Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection

Abstract

The incidence of long COVID is substantial, even in people who did not require hospitalization for acute COVID–19. The pathobiological mechanisms of long COVID and the role of early viral kinetics in its development are largely unknown. Seventy–three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS–CoV–2 RT–PCR test, and mid–turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS–CoV–2 using RT–PCR and additional test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1, 3, 6, 12, and 18 months post–COVID–19 diagnosis. Time from acute COVID–19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90 or more days from acute COVID–19 symptom onset. Brain fog and muscle pain at 90 or more days after acute COVID–19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID–19 onset with adjustment for age, sex, BMI over 25, and COVID vaccination status prior to COVID–19 (brain fog: aRR 0.46, 95% CI 0.22 – 0.95; muscle pain: aRR 0.28, 95% CI 0.08 – 0.94). This work indicates that at least two long COVID symptoms, brain fog and muscle pain, at 90 or more days from acute COVID–19 onset are specifically associated with longer time to clearance of SARS–CoV–2 RNA from the upper respiratory tract.

Association of nirmatrelvir for acute SARS‐CoV‐2 infection with subsequent Long COVID symptoms in an observational cohort study

“…“Real‐world” observational studies have found similar results, with reductions in hospitalization and mortality among higher risk and vaccinated individuals 24–29 . Higher viral loads and prolonged viral shedding have been associated with risk of Long COVID, 3,4 and nirmatrelvir results in faster viral clearance, 30,31 supporting the hypothesis that nirmatrelvir may prevent Long COVID. Second, in this cohort, the number of symptoms during acute infection is associated with Long COVID symptoms independent of vaccination and variant wave, 19 but whether reducing acute symptoms with antiviral therapy prevents Long COVID has not been demonstrated.…”

Association of Nirmatrelvir/Ritonavir Treatment with Long COVID Symptoms in an Online Cohort of Non-Hospitalized Individuals Experiencing Breakthrough SARS-CoV-2 Infection in the Omicron Era

“…A number of “real-world” observational studies have mostly found similar results, with reductions in hospitalization and mortality among higher risk individuals as well as vaccinated individuals [19-23]. Others have demonstrated faster viral clearance with nirmatrelvir/ritonavir [24, 25]; as higher viral loads and prolonged viral shedding have been previously associated with risk of Long COVID [3, 4], there is a strong rationale for the hypothesis that treatment with nirmatrelvir/ritonavir may lower the risk of Long COVID. Secondly, in this cohort, we have previously shown that the number of symptoms during acute infection is associated with Long COVID symptoms independent of vaccination and variant wave [15], but whether reducing acute symptoms with antiviral therapy reduces risk of Long COVID has not been demonstrated.…”

“…Vaccination reduces but does not eliminate the risk of Long COVID [2]. Higher acute viral load or prolonged viral shedding may be associated with increased risk of Long COVID [3, 4]. Recent studies suggest viral persistence in a subset of individuals with post-acute sequelae of COVID-19, including prolonged gastrointestinal shedding, ongoing Spike and Nucleocapsid antigen in neuronal and astrocytic exosomes, and evidence of persistent viral RNA or proteins in deep tissues [5-8].…”

“…Vaccination reduces but does not eliminate the risk of Long COVID [2]. Higher acute viral load or prolonged viral shedding may be associated with increased risk of Long COVID [3,4].…”

Intrinsic factors behind long‐COVID: II. SARS‐CoV‐2, extracellular vesicles, and neurological disorders

“…Long‐COVID symptoms such as muscle pain and brain fog are directly related to the longer period of immune clearance and the persistence of SARS‐CoV‐2 RNA and antigens in the upper respiratory tract during acute COVID‐19 167 . SARS‐CoV‐2 ORF9c and Nsp7, respectively, collaborate with mitochondrial NDUFAF1 and NDUFAF2, which are both linked to the construction of complex I of the mitochondrial electron transport chain.…”