Predictors of death in COVID-19 vaccine breakthrough infections in Brazil

Abstract

Recently, Whitaker and coworkers reported in the Journal evidences of the COVID-19 vaccine effectiveness in most clinical risk groups, with care to highlight the heterogeneity of seropositivity after 1 or 2 doses in individuals with diabetes, chronic heart disease, chronic liver, severe asthma, morbid obesity, and especially immunosuppressed, in which they observed a reduced S-antibody response and vaccine effectiveness.1Whitaker H.J. Tsang R.S. Byford R. Andrews N.J. Sherlock J. Pillai P.S. et al.Pfizer-BioNTech and Oxford AstraZeneca COVID-19 vaccine effectiveness and immune response among individuals in clinical risk groups.J Infect. 2022; Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar We read with interest the article, especially because we believe in impact of vaccination against COVID-19 in groups with comorbidities. Through a retrospective, cross-sectional study, based on data from the SIVEP-Gripe Database, the COVID-19 Immunization State Database, and the local medical reporting system, our analysis identified characteristics that may be associated with increased risk of death in vaccinates hospitalized with COVID-19 in a reference health care center. Our outcome of interest was COVID-19-related death in patients with SARS-CoV-2 infection confirmed by RT-PCR with signs/symptoms appearing 15 days or more after vaccine series completion, a period considered reasonable to establish immunity. Vaccine breakthrough infections are defined as the detection of SARS-CoV-2 RNA or antigen in a respiratory specimen collected from a person ≥14 days after they completed all recommended doses.2CDC. COVID-19 Vaccine Breakthrough Case Investigation and reporting: National Center For Immunization and Respiratory Disease; 2021 Available from: https://www.cdc.gov/vaccines/covid-19/health-departments/breakthrough-cases.html.Google Scholar Following these definitions, the patients were divided into two groups upon admission, confirmation of COVID-19 infection via RT-PCR and completed information about COVID-19 vaccination status: i) breakthrough infection and ii) unvaccinated. All variables were subjected to binary logistic regression to define variables that might predict the different clinical outcomes. To select the variables that would comprise the final model, discriminant analysis was performed with p<0.1, estimated by Rao's score test. The variables that obeyed the predefined criteria were subjected to multivariate analysis, with significance defined as p<0.05. All data were tabulated and analyzed with SPSS version 25 software (SPSS, Inc; Chicago, IL, USA). Between January 5 and September 12, 2021, 2777 (68.5%) were enrolled (Table 1). The unvaccinated patients were predominantly male (56.6%) with a mean age of 51.08 (±15.56) years, and 71.5% had one or more comorbidity. These findings are agreed with previous studies that described the clinical profile of patients hospitalized with COVID-19 since the beginning of pandemic, being the disease severity associated with risk factors such as male gender, advanced age, and the presence of comorbidities.3Chen L. Yu J. He W. Yuan G. Dong F. Chen W. et al.Risk factors for death in 1859 subjects with COVID-19.Leukemia. 2020; 34: 2173-2183Crossref PubMed Scopus (77) Google Scholar, 4Deng Y. Liu W. Liu K. Fang Y.Y. Shang J. Zhou L. et al.Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study.Chin Med J (Engl). 2020; 133: 1261-1267Crossref PubMed Scopus (406) Google Scholar, 5Guan W.J. Liang W.H. Zhao Y. Liang H.R. Chen Z.S. Li Y.M. et al.Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.Eur Respir J. 2020; 55Crossref Scopus (3) Google Scholar, 6Ranzani O.T. Bastos L.S.L. Gelli J.G.M. Marchesi J.F. Baião F. Hamacher S. et al.Characterisation of the first 250,000 hospital admissions for COVID-19 in Brazil: a retrospective analysis of nationwide data.Lancet Respir Med. 2021; 9: 407-418Abstract Full Text Full Text PDF PubMed Scopus (136) Google ScholarTable 1Characteristics of 2777 patients with COVID-19 admitted to hospital between January 5, 2021 and September 12, 2021, according to COVID-19 immunization status.Unvaccinated patientsVaccine Breakthrough Infection*p-valueO.R. CI 95%MinMaxN responsesN positive or mean% or s.d.N responsesN positive or mean% or s.d.SexMale2518142656.6%25914054.1%–Female2518109243.4%25911945.9%0.4261.10.8591.435Age251851,0815.5625973,6412.21<0.001–––> 60 