key: cord-1018678-7gy2xmff authors: Moreno-Perez, Oscar; Ribes, Isabel; Boix, Vicente; Martinez-García, María Ángeles; Otero-Rodriguez, Silvia; Reus, Sergio; Sánchez-Martínez, Rosario; Ramos, Jose Manuel; Chico-Sánchez, Pablo; Merino, Esperanza title: Hospitalized patients with breakthrough COVID-19: Clinical features and poor outcome predictors date: 2022-02-13 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.02.007 sha: 8f9dbb8ce27d46bc4bf1670a84d317ad2dbaf71e doc_id: 1018678 cord_uid: 7gy2xmff Objectives To describe breakthrough COVID-19 in patients who needed hospitalization and the factors associated with poor outcomes. Methods A retrospective study on complete (diagnosed two weeks after the second dose of the Pfizer/Moderna/AstraZeneca or first dose of the Janssen vaccine was administered) or partial vaccine scheme (CV or PV) patients hospitalized for COVID-19 between December 27, 2020, and October 17, 2021, was conducted. The main outcomes were all-cause mortality and the need for invasive mechanical ventilation (IMV). The baseline factors associated with the outcomes were analyzed by multiple logistic regression, estimating the odds ratios (OR; 95% CI). Results One hundred and forty-five patients (101 CV) were included. The CV subgroup was mainly composed of elderly males with high comorbidity (Charlson index ≥3, 72%; immunosuppression, 20%), with bilateral pneumonia in 63.4%; limited therapeutic effort (LTE) was agreed upon for 28% of the patients. In the CV subgroup, endotracheal intubation was required in 10.9%, reaching 15.3% when excluding LTE patients; the global mortality was 22.8% and 41.4% in the subgroup with LTE. Although the PV patients were younger and had fewer comorbidities, the main outcomes did not differ significantly between the CV and PV groups. The predictors of poor outcomes were age ≥ 65 years, confusion, ferritin > 500 mg/L, extensive lung infiltrates, and a Charlson index ≥ 3. Conclusions Fully vaccinated patients hospitalized due to breakthrough COVID-19 tend to be elderly, with comorbidities, and have high mortality. Vaccine breakthrough SARS-CoV-2, that is, COVID-19 appearing in fully vaccinated patients is an emerging challenge (Bahl et al., 2021) . The severity of the disease in vaccinated patients has not often been described, and data regarding the groups most at risk, and the prognosis and outcomes for hospitalized patients are scarce (CDCMMWR, 2021; Tenforde et al., 2021) . The aim of this study was to study COVID-19 in SARS-CoV-2-vaccinated patients who needed hospitalization and the factors associated with poor outcomes. This was a retrospective study of the 145 SARS-CoV-2-vaccinated patients admitted with COVID-19 at the Hospital General Universitario de Alicante, Spain, between the start of vaccinations on December 27, 2020, and October 17, 2021. The vaccine most commonly administered was Pfizer, followed by Janssen, AstraZeneca, and Moderna. We defined complete vaccination (CV) as symptom onset 14 days after the second dose of a vaccine (or a single Janssen dose), and partial vaccination (PV), as the administration of only the first dose or symptom onset within 13 days after the second dose (or a single dose of Janssen). The vaccine administration date was obtained from the electronic medical record. All the clinical and laboratory parameters were recorded at admission. Limited therapeutic effort (LTE) means no-resuscitation and no-intubation orders (on agreement with family); however, these patients could benefit from noninvasive mechanical ventilation or a high-flow nasal cannula. The main outcomes were 1. the all-cause mortality during hospital admission; 2. the need for invasive mechanical ventilation (IMV); and 3. identified associated risk factors. The results were stratified by vaccination status, comparing the CV and PV groups via the Mann-Whitney U test (for numeric traits), the chi-squared test, and Fisher's exact test (for binary outcomes), as appropriate. The baseline factors associated with outcomes were analyzed by multiple logistic regression, estimating the odds ratios (OR; 95% CI). Explanatory variables were included as covariates if they showed significant associations in simple models. The variables unavailable in more than 15% of the population were excluded. All the tests were two-tailed, and a p-value of less than 0.05 was considered to indicate significance. The final date of follow-up was December 6, 2021, unless censored (due to in-hospital death). IBM SPSS Statistics v25 (Armonk, NY, USA) was used for the analyses. The HGUA-ISABIAL Ethics Committee approved the study (expedient no. 200145). Of the 1648 patients hospitalized with COVID-19 in the study period, only 145 met the inclusion criteria and were included in the analysis. The types of vaccines administered, basal demographic characteristics, comorbidities, clinical presentations, and outcomes by vaccination status are shown in Table 1 . The median number of days at admission since complete vaccination was 81.0 (IQR: 45.0-115.5). All the patients were discharged at the end of the study. The censored time was 118.0 (IQR: 102.5-132.0) days for re-admission. The epidemiological distribution of SARS-CoV-2 variants according to genomic sequencing in our health area in the study period is provided in the Supplementary Materials ( Figure S1 ). Although the CV subpopulation was admitted between April 16, In the multivariate analysis, after adjusting for confounding factors, age ≥ 65 years, confusion, and ferritin > 500 mg/L at admission were independently associated with mortality (see Figure 1 ); a Charlson index ≥ 3, basal oximetry ≤94%, or nosocomial COVID-19 were close to statistical significance (p < 0.09); and the time from vaccination showed no association. After excluding patients with LTE and adjusting for confounding factors in the multivariate analysis, age ≥ 65 years, extensive lung infiltrates, and a Charlson index ≥ 3 were independently associated with a need for invasive