Since the first identification of the Variant of Concern (VOC), it has been established that structural modifications can alter the course of infection (1) and emerging variants have been closely monitored with the objective of promptly detecting genetic alterations that may impact transmissibility, disease severity, immunogenicity, drug response, and other features (2). The World Health Organization (WHO) has identified five VOCs: Alpha (September 2020), Beta (May 2020), Gamma (November 2020), Delta (October 2020), and Omicron (November 2021) (3, 4).

In Spain, epidemiological surveillance has been conducted since 2021 by sequencing a random sample of cases in each community and releasing information on a biweekly basis through the Spanish Surveillance System (SiViEs) (5). The report dated May 17th, 2022 includes the percentage of each variant among all sequenced samples for each week, where the prevalence of three of the five WHO-identified VOCs - Alpha, Delta, and Omicron - is evident (Annex 1) (6).

These VOCs have exhibited distinct patterns of transmission, disease severity, and immune evasion compared to earlier Wuhan SARS-CoV-2 (7, 8). From the Alpha variant, changes in the genetic code were identified, which lead to structural changes (9, 10) and are associated with increased cellular infectivity (11, 12), decreased neutralizing capacity of vaccine-induced antibodies (13–15), and failure in the detection of some diagnostic tests (16, 17). From the Delta variant, at least nine changes were identified in the spike protein that increase interaction with the ACE2 receptor, thereby enhancing virus infectivity. These changes also reduce the action of neutralizing antibodies and confer a shorter incubation period of 2 to 3 days (17). As for the Omicron variant, at least 60 changes have been identified, including changes in the spike protein that confer certain immune escape by reducing binding to some antibodies identified as neutralizing in previous variants (18). These changes also increase the binding affinity to ACE2, resulting in a higher transmission rate, which has been linked to disease progression (18–21). Although the exact mechanisms behind these disparities are still being researched, the inflammatory response and clinical manifestations of COVID-19 may also differ among these variants.

The severity of the disease’s clinical manifestation is ascertained by the extent of lung involvement, which results in varying degrees of hypoxia and respiratory failure. Inflammation is a critical element of this illness, and a heightened inflammatory reaction is linked with a poor prognosis. Therefore, employing inflammation biomarkers in the management of COVID-19 patients has become widespread during the pandemic. The improved prognosis of later waves of the disease is related mainly to the protection exerted by vaccination and greater knowledge of the disease and its management, and it might be related to the virus’s reduced capacity to provoke a systemic inflammatory response.

We hypothesize that the Wuhan SARS-Cov2 strain may elicit a more severe systemic inflammatory response compared to the more recent variants. Although these newer variants have a higher transmission rate, they Might generate a lower inflammatory response, particularly at the pulmonary level. This effect could be attributed to changes in the affinity of the variants for ACE2 receptors at the pulmonary level. The current study aims to investigate the relationship between the inflammatory response and COVID-19’s clinical characteristics across successive waves.

The hypothesis of our study was that the severity of the inflammatory response would decrease over time in relation to VOC, so that patients with the Omicron variant would show a lower elevation of inflammation biomarkers. However, we could not demonstrate that patients who required hospitalization for COVID-19 during the analyzed periods, with infections by different variants of SARS-CoV-2, presented a different inflammatory response. The values of CRP, PCT, LDH, or ferritin, biomarkers frequently used in this disease, were not different among the three groups. However, the dimer-D, which has also been considered as an inflammation marker in COVID-19 patients, was found to have a statistically significantly higher value in patients with the omicron variant. Nevertheless, when adjusting for age and severity, this significance disappears.

The severity of COVID-19 disease is partly determined by patients’ age (22, 23). In our series, although patients in the more recent variants were on average 10 years older, we could not find differences between the groups in terms of mortality or disease severity determined by the maximum score on the WHO scale. This may be influenced by higher vaccination rates in group 3 and better knowledge and management of the disease. However, lung involvement may have been more severe in group 1, as demonstrated by a higher proportion of bilateral pneumonia and greater use of anti-inflammatory drugs such as dexamethasone or tocilizumab. It is important to note that no changes were made to the COVID-19 management protocol at the hospital during the study period, and these differences could potentially be related to variability in decision making among treating physicians.

Throughout the pandemic, different specific laboratory markers have been used to help establish the risk of progression. There is abundant evidence in the literature that certain markers of inflammation, such as CRP, PCT, hematological markers (lymphocyte and neutrophil counts, D-dimer, ferritin), cardiac markers (troponin or CK-MB), or hepatic markers (AST, ALT, bilirubin), are useful in determining the prognosis of the disease (24). From the results of our study, we can confirm that patients who require hospitalization for COVID-19 present a similar inflammatory response regardless of the VOC responsible for the disease. Even the D-dimer, a recognized marker of thrombosis, is significantly higher in patients in group 3, with the Omicron VOC.

This absence of differences could be interpreted as indicating that the inflammatory response is dictated by the severity of the disease, not by the variant of virus causing it. If a patient suffers a severe enough infection to require hospitalization, the inflammatory response measured by commonly used biomarkers will be similar if the severity of the condition is similar.

Our study has some limitations. The assumption that it is a specific VOC is based on epidemiological data, not confirmation in the study patients. However, the appearance of a specific VOC is related to rapid expansion and widespread substitution of the previous variant by the new variant, so we believe that the periods analyzed reflect infections by different VOC. It is an observational, retrospective study with inevitable selection biases in this type of study. We selected consecutively hospitalized patients in the periods studied without any prior criteria, so we believe it is a selection with little bias. Nonetheless, the findings might be significant in broadening our understanding of the inflammatory reaction in individuals suffering from COVID-19.

In conclusion, the inflammatory response in hospitalized COVID-19 patients, determined by biomarkers such as CRP, ferritin, PCT or LDH, is similar between infections caused by different VOCs between 2021 and 2022. It appears that the severity of COVID-19 in hospitalized patients may determine the level of inflammatory response, rather than the particular viral strain responsible for the illness.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by García Arenillas. CEIm Hospital Clínico San Carlos. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin because the study design does not pose major risks for the participants as it is an observational and retrospective study. On the other hand, taking into account the intention to include inpatients consecutively, the fact that some of the patients have died and that it is a retrospective study covering the period from 2021 to 2022, it is practically impossible to collect the informed consent of all the study subjects. Since these aspects are fundamental for obtaining results that are faithful to reality, the requirement of individual consent would make it impractical to carry out the study.

J-RH-F: Conceptualization, Formal Analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AV: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Validation, Writing – review & editing. AG: Investigation, Validation, Writing – review & editing. NC: Conceptualization, Validation, Writing – review & editing. IO: Investigation, Validation, Writing – review & editing. EO: Conceptualization, Validation, Writing – review & editing. CF: Investigation, Validation, Writing – review & editing. MM: Conceptualization, Validation, Writing – review & editing. VE: Conceptualization, Methodology, Validation, Writing – original draft, Writing – review & editing.

Rafael Sánchez-del-Hoyo: Hospital Clınico San Carlos, IdISSC, Unidad de Apoyo Metodologico a la Investigacion y departamento preventivo, Madrid, Spain. Isabel Zarza, Valeria Cabral, Nieves Sans, Javier Rodrı́guez-Añover: Servicio de Enfermedades Infecciosas, Instituto de Investigacion Sanitaria del Hospital Cınico San Carlos (IdISSC), Hospital Clínico San Carlos, Madrid, Spain.