Long COVID is best understood as a collection of overlapping symptoms rather than a single post-viral condition, suggests a new systemic review published in eClinicalMedicine. The review identified the main symptom patterns associated with long COVID, including neurologic, respiratory, olfactory and/or gustatory, cardiopulmonary, and fatigue.
A team led by Lanzhou University researchers in Gansu, China, analyzed 64 studies from 20 countries involving 2.4 million people. They classified long-COVID patients into subtypes, either according to the co-occurrence of symptoms (30 studies), affected organ systems (16), severity of symptoms (nine), clinical indicators (three), or other factors.
Fatigue the most frequently identified symptom
Across the studies that used symptom co-occurrence as the main method of classification, fatigue was the most frequently identified symptom cluster, either on its own or together with other symptoms, such as muscle and joint pain, cognitive symptoms, or shortness of breath. Other frequently paired symptoms included loss of smell and taste, anxiety and depression, and musculoskeletal pain.
In studies that used organ systems as the primary classification, respiratory symptoms were the most common symptom cluster, affecting an estimated 47% of patients. Neurologic symptoms followed, at 31%, and gastrointestinal symptoms affected 28%. The authors emphasized that these figures reflect the proportion of long-COVID patients experiencing each symptom cluster within the studies, not the prevalence within the general population.
A handful of studies used severity as a classification, ranking symptoms as mild, moderate, or severe based on symptom scores, symptom counts, or quality-of-life assessments. Three studies categorized patients based on clinical indicators such as abnormal triglyceride levels and restrictive lung function on imaging.
Women more likely to report fatigue
The review also suggests that long-COVID subtypes are influenced by demographic, socioeconomic, and clinical factors. Women were more likely to experience fatigue and neuropsychiatric symptoms, while men more frequently reported respiratory symptoms. Older people were more likely to experience respiratory, cardio-renal, and ear, nose, and throat (ENT) symptoms.
Black and Hispanic populations were more prone to respiratory/cardiac and neuropsychiatric symptoms, and White individuals had higher rates of fatigue and musculoskeletal symptoms.
COVID variants also appeared to play a role in symptom clusters. “The Alpha variant was strongly associated with olfactory and respiratory symptoms, while the Delta variant increased the risk of ENT-related symptoms,” write the authors. Plus, “a high BMI [body mass index], socioeconomic deprivation, and comorbidities such as COPD [chronic obstructive pulmonary disease] were significantly associated with an increased risk of cardiopulmonary symptom clusters and Long COVID symptom burden.”
The findings underscore that long COVID rarely affects a single organ system in isolation and highlight common classification methods and symptom clusters that support personalized care.
The authors urge future research to focus on standardizing classification methods, uncovering underlying mechanisms, and validating specific subtype interventions. “This will be crucial for advancing precision medicine and improving outcomes for Long COVID patients,” they conclude.