mechanical ventilation (see Figure 1 ). When the time elapsed since complete vaccination was categorized into quartiles, those in the upper quartile did not show a significant increase in mortality rate (OR: 1.33 (95% CI: 0.49-3.65)) or invasive mechanical ventilation requirement (OR: 3.55 (95% CI: 0.75-16.78), after excluding patients with LTE), compared with the three lower quartiles (<115.5 vs. ≥115.5 days). Although the PV patients were younger and had fewer comorbidities, the clinical features and main outcomes did not differ significantly between the CV and PV groups. In this cohort of hospitalized patients due to breakthrough COVID-19 infection, we vaccination reduces hospitalizations and mortality in the long term (Holtkamp N, et al., 2021; Lin et al., 2022) . Therefore, host characteristics seem to be the main risk factors for severe disease and fatal outcomes. In our cohort, the time elapsed since complete vaccination and sample characteristics (high comorbidity and immunosuppression) suggest that waning immunity and impaired immune responses after vaccination could help to explain the high mortality rate. The CV subpopulation is clearly differentiated by age, long-term care residency, and comorbidity from patients with incomplete vaccination; however, the clinical features and outcomes are similar. The independent predictors of critical outcomes (mortality and IMV) are comparable to those in published series for unvaccinated patients (Alimohamadi et al., 2021; Andrés et al., 2021; Berenguer et al., 2020) . The clinical and baseline characteristics of our cohort are similar to those of the other two groups of patients hospitalized due to breakthrough COVID-19 (Bosch et al., 2021; Brosh-Nissimov et al., 2021) . Compared to unvaccinated COVID-19 admissions, those patients appear to be older, are more likely to be immunosuppressed, and have more comorbidities (Alimohamadi et al., 2021; Andrés et al., 2021; Berenguer et al., 2020) . According to this evidence, the higher levels of brain natriuretic peptide in our CV Compared to the PV patients, the CV patients that were hospitalized due to breakthrough COVID-19 were older, with more comorbidities, and had a high mortality rate. Therefore, it is essential to incorporate additional measures in this subgroup of patients, such as reinforcing the vaccination calendar with boosters to prevent severe disease and an early therapy of mild symptomatic infection with monoclonal antibodies in immunocompromised patients. To validate the effectiveness of these measures, this population must be specifically addressed in future research. The authors have nothing to disclose. This manuscript has not been previously published nor is not being considered for publication elsewhere. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. On behalf of all authors, the corresponding author states that there is no conflict of interest. Availability Days of symptoms before admission. The laboratory variables have been dichotomized, according to clinically relevant cutoff points or, failing that, according to the upper limit of the reference values of the center (Bzeizi et al., 2021; Calvo-Fernández et al., 2021; Deng et al., 2020; Garcia-Vidal et al., 2022; Sisó-Almirall et al., 2020; Wagner et al., 2021) . For the following variables, standard categorizations were followed: age ≥65 years, eGFR < 60 ml/min/m2, respectively. *P-value corresponds to the comparison between the complete and partial vaccination groups, obtained using Mann-Whitney U test, chi-squared or Fisher exact test, as appropriate. The 95% confidence intervals (CIs) of the odds ratios have been adjusted for multiple testing. Explanatory variables (demographic characteristics, comorbidities, and clinical presentation, shown in Table 1 ) were included as covariates in the logistic regression models, if they showed significant associations in simple models, and are represented as risk factors in the figure. In bold are the independent predictors associated with the outcomes. For the purpose of the logistic regression, variables were categorized according to clinically relevant cutoff points or, failing that, according to the upper limit of the reference values of the center (Bzeizi et al., 2021; Calvo-Fernández et al., 2021; Deng et al., 2020; Garcia-Vidal et al., 2022; Sisó-Almirall et al., 2020; Wagner et al., 2021) . For the following variables, standard categorizations were followed: age ≥65 years and eGFR (estimated glomerular filtration rate) < 60 mL/min/m 2 , respectively. Case fatality rate of COVID-19: a systematic review and meta-analysis Fatality and risk features for prognosis in COVID-19 according to the care approacha retrospective cohort study Vaccination reduces need for emergency care in breakthrough COVID-19 infections: A multicenter cohort study Characteristics and predictors of death among 4035 consecutively hospitalized patients with COVID-19 in Spain COVID-19 Vaccine-Breakthrough Infections Requiring Hospitalization in Mayo Clinic Florida through BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel Effect of COVID-19 on liver abnormalities: a systematic review and meta-analysis Markers of myocardial injury in the prediction of short-term COVID-19 prognosis COVID-19 Vaccine Breakthrough Infections Reported to CDC -United States COVID-19 Vaccination Associated with Reductions in COVID-19 Mortality and Morbidity in the United States, and an Approach to Valuing these Benefits The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19 Personalized Therapy Approach for Hospitalized Patients with Coronavirus Disease Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina Prognostic factors in Spanish COVID-19 patients: A case series from Vaccine manufacturer Length ICU stay (days), median (IQR) Invasive mechanical ventilation, % Global, % Group with LTE, % Group with maximum care Days of IMV, median (IQR) % Group with LTE, % Group with maximum care, % Endotracheal intubation Acknowledgments.