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BackgroundThe Covid-19 pandemic has become a global public health crisis and providing optimal patient care while preventing a collapse of the health care system is a principal objective worldwide.ObjectiveTo develop and validate a prognostic model based on routine hematological parameters to predict uncomplicated disease progression to support the decision for an earlier discharge.DesignDevelopment and refinement of a multivariable logistic regression model with subsequent external validation. The time course of several hematological variables until four days after admission were used as predictors. Variables were first selected based on subject matter knowledge; their number was further reduced using likelihood ratio-based backward elimination in random bootstrap samples.SettingModel development based on three Austrian hospitals, validation cohorts from two Austrian and one Swedish hospital.ParticipantsModel development based on 363 survivors and 78 non-survivors of Covid-19 hospitalized in Austria. External validation based on 492 survivors and 61 non-survivors hospitalized in Austria and Sweden.OutcomeIn-hospital death.Main ResultsThe final model includes age, fever upon admission, parameters derived from C-reactive protein (CRP) concentration, platelet count and creatinine concentration, approximating their baseline values (CRP, creatinine) and change over time (CRP, platelet count). In Austrian validation cohorts both discrimination and calibration of this model were good, with c indices of 0.93 (95% CI 0.90 - 0.96) in a cohort from Vienna and 0.93 (0.88 - 0.98) in one from Linz. The model performance seems independent of how long symptoms persisted before admission. In a small Swedish validation cohort, the model performance was poorer (p = 0.008) compared with Austrian cohorts with a c index of 0.77 (0.67 - 0.88), potentially due to substantial differences in patient demographics and clinical routine.ConclusionsHere we describe a formula, requiring only variables routinely acquired in hospitals, which allows to estimate death probabilities of hospitalized patients with Covid-19. The model could be used as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system. The model could further be used to monitor whether patients should be admitted to hospital in countries with health care systems with emphasis on outpatient care (e.g. Sweden).

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Interleukin‐4 (IL‐4) and its receptors (IL‐4R) promote the proliferation and polarization of macrophages. However, it is unknown if IL‐4R also influences monocyte homeostasis and if steady state IL‐4 levels are sufficient to affect monocytes. Employing full IL‐4 receptor alpha knockout mice (IL‐4Rα−/−) and mice with a myeloid‐specific deletion of IL‐4Rα (IL‐4Rαf/f LysMcre), we show that IL‐4 acts as a homeostatic factor regulating circulating monocyte numbers. In the absence of IL‐4Rα, murine monocytes in blood were reduced by 50% without altering monocytopoiesis in the bone marrow. This reduction was accompanied by a decrease in monocyte‐derived inflammatory cytokines in the plasma. RNA sequencing analysis and immunohistochemical staining of splenic monocytes revealed changes in mRNA and protein levels of anti‐apoptotic factors including BIRC6 in IL‐4Rα−/− knockout animals. Furthermore, assessment of monocyte lifespan in vivo measuring BrdU+ cells revealed that the lifespan of circulating monocytes was reduced by 55% in IL‐4Rα−/− mice, whereas subcutaneously applied IL‐4 prolonged it by 75%. Treatment of human monocytes with IL‐4 reduced the amount of dying monocytes in vitro. Furthermore, IL‐4 stimulation reduced the phosphorylation of proteins involved in the apoptosis pathway, including the phosphorylation of the NFκBp65 protein. In a cohort of human patients, serum IL‐4 levels were significantly associated with monocyte counts. In a sterile peritonitis model, reduced monocyte counts resulted in an attenuated recruitment of monocytes upon inflammatory stimulation in IL‐4Rαf/f LysMcre mice without changes in overall migratory function. Thus, we identified a homeostatic role of IL‐4Rα in regulating the lifespan of monocytes in vivo.

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