Pathophysiology of Long COVID 3: Subphenotypes

Pathophysiology of Long COVID 3: Subphenotypes

Subphenotypes can give hints about underlying causes of Long COVID. Although many patients with Long COVID experience several symptoms at once, most studies investigate symptoms separately. In an alternative approach, patients are grouped by the full spectrum of symptoms they experience. This strategy can provide insights into the pathophysiology of Long COVID and facilitate treatment.

The term Long COVID subphenotype refers to the extent to which Long COVID symptoms and conditions appear together in one patient. A large study from the United States aimed to establish these subphenotypes based on symptoms, previous medical history and other patient features like age and sex.

In this study, the researchers used electronic health record repositories of two large US clinical research networks comprising a total of 31 million patients. The study focused on 34,605 adult patients who tested positive for SARS-CoV-2 and experienced at least one Long COVID symptom between one and three months after confirmed infection.

The subphenotype in each patient was identified in a multi-step process. Based on the literature on Long COVID studies, the researchers compiled a thorough list of potential Long COVID conditions. Among the 137 diagnosis categories potentially related to Long COVID, patients were grouped according to the co-occurrence of symptoms through machine learning analysis.


There are four Long COVID subphenotypes

The study ultimately identified four distinct Long COVID subphenotypes:


Subphenotype 1 was the largest one and included patients with cardiovascular and kidney symptoms most of whom were infected during the first wave of the COVID-19 pandemic. These were the sickest patients who most frequently required hospitalization and mechanical ventilation during the acute phase of the disease. They also had more pre-existing conditions compared with other subphenotypes.


Subphenotype 2 comprised patients with respiratory conditions, sleep disorders, anxiety and symptoms such as headache and chest pain. This group included younger patients and a higher proportion of women than subphenotype 1.


Subphenotype 3 consisted of patients with mainly musculoskeletal and neurological symptoms, such as musculoskeletal pain, headaches, sleep disorders and dermatologic manifestations. Subphenotypes 3 and 4 were less prevalent than 1 and 2.


Subphenotype 4 included patients with predominately digestive system and respiratory conditions. Patients in this group experienced the mildest severity during the acute phase of SARS-CoV-2 infection with the lowest rates of mechanical ventilation and critical care admissions. These patients were also generally healthier with fewer pre-existing health issues compared with patients with other subphenotypes.


Study En V2 Zeichenfläche 1

The four Long COVID subphenotypes.


The study authors also noted that conditions in subphenotype 1, such as heart failure, pneumonia and kidney failure, were mostly identified with objective diagnostic criteria. In contrast, many symptoms in the other three subphenotypes, such as pain or nausea, were more subjective to diagnose and mainly based on patient reports.


Why are Long COVID subphenotypes valuable?

This study confirmed the major Long COVID symptoms that have been documented in several previous studies, such as cardiovascular, respiratory, neurological and digestive conditions. Altogether, these findings are important and can be beneficial not only for physicians and researchers but also for Long COVID patients.

Grouping Long COVID patients based on their symptoms can help select optimal treatments and improve overall quality of care.

Patients currently receive either symptomatic treatment (which relieves the symptoms but does not address the underlying disease) or a combination of therapies which can have plenty of side effects. So far, none of these approaches led to a cure or, at least, significant improvements of Long COVID.

This study also shed light on which patients may be at greater risk for suffering from Long COVID following acute infection with the SARS-CoV-2 virus. By taking into account factors like the severity of the initial infection, coexisting medical conditions, previous medications, age and sex, physicians and researchers can identify those who are most susceptible to developing symptoms long-term. All in all, identifying subphenotypes brings the community one step closer to improving Long COVID care.