The continued coronavirus disease 2019 (COVID-19) pandemic, brought on by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a major impact on the worldwide economy and healthcare sector.
Several studies have indicated that one out of ten patients experiences persistent symptoms for a protracted period, a condition that has been known as ‘long COVID’ or post-acute sequelae of COVID-19 (PASC). Common long COVID symptoms include breathlessness, gastrointestinal (GI) disturbance, fatigue, and memory impairment. So far, the association between disease phenotypes and mechanisms has not been clearly understood.
A recent study posted to the medRxiv* preprint server discusses the phenotypes related to long COVID inflammation.
Study: Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease.
*Essential notice: medRxiv publishes preliminary scientific reports that will not be peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
On account of the continual emergence of recent SARS-CoV-2 variants, the prevalence of long COVID has increased and can likely have long-term health effects. Thus, there may be an urgent need for targeted management of long COVID, depending on specific phenotypes and underlying mechanisms.
Although some studies have revealed the manifestation of persistent inflammation in adults with long COVID, these findings have been limited by the timing of samples, breadth of the considered immune mediators, and sample size. These limitations have led to an inconsistent association with symptoms.
Nevertheless, one recent PHOSP-COVID study revealed that the plasma proteome exhibited inflammation for many who experienced very severe long COVID symptoms, including fatigue, cognitive impairment, and breathlessness. Nevertheless, it stays unclear whether proteomic changes are specific to symptoms.
It is crucial to find out the common pathways of inflammation related to long COVID symptoms. Likewise, it can be crucial to know whether different patterns of inflammation cause specific clinical subtypes which will require personalized therapeutic intervention.
Concerning the study
The present prospective multicentred study included individuals, each female and male, above 18 years of age, without comorbidities, who were hospitalized for COVID-19 between February 2020 and January 2021. Plasma samples and relevant clinical data were collected roughly six months after hospitalization.
Based on clinical data, the patients were placed into six categories, of which included ‘Recovered,’ ‘Fatigue,’ ‘Cardiorespiratory,’ ‘GI,’ ‘Cognitive impairment,’ and ‘Depression/anxiety.’
Different scoring systems, corresponding to the dyspnoea-12 rating, Medical Research Council (MRC) breathlessness rating, patient health questionnaire 9 (PHQ-9), General Anxiety Disorder 7 (GAD-7), and Functional Assessment of Chronic Illness Therapy (FACIT) rating were used to evaluate disease severity. Inflammatory signatures were determined using different assays.
Study findings
A complete of 360 plasma proteins were measured in 719 participants six months after hospitalization attributable to severe SARS-CoV-2 infection. Herein, 35% of the cohort was categorized under ‘Recovered’, and the remaining 65% experienced long COVID symptoms.
A penalized logistic regression (PLR) model was used to evaluate the impact of patient’s demographics and immune mediators on symptoms. To this end, the feminine sex predicted all symptoms, particularly GI and cardiorespiratory symptoms.
Pre-existing conditions were identified to be a powerful risk factor for all symptoms except GI. Notably, age and disease severity weren’t linked with any symptoms.
To evaluate the link between peripheral inflammation and long COVID symptoms, immune mediators were measured within the plasma. The PLR model adjusted coefficients and determined specific predictive mediators for every symptom group. Interestingly, mediators suggestive of persistent monocytic inflammation were correlated with all symptoms.
Elevated interleukin 1R2 (IL1R2) and/or Matrilin-2 (MATN2) were consistently related to all symptoms except cognitive impairment. IL1R2 is expressed in macrophages and monocytes and influences IL1-driven inflammation. MATN2 is an extracellular matrix (ECM) protein that causes inflammation by triggering toll-like receptors and increasing the speed of monocyte infiltration into tissues.
IL-6 enhanced the chance of fatigue and cardiorespiratory symptoms. Colony stimulating factor 3 (CSF3) marginally influenced GI symptoms, fatigue, and anxiety/depression.
Increased levels of sCD58, an immunosuppressive factor, were linked with a lowering of all long COVID symptoms, particularly cardiorespiratory symptoms, and fatigue. Collectin-12 (COLEC12) was related to an increased risk of developing anxiety/depression, fatigue, and cardiorespiratory symptoms. COLEC12 initiates inflammation by triggering the choice complement pathway and modifying leucocyte recruitment.
C1QA, a component of the complement system, was identified as a predictor of long COVID symptoms, particularly cognitive impairment. Likewise, elevated levels of Neurofascin, Spondin-1, and Iduronate sulfatase also correlated with cognitive impairment.
Secretogranin 3 (SCG3), MATN2, and dipeptidyl peptidase 10 (DDP10) were related to the very best risk of GI symptoms. Comparatively, delta/notch-like EGF repeat (DNER) was linked with a reduced risk of cardiorespiratory symptoms.
The findings of this study indicate that immunosuppressive aspects and a sturdy tissue repair response might prevent cardiorespiratory symptoms after SARS-CoV-2 infection.
There was no significant difference in nasal mediator levels between those that recovered and people who developed long COVID. For people with cardiorespiratory symptoms, elevated levels of inflammatory mediators were detected within the plasma but not the upper respiratory tract.
Conclusions
Systemic monocytic inflammation and complement activation look like the underlying mechanisms related to long COVID. Subsequently, the resolution of those aspects should assist in recovery.
*Essential notice: medRxiv publishes preliminary scientific reports that will not be peer-reviewed and, subsequently, shouldn’t be thought to be conclusive, guide clinical practice/health-related behavior, or treated as established information.