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BackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management. MethodsImmunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1,164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed. FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age [≥] 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63-4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC. InterpretationIntegration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19. FundingNIH RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe did a systematic search of the PubMed database from January 1st, 2020 until April 24th, 2022 using the search terms: "hospitalized" AND "SARS-CoV-2" OR "COVID-19" AND "Pro-spective" AND "Antibody" OR "PCR" OR "long term follow up" and applying the following filters: "Multicenter Study" AND "Observational Study". No language restrictions were applied. While clinical, laboratory, and radiographic features associated with severe COVID-19 in hospitalized adults have been described, description of the kinetics of SARS-CoV-2 specific assays available to clinicians (e.g. PCR and binding antibody) and their integration with other variables is scarce for both short and long term follow up. The current literature is comprised of several studies with small sample size, cross-sectional design with laboratory data typically only recorded at a single point in time (e.g., on admission), limited clinical characteristics, variable duration of follow up, single-center setting, retrospective analyses, kinetics of either PCR or antibody testing but not both, and outcomes such as death or, mechanical ventilation that do not allow delineation of variations in clinical course. Added value of this studyIn our large longitudinal multicenter cohort, the description of outcome severity, was not limited to survival versus death, but encompassed a clinical trajectory approach leveraging longitudinal data based on time in hospital, disease severity by ordinal scale based on degree of respiratory illness, and presence or absence of limitations at discharge. Fatal COVID-19 cases had the lowest ratio of antibody to viral load levels over time as compared to non-fatal cases. Integration of PCR cycle threshold and antibody values with demographics, baseline comorbidities, and laboratory/radiographic findings identified additional risk factors for outcome severity over the first 28 days. However, female sex was the only variable associated with persistence of symptoms over time. Persistence of symptoms was not associated with clinical trajectory over the first 28 days, nor with antibody/viral loads from the acute phase. Implications of all the available evidenceThe described calculated ratio (binding IgG/PCR Ct value) is unique compared to other studies, reflecting host pathogen interactions and representing an accessible approach for patient risk stratification. Integration of SARS-CoV-2 viral load and binding antibody kinetics with other laboratory as well as clinical characteristics in hospitalized COVID-19 patients can identify patients likely to have the most severe short-term outcomes, but is not predictive of symptom persistence at one year post-discharge.
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DISCUSSION Acute regulation of sodium pump activity There is a burgeoning literature on mechanisms responsible for short term regulation of Na,K-ATPase activity (Aperia et al, 1996, 1994; Boron et al, 1997; Bertorello & Katz, 1993). Pathways linked to both generation of protein kinase C (PKC) and/or cyclic-AMP dependent protein kinase A are postulated to regulate Na,K-ATPase activity by changing the alpha catalytic subunit phosphorylation status. However, phosphorylation has been associated with both decreased activity (Aperia et al, 1994; Chibalin et al, 1995; Middleton et al, 1993; Satoh et al, 1993a, 1993b), and increased activity (Carranza et al, 1996a, 1996b), and no change in activity (Boron et al, 1997). There is also evidence that PKC causes a withdrawal of sodiuln pumps from the basolateral membranes even if there is mutation of the phosphorylation site (Boron et al, 1997). Proximal tubule Na,K-ATPase activity is also inhibited (whether directly or indirectly is not known) by activation of phospholipase A2 which stimulates production of arachidonate metabolites of cytochrome P-450 such as 20-HETE (Aperia et al, 1996; Nowicki et al, 1997; Ominato et al, 1996). Although the precise signaling mechanisms re main to be elucidated for the responses to altered blood pressure, our results indicate that the inhibition of the sodium pump activity in PT is due to structural modification of the pump itself or an associated regulator, rather than solely mediated by trafficking of active pumps to a new location, because the data demonstrate. significant changes in total ATPase activity that persist through membrane fractionation and phase partitioning, and our results implicate a role of cat P45O aa metabolism to 20-HETE in the response(Zhang et al, 1998) Altered natriuretic responses in hypertension As discussed in the introduction, an altered natriuretic response to an elevation in blood pressure is the hallmark of hypertension. The Spontaneously Hypertensive Rat (SHR)has numerous renal defects that could account for the development of hypertension. In regards to this project, the PT of SHR fail to respond normally to the natriuretic hormone dopamine (Kinoshita et al, 1989), and they have enhanced tubuloglomerular feedback (TGF) response (reviewed in Cowley & Roman, 1997). Our results indicate a distribution of apical sodium transportes in SHR is the same as in acutely hypertensive SD (Magyar et al, 1997), In summary, our findings to date suggest that the dynamic regulation of proximal tubule and loop of Henle sodium transport by fluctuations in blood pressure may be mediated by changes in sodium transporter characteristics at both the apical and basolateral membranes: 1) by reversible inhibition of basolateral Na,K-ATPase activity in the PT and activation in the TALH, and 2) relocation of a set of apical proteins, including NHE-3 and NaPi, consistent with redistribution to intermicrovillar cleft region and/or internalization to endosomal pools in the PT. The reciprocal modulation of Na,K-ATPase activity in PT and TALH contributes the driving force for activating TGF, while minimizing changes in delivery of salt and water to the hormone sensitive distal nephron.