Understanding long COVID: A call for better diagnosis and treatment

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In a recent review published in the journal Nature Reviews Microbiology, a group of authors summarized recent advancements in understanding long coronavirus disease (COVID) 's mechanisms, impacts, and research needs for better diagnostics and treatments.

Review: Long COVID: major findings, mechanisms and recommendationsReview: Long COVID: major findings, mechanisms and recommendations


Long COVID, affecting over 65 million globally, manifests through diverse, systemic symptoms regardless of initial infection severity. This condition leads to various health issues like cardiovascular diseases and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), causing widespread disability and workforce impacts. Pathogenesis theories include persistent viral presence and immune dysregulation, but no effective treatments have been established. Research has identified risk factors such as gender and socioeconomic status, although many patients had no prior conditions. Long COVID's resemblance to other post-viral syndromes underscores the urgent need for research into its mechanisms, risk factors, and treatments to enhance patient outcomes.

Immunological and virological discoveries in Long COVID

Long COVID triggers significant immune changes, particularly post-mild COVID, marked by T cell exhaustion, reduced effector memory Cluster of Differentiation (CD)4+ and CD8+ T cells, elevated Programmed Death-1 (PD1) expression, and activated innate immune responses. The scarcity of naive T and B cells, alongside sustained high type I and III interferon levels, indicates continued immune dysregulation. An altered immune cell balance, including increased non-classical monocytes, reduced dendritic cells, and low cortisol, highlights a distinct immune profile in long COVID.

Research points to autoimmunity in long COVID, highlighted by raised autoantibodies against key receptors like Angiotensin-Converting Enzyme 2 (ACE2). Viral reactivations, notably of Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV-6), which impact mitochondrial function and energy metabolism, play a significant role. The condition's development is initially linked to inadequate immune responses, including poor antibody and T-cell response. Signs of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistence across multiple body tissues suggest a potential mechanism for the enduring nature of long COVID symptoms.

Systemic impact and organ damage

SARS-CoV-2 causes widespread organ damage beyond the respiratory system, affecting the circulatory system through endothelial dysfunction and increased thrombosis risks. Long-term alterations in blood properties and vascular density contribute to the heightened prevalence of cardiovascular diseases post-COVID, demonstrating the virus's systemic and lasting effects.

Neurological impact

Long COVID induces neurological and cognitive issues, such as memory loss and cognitive impairment, with effects comparable to significant aging. Potential underlying mechanisms like neuroinflammation and neuronal damage link these symptoms to Alzheimer's-like pathology, highlighting severe brain impacts.

ME/CFS and related conditions

There is a notable overlap between long COVID and ME/CFS, with many patients meeting the criteria for the latter. This relationship underscores commonalities like immune alterations and mitochondrial dysfunction, with dysautonomia commonly co-occurring, suggesting shared pathophysiological mechanisms.

Reproductive and respiratory concerns

Long COVID's reproductive effects call for focused research on sex-specific impacts, while persistent respiratory symptoms underscore lasting lung damage. These aspects illustrate the condition's broad spectrum of effects.

Gastrointestinal symptoms and chronicity

Persistent gastrointestinal issues and altered gut microbiota in long COVID patients emphasize its systemic nature. The diverse onset and duration of symptoms across patients highlight the condition's complexity and the challenge of predicting individual outcomes.

Diagnostic advances and challenges

Diagnostic approaches for long COVID are under development, with existing techniques like tilt table tests and Magnetic Resonance Imaging (MRI) scans often failing to detect the condition effectively. Emerging diagnostics, including microclot imaging, corneal microscopy, and novel Electrocardiogram (ECG) markers, offer hope for more precise identification. Research into biomarkers and unconventional methods, such as scent detection by dogs, highlights the innovative directions being explored to improve long COVID diagnosis.

Treatment landscape and future directions

Current treatment strategies for long COVID are primarily symptom-focused, with some success using methods adapted from ME/CFS management. Innovations such as low-dose naltrexone and anticoagulant therapy show promise, while experimental treatments like Paxlovid and probiotics are beginning to demonstrate potential benefits. Nonetheless, the need for rigorous clinical trials to establish effective treatments remains critical, underscoring the initial stage of long COVID care and the importance of ongoing research.

Vaccine impact and the role of variants

Vaccination's impact on long COVID varies, showing both minimal and reduced risk. Variants and vaccine doses may affect long COVID chances, with early studies hinting at variant-dependent risks and vaccine efficacy. Reinfections, particularly multiple ones, could heighten long COVID risks, stressing the importance of continuous research and monitoring.

Diagnosing Long COVID: obstacles and solutions

The early pandemic's diagnostic challenges, such as limited polymerase chain reaction (PCR) test availability and high false-negative rates, led to widespread underdiagnosis, affecting mainly non-hospitalized individuals. Compounded by unreliable antibody tests, particularly among specific groups like women, children, and those with mild infections, these issues have significantly hindered long COVID research and patient care. Misclassification and study exclusion have clouded our understanding of the condition. A comprehensive approach incorporating insights from ME/CFS and dysautonomia is essential to improve long COVID research. Emphasizing clinical trials, diverse participant inclusion, and engaging patient communities, alongside updated healthcare training, will enhance patient outcomes and advance our knowledge of long COVID.

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    


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