Post-Acute COVID-19 Syndrome

Last updated: January 20, 2021

On this page:

• Overview
• Key Literature
• Resources

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

When the COVID-19 pandemic began, initial descriptions of the symptomology focused on the clinical presentations of patients in the acute, inpatient setting. In the months since, information on how patients with mild disease present has become available (Gandhi, April 2020), along with information on the fairly common occurrence of asymptomatic disease (Moriarty, March 2020; Kimball, April 2020; Wei, April 2020; He, April 2020).

More recently, data have emerged that some patients continue to experience symptoms related to COVID-19 after the acute phase of infection. There is currently no clearly delineated consensus definition for the condition: terminology has included “long COVID,” “post-COVID syndrome” and “post-acute COVID-19 syndrome.” Among the lay public, the phrase “long haulers” is also being used. Here we review the current literature on post-acute symptoms in patients with COVID-19, using the term “post-acute COVID-19 syndrome.”

 

Key Literature

In summary: Preliminary reports indicate some patients may develop a so-called “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. 

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study (Huang, January 2021). 

Patient population: 

• Cohort study of 1,733 patients with laboratory confirmed COVID-19 who were discharged from Jin Yin-tan Hospital in Wuhan, China between January 7 and May 29, 2020. 
• Patients had a median age of 57.0 (IQR 47.0–65.0) years and 897 (52%) were men.  

Primary endpoint: 

• To describe the long-term consequences of COVID-19 in patients 6 months after hospital discharge and identify the potential risk factors, including disease severity, associated with these consequences. 
• Results were grouped into 3 categories according to the severity of the patients’ initial illnesses: patients who did not require supplemental oxygen, patients who did, and patients who needed more intense oxygen such as high-flow nasal oxygen, non-invasive devices (similar to CPAP machines), and invasive mechanical ventilation (i.e., intubated and on breathing machines). 
• All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-minute walking test and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. 

Key findings: 

• The follow-up study was performed from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186.0 (175.0–199.0) days.  
• At 6 months, 76% of all patients had at least one of the listed symptoms, which range from fatigue/muscle weakness (63%), difficulty sleeping (26%), hair loss (22%), difficulty with smell and taste (11 and 9%), and trouble with mobility (7%).  
• The proportions of median 6-minute walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4.0 (3.0–5.0) for scale 4, and 5.0 (4.0–6.0) for scale 5–6.  
• After multivariable adjustment, patients showed an odds ratio (OR) 1.61 (95% CI 0.80–3.25) for scale 4 versus scale 3 and 4.60 (1.85–11.48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0.88 (0.66–1.17) for scale 4 versus scale 3 and OR 1.77 (1.05–2.97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0.74 (0.58–0.96) for scale 4 versus scale 3 and 2.69 (1.46–4.96) for scale 5–6 versus scale 3 for fatigue or muscle weakness.  
• Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96.2% vs 58.5%) and median titers (19.0 vs 10.0) of the neutralizing antibodies were significantly lower compared to the acute phase.  
• 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1.73 m² or more at acute phase had eGFR less than 90 mL/min per 1.73 m² at follow-up.  

Limitations: 

• Baseline data regarding pulmonary function and 6-minute walking distance were unavailable. However, the proportion of patients with chronic pulmonary and heart disease in this cohort was fairly low, although self-reporting by patients might have resulted in underestimation. The observed impaired pulmonary function and exercise capacity cannot be directly attributed to COVID-19.  
• For new symptom onset after COVID-19, the data were not stratified further to determine if the symptoms were persistent following COVID-19, worsened after COVID-19 recovery, or occurred post-discharge.  
• The number of participants with SARS-CoV-2 antibody test results both at acute phase and follow-up was limited. In the future, a larger sample is needed to clarify the dynamic changes of antibodies against SARS-CoV-2.  

Overall, in this large cohort study of 1,733 patients with COVID-19 assessed 6 months after discharge, most patients exhibited at least one symptom, particularly fatigue or muscle weakness, sleep difficulties, and anxiety or depression. More severely ill patients had increased risk of pulmonary diffusion abnormality, fatigue or muscle weakness, and anxiety or depression. The seropositivity and titers of the neutralizing antibodies were significantly lower than at acute phase. 

Sixty-Day Outcomes Among Patients Hospitalized With COVID-19 (Chopra, November 2020). 

Patient population: 

• Observational cohort of 1,648 patients hospitalized with COVID-19 at 38 Michigan hospitals who were discharged between March 16 and July 1, 2020. 

Primary endpoint: 

• To describe 60-day post-discharge clinical, financial, and mental health outcomes of patients with COVID-19. 

