When the COVID-19 pandemic was at its peak, it posed a significant threat to human life and flourishing; to human life in its infectiousness and propensity to kill, and to human flourishing in the strict lockdowns that followed. 

The immediate concern of health governing bodies around the world was to control the spread of the virus and to therefore reduce mortality rates to a minimum; there was a recognition that this was a once in a generation health threat that deserved unprecedented preventative measures. Now that the virus has subsided, the scientific community continues to evaluate various aspects of the pandemic—how it happened, the comorbidities attached, and a similar pandemic can be prevented in the future. 

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The Emergence of Comorbidities 

Even in the midst of the pandemic, researchers began to be concerned that health problems did not end for some patients when the virus was treated. Among adverse effects that precipitated during infection or shortly after were cognitive impairments, palpitations, smell/taste dysfunction, myalgia, cardiac disease, and gastrointestinal issues. 

In a study published in Infectious Diseases, researchers tracked how these symptoms were dealt with by the medical community. Initially, there were some doubts that lingering post COVID symptoms were really linked to the infection. Some doctors suggested that these symptoms were psychosomatic in nature, including bodily manifestations of mental health difficulties. However, the evidence was soon to be overwhelming and a new term for this group of symptoms was coined: long COVID. 

There remains some debate as to what constitutes “long COVID,” but generally it has been used as an umbrella term for any pathology that began during infection that lingered on, or unexplained symptoms that arose shortly after (or even before). Some patients with long COVID find that their symptoms self-resolve within a few months. Others continue to experience them, years after initial infection. 

There are a number of theories as to what causes long COVID. The prevailing theory is that COVID-19 infection causes long-term tissue damage and pathological inflammation that may give rise to the symptoms experienced by patients. For example, tissue damage in the lungs may cause persistent dyspnea and coughing, while unresolved inflammation in the gut might cause change in bowel habits. 

Because long COVID symptoms are heterogenous, physicians mostly treat symptoms as they appear. As research continues, a new consensus may emerge regarding best practices in dealing with long COVID. Nevertheless, the emergence of long COVID demonstrates what many researchers have suspected: COVID-19 infection is categorically different from normal flu in that it is associated with unusual comorbidities that may share with it a common pathophysiology. 

Association With NMOSD 

“A growing body of case reports or series has documented the emergence of neuromyelitis optica spectrum disorder (NMOSD) subsequent to COVID-19 infection or COVID-19 vaccination,” Sun and colleagues wrote in Frontiers in Immunology. “Although these studies show a clear chronological sequence, it remains uncertain whether COVID-19 infection caused or triggered latent NMOSD.”

To further investigate possible links between COVID-19 and NMOSD, Sun et al used Mendelian randomization. Mendelian randomization is a sturdy approach to evaluating potentially causal relationships between exposure factors and outcomes. It is also useful in that it mitigates the issues of residual confounding and reverse causality. 

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The authors of the study accessed comprehensive COVID-19 hospitalization data from the COVID-19 Host Genetics Initiative (updated in April 2022), encompassing COVID-19 susceptibility analysis of 159,840 cases (and 2,789,977 controls), 44,986 cases of COVID-19 hospitalization (and 2,356,386 controls), as well as 18,152 cases of severe COVID-19 (and 1,145,546 controls). The researchers then analyzed the NMOSD trait derived from a comprehensive genome-wide association study (GWAS) subset, encompassing 215 individuals diagnosed with NMOSD (and a control group of 1,244 healthy individuals). 

The researchers reported that there was neither a statistically significant relationship between COVID-19 susceptibility and increased risk of NMOSD or aquaporin-4 antibody-negative NMOSD (AQP4-NMOSD), nor was there a statistically significant relationship between COVID-19 hospitalization and severity on NMOSD, AQP4-NMOSD, or AQP4+NMOSD. However, using the inverse-variance weighted method, a “nominal” relationship was found between COVID-19 susceptibility and AQP4+ NMOSD (odds ratio = 4.958; 95% confidence interval: 1.322 to 18.585; P =.018). 

“To our knowledge, we have comprehensively assessed the causal association between COVID-19 phenotypes and NMOSD for the first time,” the research team wrote. “In this [Mendelian randomization] study, our findings showed that genetically predicted COVID-19 susceptibility was associated with a high risk of AQP4+ NMOSD.” 

The implication of this finding is that it further adds to the evidence that COVID-19 has a relationship with unusual comorbidities not typically seen in seasonal flu. More specifically, it adds to a growing body of evidence showing a relationship between COVID-19 infection and neuroimmune disorders. This strongly suggests that the COVID-19 infection can trigger autoimmunity in some individuals via viral mimicry, epitope propagation, bystander activation, and cryptogenic antigen presentation. 

In this sense, NMOSD can be classified as another possible manifestation of long COVID. However, what we do understand about the pathophysiological mechanisms underlying COVID-19 infection contrasts strongly with what we have not yet grasped; specifically, we have yet to understand how all these comorbidities relate to the initial infection and how best to treat them. Future research is undoubtedly warranted. 


Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatmentsInfect Dis (Lond). Published online May 22, 2021. doi:10.1080/23744235.2021.1924397

Sun D, Du Q, Wang R, Shi Z, Chen H, Zhou H. COVID-19 and the risk of neuromyelitis optica spectrum disorder: a Mendelian randomization studyFront Immunol. Published online July 27, 2023. doi:10.3389/fimmu.2023.1207514