Cytokine Signatures and Hematological Alterations as Predictors of Covid-19 Severity and Mortality in a Brazilian Cohort From Central-south Mato Grosso

Cytokine Signatures and Hematological Alterations as Predictors of Covid-19 Severity and Mortality in a Brazilian Cohort From Central-south Mato Grosso | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cytokine Signatures and Hematological Alterations as Predictors of Covid-19 Severity and Mortality in a Brazilian Cohort From Central-south Mato Grosso Thais Campos Dias Cruz, Gessica Fernanda Colnago Lima, Valéria Dutra, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8322000/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hyperinflammation is a key driver of diffuse alveolar damage in COVID-19. This cohort study investigated the association between cytokine dysregulation, hematological parameters, and disease severity in 137 unvaccinated hospitalized COVID-19 patients. The mild group (n = 36) showed decreased IL-6, IP-10, and MCP-1 (p < 0.001) and increased IFN-γ, IL-7 (p < 0.001), IL-2 (p < 0.05), IL-10, IL-12p70, and TNF-α (p < 0.001) compared with the moderate group (n = 36). The severe group (n = 65) had elevated IL-4, IL-6, IL-7, IL-8, TNF-α (p < 0.001), IL-2, IP-10, MCP-1, and GM-CSF (p < 0.001), but reduced IFN-α2 (p < 0.01), IFN-γ (p < 0.05), and IL-7 (p < 0.01) compared to the moderate group. Increased IL-6, IL-8, MCP-1, IL-10, IP-10, and TNF-α correlated with metabolic, respiratory, and cardiovascular comorbidities. Higher IL-6, IL-8, IL-10, IP-10, MCP-1, TNF-α (p < 0.01), and IL-7 (p < 0.02) levels were associated with mortality (64.2%). Negative correlations were observed between erythrocyte count, hemoglobin, and TNF-α, IL-6, IFN-α2 (p < 0.05); hematocrit and TNF-α (p < 0.05); lymphocytes and MCP-1 (p < 0.01). Positive correlations occurred between leukocyte and neutrophil counts with IL-8, MCP-1, TNF-α; CRP with IL-6, IL-8, MCP-1, TNF-α; and platelets with IL-17A and TNF-α (all p < 0.05). These findings indicate that elevated pro-inflammatory cytokines are linked to hematological markers typical of severe COVID-19—lymphopenia, anemia, and neutrophilic leukocytosis—contributing to poor outcomes. Conversely, IL-4, IL-7, and IFN-α may play protective roles associated with milder disease and recovery. The study underscores immune balance as critical in COVID-19 progression and highlights potential biomarkers for prognosis and therapeutic targeting. COVID-19 Pro-inflammatory cytokines Hematological parameters Prognostic biomarkers ARDS (acute respiratory distress syndrome) Figures Figure 1 Figure 2 Introduction SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a Sarbecovirus from genus Betacoronavirus , family Coronaviridae , emerged as a novel agent of viral pneumonia in Wuhan, China [ 1 , 2 ]. In February 2020, COVID-19 (Coronavirus Disease 2019) was declared a public health emergency of international concern by the World Health Organization [ 1 ]. Unlike the other coronaviruses causing acute severe respiratory distress syndrome (ARDS), SARS-CoV-1 and MERS-CoV, SARS-CoV-2 demonstrated a high transmissibility pattern that begins during the incubation period. This feature facilitated rapid global spread, resulting in high morbidity and mortality rates [ 3 ]. Clinically, the disease can be classified as pre-symptomatic and mild, accounting for 80 to 85% of infections; as moderate disease, characterized by oxygen saturation below 95% during mild exertion, representing approximately 15% of cases. The severe critical phase, affecting less than 5% of patients, is marked by oxygen saturation below 90%, pneumonia, severe respiratory distress, and inability to complete sentences. This critical phase, defined by the criteria for ARDS, is often accompanied by hyperinflammation, sepsis and septic shock, which can progress to multiple organ failure [ 4 – 8 ]. Bone marrow hematopoietic precursor cell depletion, T-cell lymphopenia, CD4 + and CD8 + T cells functional impairment have been correlated with disease severity. Conversely, the development of high levels of specific CD4 + and CD8 + T cells in nearly 50% of patients during the acute phase and in over 80% during convalescence associated with a well-coordinated antiviral immune response leading to recovery [ 9 ]. Th1 phenotype of CD4 + T cells has been linked to mild disease and recovery, whereas Th17 phenotype has been implicated in Th2 activation, suppression of Treg and Th1 responses, and COVID-19 progression [ 10 – 11 ]. Persistency of SARS-CoV-2 replication led to inflammatory cells recruitment and endothelial activation, tissue injury, and dysregulated release of pro-inflammatory cytokines. These cytokines mediate biological signals to target cells through interactions with specific high-affinity receptors, playing a pivotal role in immunoregulation and leukocyte chemotaxis to inflamed tissues [ 12 – 13 ]. Elevated levels of pro-inflammatory cytokines can exacerbate disease progression by promoting hyperinflammation, pulmonary capillary vasodilation, and other dysfunctions that contribute to ARDS and multi-organ failure [ 14 ]. Studies have shown that altered serum levels of interleukins (IL) as IL-1β, IL-2, IL-6, IL-10, type II interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), IFN-γ inducible protein 10 (IP-10), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1) correlate with diffuse alveolar damage and ARDS severity in COVID-19 [ 15 – 18 ]. The complex interplay between these cytokines and hematological changes, as well as their impact on clinical outcomes, remains incompletely understood. The elucidation of these relationships is crucial for identifying prognostic biomarkers and potential therapeutic targets. This study aimed to characterize the profile of cytokines and their interplay with hematological parameters and underlying clinical characteristics that define the disease course of hospitalized COVID-19 patients. Material and Methods Sampling and ethical aspects In total, 137 unvaccinated patients over 18 years of age with laboratory-confirmed SARS-CoV-2 infection (positive RT-qPCR in nasopharyngeal swabs), admitted to a COVID-19 referral unit in Várzea Grande, Mato Grosso, between March 2020 and May 2021, had their clinical history, laboratory data, and biological samples collected upon admission. This study was previously approved by the Institutional Ethics Committee (CEP-HUJM; CAAE 32361020.0.0000.5541) and has been conducted in accordance with National Health Council Resolution 466/2012. Epidemiological, clinical, virological, and laboratory data from these patients have been previously described [ 19 ]. Human cytokine dosage in the serum of COVID-19 patients Serum samples were subjected to simultaneous quantification, in duplicate, of IL-6, IL-2, IL-4, IL-10, IL-12p70, IL-7, IL-8, IL-17A, GM-CSF, IFN-α, IFN-γ, IP-10, MCP-1, and TNF-α. After homogenization, samples were centrifuged at room temperature (14,000 × g for 5 minutes), diluted 1:10 in assay buffer, and analyzed using the Milliplex Millipore HCYTA-60K-14 kit (Merck Millipore, Massachusetts, USA) on a Luminex MAGPIX Multiplexing System (XMAP Technology, Texas, USA), according to the manufacturer’s instructions. Biomarker concentrations were determined by generating standard curves in Luminex xPONENT v. 3.1 (Merck Millipore, Massachusetts, USA) and expressed in pg/mL. Statistical analysis Serum cytokine levels were analyzed