Key findings: 

• Of 1,648 patients, 398 (24.2%) died during hospitalization and 1,250 (75.8%) survived.  
• Of 1,250 patients discharged alive, 975 (78.0%) went home. 
• Of patients alive 60 days after discharge, 488 (41.8%) were successfully contacted and completed the 60-day post-discharge telephone survey. 
• Cardiopulmonary symptoms (such as cough and dyspnea) were reported by 159 patients, including 92 with new or worsening symptoms and 65 with persistent loss of taste or smell.  
• 58% of patients reported new or worsening difficulty completing activities of daily living.  
• Among 195 patients who were employed before hospitalization, 117 had returned to work while 78 could not because of ongoing health issues or job loss.  
  • Of the 117 patients who returned to work, 30 reported reduced hours or modified duties due to health reasons. 
• 238 of 488 patients reported being emotionally affected by their health, and 28 sought care for mental health after discharge.  
• 179 patients reported at least a mild financial impact from their hospitalization, with 47 reporting using most or all of their savings and 35 rationing food, heat, housing, or medications due to cost. 

Limitations: 

• This was a survey with patients lost to follow-up, potentially undercounting the prevalence of post-acute syndrome. 
• Although post-discharge chart review was completed for all patients, telephone contact occurred in fewer than half. 

Overall, in this observational cohort of patients hospitalized with COVID-19 in Michigan, nearly 1 in 3 patients died during hospitalization or within 60 days of discharge. For most patients who survived, ongoing morbidity, including the inability to return to normal activities, physical and emotional symptoms, and financial loss, was common, confirming that the toll of COVID-19 extends well beyond hospitalization. 

Follow-up of adults with non-critical COVID-19 two months after symptoms' onset (Carvalho-Schneider, October 2020).

Patient population: 

• Descriptive clinical follow-up study of 150 patients with non-critical COVID-19 on days 7, 30 and 60 after confirmation by RT-PCR at Tours University Hospital from March 17-June 3, 2020. 
• The mean age was 49 ± 15 years. 
• More than half of the patients (54%, n=80/150) had at least one comorbid condition and half were health care professionals (n=75/150). 
• The most common symptoms at disease onset were flu-like symptoms (87%, n=129/150), anosmia/ageusia (59%, n=89/150) and fever (51%, n=76/150). 
• Patients with or without clinical signs of pneumonia but without need for oxygen therapy were defined as having mild/moderate COVID-19.  
• Patients with signs of pneumonia requiring oxygen therapy but not needing ICU admission were defined as having severe COVID-19, according to the WHO definition.  

Primary endpoint: 

• To describe the clinical evolution and predictors of symptom persistence during 2-month follow-up in adults with non-critical COVID-19.  

Key findings: 

• For the follow-up at D30 and D60, phone calls were performed at a mean of 32.7 ± 2.5 days (range 27 to 37) and 59.7 ±1.7 (range 57 to 67) after symptom onset. 
• Persisting symptoms were defined by the presence at day 30 or day 60 of at least one of the following: weight loss ≥ 5%, severe dyspnea or asthenia, chest pain, palpitations, anosmia/ageusia, headache, cutaneous signs, arthralgia, myalgia, digestive disorders, fever or using sick leave.  
• At D30, 68% (n=103/150) of patients presented at least one symptom, falling to 66% (n=86/130) at D60.  
• The most common persistent symptom was anosmia/ageusia: 59% (n=89/150) at symptom onset, 28% (n=40/150) at D30 and 23% (n=29/130) at D60. 
• Dyspnea occurred in 36.7% (n=55/150) patients at D30 and 30% (n=39/130) at D60. 
• Asthenia occurred in half of patients (n=74/150) at D30 and 40% (n=52/130) at D60. 
• Persistent symptoms at D60 were significantly associated with age of 40 to 60 years, hospital admission and abnormal auscultation at symptom onset. 
• At D30, severe COVID-19 and/or dyspnea at symptom onset were additional factors associated with persistent symptoms. 

Limitations: 

• The patient population was younger in age and half were health care professionals, so findings may not be generalizable to the general public. 
• Single-center study. 
• Only non-critical COVID-19 patients were included. 

Overall, in this descriptive clinical follow-up study of 150 non-critical patients with COVID-19, two-thirds of adults experienced persistent symptoms up to 2 months after symptom onset, primarily anosmia/ageusia, dyspnea or asthenia. 

Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19 (Garrigues, August 2020).

Patient population:

• Phone-based survey study of patients diagnosed with COVID-19 who had been discharged.
• After excluding patients who died, had dementia, were bedridden, were not reachable, didn’t speak French or declined to participate, 120 patients were included in the study (96 who had not been in the ICU and 24 who had been in the ICU).

