Studying the pathological sequelae of Long COVID presents with a slight problem - PASC symptoms were hard to classify and identify. This difficulty in identifying symptoms called for a consensus on what criteria a post-acute COVID symptom must pass to be classed as PASC. As a proposed guideline, the National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners describe Post-acute COVID-19 Syndrome (PASC) as “signs and symptoms consistent with COVID-19 that are present for more than 12 weeks after infection and not attributed to alternative diagnosis” (Shah et al., 2021).
However, the US Center for Disease Control and Prevention describes 'post-COVID conditions' as a wide range of health consequences presented as ≥ four weeks after an acute infection phase with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The pathological sequelae and symptoms presentation in patients with COVID appears to be more pronounced in patients with severe diseases and those with a preexisting medical condition. In many documented cases, the pathological sequelae also directly depend on the host's immune response. Immune response to SARS-CoV-2 also impacts the biological drivers of PASC symptomatology. In long COVID, the continued replication of SARS-CoV-2 increases the risk of host immune system evasion, with proinflammatory responses consequently pronounced. Although the pathophysiological bridge between acute-COVID and long-COVID remains largely unclear, a careful annotation of the clinical symptomatology of PASC helps this switch. The most common symptoms reported in study reviews for PASC include systemic, neuropsychiatric, respiratory, and cardiovascular impairments. However, these symptoms do not present with a definite sequence in PASC patients. Their presentation and severity seem to depend on myriads of factors that vary significantly within the human population.
Lung involvement in severe COVID is a huge interest in the medical community. Pulmonary symptoms corresponding with the onset of long-COVID include cough and shortness of breath. Other symptoms of respiratory concern, as documented in Long Haulers, include difficulty weaning off ventilators, prolonged oxygen requirement, and abnormal lung functions (Chopra et al., 2021). In addition to the commonly reported neuropsychiatric symptoms in acute COVID, long haulers also present with protracted psychiatric symptomatology. Neuropsychiatric manifestations consistent with these patients include psychoses, gustatory impairments, sleep abnormalities, and chronic headaches. Other psychiatric disorders reported in Long Haulers include depression, anxiety, and post-traumatic disorder (PTSD).
In acute COVID, patients present with symptoms indicative of chest pain, chest tightness, and unexplained palpitations. These symptoms were also documented in Long Haulers and myocarditis, acute heart failure, and myocardial injury. Moody et al. (2021) demonstrated evidence of ventricular remodeling in patients initially hospitalized with COVID-19-associated pneumonia. This study and similar others created evidence for cardiac sequelae in long-COVID. The high concentration of Angiotensin-converting enzyme 2 (ACE2) on the brush border of the small intestinal mucosa explains the gastrointestinal-associated symptoms of acute COVID. In addition to nausea and vomiting, abdominal pains, and diarrhea, Long Haulers have also presented with loss of appetite, weight loss, and irritable bowel syndrome. Endocrine manifestations consistent with PASC include significantly high fasting insulin and C-peptide levels. As a direct impact, the endocrine abnormalities in long-COVID include subacute thyrotoxicosis, Graves' disease, altered bowel motility patterns, and Hashimoto's thyroiditis (Montefusco et al., 2021; Brancatella et al., 2020; Tee et al., 2020).
Fig 2: Timeline and Symptom Profile of Long COVID
Source: (Nalbandian et al., 2021)