as counts and percentages or as median and interquartile ranges (IQR) using GraphPad Prism v. 5.0. Differences among the clinical groups and epidemiological waves were assessed by one-way analysis of variance (ANOVA), followed by Newman-Keuls post hoc test, and by Kruskal-Wallis multiple comparisons. Cytokine levels and mortality were compared with t-test followed by the Mann-Whitney test. The association between cytokine levels and hematological parameters was evaluated using Pearson’s correlation coefficient. Results Clinical classification at hospital admission was used to stratify patients into mild (n = 36; 26.28%), moderate (n = 36; 26.28%), and severe (n = 65; 47.45%) groups. Clinical follow up revealed 88/137 (64.23%) patients, 11/36 (30.55%) from the mild group, 18/36 (50.00%) from moderate, and 59/65 (90.77%) in the severe group represent fatal cases. Cytokine levels in the serum of COVID-19 patients Mean cytokine levels stratified by epidemiological wave in these clinical groups (Table I), showed significant decreases in IL-6, IP-10, and MCP-1 (p < 0.001) levels in the mild group, compared to the moderate group during the first epidemiological wave. Moderate clinical group exhibited decreased levels of IFN-γ, IL-7 (p < 0.001), and IL-2 (p < 0.05) during the first wave, and IFN-γ (p < 0.05), IL-10, IL-12p70, and TNF-α (p < 0.001) in the second wave, compared to the mild group. Severe patients showed increased mean levels of IL-4, IL-6, IL-7, IL-8, and TNF-α (p < 0.001) during the first wave, and IL-2, IL-6, IL-8, IP-10, TNF-α, MCP-1, and GM-CSF (p < 0.001) during the second wave, compared to the mild group. They also exhibited decreased IFN-α2 (p < 0.01) and IFN-γ (p < 0.05) in both waves, and IL-7 (p < 0.01) in the second wave, when compared to the moderate group. When comparing epidemiological waves, mean GM-CSF levels were higher during the first wave (p < 0.01), while IL-4, IL-12p70, and IL-17A (p < 0.01) were increased in patients sampled during the second wave. Mean IL-6, IL-8, IP-10, and MCP-1 levels increased according to disease severity in both waves (Table I). When considering clinical outcome, significant higher mean levels of IL-6, IL-8, IL-10, IP-10, MCP-1, and TNF-α (p < 0.01) and IL-7 (p < 0.02) correlated with mortality, regardless of the clinical classification at hospital admission (Table II). Stratification of clinical classification by clinical outcome revealed IL-6 increased levels correlated with mortality across all three clinical groups (p < 0.01, p < 0.01, and p < 0.02, respectively). In the mild group, higher IL-10, IP-10 (p < 0.03) and TNF-α (p < 0.01) levels also correlated with mortality. Fatal cases from the moderate group showed increased levels of IL-8 (p < 0.01), IP-10 (p < 0.04), MCP-1 (p < 0.02), and TNF-α (p < 0.04) compared to recovered patients. In the severe group, IL-8 (p < 0.02) and MCP-1 (p < 0.04) increased levels correlated with mortality (Table III). When these data were compared between clinical groups only considering patients with the same clinical outcome, significantly increased IFN-γ (p < 0.01 and p < 0.05), IL-4 (p < 0.05), IL-6 (p < 0.001), IL-7 (p < 0.01 and p < 0.05), IL-8 (p < 0.001), IL-10 (p < 0.001 and p < 0.01) mean levels significantly increased from mild to severe, moderate to severe group of patients, and IP-10 (p < 0.05), in the mild vs. severe group comparison, in the mortality group. Among patients who recovered, stratified by clinical classification, only IL-4 showed a significant increase (p < 0.05) in mild and in moderate groups compared to severe cases (Table IV). Presence of risk factors correlated with decreased IL-8 levels (p < 0.05). GM-CSF levels (p < 0.001) were significantly lower in patients with immunologic comorbidities. IL-6 (p < 0.005), IL-8 (p < 0.02), MCP-1 (p < 0.001), IP-10 (p < 0.003), and TNF-α (p < 0.03) levels were increased in patients with metabolic comorbidities. IL-8 was increased in patients with respiratory (p < 0.05) and cardiac (p < 0.04) comorbidities. IL-10 levels were decreased (p < 0.05) in patients with immunologic comorbidities and increased in those with metabolic (p < 0.001) and respiratory (p < 0.05) comorbidities (Table V). Hematological parameters of COVID-19 patients Hematological parameters of mild, moderate, and severe gruops stratified by clinical outcome (Table VI), revealed mild fatal cases had significantly decreased erythrocyte count (p < 0.03), hemoglobin (p < 0.01), hematocrit (p < 0.01), and lymphocyte count (p < 0.01), along with increased RDW (p < 0.03), leukocyte count (p < 0.02), neutrophil/segmented cell counts (p < 0.01) at admission, compared to recovered mild cases. In the moderate group, patients with a fatal outcome showed increased leukocyte (p < 0.02), neutrophil and segmented cell counts (p < 0.01), and decreased lymphocyte counts (p < 0.01), compared to recovered patients. Severe fatal cases showed a significant decreased platelet count (p < 0.01) compared to the few severe recovered patients. C-reactive protein levels were significantly higher in fatal cases across all three clinical groups (p < 0.01 - p < 0.02). Significant negative Pearson correlations were observed between erythrocyte count and hemoglobin levels with TNF-α levels (r = − 0.23, p < 0.05; r = − 0.25, p < 0.05), IL-6 (r = − 0.20, p < 0.05; r = − 0.18, p < 0.05), and IFN-α2 levels (r = − 0.21, p < 0.05; r = − 0.20, p < 0.05); between hematocrit and TNF-α (r = − 0.20, p < 0.05); and between lymphocyte count and MCP-1 (r = − 0.31, p < 0.01) (Fig. 1 ). Positive correlations were found between mean corpuscular volume and IL-6 (r = 0.24, p < 0.05) and MCP-1 (r = 0.25, p < 0.01); between leukocyte and neutrophil count and IL-8 (r = 0.31, p < 0.001; r = 0.22, p < 0.01), MCP-1 (r = 0.36, p < 0.001; r = 0.28, p < 0.01), and TNF-α (r = 0.20, p < 0.05; r = 0.16, p < 0.05); between C-reactive protein (CRP) levels with IL-6 (r = 0.25, p < 0.01), IL-8 (r = 0.30, p < 0.001), MCP-1 (r = 0.36, p < 0.001), and TNF-α (r = 0.23, p < 0.01) and between platelet count with IL-17A (r = 0.20, p < 0.05) and TNF-α (r = 0.19, p 0.5) were observed between MCP-1 with IP-10 and IL-6 (p < 0.001); TNF-α with IL-10 (p < 0.001); between IL-17A and IL-12p70, IFN-γ, IFN-α2 (p < 0.001); IL-12p70 and IFN-γ (p < 0.001) (Fig. 2 ). Discussion Previously, we observed a significant correlation between COVID-19 severity and mortality, particularly in patients with advanced age, extensive ground-glass opacities on imaging, and underlying comorbidities, with higher viral load and reductions in mean erythrocyte count, hemoglobin, hematocrit, and lymphocytes (consistent with anemia and lymphopenia), elevated C-reactive protein and increased neutrophil and leukocyte counts, suggestive of an inflammatory profile characterized by neutrophilic leukocytosis. Unfavorable clinical outcomes associated with elevated Neutrophil-to-Platelet, Neutrophil-to-Lymphocyte, and Monocyte-to-Lymphocyte ratios [ 19 ]. These findings motivated the present investigation, to determine the cytokine profile in a cohort of unvaccinated, hospitalized COVID-19 patients, stratified at admission into mild, moderate, or severe clinical groups, and correlate the findings with hematological changes and clinical outcome. Our data corroborates elevated mean levels of IL-6, IL-8, TNF-α, IP-10, and MCP-1 associated with worse clinical outcomes and mortality [ 20 – 22 ]. TNF-α and IL-6 have been widely implicated