Early on in the COVID-19 pandemic, scientists forewarned of a potential medium to long-term post-acute sequelae in patients infected with SARS-CoV-2, similar to that documented in bacterial,
1 protozoan and viral infections including Epstein-Barr virus,
2 Ebola virus,
3 dengue virus,
4 Chikunguña virus,
5 going far back to the influenza pandemic in 1918.
6 These varied symptoms following acute SARS-CoV-2 infection is now termed as long COVID and is also known as long-haulers syndrome, post COVID-19 condition (PCC),
7 ‘post-acute sequelae of SARS-CoV-2 infection (PASC)’,
7 ‘chronic COVID’ and many other terms. The Department of Health and Human Services in collaboration with the US Centers for Disease Control and Prevention broadly defines long COVID as ‘signs, symptoms, and conditions that continue or develop after initial COVID-19 infection’.
8 Through a global consensus, the WHO, in October 2021, defined post COVID-19 condition as ‘the presence of symptoms usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis’.
9 In February 2023, the WHO issued a new definition for post COVID-19 in children and adolescents.
10 Endorsing the definition by WHO, the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) was developed and classified this condition as ‘Diagnosis Code U09.9 (Post COVID-19 condition, unspecified)’.
11
The heterogeneity of long COVID results in a single or complex presentation of ailments
12 13 with over 200 symptoms reported, affecting every organ system in the body, irrespective of the viral variant and vaccination status. Patients with long COVID may have residual symptoms, worsening of existing symptoms or the development of new symptoms at any time following acute infection, unrelated to initial disease severity. Zhang
et al’s study identified four reproducible PASC subphenotypes, dominated by cardiac and renal; respiratory, sleep and anxiety; musculoskeletal and nervous system; and digestive and respiratory system sequelae.
14 These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. These constellation of symptoms are also seen in chronic disease, in patients with severe illness following critical care, known as post-intensive care syndrome
15 or as a delayed complication such as multisystem inflammatory syndrome in children.
16 Longitudinal studies have shown that patients feel better through time,
17 but some studies have documented an impairment of daily activities for longer than 1–2 years.
18 Among this heterogeneous presentation, distinct subtypes have been identified to support the integration of individuals into specific care pathways.
There is still an open debate as to what entails long COVID, including confusion over appropriate terminology, due to the heterogeneous phenotypes, multiple case definitions, lack of a specific diagnostic, exacerbation of existing conditions (eg, diabetes mellitus), and because there is a significant overlap with other chronic conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome.
19
Both POTS and small fibre neuropathy are commonly seen in long COVID, where POTS often occurs following a viral infection
20 and is most often comorbid with ME/CSF. There is evidence that autonomic dysfunction may contribute to long COVID
21 as it does in ME/CFS.
22 There is also evidence that, as in ME/CFS, autoantibodies may be contributing to long COVID.
23 When various factors (eg, infection, injury, cold temperatures, lack of sufficient nutrients) threaten the viability of a cell or of an organism, it may give rise to ME/CSF. Although many patients with ME/CSF report a prodrome consistent with infection, no single agent is consistently implicated. A diagnosis of ME/CFS is based on symptoms as there is no specific diagnostic test with adequate sensitivity and specificity.
