Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease

Abstract

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Long COVID—ACOEM Guidance Statement

“…This set of elevated markers were also seen in patients with cardio-respiratory symptoms, and with anxiety and depression. 2 Occupational medicine physicians may be asked to evaluate workers with fatigue after acute COVID-19 to assess their ability to work or recommend accommodations. Workers with fatigue should be evaluated with a thorough history, physical examination, and appropriate laboratory tests to determine whether there are other or additional causes of fatigue besides long COVID, including depression or sleep apnea.…”

“…81,82 Cognitive impairment after recovery from COVID-19 was associated with several elevated plasma markers that suggest neuroinflammation and tissue repair. 2 Wong et al 44 hypothesize that some people with neurocognitive symptoms have reduced serotonin levels as a result of diminished intestinal absorption of the serotonin precursor tryptophan, and possibly other mechanisms. Reduced serotonin could impede the activity of the vagus nerve, resulting in impaired hippocampal responses and memory.…”

“…121 In patients with gastrointestinal symptoms 6 months after hospitalization for COVID-19, increased levels of three plasma proteins were observed that promote inflammation and are associated with dysregulation of the brain-gut axis. 2 Workers with inflammatory bowel disease or irritable bowel syndrome may need accommodations for schedules and breaks. If a worksite has a cafeteria, it would be helpful if available options include foods compatible with a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet.…”

“…By late 2022, it was estimated that 70% of adults in the United States had been infected with SARS-CoV-2. 1,2 The pandemic has gone through a series of peaks driven by variants that have become increasingly contagious and the trajectory of the disease continues to evolve. People who become infected with SARS-CoV-2 may be asymptomatic and may have mild illness, or the infection may lead to a series of complications and for some may be fatal.…”

“…The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, began in China in late 2019, with clinical cases first identified in the United States (US) in early 2020. By late 2022, it was estimated that 70% of adults in the United States had been infected with SARS-CoV-2 1,2 . The pandemic has gone through a series of peaks driven by variants that have become increasingly contagious and the trajectory of the disease continues to evolve.…”