in cytokine storm, characteristic of severe COVID-19 [ 23 ]. MCP-1 and IP-10 play central roles in promoting the recruitment and infiltration of inflammatory cells into damaged tissues, thereby contributing to inflammation and disease progression. IP-10 is released in response to antiviral IFN-γ and acts as a chemoattractant for T cells, NK cells, monocytes/macrophages, and dendritic cells. Additionally, it inhibits bone marrow colony formation and angiogenesis, contributing to impaired endothelial repair. MCP-1 primarily recruits monocytes and basophils to tissue injury sites [ 24 ]. IL-8 is a potent chemoattractant cytokine for neutrophil and monocyte recruitment to the lungs and, has consistently been associated with poor COVID-19 prognosis. In our study, IL-8 levels were also elevated in patients with metabolic, cardiovascular, and respiratory comorbidities - conditions known to predispose individuals to severe COVID-19 and mortality [ 25 ]. Second epidemiological wave was represented by increased levels of cytokines as IL-4, IL-12p70, IL-17 and INF-α2, indicating this wave was essentially marked by increased inflammatory disturbs. There are evidences of robust IFN-I response in severe COVID-19 patients, which contrast with the late suppressed response observed mainly in the beginning of infection, contributing for the exacerbation of TNF-α and IL-1 induced inflammation and for severe COVID-19 progression [ 26 ]. In our study, IFN-γ, IL-4, IL-6, IL-7, IL-8, IL-10, and IP-10 showed a substantial increase in the severe group compared to the mild and moderate groups. IL-6, one of the main biomarkers of COVID-19 severity, promotes the differentiation of T-helper (Th) 17 cells, which secrete both anti-inflammatory cytokines such as IL-10 and pro-inflammatory cytokines such as IP-10. This profile indicates immunological dysregulation, consistent with COVID-19 pathogenesis [ 27 ]. Huang et al. (2020) reported that patients infected with SARS-CoV-2 exhibit a significant increase in serum levels of pro-inflammatory cytokines, especially IL-1β, IFN-γ, IP-10, and MCP-1, which may trigger the activation of Th1 cell responses. Moreover, patients requiring ICU admission showed higher concentrations of G-CSF, IP-10, MCP-1, MIP-1α, and TNF-α compared to those not admitted to the ICU, corroborating that cytokine storm is associated with disease severity [ 3 ]. Interestingly, only patients in the severe group who were discharged showed a significant increase in IL-4 levels compared to the mild and moderate groups. In the context of inflammation, interleukin 4 (IL-4) plays a key role in B cell differentiation and survival, as well as in the polarization of M2 macrophages, which exhibit anti-inflammatory activity. IL-4 also inhibits the differentiation of Th1 lymphocytes and the production of pro-inflammatory cytokines such as IFN-γ [ 28 ]. Moreover, IL-4 has been shown to reduce the expression of angiotensin-converting enzyme 2 (ACE2), the cellular receptor used by SARS-CoV-2 for entry, suggesting that IL-4 may contribute to decreased viral virulence and attenuated disease progression in COVID-19 [ 29 ]. Previously, IL-4 was demonstrated to be increased in the pulmonary tissue of fatal COVID-19 cases [ 30 ]. Severe COVID-19 can typically be linked to risk factors as advanced age combined with diabetes and cardiovascular diseases. Our patients with metabolic diseases had a significant increase in IL-6, IL-8 and IP-10 levels, while those with respiratory comorbidities had increased IL-8 and IL-10, and with cardiovascular comorbidities only IL-8. Acute hyperinflammatory response in COVID-19 primarily affects the respiratory tract, evolving to a multisystemic immune dysregulation exacerbating disease progression specially in those patients with impaired innate and adaptative responses related to chronic comorbidities as diabetes and hypertension [ 31 ]. Circulating levels of IFN-α play a crucial role in the early innate immune response against SARS-CoV-2 and have been associated with milder forms of COVID-19 and favorable outcomes, consistent with our findings [ 32 ]. Patients classified as having moderate disease exhibited significantly higher mean levels of IFN-α2 compared to severe group. Additionally, moderate patients had significantly lower levels of IFN-γ when compared to mild cases. Although not statistically significant, a similar trend of reduced IFN-γ was observed in severe patients. IFN-γ is essential for promoting the Th1 immune response and for the proper activation of CD8⁺ cytotoxic T cells, both critical for effective antiviral defense and viral clearance [ 10 , 11 ]. In this study, IL-2 and IL-7 levels were increased in mild COVID-19 patients compared to moderate and severe groups. IL-2 plays a critical role in the proliferation and maturation of T and B lymphocytes. Consistent with our results, the inhibition of IL-2/IL-2 receptor pathway has been shown to downregulate CD8 + T cell activation via the JAK1-STAT5 signaling pathway in critically ill COVID-19 patients [ 30 ]. IL-7, a hematopoietic growth factor involved in lymphocyte development within primary immune organs, has also been associated with milder disease forms and recovery in COVID-19, as seen in our findings [ 31 ]. Mortality associated with decreased erythrocyte counts, hemoglobin, hematocrit, RDW, and lymphocyte counts, alongside increased leukocyte, neutrophil, and C-reactive protein (CRP) levels in this cohort [ 19 ]. Mild patients who experienced fatal outcomes exhibited these hematological alterations at admission (Table 3). Although these differences were not statistically significant between fatal and recovered severe cases (Table 5), mean values tended to be more pronounced in the severe group compared to moderate and mild patients, likely reflecting their more compromised condition upon admission to the referral center. Hyperinflammation, lymphopenia, neutrophilic leukocytosis, coagulopathy, and vasculopathy have been consistently reported in the literature as biomarkers of poor prognosis in COVID-19 [ 6 , 32 , 19 ]. The observed correlations between decreased erythrocyte and hemoglobin counts and increased TNF-α, IL-6, and IFN-α2, decreased hematocrit and increased TNF-α, lymphopenia and elevated MCP-1, neutrophilic leukocytosis and increased IL-8, MCP-1, and TNF-α, and raised CRP levels alongside IL-6, IL-8, MCP-1, and TNF-α, are consistent with hyperinflammation and impaired antiviral immune response in severe and fatal COVID-19 cases. SARS-CoV-2 replication in hematopoietic precursor cells such as megakaryocytes and lymphocytes contributes to lymphopenia and anemia [ 33 ]. Additionally, the cytokine storm has been shown to induce lymphocyte apoptosis and lymphoreticular dysfunction, thereby impairing lymphocyte turnover [ 34 ]. IL-6 facilitates neutrophil mobilization from the bone marrow, promoting neutrophilic leukocytosis during hyperinflammation in severe COVID-19, while TNF-α suppresses hematopoiesis [ 35 , 19 ]. Increased platelet count associated with increased IL-17A and TNF-α. Severe COVID-19 coagulopathies and procoagulant endothelial phenotype have been well documented in literature [ 36 ]. IL-17A recruits immune cells to inflamed tissues and is synergic with other cytokines such as TNF-α and GM-CSF. IL-17A induces the release of IL-1, IL-6, TNF-α and contributes to cytokine storm in COVID-19 [ 37 ]. In summary, our study highlights the intricate