants (123/442) experienced at least one symptom (anosmia, ageusia, fatigue or shortness of breath) at 4 months after acute COVID-19 infection; 34.8% (123/353) experienced at least one symptom at 7 months. 
  • At 4 months, 8.6% of patients experienced shortness of breath, 12.4% reported anosmia, 11.1% reported ageusia and 9.7% had fatigue. 
  • At 7 months, symptom distribution was similar with 13.6% experiencing shortness of breath, 14.7% reporting anosmia, 11.0% reporting ageusia and 14.7% with fatigue. 
  • The presence of post-acute COVID-19 symptoms was more frequently associated with female sex (male sex 0.59 [0.36–0.98]), lower serum IgG titers 1.90 (1.13–3.18), and diarrhea at disease onset 1.50 (0.78–2.91). 

Limitations: 

  • High drop-out rate suggests that true incidence of post-acute COVID-19 syndrome is likely lower as asymptomatic patients are more likely to not show up for follow-up visits. 

 

Post-Acute COVID-19 Syndrome Incidence and Risk Factors: A Mediterranean Cohort Study (Moreno-Pérez, January 2021). 

Overall, in this prospective cohort study, post-acute COVID-19 syndrome was reported in almost half of the patients who recovered from acute infection. 

Study population: 

  • Prospective cohort study of 277 adult patients who recovered from mild (34.3%) or severe (65.7%) COVID-19 infection and were evaluated 77 days after disease onset. 
  • Systematic assessment 10-14 weeks after disease onset. 

Primary endpoint:  

  • Post-acute COVID-19 syndrome was defined as the persistence of at least one clinically relevant symptom or abnormalities in spirometry or chest radiology. 

Key findings:  

  • 50.9% (141/277) patients developed symptoms consistent with post-acute COVID-19 syndrome. 
  • Alterations in spirometry were noted in 9.3% of patients (25/269); alterations in radiographs were noted in 18.9% (51/277). 
  • Symptoms are mostly mild and improved with time, and with no identified predictors. 
  • Post-acute COVID-19 syndrome is not limited to severe acute COVID-19 patients. 

Illness Duration and Symptom Profile in Symptomatic UK School-Aged Children Tested for SARS-CoV-2 (Molteni, August 2021). 

This study of U.K. school-aged children confirms that COVID-19 is usually of short duration and low symptom burden in children.

Study population: 

  • Prospective cohort study.  
  • U.K. school-aged children (age 5-17 years) reported by an adult proxy. 
  • Participants were voluntary and used a mobile application (app) launched jointly by Zoe Limited and King's College London. 

Primary endpoint: 

  • Illness duration and symptom burden in children who tested positive for SARS-CoV-2 and in matched children who tested negative. 

Key findings: 

  • Only 25 (1.8%) of 1,379 children experienced symptoms for at least 56 days. 
  • Almost all children had symptom resolution by 8 weeks. 
  • Symptom burden in children with negative SARS-CoV-2 tests was similar (0.9%). 

Limitations: 

  • Proxy reported outcomes (common for children). 
  • No linkage to hospital or outpatient records. 

Long-Term Symptoms After SARS-CoV-2 Infection in Children and Adolescents (Radtke, July 2021). 

This study found a low prevalence of symptoms compatible with long COVID in a randomly selected cohort of children assessed 6 months after serologic testing.  

Study population: 

  • Longitudinal cohort study in 55 randomly selected schools in Zurich, Switzerland.  
  • All children of randomly selected classes invited to participate. 
  • 1,355 children were included with median age 11 years (IQR, 9-13); 54% girls. 

Primary endpoint: 

  • Parents reported their children’s symptoms occurring since October 2020 and lasting for at least 4 weeks, as well as whether the symptoms persisted for more than 12 weeks. 
  • Compared children who tested positive for SARS-CoV-2 antibodies in October or November 2020 with those who tested negative. 