years251872728.9%25923088.8%<0.00119.53813.15329.024Comorbidities2518180171.5%25924795.4%<0.0018.1944.56214.721Recent childbirth1801100.6%24710.4%0.7620.7280.0935.712Cardiopathy1801108960.5%24721486.6%<0.0014.242.9046.191Hematological disorder1801311.7%24720.8%0.2860.4660.1111.96Liver disorder1801311.7%24731.2%0.5590.7020.2132.314Asthma1801744.1%247104.0%0.9640.9850.5021.932Diabetes180158432.4%24710843.7%<0.0011.6191.2362.121Neurological disorder1801884.9%2473313.4%<0.0013.1242.1184.876Pneumopathy1801844.7%247228.9%<0.0013.1522.0574.831Immunocompromised status1801764.2%247218.5%0.0012.2191.3543.639Kidney disorder1801955.3%2473514.2%0.041.6691.022.731Obesity180162334.6%2474518.2%<0.0010.4210.3010.59Symptoms at hospital admissionFever2518134053.2%25910741.3%<0.0010.6190.4770.802Cough2518171668.1%25916664.1%0.1830.8340.6391.090Sore throat251835314.0%2593312.7%0.5710.8960.6111.312Dyspnea2518229991.3%25923088.8%0.1790.7560.5011.114Respiratory distress2518174369.2%25917768.3%0.770.9600.7291.264Low oxygen saturation2518239495.1%25925297.3%0.1081.8650.8614.037Diarrhea251831512,5%2592710.4%0.3310.8140.5371.233Vomiting25181385.5%258207.8%0.1341.4490.8902.359Abdominal pain2518803.2%25972.7%0.6760.8470.3871.853Fatigue2518105241.8%25914054.1%<0.0011.6391.2682.120Anosmia25181495.9%25951.9%0.0080.3130.1270.770Ageusia25181405.6%25862.3%0.0270.4040.1770.925ICU care required2518139055.2%25913752.9%0.4770.9110.7051.178Death248564726.0%24511245.7%0.777–––Vaccinated251800259259100%NA––– Open table in a new tab In contrast, the vaccinated patients were an average of 73.64 (±12.21) years old, and 95.4% had comorbidities. Being statically higher in this (p<0.001, in both cases) (Table 1). Correlation between complete vaccination, comorbidities, and advanced age was expected according to the definition of priority groups for immunization, which focused on age and comorbidities. This consideration is crucial when analyzing data from vaccinated patients to avoid erroneous associations between vaccination status and hospitalization. The values for Spearman's correlation coefficient confirmed this observation once it was negatively correlated with complete vaccination series when controlling for age and comorbidities (ρ = - 0.005; p = 0.777). In our data analysis according to vaccine status to define death risk, the univariate analysis identified age > 60 years, presence of comorbidities, cardiopathy, liver disorder, diabetes, neurological disorder, immunocompromised status, pneumopathy, and kidney disease as predictors of death in unvaccinated patients. The discriminant analyses selected six variables (age > 60 years, female sex, liver disorder, kidney disease, obesity, immunocompromised status) that were statistically significant when subjected to multivariate analysis (Table 2). Our data depict a second wave of the pandemic in which different variants of the virus were circulating in the country and concerns addressed the impact on younger adults. A change in age profile was observed particularly after the emergence of the P1 (Gamma) variant in Manaus, with higher mortality seen among hospitalized patients in the 20–59 age range compared to the first wave of COVID-19.7Freitas A.R.R. Beckedorff O.A. Cavalcanti L.P.G. Siqueira A.M. Castro D.B. Costa C.F.D. et al.The emergence of novel SARS-CoV-2 variant P.1 in Amazonas (Brazil) was temporally associated with a change in the age and sex profile of COVID-19 mortality: a population based ecological study.Lancet Reg Health Am. 2021; 1100021Google Scholar Our data correspond precisely to the circulation of the Gamma variant in the city and region and consequent overload of the local health system, as already reported.8Banho C.A. Sacchetto L. Campos G.R.F. Bittar C. Possebon F.S. Ullmann L.S. et al.Effects of SARS-CoV-2 P.1 introduction and the impact of COVID-19 vaccination on the epidemiological landscape of São José Do Rio Preto, Brazil.medRxiv. 