relationship between cytokine dysregulation, hematological alterations, and COVID-19 severity. Elevated levels of pro-inflammatory cytokines such as IL-6, IL-8, TNF-α, IP-10, and MCP-1 were strongly associated with severe disease and fatal outcomes, alongside characteristic hematological markers including lymphopenia, anemia, and neutrophilic leukocytosis. Conversely, cytokines like IL-4, IL-7, and IFN-α appeared to play protective roles, particularly in milder cases and recovery. These findings reinforce the critical role of immune response balance in COVID-19 progression and suggest potential biomarkers for prognosis and therapeutic targeting. Future studies should focus on longitudinal monitoring of cytokine profiles and hematological parameters to better understand the dynamics of immune responses, and on investigating targeted immunomodulatory interventions to improve clinical outcomes in COVID-19 patients. Conclusion This study highlights distinct cytokine profiles and hematological alterations associated with COVID-19 severity in hospitalized patients from Central-South Mato Grosso, Brazil. Elevated pro-inflammatory cytokines correlated with worse clinical outcomes and hematological dysregulation, including anemia, lymphopenia, and neutrophilic leukocytosis. A protective role for IL-4, IL-7 and IFN-α also has been identified. These findings reinforce the role of immune dysregulation and hyperinflammation in COVID-19 pathogenesis and emphasize the potential of cytokine and hematological markers as prognostic indicators to guide clinical care and therapeutic interventions. Declarations The authors have declared that no competing interest exist. Acknowledgments To Eduarda Pavan for her help with Cytokine raw data interpretation. TCDC received a CAPES Doctoral schoolarship (The Brazilian Government CAPES code 001). VD, LN and RDS receive a PQ grant from CNPq (309750/2020-2). This study received a Research grant from PROPEQ/UFMT (2021). Author credit statement TCDC: methodology, patient recruitment, data analysis and interpretation, manuscript preparation. GFCL, VD, LN, FKSA: patient recruitment, sample collection, sample testing, laboratorial data collection, manuscript revision. MPL, ECS: data analysis, statistics, manuscript edition. 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Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369(6504):718–24. 10.1126/science.abc6027 . Shi H, Wang W, Yin J, Ouyang Y, Pang L, Feng Y, Qiao L, Guo X, Shi H, Jin R, Chen D. The inhibition of IL-2/IL-2R gives rise to CD8 + T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia. Cell Death Dis. 2020;11(6):429. 10.1038/s41419-020-2636-4 . Hasanvand A. COVID-19 and the role of cytokines in this disease. Inflammopharmacol. 2022;30(3):789–98. 10.1007/s10787-022-00992-2 . Woll GD, Muller JL. The Impact of COVID-19 Disease on Platelets and Coagulation. Pathofisiol. 2020;88(1):15–27. https://doi.org/10.1159/000512007 . Maione F, Casilo GM, Raucci F, Salvatore C, Ambrosini G, Costa L, Scarpa R, Caso F, Bucci M. Interleukin-17A (IL-17A): A silent amplifier of COVID-19. Biomed Pharmacother. 2021;142:111980. https://doi.org/10.1016/j.biopha.2021.111980 . 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1","display":"","copyAsset":false,"role":"figure","size":1423339,"visible":true,"origin":"","legend":"\u003cp\u003ePearson Correlation Matrix of serum cytokine levels and hematological parameters of COVID-19 patients. MCV: Mean Corpuscular Volume; MCHC: Mean Corpuscular Hemoglobin Concentration; RDW: Red Cell Distribution Width. Statistical significance: *p\u0026lt;0.05; **p\u0026lt;0.01; ***p\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8322000/v1/0ac86f6d1d01db223984d120.png"},{"id":98435790,"identity":"92f7fce1-b373-4005-ac72-f62d71db29bc","added_by":"auto","created_at":"2025-12-17 16:54:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":383580,"visible":true,"origin":"","legend":"\u003cp\u003ePearson Correlation Matrix of serum cytokine levels of COVID-19 patients. *p\u0026lt;0.05; **p\u0026lt;0.01; ***p\u0026lt;0.001. IL-2 remained with 0.0 values in the axys X, while IL-8 had 0.0 values in the Y axys (data not shown).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8322000/v1/d78fafed1b6d9103d11977ae.png"},{"id":99313965,"identity":"826dad57-891b-4039-be03-2ff86a0952c1","added_by":"auto","created_at":"2025-12-31 16:20:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2431441,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8322000/v1/e0e64d98-630d-4087-8c93-d5937e62b371.pdf"},{"id":98294022,"identity":"33cbfa03-071f-4d6a-b97d-fa3c38b867de","added_by":"auto","created_at":"2025-12-16 09:04:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":57089,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8322000/v1/71ef7a4bdb0931a1f7ae4f36.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eCytokine Signatures and Hematological Alterations as Predictors of Covid-19 Severity and Mortality in a Brazilian Cohort From Central-south Mato Grosso\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), a \u003cem\u003eSarbecovirus\u003c/em\u003e from genus \u003cem\u003eBetacoronavirus\u003c/em\u003e, family \u003cem\u003eCoronaviridae\u003c/em\u003e, emerged as a novel agent of viral pneumonia in Wuhan, China [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In February 2020, COVID-19 (Coronavirus Disease 2019) was declared a public health emergency of international concern by the World Health Organization [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Unlike the other coronaviruses causing acute severe respiratory distress syndrome (ARDS), SARS-CoV-1 and MERS-CoV, SARS-CoV-2 demonstrated a high transmissibility pattern that begins during the incubation period. This feature facilitated rapid global spread, resulting in high morbidity and mortality rates [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinically, the disease can be classified as pre-symptomatic and mild, accounting for 80 to 85% of infections; as moderate disease, characterized by oxygen saturation below 95% during mild exertion, representing approximately 15% of cases. The severe critical phase, affecting less than 5% of patients, is marked by oxygen saturation below 90%, pneumonia, severe respiratory distress, and inability to complete sentences. This critical phase, defined by the criteria for ARDS, is often accompanied by hyperinflammation, sepsis and septic shock, which can progress to multiple organ failure [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBone marrow hematopoietic precursor cell depletion, T-cell lymphopenia, CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T cells functional impairment have been correlated with disease severity. Conversely, the development of high levels of specific CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T cells in nearly 50% of patients during the acute phase and in over 80% during convalescence associated with a well-coordinated antiviral immune response leading to recovery [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Th1 phenotype of CD4\u0026thinsp;+\u0026thinsp;T cells has been linked to mild disease and recovery, whereas Th17 phenotype has been implicated in Th2 activation, suppression of Treg and Th1 responses, and COVID-19 progression [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePersistency of SARS-CoV-2 replication led to inflammatory cells recruitment