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Comparing post–COVID-19 symptoms two years after SARS-CoV-2 infection

In a recent study published in JAMA Network Open, researchers compared the presence of post–coronavirus disease 2019 (COVID-19) symptoms among hospitalized and nonhospitalized patients in Spain.

Study: Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients. Image Credit: TZIDO SUN/Shutterstock

Additionally, the researchers identified potential risk factors associated with developing post–COVID-19 symptoms two years after acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Many countries are optimistic that the COVID-19 pandemic is turning into an endemic. However, the occurrence or persistence of symptoms after the acute phase of SARS-CoV-2 infection, colloquially called 'long COVID', is the new pressing issue that demands the attention of researchers and governments alike.

Studies have reported over 100 post–COVID-19 symptoms affecting multiple human organs (e.g., cardiovascular, neurologic, respiratory, and musculoskeletal). Several reviews have evidenced that people experiencing post–COVID-19 symptoms have worsened health-related quality of life.

Although there isn't a lack of studies and meta-analyses evaluating the prevalence of post–COVID-19 symptoms, most had pooled data from hospitalized and nonhospitalized patients. Also, their follow-up periods have remained consistently shorter than six months.

More recently, some meta-analyses directly compared hospitalized versus nonhospitalized patients with a follow-up period of up to six months after acute infection. Comparative data with follow-up periods longer than one year after acute SARS-CoV-2 infection are still lacking.

About the study

In the present study, researchers recruited patients hospitalized with COVID-19 from two urban hospitals in Spain and another group of hospitalized patients infected with SARS-CoV-2 from an outpatient setting managed by their general practitioners. They used Microsoft randomization software to select 400 patients for each study group. The current cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. All the study participants had contracted SARS-CoV-2 infections during the first wave of the COVID-19 pandemic between March 20 and April 30, 2020. Notably, they had not suffered from breakthrough infections by other SARS-CoV-2 variants.

The team ascertained a SARS-CoV-2 infection in these individuals via the results of reverse transcription–polymerase chain reaction (RT-PCR) assay of their nasopharyngeal or oral swab samples. They used medical records to confirm their demographic (age, gender), clinical, and hospitalization data. Further, they scheduled a telephone interview by trained researchers for all participants who agreed to a follow-up two years after the acute infection. In the interview, they enquired about symptoms appearing after hospitalization or the acute infection phase. Also, they ensured whether or not these symptoms persisted during the study duration.

The researchers considered symptoms attributed only to COVID-19 and with an onset no later than one month after SARS-CoV-2 infection. The team systematically assessed multiple post–COVID-19 symptoms during the study; examples include dyspnea, fatigue, anosmia, pain symptoms, and brain fog. However, they allowed all participants to report any other symptom they experienced and considered relevant.

The researchers pursued evidence of the emotional and societal impact of the COVID-19 pandemic. So they used the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI) for anxiety & depressive symptoms, and sleep quality assessments, respectively. For the HADS-A and HADS-D, a cutoff score of 12 or 10 points or more indicated anxiety and depressive symptoms, respectively. Likewise, for the PSQI, a cutoff of 8 points or more was considered indicative of poor sleep quality.

Finally, the researchers presented data as mean or percentages. They computed adjusted odds ratios (ORs) with 95% confidence intervals (CIs). For the primary outcome, they compared the differences in post–COVID-19 symptoms among the two study cohorts using the χ2 test or one-way analysis of variance tests. Furthermore, they used multivariate logistic regressions to identify the potential association of post–COVID-19 symptoms with variables identified at the acute phase, which adjusted the covariates in the two study groups separately.

Study findings

According to the authors, this study is the largest follow-up comparison between hospitalized and nonhospitalized patients. Its findings showed the presence of at least one post–COVID-19 symptom in 59.7% and 67.5% of hospitalized and nonhospitalized patients, respectively, two years after SARS-CoV-2 infection. Another study by Huang et al. also showed that 55% of hospitalized patients exhibited post–COVID-19 symptoms two years after hospital discharge. However, there isn't another study to directly compare this study's data for nonhospitalized patients.

The researchers noted that dyspnea and anosmia were the most prevalent COVID-19–associated symptoms at onset among hospitalized and nonhospitalized patients, respectively. While the former is an annoying symptom experienced during severe illness, the latter delineates COVID-19 from clinical manifestations of other respiratory infections. Also, people experiencing anosmia often did not seek hospital admission.

Fatigue, like musculoskeletal pain, is the most prevalent symptom in the first year following SARS-CoV-2 infection, establishing its association with a higher post–COVID-19 burden. Studies propose that post–COVID-19 fatigue shares features with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Analysis of the exponential recovery curve revealed that dyspnea reduced in the years following COVID-19. However, intriguingly, fatigue did not reduce but persisted two years after COVID-19, indicating that it is the most prevalent and long-lasting post–COVID-19 symptom.

A study by Estiri et al. suggested that female sex and count of COVID-19 onset symptoms at hospital admission, but not disease severity were potential risk factors for long COVID. The researchers did not identify these risk factors in a hospitalized cohort of this study because preexisting medical comorbidities were the only variable associated with post–COVID-19 fatigue and dyspnea. Instead, they observed that the number of symptoms in the acute phase was a risk factor for post–COVID-19 fatigue among nonhospitalized patients. A possible explanation could be that those with acute infection had a higher viral load, which is associated with a stronger immune response, which, in turn, facilitated the development of long COVID.

Patients in both the study groups did not exhibit symptoms of anxiety and depression, as indicated by their mean HADS-A and HADS-D scores.


Overall, the current study findings indicated negligible differences in COVID-19 onset and post–COVID-19 symptoms among hospitalized and nonhospitalized COVID-19 survivors, reinstating the notion that there is no correlation between the development of long COVID and COVID-19 severity during the acute phase of infection.

Since the observed rates of post–COVID-19 symptoms were comparable between hospitalized and nonhospitalized patients, it is crucial to monitor and treat long COVID in all the patients who ever contracted COVID-19.

Journal reference:
  • Fernández-de-las-Peñas C, Rodríguez-Jiménez J, Cancela-Cilleruelo I, et al. (2022). Post–COVID-19 Symptoms 2 Years After SARS-CoV-2 Infection Among Hospitalized vs Nonhospitalized Patients. JAMA Network Open. doi: 0.1001/jamanetworkopen.2022.42106

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Anosmia, Anxiety, Assay, Brain, Brain Fog, Chronic, Chronic Fatigue Syndrome, Coronavirus, Coronavirus Disease COVID-19, covid-19, Depression, Dyspnea, Encephalomyelitis, Epidemiology, Fatigue, Hospital, Immune Response, Musculoskeletal, Myalgic Encephalomyelitis, Nasopharyngeal, Pain, Pandemic, Polymerase, Polymerase Chain Reaction, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Sleep, Syndrome, Transcription

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Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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