Antoniazzi, Lucas Quadros

Cunha, Sainan Voss da

Cury, Vinicius Ferraz

Fontanari, Clara

Frison, Guilherme Cristianetti

Moretto, Enrico Emerim

Oliveira, João Pedro Souza

Oliveira, Paulo Henrique Kranz de

Oliveira, Verônica Almeida

Seligman, Renato

MedComm

English

Lume 5.8

Received: 26 October 2022 Revised: 25 February 2023 Accepted: 28 February 2023DOI: 10.1002/mco2.243LETTERCOPD, diabetes, lymphopenia, and increased LDH causehigher mortality in hospitalized COVID-19 patientsDear Editor,The clinical presentation of COVID-19 has a wide spec-trum, from asymptomatic to severe cases that requirehospitalization for ventilatory support. To optimize care,it is necessary to identify which patients have the great-est potential for a serious outcome. Several comorbiditiesand biomarkers have been studied to assess the prognosisof patients with severe acute respiratory syndrome (SARS)CoV-2 infection.The aim of the present study was to evaluate riskfactors for mortality in patients with Covid-19 admit-ted with SARS, to Hospital de Clinicas de Porto Alegre,Brazil, a teaching general hospital. We conducted a cross-sectional study, nested to a retrospective observationalcohort that comprised a sample of 936 patients aged 18years or older with COVID-19, confirmed by positive realtime polymerase chain reaction (RT-PCR) or antigen test-ing and SARS, included from March 2020 to May 2021,to assess risk factors for pulmonary thromboembolism(PTE) (Figure 1A). We included all patients submitted topulmonary angiotomography due to worsening of oxy-genation and suspicion of PTE. Clinical and laboratorialdata were collected in the electronic medical records of allpatients. A total of 680 patients were admitted to inten-sive care unit (ICU) and 256 to a dedicated COVID-19area to receive oxygen support, including high-flow nasaloxygen therapy and noninvasive ventilation. From these936 patients, 285 did not perform laboratory tests includedin research protocol and were not enrolled for analysis.Patients were divided into survivors and nonsurvivors.Lymphopenia was defined as lower than 690 cells/μL,and lactate dehydrogenase (LDH), defined elevated whensuperior to 482U/L (Figure 1C).WemodeledD-dimers intoa categorical variable, taking a positive result to be equal orgreater than five times the reference value, considering theelevation of D-dimers caused by COVID-19 inflammationpreviously reported.1 Materials and Methods are detailedin supplementary materials.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided theoriginal work is properly cited.© 2023 The Authors.MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.As expected, there was significant increase in mor-tality among patients admitted to ICU. Hypertension,diabetes, chronic kidney disease, dialysis, neurologicdiseases, and chronic obstructive pulmonary disease(COPD) were also significant predictors in univariateanalysis. There was no difference in mortality betweengenders, cerebrovascular disease, heart disease, asthma,lung diseases other than asthma and COPD, tobaccoconsumption, liver cirrhosis, non-active malignancy,immunosuppression, previous organ transplant and HIVcarriers.Results of various laboratory tests were dif-ferent between survivors and nonsurvivors. Thebiomarkers C-reactive protein (CRP), LDH, troponin,creatine phosphokinase (CPK), creatinine, lactate,hemoglobin, platelets, neutrophils, lymphocytes, neu-trophil/lymphocyte rate and D-dimers ≥2.5 mg/dL wereassociated with mortality (p < 0.05). Bilirubin, urea,monocytes, fibrinogen, and activated partial thromboplas-tin time were not predictors. All observed variables arelisted in Supplementary Materials (Table S1).Our results demonstrated that COPD, diabetes, lym-phopenia, and LDH were significant independent predic-tors of mortality in multivariate logistic regression model,even after adjusting for hypertension, chronic kidneydisease, neurologic diseases, CRP, troponin, CPK, crea-tinine, hemoglobin, platelets, neutrophils, and D-dimers≥2.5 mg/dL (Figure 1B,D).We observed in univariate analysis that increased levelsof LDH (odds ratio (OR) 1.12; CI 1.06–1.19) and lymphope-nia (OR 1.73; CI 1.41–2.28) corresponded, respectively, toa 12% and 73% increase in mortality. Multivariate logis-tic regression model showed similar values, presenting12% increase in mortality (OR: 1.12; 95% CI: 1.03–1.25) forLDH and 70% (OR 1.70; CI 1.21–2.40) for lymphopenia,demonstrating the practical prognostic relevance of LDHand lymphocyte count, both isolated or in association withother markers.MedComm. 