and endothelial activation, tissue injury, and dysregulated release of pro-inflammatory cytokines. These cytokines mediate biological signals to target cells through interactions with specific high-affinity receptors, playing a pivotal role in immunoregulation and leukocyte chemotaxis to inflamed tissues [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Elevated levels of pro-inflammatory cytokines can exacerbate disease progression by promoting hyperinflammation, pulmonary capillary vasodilation, and other dysfunctions that contribute to ARDS and multi-organ failure [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have shown that altered serum levels of interleukins (IL) as IL-1β, IL-2, IL-6, IL-10, type II interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), IFN-γ inducible protein 10 (IP-10), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1) correlate with diffuse alveolar damage and ARDS severity in COVID-19 [\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The complex interplay between these cytokines and hematological changes, as well as their impact on clinical outcomes, remains incompletely understood. The elucidation of these relationships is crucial for identifying prognostic biomarkers and potential therapeutic targets. This study aimed to characterize the profile of cytokines and their interplay with hematological parameters and underlying clinical characteristics that define the disease course of hospitalized COVID-19 patients.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSampling and ethical aspects\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn total, 137 unvaccinated patients over 18 years of age with laboratory-confirmed SARS-CoV-2 infection (positive RT-qPCR in nasopharyngeal swabs), admitted to a COVID-19 referral unit in V\u0026aacute;rzea Grande, Mato Grosso, between March 2020 and May 2021, had their clinical history, laboratory data, and biological samples collected upon admission. This study was previously approved by the Institutional Ethics Committee (CEP-HUJM; CAAE 32361020.0.0000.5541) and has been conducted in accordance with National Health Council Resolution 466/2012. Epidemiological, clinical, virological, and laboratory data from these patients have been previously described [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHuman cytokine dosage in the serum of COVID-19 patients\u003c/h3\u003e\n\u003cp\u003eSerum samples were subjected to simultaneous quantification, in duplicate, of IL-6, IL-2, IL-4, IL-10, IL-12p70, IL-7, IL-8, IL-17A, GM-CSF, IFN-α, IFN-γ, IP-10, MCP-1, and TNF-α. After homogenization, samples were centrifuged at room temperature (14,000 \u0026times; g for 5 minutes), diluted 1:10 in assay buffer, and analyzed using the Milliplex Millipore HCYTA-60K-14 kit (Merck Millipore, Massachusetts, USA) on a Luminex MAGPIX Multiplexing System (XMAP Technology, Texas, USA), according to the manufacturer\u0026rsquo;s instructions. Biomarker concentrations were determined by generating standard curves in Luminex xPONENT v. 3.1 (Merck Millipore, Massachusetts, USA) and expressed in pg/mL.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSerum cytokine levels were analyzed as counts and percentages or as median and interquartile ranges (IQR) using GraphPad Prism v. 5.0. Differences among the clinical groups and epidemiological waves were assessed by one-way analysis of variance (ANOVA), followed by Newman-Keuls post hoc test, and by Kruskal-Wallis multiple comparisons. Cytokine levels and mortality were compared with t-test followed by the Mann-Whitney test. The association between cytokine levels and hematological parameters was evaluated using Pearson\u0026rsquo;s correlation coefficient.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eClinical classification at hospital admission was used to stratify patients into mild (n\u0026thinsp;=\u0026thinsp;36; 26.28%), moderate (n\u0026thinsp;=\u0026thinsp;36; 26.28%), and severe (n\u0026thinsp;=\u0026thinsp;65; 47.45%) groups. Clinical follow up revealed 88/137 (64.23%) patients, 11/36 (30.55%) from the mild group, 18/36 (50.00%) from moderate, and 59/65 (90.77%) in the severe group represent fatal cases.\u003c/p\u003e\n\u003ch3\u003eCytokine levels in the serum of COVID-19 patients\u003c/h3\u003e\n\u003cp\u003eMean cytokine levels stratified by epidemiological wave in these clinical groups (Table I), showed significant decreases in IL-6, IP-10, and MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) levels in the mild group, compared to the moderate group during the first epidemiological wave. Moderate clinical group exhibited decreased levels of IFN-γ, IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and IL-2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) during the first wave, and IFN-γ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-10, IL-12p70, and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the second wave, compared to the mild group. Severe patients showed increased mean levels of IL-4, IL-6, IL-7, IL-8, and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) during the first wave, and IL-2, IL-6, IL-8, IP-10, TNF-α, MCP-1, and GM-CSF (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) during the second wave, compared to the mild group. They also exhibited decreased IFN-α2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and IFN-γ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in both waves, and IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in the second wave, when compared to the moderate group.\u003c/p\u003e \u003cp\u003eWhen comparing epidemiological waves, mean GM-CSF levels were higher during the first wave (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), while IL-4, IL-12p70, and IL-17A (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were increased in patients sampled during the second wave. Mean IL-6, IL-8, IP-10, and MCP-1 levels increased according to disease severity in both waves (Table I).\u003c/p\u003e \u003cp\u003eWhen considering clinical outcome, significant higher mean levels of IL-6, IL-8, IL-10, IP-10, MCP-1, and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02) correlated with mortality, regardless of the clinical classification at hospital admission (Table II). Stratification of clinical classification by clinical outcome revealed IL-6 increased levels correlated with mortality across all three clinical groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, and p\u0026thinsp;\u0026lt;\u0026thinsp;0.02, respectively). In the mild group, higher IL-10, IP-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.03) and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) levels also correlated with mortality. Fatal cases from the moderate group showed increased levels of IL-8 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), IP-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.04), MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02), and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.04) compared to recovered patients. In the severe group, IL-8 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02) and MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.04) increased levels correlated with mortality (Table III).