Study reveals widespread long-COVID symptoms, challenging WHO definition

New research highlights the need for a more specific definition of long-COVID, as nearly one in five SARS-CoV-2 negative patients also reported long-term symptoms, raising concerns about overdiagnosis.

A study published in the journal Nature Communications provides an overview of post-coronavirus disease 2019 (COVID-19) symptoms among emergency department patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Background

The COVID-19 pandemic has significantly burdened global healthcare and economic systems, with more than 775 million reported infections worldwide. A large proportion of COVID-19 survivors are still experiencing persistent or recurring symptoms, which the World Health Organization (WHO) collectively defines as the post-COVID or long-COVID condition.

According to the WHO definition, long-COVID occurs in individuals with a history of suspected or confirmed SARS-CoV-2 infection. The long-COVID symptoms, which an alternative diagnosis cannot explain, typically appear three months after the onset of COVID-19 and last for at least two months.

Vaccination status had no protective effect: The study found no significant difference in long-COVID outcomes between vaccinated and unvaccinated patients, suggesting that vaccination does not fully prevent the onset of long-COVID.

The WHO has listed more than 50 symptoms of long-COVID, including dyspnea, post-exertional malaise (PEM), anosmia, and cough, among others. However, many of these symptoms could overlap with other viral infections or medical conditions, leading to diagnostic challenges. This makes it difficult to distinguish long-COVID from other health conditions, raising concerns about its diagnostic specificity.

In this study, scientists compared the proportion of emergency department patients who developed WHO-defined long-COVID symptoms between SARS-CoV-2-positive and SARS-CoV-2-negative patients. The study also evaluated whether the WHO’s current definition may be too broad, potentially leading to overdiagnosis in some instances.

Study design

The study was conducted on patients registered in the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN), a pan-Canadian collaboration collecting data on patients who were tested for SARS-CoV-2 in 50 emergency departments in eight provinces.

A total of 6,723 emergency department patients were recruited for the study, of which 58.5% were SARS-CoV-2 positive.

The study's primary outcome was to determine the proportion of patients reporting at least one WHO-defined long-COVID symptom at three months. Secondary outcomes included the proportion of patients with persistent symptoms at 6 and 12 months.

Pre-Omicron vs. Omicron differences: Patients infected during the Omicron variant wave reported more memory, concentration problems, and dizziness compared to those infected in earlier waves, hinting at different symptom profiles across variants.

Important observations

The proportion of SARS-CoV-2 positive patients who reported at least one long-COVID symptom at three months was 38.9%, compared to 20.7% of SARS-CoV-2 negative patients. Among SARS-CoV-2 positive patients, 45.5% of females reported long-COVID symptoms compared to 32.8% of males, indicating a significant gender disparity.

The proportions of SARS-CoV-2 positive patients who reported at least one long-COVID symptom at 6 and 12 months were 38.2% and 33.1%, respectively, compared to 19.5% and 17.3% of SARS-CoV-2 negative patients. The proportions of test-positive and test-negative patients with at least one ongoing long-COVID-consistent symptom at 12 months were 5.8% and 3.4% lower, respectively, than the proportion of symptomatic patients at three months.

The most significant risk factor for reporting long-COVID symptoms at three months was testing positive for SARS-CoV-2 during an emergency department visit (adjusted odds ratio, aOR = 4.42, 95% CI: 3.60–5.43). Other risk factors included ICU admission (aOR = 1.84, 95% CI: 1.34–2.51), female gender (aOR = 1.51, 95% CI: 1.33–1.73), and presenting with loss of taste or smell (aOR = 1.38, 95% CI: 1.03–1.85) during the emergency department visit.

Further risk analysis showed that patients reporting "managing well" at baseline were at higher risk of developing long-COVID symptoms than those reporting "fit and well" (aOR = 1.31, 95% CI: 1.14–1.52). Notably, a lower risk of symptom development was observed in patients with lower educational backgrounds (aOR = 0.75, 95% CI: 0.58–0.97).

Study significance

The study finds that more than one-third of emergency department patients with a laboratory-confirmed acute SARS-CoV-2 infection exhibit long-COVID symptoms three months after their initial emergency department visit. The researchers also highlight that one in five patients who tested negative for SARS-CoV-2 infection met the WHO criteria for long-COVID, raising concerns about the broad scope of the clinical definition.

A key finding is that the high rate of long-COVID symptoms observed in SARS-CoV-2 negative patients suggests that the current WHO definition may lead to overdiagnosis. The overlap of non-specific symptoms with other conditions presents a challenge for accurately diagnosing long-COVID.

Furthermore, the study finds that about one in five patients with no history of SARS-CoV-2 infection also exhibit long-COVID symptoms, complicating distinguishing true long-COVID cases.

A high rate of long-COVID symptoms observed in SARS-CoV-2 negative patients at three months indicates that the development of long-COVID after suspected but not confirmed SARS-CoV-2 infection is non-specific and can occur in SARS-CoV-2 naïve patients.

According to the WHO definition, long-COVID is a non-specific syndrome that occurs in many patients who present to the emergency department for an acute illness requiring SARS-CoV-2 testing. However, the current study findings highlight the need for a more specific WHO definition, potentially used in combination with serology or biomarker testing to identify the underlying processes that contribute to the development of long-COVID.

The study finds that SARS-CoV-2 positive patients more frequently exhibit three or more symptoms or certain symptoms, such as loss of taste and smell, dyspnea, and newly persistent cough, as compared to SARS-CoV-2 negative patients.

Existing evidence indicates that most COVID-19 patients experience olfactory symptoms (loss of taste and smell) during the acute infection phase. These symptoms typically subside within one month of infection. However, the persistent presence of olfactory symptoms observed in this study indicates that the presence of these symptoms during acute infection may predict long-COVID.

The scientists highlight the need for future studies to more conclusively understand long-COVID pathophysiology and develop more specific diagnostic criteria.