Key findings: 

  • Four of 109 seropositive children (4%) versus 28 of 1,246 seronegative ones (2%) reported at least one symptom lasting beyond 12 weeks. 
  • Most frequently reported symptoms lasting more than 12 weeks among seropositive children were tiredness (3/109, 3%), difficulty concentrating (2/109, 2%) and increased need for sleep (2/109, 2%) 

Limitations: 

  • Relatively small number of seropositive children.  
  • Lack of information on the exact time of SARS-CoV-2 infection. 
  • Possible misclassification of some children with false seropositive results. 
  • Potential recall bias. 
  • Parental report of child’s symptoms. 
  • Lack of information on symptom severity. 
  • Noncompletion of the questionnaire. 

Additional Literature 

Long-term Cardiovascular Outcomes of COVID-19 (Xie, February 2022): This study of U.S. Department of Veteran Affairs data highlights that the risk and one-year burden of cardiovascular disease in survivors of acute COVID-19 infection are substantial.

Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19 (Heesakkers, January 2022): In this exploratory study of 11 Dutch hospitals, patients frequently reported physical, mental or cognitive symptoms one year after ICU admission for COVID-19.

Mild Respiratory Sars-cov-2 Infection can Cause Multi-lineage Cellular Dysregulation and Myelin Loss in The Brain (Fernández-Castañeda, January 2022 - preprint, not peer-reviewed): Persons with COVID-19 infection frequently experience lingering neurological symptoms, which share many features with the syndrome of cancer therapy-related cognitive impairment.

Association Between Vaccination Status and Reported Incidence of Post-acute COVID-19 Symptoms in Israel: a Cross-sectional Study of Patients Infected Between March 2020 and November 2021 (Kuodi, January 2022 - preprint, not peer-reviewed): Vaccination with at least two doses of SARS-COV-2 vaccine was associated with reduced reporting of post- COVID conditions.

Association of Self-reported COVID-19 Infection and SARS-CoV-2 Serology Test Results With Persistent Physical Symptoms Among French Adults During the COVID-19 Pandemic (Matta, November 2021): This population-based study suggests that persistent physical symptoms after COVID-19 infection may be associated more with the belief of being infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection.

Risk Factors and Disease Profile of Post-Vaccination SARS-CoV-2 Infection in UK Users of the COVID Symptom Study App: A Prospective, Community-Based, Nested, Case-Control Study (Antonelli, September 2021): Compared with unvaccinated controls, after their second vaccine dose, individuals were less likely to have prolonged illness (symptoms for ≥28 days).

Twelve-Month Systemic Consequences of COVID-19 in Patients Discharged from Hospital: A Prospective Cohort Study in Wuhan, China (Liu, August 2021): 169 (40.0%) and 138 (28.4%) patients had at least one symptom at 6 months and 12 months respectively after discharge from COVID hospitalization. Most laboratory parameters returned to normal, whereas increased incidence of abnormal liver and renal function and cardiovascular injury were evidenced after discharge.

1-year Outcomes in Hospital Survivors With COVID-19: A Longitudinal Cohort Study (Huang, August 2021): Largest longitudinal cohort study of patients with COVID-19. Highlights two important points: Some patients may have persistent symptoms at 1 year from infection, but this number is significantly lower from 6 months after infection (despite limitations: single center design, potential for bias, no previous health information).

Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact (Davis, July 2021): Online survey of patients with suspected and confirmed COVID-19, distributed via COVID-19 support groups and social media. Time to recovery from post-COVID conditions exceeded 35 weeks in 91% of respondents (limitations: survey design, bias, diagnosis not clearly defined, no control group or previous health information).

Post-Acute COVID-19 Syndrome and its Prolonged Effects: An Updated Systematic Review (Malik, May 2021 - preprint, not peer-reviewed): This systematic review estimates the demographics, clinical characteristics and prevalence of post-acute COVID-19 symptoms.

Post-Acute COVID-19 Syndrome (Nalbandian, March 2021): This comprehensive review of the current literature on post-acute COVID-19 syndrome, its pathophysiology and its organ-specific sequelae includes a table summarizing findings from clinical studies on the prevalence of post-acute COVID-19 syndrome.

 

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