Decoding long COVID, pathophysiology, epidemiology, diagnosis, and management

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In a recent review published in Signal Transduction and Targeted Therapy, researchers comprehensively reviewed existing data concerning post-acute sequelae of coronavirus disease 2019 (PASC), also known as long COVID, pathophysiology, epidemiology, diagnosis and management.

Tired woman asleep at her desk

Study: The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID. Image Credit: fizkes/

There is an increasing community of recovered COVID-19 sufferers experiencing long-term effects of the disease. The disease's symptoms, which include the cardiovascular, pulmonary, neuropsychiatric, gastrointestinal, reproductive, and musculoskeletal systems, can persist beyond the acute phase, impacting individuals throughout the entire range of disease severity.

Identifying long COVID symptoms and understanding their underlying mechanisms is critical to managing the condition, and curtailing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission.

About the review

In the present review, researchers presented long COVID data published in the Cochrane Library, Web of Science, EMBASE, and PubMed databases in English between January 2020 and June 2023. Two researchers independently screened the data, and a third researcher resolved the discrepancies.

Long COVID: pathophysiology and epidemiology

Long COVID, also known as continuing symptomatic COVID-19, is a chronic condition that lasts four to twelve weeks or a post-acute syndrome that lasts more than 12 weeks following acute symptom onset. Long COVID symptoms include fatigue, tiredness, diarrhea, dyspnea, restricted exercise tolerance, endocrine problems, taste and smell dysfunction, and depression.

Due to inflammation, autoimmunity, endothelial dysfunction, blood clotting, and gut microbiota dysbiosis, long-term COVID harms the respiratory, cardiovascular, neuropsychic, digestive, circulatory, musculoskeletal, and reproductive systems. Organs affected include the heart, brain, lungs, liver, kidneys, pancreas, and blood vessels.

Opportunistic gut microorganisms are associated with chronic respiratory symptoms. Actinomyces naeslundii and Clostridium innocuum, two common nosocomial infections, have been linked to tiredness and neuropsychiatric symptoms.

Long COVID is a serious and potentially fatal condition that can lead to serious health consequences. According to a study conducted across 56 countries, 65% of COVID-19 patients experienced at least one symptom within six months, with typical clinical symptoms including tiredness, post-exercise weakness, and cognitive impairment.

In China, 63% of patients had physical weakness or exhaustion, while 23% had sleep difficulties and 23% had depression/anxiety. Long COVID morbidity reduced from 68% after six months to 55% after two years.

The frequency of long COVID sequelae, on the other hand, remains high. Similar findings have been found in European research, with 66% of patients reporting at least one sequela 60 days following symptom start.

Long COVID is more common among individuals aged above 65 (45%) compared to those aged between 18 to 64 years (35%). As a result, preventative methods for long COVID sequelae should be prioritized, particularly in older COVID-19 patients.  

Long COVID diagnosis and management

Early identification of long COVID is critical and includes medical imaging and laboratory investigations. The combination of immunoglobulin G (IgG)/IgM, antigen, and polymerase chain reaction (PCR) testing has demonstrated ≤96% sensitivity for COVID-19 diagnosis. Echocardiography, cardiac biomarkers, and magnetic resonance imaging (MRI) are used to diagnose heart injury and arrhythmia.

Chest imaging and pulmonary function tests are used to diagnose lung damage and dyspnea. 18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) aids in identifying neuropsychic pathologies. The makeup of the gut microbiota can predict the incidence of protracted COVID and particular symptoms.

Liquid biopsy research demonstrates excellent prognostic and diagnostic potential for long COVID. For example, it has been shown that kynurenine can be increased in the blood and saliva of long COVID-19 patients for over 20 weeks.

Biomarkers of vascular change offer high specificity and sensitivity for long COVID diagnosis and monitoring. Extracellular vesicles generated from neurons include components associated with concealed neuronal damage, implying the ability to monitor neuropsychiatric signs of protracted COVID. Coagulation studies are performed to assess endothelial dysfunction, and endoscopy is performed for gastrointestinal symptoms.

Long-term COVID management methods include avoiding pollutants, stopping smoking, exercising regularly, and receiving umbilical cord-derived mesenchymal stem cell (UC-MSC) therapy. Beta-adrenergic blockers and exercise training are used to treat cardiovascular issues.

Non-pharmacological therapies for postural orthostatic tachycardia syndrome (POTS) include health education and exercise training, while pharmacological treatments include β-blockers and vasoactive drugs. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) management comprises energy management, customized exercise, sleep management, food control, and oxygen-ozone autohemotherapy.

SIM01 may help with digestive problems, whereas anticoagulant treatment, L-arginine with vitamin C, and low-dose naltrexone can help with endothelial dysfunction. MASC is treated with H1 and H2 antihistamines, nasal irrigation for olfactory abnormalities, palmitoylethanolamide with luteolin for memory and olfactory impairment, and nirmatrelvir for viral persistence.

Transcranial magnetic stimulation (TMS) can be used to treat neuropsychiatric symptoms. Adequate nourishment is also essential, and supplements such as Morinda citrifolia and fermented Carica papaya have shown promising results. Potential therapies include artificial intelligence-based treatments, non-coding ribonucleic acids (RNAs), and immunotherapies such as tumor growth factor-beta (TGF-β) inhibitors.


Overall, the review findings highlighted long COVID pathophysiology, epidemiology, diagnosis, and management. However, further research is required to improve understanding of the biological mechanisms underlying the spectrum of long COVID manifestations and develop targeted therapy to improve the standard of care for long COVID patients.

Early detection can enable prompt treatment to lower the disease burden and enhance the quality of life of affected individuals.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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