\u003c/p\u003e \u003cp\u003eWhen these data were compared between clinical groups only considering patients with the same clinical outcome, significantly increased IFN-γ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-4 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-8 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IL-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) mean levels significantly increased from mild to severe, moderate to severe group of patients, and IP-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), in the mild vs. severe group comparison, in the mortality group. Among patients who recovered, stratified by clinical classification, only IL-4 showed a significant increase (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in mild and in moderate groups compared to severe cases (Table IV).\u003c/p\u003e \u003cp\u003ePresence of risk factors correlated with decreased IL-8 levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). GM-CSF levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were significantly lower in patients with immunologic comorbidities. IL-6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.005), IL-8 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02), MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IP-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.003), and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.03) levels were increased in patients with metabolic comorbidities. IL-8 was increased in patients with respiratory (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and cardiac (p\u0026thinsp;\u0026lt;\u0026thinsp;0.04) comorbidities. IL-10 levels were decreased (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in patients with immunologic comorbidities and increased in those with metabolic (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and respiratory (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) comorbidities (Table V).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHematological parameters of COVID-19 patients\u003c/h2\u003e \u003cp\u003eHematological parameters of mild, moderate, and severe gruops stratified by clinical outcome (Table VI), revealed mild fatal cases had significantly decreased erythrocyte count (p\u0026thinsp;\u0026lt;\u0026thinsp;0.03), hemoglobin (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), hematocrit (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and lymphocyte count (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), along with increased RDW (p\u0026thinsp;\u0026lt;\u0026thinsp;0.03), leukocyte count (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02), neutrophil/segmented cell counts (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) at admission, compared to recovered mild cases. In the moderate group, patients with a fatal outcome showed increased leukocyte (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02), neutrophil and segmented cell counts (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and decreased lymphocyte counts (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), compared to recovered patients. Severe fatal cases showed a significant decreased platelet count (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the few severe recovered patients. C-reactive protein levels were significantly higher in fatal cases across all three clinical groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 - p\u0026thinsp;\u0026lt;\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003eSignificant negative Pearson correlations were observed between erythrocyte count and hemoglobin levels with TNF-α levels (r = \u0026minus;\u0026thinsp;0.23, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; r = \u0026minus;\u0026thinsp;0.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-6 (r = \u0026minus;\u0026thinsp;0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; r = \u0026minus;\u0026thinsp;0.18, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and IFN-α2 levels (r = \u0026minus;\u0026thinsp;0.21, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; r = \u0026minus;\u0026thinsp;0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); between hematocrit and TNF-α (r = \u0026minus;\u0026thinsp;0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); and between lymphocyte count and MCP-1 (r = \u0026minus;\u0026thinsp;0.31, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePositive correlations were found between mean corpuscular volume and IL-6 (r\u0026thinsp;=\u0026thinsp;0.24, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and MCP-1 (r\u0026thinsp;=\u0026thinsp;0.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01); between leukocyte and neutrophil count and IL-8 (r\u0026thinsp;=\u0026thinsp;0.31, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; r\u0026thinsp;=\u0026thinsp;0.22, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), MCP-1 (r\u0026thinsp;=\u0026thinsp;0.36, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; r\u0026thinsp;=\u0026thinsp;0.28, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and TNF-α (r\u0026thinsp;=\u0026thinsp;0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; r\u0026thinsp;=\u0026thinsp;0.16, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); between C-reactive protein (CRP) levels with IL-6 (r\u0026thinsp;=\u0026thinsp;0.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), IL-8 (r\u0026thinsp;=\u0026thinsp;0.30, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), MCP-1 (r\u0026thinsp;=\u0026thinsp;0.36, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and TNF-α (r\u0026thinsp;=\u0026thinsp;0.23, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and between platelet count with IL-17A (r\u0026thinsp;=\u0026thinsp;0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and TNF-α (r\u0026thinsp;=\u0026thinsp;0.19, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003ePearson correlation between cytokine levels revealed exclusively positive correlations. Strong correlations (\u0026gt;\u0026thinsp;0.5) were observed between MCP-1 with IP-10 and IL-6 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); TNF-α with IL-10 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); between IL-17A and IL-12p70, IFN-γ, IFN-α2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); IL-12p70 and IFN-γ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePreviously, we observed a significant correlation between COVID-19 severity and mortality, particularly in patients with advanced age, extensive ground-glass opacities on imaging, and underlying comorbidities, with higher viral load and reductions in mean erythrocyte count, hemoglobin, hematocrit, and lymphocytes (consistent with anemia and lymphopenia), elevated C-reactive protein and increased neutrophil and leukocyte counts, suggestive of an inflammatory profile characterized by neutrophilic leukocytosis. Unfavorable clinical outcomes associated with elevated Neutrophil-to-Platelet, Neutrophil-to-Lymphocyte, and Monocyte-to-Lymphocyte ratios [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These findings motivated the present investigation, to determine the cytokine profile in a cohort of unvaccinated, hospitalized COVID-19 patients, stratified at admission into mild, moderate, or severe clinical groups, and correlate the findings with hematological changes and clinical outcome.