Primary endpoint:

• To assess the persistence of symptoms and health-related quality of life challenges after discharge in patients who had been hospitalized with COVID-19.

Key findings:

• The mean age was 63.2 (standard deviation, 15.7 days), and 62.5% were male.
• The most common comorbidities included hypertension (46.7%), an elevated body mass index (47.5%) and diabetes (21.7%).
• The mean time of interview after admission was 110.9 days (SD of 11.1 days).
• The most common reported symptoms were fatigue (55%), dyspnea (42%), memory loss (34%), sleep disorders (30.8%) and difficulty with concentration (28%).
• Comparisons between ICU and non-ICU patients showed no statistically significant differences regarding these symptoms.
• Before their infection, 46.7% were active workers; of these, 69.1% had gone back to work at the time of the phone interview.

Limitations:

• Single-center study with a small number of patients and without a control group of patients discharged for other reasons. Over half of the sample was not included in the analysis; this may affect the generalizability of the results.
• The study relied on patient self-report and may have been subject to incomplete recall or recall bias.
• There was a lack of information on symptom history before acute COVID-19 illness.
• There was a lack of details on symptom severity.
• The presence of comorbidities may have impacted self-reported symptoms.

Overall, in this study of patients with COVID-19 discharged from the hospital and interviewed over 3 months post diagnosis, the majority of patients experienced continued symptoms, most commonly including fatigue and dyspnea.

Persistent symptoms in patients after acute COVID-19 (Carfi, July 2020).

Patient population:

• 143 COVID-19 patients discharged from a hospital in Italy who had no fever for 3 days, improvement in symptoms and 2 negative SARS-CoV-2 test results 24 hours apart.
• The mean age was 56.5 years (SD 14.6; range 19-84). 53 (37%) were women. 10% were active smokers.

Primary endpoint:

• To assess persistent symptoms in patients discharged from hospitalization for COVID-19.

Key findings:

• The most common comorbidity was hypertension (35%), followed by thyroid disease (18%), immune disorders (11%), COPD (9%) and diabetes (7%); rates of other comorbidities were less than 5%.
• 63% engaged in regular physical activity prior to admission.
• 7% of participants had evidence of interstitial pneumonia during their hospitalization, and 54% required oxygen therapy.
• Mean length of hospital stay was 13.5 days (SD 9.7).
• 21 patients (15%) received noninvasive ventilation; 7 patients (5%) received invasive ventilation.
• Patients were assessed a mean 60.3 days after onset of the first COVID-19 symptom (SD 13.6).
• 87% of patients had persistent symptoms.
  • 32% had 1 or 2 persistent symptoms, while 55% had 3 or more persistent symptoms.
• Most common reported symptoms were fatigue (53%), dyspnea (43%), arthralgias (27%) and chest pain (22%).
• 1% of patients reported a worsened quality of life.
• No patients had fever at time of interview.

Limitations:

• There was a lack of information on symptom history before acute COVID-19 illness.
• There was a lack of details on symptom severity.
• The presence of comorbidities may have impacted self-reported symptoms.
• The majority of patients had at least moderate disease, as evidenced by the need for oxygen; this limits the generalizability of the findings to patients with mild disease.
• Single-center study with a small number of patients and without a control group of patients discharged for other reasons.

Overall, in this study of patients with COVID-19 discharged from the hospital with SARS-CoV-2 RNA clearance by RT-PCR and interviewed approximately 2 months after diagnosis, the majority of patients experienced continued symptoms, with the most common symptoms being fatigue and dyspnea.

Post-discharge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation (Halpin, July 2020).

Patient population:

• Telephone survey study of 100 patients with COVID-19 discharged from the hospital at least 4 weeks prior to study enrollment; 32 patients had been in the ICU.

Primary endpoint:

• To assess patients’ symptoms post-discharge and the impact on their daily life.

Key findings:

• The median age of the patients was 58.5 (IQR 34-84) in the ICU group and 70.5 (IQR 20-93) in the non-ICU group.
• 7% required some form of oxygenation support.
• 4% of patients in the ICU group and 51.5% of the non-ICU group were men.
• The most common comorbidity was hypertension (43.8% in the ICU group and 39.7% in the non-ICU group).
• Other common comorbidities were being overweight or obese (35% in the ICU group, 54.4% in the non-ICU group), type 2 diabetes (28.1% in the ICU group, 27.9% in the non-ICU group) and gastrointestinal disease (15.6% in the ICU group, 29.4% in the non-ICU group).
• 3% of patients in the ICU group and 70.6% in the non-ICU group had 3 or more significant comorbidities.
• Patients were interviewed between 29 and 71 days (mean 48 days) post-
• New fatigue was the most common reported symptom.
  • 72% of participants in the ICU group reported fatigue, while 60.3% in the non-ICU group did.
• The next most common symptoms were dyspnea (65.6% in the ICU group and 42.6% in the non-ICU group) and psychological distress (46.9% in the ICU group and 23.5% in the non-ICU group).
• 8% of patients in the ICU group and 45.6% in the non-ICU group reported a decline in their health status, as measured by the EQ-5D.