2023;4:e243. wileyonlinelibrary.com/journal/mco2 1 of 4https://doi.org/10.1002/mco2.243 26882663, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.243 by CAPES, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License2 of 4 LETTERF IGURE 1 (A) Flowchart of the study cohort. (B) Odds ratio for mortality in COVID-19 patients. Univariate and multivariate analyses.(C) Receiver operating characteristic curve analysis of laboratory values taken on admission at different cutoffs in predicting mortality ofCOVID-19 patients. (D) Forrest plot ratio for mortality in COVID-19 Patients.Our data showed increased LDH levels on hospitaladmission can predict mortality in COVID-19 patients.These results are comparable to a recent meta-analysisthat found a six-fold increase in mortality associated withelevated LDH. On aerobic conditions human body cellsconvert pyruvate to acetyl-CoA,which enters the citric acidcycle and produces adenosine triphosphate (ATP). How-ever, under anaerobic conditions, such as tissue hypoxiaprovoked by COVID-19, the enzyme LDH promotes a devi-ation of this mechanism towards the production of lactatethrough pyruvate.2We found lower absolute lymphocyte count (ALC)was associated with increased COVID-19 mortality. Thisassociation remained significant in multivariate analysis.Lymphopenia is consistently described to be indepen-dently associated with adverse clinical outcomes inCOVID-19, namely ICU admission, the use of mechan-ical ventilation and in-hospital mortality. Althoughother studies used different ALC cutoff values, weappraised 696 lymphocytes as the most accurate cutoffvalue. A possible explanation for the high mortalityin low lymphocyte count COVID-19 patients may bedue to an increased cellular exhaustion mediated byNKG2A+ receptors. It is well known that cytotoxic Tlymphocytes (CTL) and natural killer (NK) cells play anessential role in controlling viral infection. In severely 26882663, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.243 by CAPES, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseLETTER 3 of 4COVID-19 ill patients, NKG2A+ expression was upreg-ulated on NK cells and CTLs, correlating with areduced ability to produce CD107a, Interferon-γ (IFN-γ),Interleukin-2 (IL-2), granzyme B, and Tumor NecrosisFactor-α (TNF-α), resulting in disease progression.3Consistent with studies that identified diabetes a riskfactor, our results showed anOR 1.88 (1.42–2.49) in univari-ate and 1.58 (95% CI 1.06–2.34) in multivariate analysis formortality. During the H1N1 infection outbreak, the OR forICU admission among hospitalized patients with diabeteswas four times of those without it. Moreover, a knownhistory of diabetes was attributed to be an independentpredictor of death in the SARS-COV1 outbreak. Hypothe-ses to justify the relationship between these two entitieshave already been explored. For instance, angiotensin-converting enzyme (ACE2) works as a receptor for SARS-CoV-2. High ACE2 levels are often described in diabeticpatients.4 Diabetes mellitus inhibits neutrophil chemo-taxis, phagocytosis, and intracellular killing of microbes,diminishes T cell function, and lowers innate and adaptiveimmunity.Finally, we found COPD a significant independentpredictor of mortality, with OR of 2.89 (1.70–4.91) in uni-variate and 3.26 (1.73–6.15) in multivariate analysis. It isknown that acute worsening of COPD has its main trig-ger in viral infections, including seasonal coronaviruses.Several studies that demonstrated COPD as indepen-dent predictor of mortality in patients with COVID-19support this association. Increased ACE-2 expression inCOPD seems to be one of the mechanisms involved ingreater severity of COVID-19.5 In addition, viral condi-tions can cause exacerbation of systemic inflammationin COPD patients and the associated cytokine stormleads to acute respiratory distress syndrome. These mech-anisms, with lower baseline lung function, anatomicabnormalities and immune dysfunction found in COPDpatients, seem to be the main explanations for the greaterseverity.One of the limitations of this study is that the stageof chronic lung disease severity was not evaluated. More-over, we only evaluated lymphocyte count and LDH onthe day of hospital admission, not observing the kinet-ics throughout the treatment. Furthermore, the severity