\u003c/p\u003e \u003cp\u003eOur data corroborates elevated mean levels of IL-6, IL-8, TNF-α, IP-10, and MCP-1 associated with worse clinical outcomes and mortality [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. TNF-α and IL-6 have been widely implicated in cytokine storm, characteristic of severe COVID-19 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. MCP-1 and IP-10 play central roles in promoting the recruitment and infiltration of inflammatory cells into damaged tissues, thereby contributing to inflammation and disease progression. IP-10 is released in response to antiviral IFN-γ and acts as a chemoattractant for T cells, NK cells, monocytes/macrophages, and dendritic cells. Additionally, it inhibits bone marrow colony formation and angiogenesis, contributing to impaired endothelial repair. MCP-1 primarily recruits monocytes and basophils to tissue injury sites [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. IL-8 is a potent chemoattractant cytokine for neutrophil and monocyte recruitment to the lungs and, has consistently been associated with poor COVID-19 prognosis. In our study, IL-8 levels were also elevated in patients with metabolic, cardiovascular, and respiratory comorbidities - conditions known to predispose individuals to severe COVID-19 and mortality [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSecond epidemiological wave was represented by increased levels of cytokines as IL-4, IL-12p70, IL-17 and INF-α2, indicating this wave was essentially marked by increased inflammatory disturbs. There are evidences of robust IFN-I response in severe COVID-19 patients, which contrast with the late suppressed response observed mainly in the beginning of infection, contributing for the exacerbation of TNF-α and IL-1 induced inflammation and for severe COVID-19 progression [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, IFN-γ, IL-4, IL-6, IL-7, IL-8, IL-10, and IP-10 showed a substantial increase in the severe group compared to the mild and moderate groups. IL-6, one of the main biomarkers of COVID-19 severity, promotes the differentiation of T-helper (Th) 17 cells, which secrete both anti-inflammatory cytokines such as IL-10 and pro-inflammatory cytokines such as IP-10. This profile indicates immunological dysregulation, consistent with COVID-19 pathogenesis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Huang et al. (2020) reported that patients infected with SARS-CoV-2 exhibit a significant increase in serum levels of pro-inflammatory cytokines, especially IL-1β, IFN-γ, IP-10, and MCP-1, which may trigger the activation of Th1 cell responses. Moreover, patients requiring ICU admission showed higher concentrations of G-CSF, IP-10, MCP-1, MIP-1α, and TNF-α compared to those not admitted to the ICU, corroborating that cytokine storm is associated with disease severity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterestingly, only patients in the severe group who were discharged showed a significant increase in IL-4 levels compared to the mild and moderate groups. In the context of inflammation, interleukin 4 (IL-4) plays a key role in B cell differentiation and survival, as well as in the polarization of M2 macrophages, which exhibit anti-inflammatory activity. IL-4 also inhibits the differentiation of Th1 lymphocytes and the production of pro-inflammatory cytokines such as IFN-γ [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Moreover, IL-4 has been shown to reduce the expression of angiotensin-converting enzyme 2 (ACE2), the cellular receptor used by SARS-CoV-2 for entry, suggesting that IL-4 may contribute to decreased viral virulence and attenuated disease progression in COVID-19 [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Previously, IL-4 was demonstrated to be increased in the pulmonary tissue of fatal COVID-19 cases [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSevere COVID-19 can typically be linked to risk factors as advanced age combined with diabetes and cardiovascular diseases. Our patients with metabolic diseases had a significant increase in IL-6, IL-8 and IP-10 levels, while those with respiratory comorbidities had increased IL-8 and IL-10, and with cardiovascular comorbidities only IL-8. Acute hyperinflammatory response in COVID-19 primarily affects the respiratory tract, evolving to a multisystemic immune dysregulation exacerbating disease progression specially in those patients with impaired innate and adaptative responses related to chronic comorbidities as diabetes and hypertension [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCirculating levels of IFN-α play a crucial role in the early innate immune response against SARS-CoV-2 and have been associated with milder forms of COVID-19 and favorable outcomes, consistent with our findings [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Patients classified as having moderate disease exhibited significantly higher mean levels of IFN-α2 compared to severe group. Additionally, moderate patients had significantly lower levels of IFN-γ when compared to mild cases. Although not statistically significant, a similar trend of reduced IFN-γ was observed in severe patients. IFN-γ is essential for promoting the Th1 immune response and for the proper activation of CD8⁺ cytotoxic T cells, both critical for effective antiviral defense and viral clearance [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, IL-2 and IL-7 levels were increased in mild COVID-19 patients compared to moderate and severe groups. IL-2 plays a critical role in the proliferation and maturation of T and B lymphocytes. Consistent with our results, the inhibition of IL-2/IL-2 receptor pathway has been shown to downregulate CD8\u003csup\u003e+\u003c/sup\u003e T cell activation via the JAK1-STAT5 signaling pathway in critically ill COVID-19 patients [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. IL-7, a hematopoietic growth factor involved in lymphocyte development within primary immune organs, has also been associated with milder disease forms and recovery in COVID-19, as seen in our findings [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMortality associated with decreased erythrocyte counts, hemoglobin, hematocrit, RDW, and lymphocyte counts, alongside increased leukocyte, neutrophil, and C-reactive protein (CRP) levels in this cohort [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Mild patients who experienced fatal outcomes exhibited these hematological alterations at admission (Table\u0026nbsp;3). Although these differences were not statistically significant between fatal and recovered severe cases (Table\u0026nbsp;5), mean values tended to be more pronounced in the severe group compared to moderate and mild patients, likely reflecting their more compromised condition upon admission to the referral center. Hyperinflammation, lymphopenia, neutrophilic leukocytosis, coagulopathy, and vasculopathy have been consistently reported in the literature as biomarkers of poor prognosis in COVID-19 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe observed correlations between decreased erythrocyte and hemoglobin counts and increased TNF-α, IL-6, and IFN-α2, decreased hematocrit and increased TNF-α, lymphopenia and elevated MCP-1, neutrophilic leukocytosis and increased IL-8, MCP-1, and TNF-α, and raised CRP levels alongside IL-6, IL-8, MCP-1, and TNF-α, are consistent with hyperinflammation and impaired antiviral immune response in severe and fatal COVID-19 cases. SARS-CoV-2 replication in hematopoietic precursor cells such as megakaryocytes and lymphocytes contributes to lymphopenia and anemia [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, the cytokine storm has been shown to induce lymphocyte apoptosis and lymphoreticular dysfunction, thereby impairing lymphocyte turnover [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. IL-6 facilitates neutrophil mobilization from the bone marrow, promoting neutrophilic leukocytosis during hyperinflammation in severe COVID-19, while TNF-α suppresses hematopoiesis [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Increased platelet count associated with increased IL-17A and TNF-α. Severe COVID-19 coagulopathies and procoagulant endothelial phenotype have been well documented in literature [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. IL-17A recruits immune cells to inflamed tissues and is synergic with other cytokines such as TNF-α and GM-CSF. IL-17A induces the release of IL-1, IL-6, TNF-α and contributes to cytokine storm in COVID-19 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn summary, our study highlights the intricate relationship between cytokine dysregulation, hematological alterations, and COVID-19 severity. Elevated levels of pro-inflammatory cytokines such as IL-6, IL-8, TNF-α, IP-10, and MCP-1 were strongly associated with severe disease and fatal outcomes, alongside characteristic hematological markers including lymphopenia, anemia, and neutrophilic leukocytosis. Conversely, cytokines like IL-4, IL-7, and IFN-α appeared to play protective roles, particularly in milder cases and recovery. These findings reinforce the critical role of immune response balance in COVID-19 progression and suggest potential biomarkers for prognosis and therapeutic targeting. Future studies should focus on longitudinal monitoring of cytokine profiles and hematological parameters to better understand the dynamics of immune responses, and on investigating targeted immunomodulatory interventions to improve clinical outcomes in COVID-19 patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study highlights distinct cytokine profiles and hematological alterations associated with COVID-19 severity in hospitalized patients from Central-South Mato Grosso, Brazil. Elevated pro-inflammatory cytokines correlated with worse clinical outcomes and hematological dysregulation, including anemia, lymphopenia, and neutrophilic leukocytosis. A protective role for IL-4, IL-7 and IFN-α also has been identified. These findings reinforce the role of immune dysregulation and hyperinflammation in COVID-19 pathogenesis and emphasize the potential of cytokine and hematological markers as prognostic indicators to guide clinical care and therapeutic interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eThe authors have declared that no competing interest exist.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo Eduarda Pavan\u003csup\u003e\u0026nbsp;\u003c/sup\u003efor her help with Cytokine raw data interpretation. TCDC received a CAPES Doctoral schoolarship (The Brazilian Government CAPES code 001). VD, LN and RDS receive a PQ grant from CNPq (309750/2020-2). This study received a Research grant from PROPEQ/UFMT (2021).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor credit statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTCDC: methodology, patient recruitment, data analysis and interpretation, manuscript preparation.\u003c/p\u003e\n\u003cp\u003eGFCL, VD, LN, FKSA: patient recruitment, sample collection, sample testing, laboratorial data collection, manuscript revision.\u003c/p\u003e\n\u003cp\u003eMPL, ECS: data analysis, statistics, manuscript edition.\u003c/p\u003e\n\u003cp\u003eRDS: project coordinator, methodology, ethical approvals, data analysis, manuscript revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWHO \u0026ndash; World Health Organization. (2020). 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Biomed Pharmacother. 2021;142:111980. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.biopha.2021.111980\u003c/span\u003e\u003cspan address=\"10.1016/j.biopha.2021.111980\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, Pro-inflammatory cytokines, Hematological parameters, Prognostic biomarkers, ARDS (acute respiratory distress syndrome)","lastPublishedDoi":"10.21203/rs.3.rs-8322000/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8322000/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHyperinflammation is a key driver of diffuse alveolar damage in COVID-19. This cohort study investigated the association between cytokine dysregulation, hematological parameters, and disease severity in 137 unvaccinated hospitalized COVID-19 patients. The mild group (n\u0026thinsp;=\u0026thinsp;36) showed decreased IL-6, IP-10, and MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and increased IFN-γ, IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IL-2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), IL-10, IL-12p70, and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared with the moderate group (n\u0026thinsp;=\u0026thinsp;36). The severe group (n\u0026thinsp;=\u0026thinsp;65) had elevated IL-4, IL-6, IL-7, IL-8, TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), IL-2, IP-10, MCP-1, and GM-CSF (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but reduced IFN-α2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), IFN-γ (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to the moderate group. Increased IL-6, IL-8, MCP-1, IL-10, IP-10, and TNF-α correlated with metabolic, respiratory, and cardiovascular comorbidities. Higher IL-6, IL-8, IL-10, IP-10, MCP-1, TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and IL-7 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.02) levels were associated with mortality (64.2%). Negative correlations were observed between erythrocyte count, hemoglobin, and TNF-α, IL-6, IFN-α2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); hematocrit and TNF-α (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05); lymphocytes and MCP-1 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Positive correlations occurred between leukocyte and neutrophil counts with IL-8, MCP-1, TNF-α; CRP with IL-6, IL-8, MCP-1, TNF-α; and platelets with IL-17A and TNF-α (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These findings indicate that elevated pro-inflammatory cytokines are linked to hematological markers typical of severe COVID-19\u0026mdash;lymphopenia, anemia, and neutrophilic leukocytosis\u0026mdash;contributing to poor outcomes. Conversely, IL-4, IL-7, and IFN-α may play protective roles associated with milder disease and recovery. The study underscores immune balance as critical in COVID-19 progression and highlights potential biomarkers for prognosis and therapeutic targeting.\u003c/p\u003e","manuscriptTitle":"Cytokine Signatures and Hematological Alterations as Predictors of Covid-19 Severity and Mortality in a Brazilian Cohort From Central-south Mato Grosso","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 09:04:36","doi":"10.21203/rs.3.rs-8322000/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63f95928-e711-4d41-8617-32309d26d5d9","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-26T05:38:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 09:04:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8322000","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8322000","identity":"rs-8322000","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}