Limitations:

• There was a lack of information on symptom history before acute COVID-19 illness.
• There was a lack of details on symptom severity.
• The presence of comorbidities may have impacted self-reported symptoms.
• The majority of patients had at least moderate disease, as evidenced by the need for oxygen; this limits the generalizability of the findings to patients with mild disease.
• Single-center study with a small number of patients and without a control group of patients discharged for other reasons.
• Telephone contact was made at a single point, with data collection not capturing how problems evolved over time.

Overall, in this study of patients with COVID-19 discharged from the hospital at least 4 weeks prior to study enrollment, the majority of patients experienced continued symptoms, with the most common symptoms being fatigue and dyspnea.

Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multi-state health care systems network — United States, March–June 2020 (Tenforde, July 2020).

Patient population:

• A multi-state telephone interview study of a random sample of 274 patients with a positive SARS-CoV-2 RT-PCR test at an outpatient visit at one of 14 academic centers in 13 U.S.

Primary endpoint:

• To compare characteristics among respondents who reported returning or not returning to their usual state of health by the date of the interview.

Key findings:

• A phone call was attempted for 582 patients; of these, 325 (56%) completed an interview.
• Interviews were conducted 12-41 days after the patients were tested; the median time between the outpatient visit and the interview was 16 days.
• After excluding patients who were interviewed by proxy, had a prior COVID-19 diagnosis before the outpatient visit or who did not answer all the questions, 292 patients remained.
  • Of these, 274 (94%) reported one or more symptoms at testing and were included in this data analysis. 
• The median age of symptomatic respondents was 42.5 years (IQR = 31–54 years); 142 (52%) were female.
• The median number of days respondents reported feeling unwell before being tested for SARS-CoV-2 was 3 (IQR = 2–7 days).
• Of the 262 patients for whom data were available regarding subsequent hospitalization, 93% were not hospitalized.
• Among 270 patients for whom data were available, 35% reported not having returned to their usual state of health.
  • Most common symptoms included cough (43%), fatigue (35%) and dyspnea (29%).
• Among patients ≥50 years of age, 47% reported not having returned to their usual state of health.
• 57% of patients with ≥3 chronic conditions reported not having returned to their baseline state of health.
• After adjusting for other factors, age ≥50 versus 18–34 years (aOR 2.29; 95% confidence interval [CI] = 1.14–4.58) and reporting three or more versus no chronic medical conditions (aOR 2.29; 95% CI = 1.07–4.90), obesity (aOR 2.31, 95% CI = 1.21–4.42) and presence of an underlying psychiatric condition (aOR 2.32, 95% CI = 1.17–4.58) were associated with not having returned to usual health.

Limitations:

• The response rate was somewhat low; this may affect the generalizability of the results.
• Complete patient data was not available for several of the analyses performed.
• The study relied on patient self-report and may have been subject to incomplete recall or recall bias.

Overall, in this study of patients who were diagnosed with COVID-19 in the outpatient setting, primarily had mild disease and were interviewed a median of 16 days post diagnosis, the majority had continued symptoms. The most common symptoms included cough and fatigue.

Additional Literature

Post-acute COVID-19 Syndrome incidence and risk factors: a Mediterranean cohort study (Moreno-Perez, January 2021). Prospective cohort study to analyze the incidence of post-acute COVID-19 syndrome and its components. 277 adult patients who had recovered from COVID-19 (February 27-April 29, 2020) confirmed by PCR or subsequent seroconversion, with a systematic assessment 10-14 weeks after disease onset, and were evaluated 77 days (IQR 72-85) after disease onset. 34.3% patients had mild SARS-CoV-2 and 65.7% had severe SARS-CoV-2. Post-acute COVID-19 syndrome was detected in 141 patients (50.9%; 95% CI 45.0-56.7%). The cumulative incidence was 58.2% (95%CI 51.0-65.2), 36.6% (95% CI 23.5-51.8) and 37.0% (95% CI 25.4-50.3) in patients with severe pneumonia, mild pneumonia and without pneumonia, respectively (p=0.003). The most frequent symptoms were dyspnea and fatigue. Symptoms were mostly mild. Alterations in spirometry were noted in 25/269 (9.3%), while in radiographs in 51/277 (18.9%). No baseline clinical features behaved as independent predictors of post-acute COVID-19 syndrome development. 

 

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