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.

Discussion

In this cohort of hospitalized patients due to breakthrough COVID-19 infection, we reported the clinical profile and evolution by vaccination status, with an overall all-cause mortality rate of around 20%. Why fully vaccinated patients develop severe disease is unknown. While the time elapsed since vaccination (there is a loss of effectiveness after six months) and new variants (Omicron in patients with two or fewer doses of the vaccine) are important factors in breakthrough infection, COVID-19 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 patients could translate into a high cardiovascular comorbidity rate and worse renal function, besides being a biomarker of myocardial damage in COVID-19 (Calvo-Fernández et al., 2021).

Our mortality rate and that found by Brosh-Nissimov (Brosh-Nissimov et al., 2021) in 152 fully vaccinated hospitalized breakthrough cases from Israel (22%) are similar, and a composed primary outcome of IMV or death is overlapping (26.7 vs. 25%).

Although vaccines are very effective at preventing severe cases of COVID-19, when these occur and require hospitalization, this breakthrough could identify patients with extreme vulnerability and a higher risk of poor outcomes.

Limitations

Some important limitations need to be addressed. First, this was a retrospective, single-center study, without a comparison between vaccinated and unvaccinated patients. The population under study received different commercial vaccines. Length of study could entail different scenarios in terms of virus variants and treatment protocols; however, most of the variants detected in our health area were Delta and there were no substantial changes in treatment protocols during 2021. Although an effort was made to control for relevant confounders, unmeasured confounding variables may still have been present. Sample-size limitations prevented analysis by vaccine type, SARS-CoV-2 variant, and time elapsed between vaccination and symptom onset.

Conclusions

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.

Disclosure Statement

The authors have nothing to disclose.

This manuscript has not been previously published nor is not being considered for publication elsewhere.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Availability of data and material

O.M-P, I.R and E.M have full access to the data and are the guarantor for the data.

Authors´contributions

We encourage authors to disclose their personal contribution to the research and article (Writing – Original Draft: I.R, E.M. and O.M-P.; Writing – Review & Editing: I.R., E.M., O.M-P., J.M-R, V.B., R.S-M., M.A.M-G., S.O-R., P.C-S., S.R.; Conceptualization: I.R, E.M. and O.M-P.; Investigation: I.R., E.M., O.M-P., J.M-R, V.B., R.S-M., M.A.M-G., S.O-R., P.C-S., S.R.; Methodology: I.R, E.M. and O.M-P.; Formal Analysis: I.R, E.M. and O.M-P.; Project Administration: E.M; Funding Acquisition: not applicable)

Ethics approval

HGUA-ISABIAL ethics committee approved the study (expedient no. 200145)

Consent to participate written informed consent was obtained from all the participants.

Acknowledgments

The members of COVID19-ALC research group are:

Esperanza Merino, Joan Gil, Vicente Boix, Ximo Portilla, Oscar Moreno-Pérez, Mariano Andrés, Jose-Manuel Leon-Ramirez, Santos Asensio, Cleofé Fernandez, Alfredo Candela, Mª del Mar García, Rosario Sánchez, Diego Torrus, Sergio Reus, Pilar González, Silvia Otero, Jose M Ramos, Beatriz Valero, Alex Scholz, Antonio Amo, Héctor Pinargote, Paloma Ruiz, Raquel García-Sevila, Ignacio Gayá, Violeta Esteban, Isabel Ribes, Julia Portilla, Cristina Herreras, Alejando Cintas, Alicia Ferradas, Ana Martí, Blanca Figueres, Marcelo Giménez, María-Ángeles Martínez, María-Mar García-Mullor, María Angeles Martínez, Irene Calabuig, Marisa Peral, Ernesto Tovar, M Carmen López, Paloma Vela, Pilar Bernabeú, Ana Yuste, José Ponce, Bertomeu Massuti, Vicente Climent, Vicente Arrarte, Fernando Torres, Laura Valverde, Laura Delegido, Cristina Cambra, Miriam Sandín, Teresa Lozano, Amaya García-Fernández, Alejandro Do Campo, Eduardo Vergara, Nicolás López, Elena Elvira, Fátima López, Fernando Dahl, Blanca Serrano, Sarai Moliner, Carmina Díaz, Dolores Castaño, Beatriz López; Antonio Picó, Joaquín Serrano, Sol Serrano, María Marín-Barnuevo, María Díaz, Cristina Gilabert, Estela Martínez, Elena Vivó, Noelia Balibrea, Miguel Perdiguero, Carolina Mangas, Lucía Medina, Oscar Murcia, María Rodríguez, Rodrigo Jover, Javier López, Marina Morillas, Mercedes Khartabil, Cristina Gil, Carlos Salazar, Eva Vera, Helena López, Vanesa Rodríguez, Sandra Baile, Norma Guerra, Mar Blanes, Jaime Guijarro, José Carlos Pascual, Iris Gonzalez, Pedro Sanso, José Manuel Ramos, Jaime Javaloy, Clara Llopis, Olga Coronado, Esther García, Gonzalo Rodríguez, Paola Melgar, Mariano Franco, Félix Lluís, Carmen Zaragoza, Cándido Alcaraz, Ana Carrión, Celia Villodre, Emilio Ruiz de la Cuesta, Cristina Alenda, Francisca Peiró, María Planelles, Laura Greco, Sandra Silvia, Antonio Francia, Iván Verdú, Juan Sales, Ana Palacios, Hortensia Ballester, Antonio García-Valentín, Marta Márquez, Eva Canelo, Andrea Juan, Elena Vives, Andrea Revert, Gonzalo Fuente, Ester Nofuentes, Carolina Mangas, Eva Vera, Alicia Ferradas, Helena López, Cristian Herrera, Beatriz López, Marina Morillas, Vanesa Rodríguez, Mercedes Khartabil, Mario Giménez, Ernesto Tovar, Estela Martínez, Lucia Medina, Sandra Baile, Carlos Salazar, Norma Guerra, Sarai Moliner, Mari-Carmen López-González, Blanca Figueres.

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