Chronic Comorbidities in Middle Aged Patients Contribute to Ineffective Emergency Hematopoiesis in Covid-19 Fatal Outcomes

Abstract

Background and aims: Mexico is among the countries with the highest estimated excess mortality rates due to the COVID-19 pandemic, with more than half of reported deaths occurring in adults younger than 65 years old. Although this behavior is presumably influenced by the young demographics and the high prevalence of metabolic diseases, the underlying mechanisms have not been determined.

Methods: The age-stratified case fatality rate (CFR) was estimated in a prospective cohort with 245 hospitalized COVID-19 cases, followed through time, for the period October 2020-September 2021. Cellular and inflammatory parameters were exhaustively investigated in blood samples by laboratory test, multiparametric flow cytometry and multiplex immunoassays.

Results: The CFR was 35.51%, with 55.2% of deaths recorded in middle-aged adults. On admission, hematological cell differentiation, physiological stress and inflammation parameters, showed distinctive profiles of potential prognostic value in patients under 65 at 7 days follow-up. Pre-existing metabolic conditions were identified as risk factors of poor outcomes. Chronic kidney disease (CKD), as single comorbidity or in combination with diabetes, had the highest risk for COVID-19 fatality. Of note, fatal outcomes in middle-aged patients were marked from admission by an inflammatory landscape and emergency myeloid hematopoiesis at the expense of functional lymphoid innate cells for antiviral immunosurveillance, including NK and dendritic cell subsets.

Conclusions: Comorbidities increased the development of imbalanced myeloid phenotype, rendering middle-aged individuals unable to effectively control SARS-CoV-2. A predictive signature of high-risk outcomes at day 7 of disease evolution as a tool for their early stratification in vulnerable populations is proposed.

Keywords: COVID–19; Chronic comorbidities; Chronic kidney disease; Emergency hematopoiesis; Inflammation; Middle adulthood.

Graphical abstract

Figure 1

Patients under 65 and over 65 years of age differ in hematologic values that predict outcomes. A. Alluvial plots for hematological cell populations in patients under 65 or over 65. No apparent relation between hematological parameters and outcomes is recorded at admission, while after 7 days, case clusters are obvious for some conditions. In elderly, higher WBC counts and NLR, low levels of lymphocytes and monocytes, and high levels of neutrophils and eosinophils relates to poor or fatal outcomes. Meanwhile, survivors are more frequent at younger ages, concomitant to low WBC and NLR and high numbers of lymphocytes. B. Alluvial plots for inflammatory markers expression at admission and followed by 7 days in survivors and deceased patients. Prediction of outcomes according to inflammatory parameters is clearer in middle age than in older adults. Low values of LDH, CRP and D–dimer are associated with better outcomes. Reference values: white blood cells (WBC): 4–11×10³ cells/µL, neutrophil/lymphocyte ratio (NLR): 1–3, Lymphocytes: 17–45%, Monocytes: 2–12%, Neutrophils: 37–75%, Eosinophils: 1–7%, Basophils: 0.3–2%, Erythrocytes: 4–5×10⁶ cells/µL, Hematocrit: 35–52%, Platelets: 130–400×10³ cells/µL, lactate dehydrogenase (LDH): 240–480 U/L, C–reactive protein (CRP): 0–5 mg/L, D–dimer: 0–500 U/L, Fibrinogen: 308–613 mg/dL, Bilirubin: 1–1.2 mg/dL, Creatinine: 0.7–1.2 mg/dL. ND, no data.

Figure 2

Morbi–mortality of the Atlixco cohort. A. Relative risk of death (RRd) by gender, age group, number and combination of comorbidities is depicted. Dotted vertical line marks RRd = 1. RRd were calculated by gender as male vs female; by age group as each age group vs 30–39 yo group (age group with p <0.05.

Figure 3

An inflammatory profile is revealed in middle–aged non–survivors. Cytokine concentration at admission, 7 days and 4 weeks later were analyzed for patients under 65 years old. Conval, convalescence; d, days.

Figure 4

Poor outcome in middle–aged patients is related to myeloid emergency hematopoiesis at the expense of innate immune response effector cells. Immune cell populations were evaluated in middle–aged patients by flow cytometry at admission, 7 days and 4 weeks later. In contrast to survivor patients, significant decrease in lymphocytes, monocytes, NK cells, pDC, CD11c⁺ DC (cDC2), basophils and functional neutrophils and monocytes is observed in non–survivors. CD16 and HLA–DR expression levels in neutrophils and monocytes, respectively, in poor outcome patients are shown A. Chronic comorbidities contribute to the pathogenic myeloid emergency hematopoiesis along to a defective lymphoid emergency compartment in middle aged COVID–19 patients. Hematological cell frequencies and CD16 and HLA–DR expression levels in neutrophils and monocytes, respectively, in COVID–19 survivors with no comorbidities are compared to their counterpart in non–survivors with comorbidities, at admission and upon 7 days of hospitalization. Healthy donor values are shown as control. Myeloid– and lymphoid– lineage cells related to emergency hematopoiesis are shown in B. MFI, median fluorescence intensity; d, days; Conval, convalescence.

Figure 4

Poor outcome in middle–aged patients is related to myeloid emergency hematopoiesis at the expense of innate immune response effector cells. Immune cell populations were evaluated in middle–aged patients by flow cytometry at admission, 7 days and 4 weeks later. In contrast to survivor patients, significant decrease in lymphocytes, monocytes, NK cells, pDC, CD11c⁺ DC (cDC2), basophils and functional neutrophils and monocytes is observed in non–survivors. CD16 and HLA–DR expression levels in neutrophils and monocytes, respectively, in poor outcome patients are shown A. Chronic comorbidities contribute to the pathogenic myeloid emergency hematopoiesis along to a defective lymphoid emergency compartment in middle aged COVID–19 patients. Hematological cell frequencies and CD16 and HLA–DR expression levels in neutrophils and monocytes, respectively, in COVID–19 survivors with no comorbidities are compared to their counterpart in non–survivors with comorbidities, at admission and upon 7 days of hospitalization. Healthy donor values are shown as control. Myeloid– and lymphoid– lineage cells related to emergency hematopoiesis are shown in B. MFI, median fluorescence intensity; d, days; Conval, convalescence.