Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study, 2024, Ozonoff et al.

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Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study
Ozonoff, Al; Jayavelu, Naresh Doni; Liu, Shanshan; Melamed, Esther; Milliren, Carly E.; Qi, Jingjing; Geng, Linda N.; McComsey, Grace A.; Cairns, Charles B.; Baden, Lindsey R.; Schaenman, Joanna; Shaw, Albert C.; Samaha, Hady; Seyfert-Margolis, Vicki; Krammer, Florian; Rosen, Lindsey B.; Steen, Hanno; Syphurs, Caitlin; Dandekar, Ravi; Shannon, Casey P.; Sekaly, Rafick P.; Ehrlich, Lauren I. R.; Corry, David B.; Kheradmand, Farrah; Atkinson, Mark A.; Brakenridge, Scott C.; Higuita, Nelson I. Agudelo; Metcalf, Jordan P.; Hough, Catherine L.; Messer, William B.; Pulendran, Bali; Nadeau, Kari C.; Davis, Mark M.; Sesma, Ana Fernandez; Simon, Viviana; van Bakel, Harm; Kim-Schulze, Seunghee; Hafler, David A.; Levy, Ofer; Kraft, Monica; Bime, Chris; Haddad, Elias K.; Calfee, Carolyn S.; Erle, David J.; Langelier, Charles R.; Eckalbar, Walter; Bosinger, Steven E.; Peters, Bjoern; Kleinstein, Steven H.; Reed, Elaine F.; Augustine, Alison D.; Diray-Arce, Joann; Maecker, Holden T.; Altman, Matthew C.; Montgomery, Ruth R.; Becker, Patrice M.; Rouphael, Nadine

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge.

Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters.

Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Link | PDF (Nature Communications)

 

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In this large prospective study that followed participants from the time of acute COVID-19 hospitalization, more than half of the participants hospitalized with COVID-19 had persistent symptoms lasting 3 or more months after discharge, consistent with other studies. The clustering of Patient-Reported Outcomes (PROs) by predominant deficit (physical predominant, mental/cognitive predominant, and multidomain deficits) supports PASC as a heterogeneous clinical entity with distinct sub-phenotypes associated with unique perturbations of the immune system in the acute phase of the illness. This cluster-based analysis also revealed a specific participant phenotype associated with persistent mental and cognitive impairments that were distinct from phenotypes associated with broader physical dysfunction.

Exclusion of non-hospitalized patients also affects the generalizability of our findings to patients with COVID-19 not requiring hospitalization. Also, our study did not include control groups: (1) who did not have COVID, (2) hospitalized for a non-COVID-19 respiratory viral infection, and/or (3) hospitalized for elective procedures where the length of stay is similar to COVID-19.

While numerous cytokines have been associated with PASC in other studies, in this study, we found that only fibroblast growth factor 21 (FGF21) was significantly associated with the PRO clusters. FGF21 is a cytokine known to regulate systemic glucose and lipid metabolism that is secreted from muscle in response to stress or even infection, particularly mitochondrial myopathy supporting a potential catabolic role of FGF21 on human muscle health.

In our metabolomics data, we found a significant association between global metabolomics module 3 (methylhistidine metabolism) and the PRO clusters, consistent with the inverse relationship between 3-methylhistidine (3MH) and FGF21, thought to be mediated by insulin sensitivity. This observation is also consistent with the relationship between 3-methylhistidine and muscle cells, in which 3MH is a potential biomarker for muscle atrophy and skeletal muscle toxicity. Whether the association we observed with FGF21 reflects underlying mitochondrial dysfunction as the pathobiological basis for PASC is unclear and deserves further investigation.

Elevation of plasma FGF21 has also been noted in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an entity with clinical features that overlaps with PASC including fatigue, post-exertional malaise, sleep disturbance, and brainfog [44].

[44] Are Circulating FGF21 and NT-proBNP promising novel biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? (2020, Antioxidants and Redox Signaling)