2021; (2021.07.28.21261228)Google ScholarTable 2Predictor variables of death among the 1838 unvaccinated patients with COVID-19 admitted to hospital.CureDeathN responsesN positive or mean% or s.d.N responsesN positive or mean% or s.d.p-valueO.R. CI 95%MinMaxUNVACCINATED PATIENT1. Univariate analysisSexMale1838101855.4%64738960.1%1.000–––Female183882044.6%64725839.9%0.0370.8230.6860.988Age183848.4514.9364758.914.91<0.0011.0491.0421.056> 60 years183840321.9%64732450.1%<0.0013.5722.9554.318Comorbidities1838119364.9%64758790.7%<0.0015.2893.9887.015Recent childbirth119380.7%58720.3%0.390.5060.1072.392Cardiopathy119368657.5%58739467.1%<0.0011.5091.2271.856Hematological disorder1193211.8%58791.5%0.7270.8690.3961.909Liver disorder1193131.1%587183.1%0.0042.8711.3975.901Asthma1193514.3%587233.9%0.7230.9130.5521.509Diabetes119336130.3%58721837.1%0.0041.3621.1061.677Neurological disorder1193453.8%587437.3%0.0012.0171.3113.101Pneumopathy1193403.4%587427.2%<0.0012.2211.4243.466Immunocompromised status1193322.7%587447.5%<0.0012.9401.8444.688Kidney disorder1193443.7%587518.7%<0.0012.4851.6393.767Obesity119341234.5%58719933.9%0.7910.9720.7891.1982. Multivariate analysisAge––––––<0.0011.0481.041.057Sex (female)––––––<0.0010.6390.5160.791Liver disorder––––––0.0013.4091.6057.24Kidney disorder––––––0.0012.1661.3813.396Obesity––––––<0.0011.8451.4472.353Immunocompromised status––––––<0.0013.2321.9415.381VACCINETED PATIENTS1. Univariate analysisSexMale1336951.9%1126356.3%1–––Female1336448.1%1124943.8%0.4940.8380.5061.390Age13370.2614.1011277.78.03< 0.0011.0641.0341.194> 60 years13310881.2%11211098.2%0.00112.7312.94355.071Comorbidities13312392.5%11211098.2%0.0574.4720.95920.854Recent childbirth12310.8%11000.0%1.000–––Cardiopathy12310383.7%11010090.9%0.1071.9420.8664.354Hematological disorder12310.8%11010.9%0.9371.1190.06918.111Liver disorder12310.8%11021.8%0.5082.2590.20225.265Asthma12343.3%11065.5%0.4131.7160.4716.249Diabetes1234536.6%1105348.2%0.0741.6120.9542.722Neurological disorder1231613.0%1101412.7%0.9490.9750.4522.103Pneumopathy12397.3%1101110.0%0.4671.4070.5603.536Immunocompromised status123108.1%1101110.0%0.6191.2560.5123.082Kidney disorder123108.1%1102220.0%0.0112.8251.2726.273Obesity1232217.9%1102119.1%0.8131.0830.5592.101Time between final vaccine dose and symptom onset13386.3740.4511279.0837.080.1460.9950.9891.0022. Multivariate AnalysisAge––––––<0.0011.0611.0291.093Kidney disease––––––0.0112.8871.2766.529 Open table in a new tab In contrast, the vaccinated patients in our study presented a different profile. While several comorbidities were important predictors of death in unvaccinated patients, in the vaccinated group only age >59 and the presence of kidney disorders were predictors of death in univariate analysis and remained in the multivariate analysis (Table 2). The impact of renal disease, in its various stages, on the formulation of effective immunity after immunization against COVID-19 has been investigated. As reviewed by Hou et al., vaccines are important tools in the prevention of critical COVID-19 in such patients, however the advanced stage of kidney disease and the use of immunosuppressive agents may influence the efficacy of immunizing and the formulation of neutralizing antibodies.9Hou Y.C. Lu K.C. Kuo K.L. The Efficacy of COVID-19 Vaccines in Chronic Kidney Disease and Kidney Transplantation Patients: a Narrative Review.Vaccines (Basel). 2021; 9Google Scholar We believe our data complement the findings of Whitaker et coworker, as they demonstrate the effectiveness of the vaccine even in special groups, such as immunosuppressed and especially in a regimen with at least two doses, and we demonstrated that vaccination with a complete regimen with at least two doses can result in a change in the clinical profile of patients hospitalized by COVID-19. Once breakthrough infection is expected, it is essential to understand the profile of patients who require hospitalization even after complete COVID-19 vaccination for more effective management. In our sample, breakthrough infections associated with hospitalization and death were more frequent in older patients (age ≥60 years) and those with kidney disorders. Although this study is retrospective, it is based on a large dataset. Our propose is highlighting to individual characteristics that should be considered when caring for patients, in addition to signs and symptoms. Our findings demonstrate how vaccination and nonpharmaceutical interventions have changed the profile of COVID-19 in our population, particularly in terms of predictors of death in hospitalized patients: many comorbidities associated with greater risk in the general population are no longer considered risk factors in vaccinated people. Conceptualization: CFE, MLN. Methodology: CFE, MLN. Investigation: CFE, CAB, LS, GRFC, MMM, TILS, GFF, GCDS, FQ, LMM, AFN, MDB. Data Curation: CFE, MLN. Writing – Original Draft: CFE, MLN. Writing – Review and Editing: CFE, GFF, FQ, MLMS, MLN. Acquisition of Funding: MLN. All authors read and approved the final manuscript. CFE and MLN has received research grants from Instituto Butantan, Janssen Vaccines & Prevention B.V., Medicago R&D Inc, and Pfizer/BioNTech SE.