ofcases included in our sample does not correspond to allpatients with Covid-19. Cases that did not require hospital-ization were not included and for these our results shouldnot be extrapolated. However, our study has strengths. Thelarge sample size is one of the advantages of our study, withindividualized review of the medical records conductedby the team of researchers. Moreover, the automationof our laboratory, integrated with the electronic medicalrecord of patients, guarantees fidelity of results, avoidingtranscription errors.Much remains to be understood about Covid-19. Evi-dence is being researched, with controversial results oncertain topics. Our study provides additional data aboutthe association of lower lymphocytes, increased LDH,COPD, diabetesmellitus to the risk of death in hospitalizedCOVID-2019 patients. These biomarkersmay serve as prog-nostic tools, highlighting the need for intensive treatmentregimens for patients at risk of severe disease. These resultssuggest further studies to confirm our findings in otherCOVID-19 settings and to investigate other managementoptions for these patients.AUTH OR CONTRIBUT IONSRS conceived the protocol and drafted the manuscript.GCF, SVC, LQA, PHKO, JPSO, VFC, CF, EEM, and VAOcollected the literatures, extracted, and analyzed the data,and revised the manuscript drafts. All authors contributedto the final revision of manuscript drafts and approved thismanuscript for publication.ACKNOWLEDGMENTSThe authors thank Rogerio Boff Borges for statisticalanalysis.FUNDING INFORMATIONThe authors received no specific funding for this work.CONFL ICT OF INTEREST STATEMENTThe authors declare that they have no conflict of interest.DATA AVAILAB IL ITY STATEMENTThe data supporting this study are available from thecorresponding author upon reasonable request.ETH ICS STATEMENTThis study was approved by the Hospital de Clinicasde Porto Alegre Research Ethics Committee. Patients’informed consent was waived due to its retrospectivenature. Ethics approval number: 3.850.336.Guilherme C. Frison1Sainan V. da Cunha1Lucas Q. Antoniazzi1Paulo H. K. de Oliveira1Joao P. S. Oliveira1Vinicius F. Cury1Clara Fontanari1Enrico E. Moretto1Verônica A. Oliveira1Renato Seligman1,2,∗1School of Medicine, Federal University of Rio Grande doSul, Porto Alegre, Rio Grande do Sul, Brazil 26882663, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.243 by CAPES, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License4 of 4 LETTER2Internal Medicine Service, Hospital de Clinicas de PortoAlegre, Porto Alegre, Rio Grande do Sul, Brazil∗CorrespondenceRenato Seligman, School of Medicine, Federal Universityof Rio Grande do Sul, Porto Alegre, Brazil.Email: reseligman@hcpa.edu.brORCIDRenato Seligman https://orcid.org/0000-0002-2398-6963REFERENCES1. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy andsafety of therapeutic-dose heparin vs standard prophylactic orintermediate-dose heparins for thromboprophylaxis in high-riskhospitalized patients with COVID-19: the HEP-COVID random-ized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620.2. Cohen SL, Gianos E, Barish MA, et al. Prevalence and predictorsof venous thromboembolism ormortality in hospitalized COVID-19 patients. Thromb Haemost. 2021;121(8):1043-1053.3. Zheng M, Gao Y, Wang G, et al. Functional exhaustion ofantiviral lymphocytes in COVID-19 patients. Cell Mol Immunol.2020;17(5):533-535.4. Rao S, Lau A, So HC. Exploring diseases/traits and bloodproteins causally related to expression of ACE2, the putativereceptor of SARS-CoV-2: a Mendelian randomization analysishighlights tentative relevance of diabetes-related traits. DiabetesCare. 2020;43(7):1416-1426.5. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molec-ular mechanisms and potential therapeutic target. Intensive CareMed. 2020;46(4):586-590.SUPPORT ING INFORMATIONAdditional supporting information can be found onlinein the Supporting Information section at the end of thisarticle. 26882663, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mco2.243 by CAPES, Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

COPD, diabetes, lymphopenia, and increased LDH cause higher mortality in hospitalized COVID-19 patients

https://lume.ufrgs.br/bitstream/10183/257127/1/001165527.pdf

COPD, diabetes, lymphopenia, and increased LDH cause higher mortality in hospitalized COVID-19 patients

Abstract

Similar works

Full text

Available Versions

Lume 5.8