The treatment of hospitalized patients with COVID-19 has undergone profound changes since March 2020, and interventions varied over time as a result of accumulating evidence from both observational and randomized studies conducted across different waves of the pandemic (1–3). This is particularly true for monoclonal antibodies. Since the beginning of the pandemic, it was understood that they could play a role in treating COVID-19 disease especially during the viral phase of the infection, as proved to be effective in animal models and in vitro studies on rapid culture conversion of SARS-CoV-2 infection (4, 5). Indeed, several monoclonal antibodies, when tailored against the specific predominant circulating viral variant, were shown to be effective in preventing SARS-CoV-2 infection (especially in immunocompromised individuals) and hospitalization if administered within the first 5–7 days after the infection (6–10).

Concerning hospitalized patients, since patients in this setting are typically in the inflammatory phase of COVID-19, the role of these compounds is more unclear. Indeed, two placebo-controlled randomized trials, one with bamlanivimab and one with either sotrovimab or the combination of BRII-196 and BRII-198, were terminated earlier due to futility (11–13).

Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, which bind specifically to the receptor-binding domain of the spike glycoprotein of SARS-CoV-2, thereby blocking viral entry into host cells (14). Recently, two randomized trials were conducted among hospitalized patients with CAS/IMV: the RECOVERY platform trial and a smaller trial conducted in the USA on 1,336 patients (6, 15). The RECOVERY trial showed a clear benefit in terms of survival, particularly when restricting the analysis to patients with a negative antibody status at hospital admission (RR 0.79, 95% CI 0.69–0.91; P = 0.0009). A similar result in terms of survival, still when restricting the analysis to seronegative patients, was obtained in another recently published study (15). Based on these results, all international guidelines suggested monoclonal antibodies for hospitalized subjects seronegative for SARS-CoV-2 in the pre-Omicron era.

To our knowledge, no real-life data on CAS/IMV outcomes in hospitalized patients with severe COVID-19 pneumonia have been published until now. With these premises, the aim of our analysis was twofold: first, we aimed to estimate the in-hospital day-28 risk of mechanical ventilation (MV) and death in a large cohort of patients admitted to hospital with SARS-CoV-2 pre-omicron variants of concern (VoCs) and treated with CAS/IMV. Second, we aimed at identifying variables measured at the time of hospital admission that could predict these poor outcomes as well as derive a prediction algorithm for clinical use (16–18).

This multi-center observational study analyzed individuals who confirmed positive for SARS-CoV-2 through nasal swab tests and hospitalized patients with severe COVID-19 who were treated with CAS/IMV in 12 tertiary care hospitals in Italy. Among the 12 hospitals, nine hospitals provided data for the training set and three hospitals provided for the test set (Supplementary Table S3). All adult patients consecutively hospitalized with severe COVID-19 and treated with CAS/IMV from November 2021 to March 2022 were included. Severe COVID-19 was defined in accordance with the NIH (National Institute of Health) guidelines. We excluded patients for whom there was no confirmation of the SARS-CoV-2 positive test, those who were not eligible for treatment with CAS/IMV, and those who started other treatments. The retrospective data were fully anonymized and were last assessed on February 2023. CAS/IMV were administered intravenously at the dose of 4 g for each antibody.

To our knowledge, this study can be considered the largest real-world analysis evaluating the effectiveness of CAS/IMV on mortality and MV in subjects with severe COVID-19 at hospital admission. The main result is that, in our setting, where 80% tested SARS CoV-2 negative and approximately 20% of the study population received vaccination for SARS-CoV-2, the risk of day 28 MV/death remained high. Indeed, our cohort exhibited a mortality rate of 6%, with 12% of the patients experiencing the primary end-point MV/death. However, these estimates are much lower than those observed in the RECOVERY trial (24% by day 28 in seronegative patients receiving CAS/IMV vs. 30% of the controls receiving usual care). In contrast, our estimates are similar to those of a recently published study conducted in the USA, which reported a mortality rate of 6% among seronegative patients treated with CAS/IMV compared to 15% of those receiving placebo (15). This difference in the mortality rate across studies is not unexpected and might be explained by the period in which these studies were conducted. Indeed, the randomized studies were conducted between June 2020 and May 2021, before the start of the COVID-19 vaccination campaign. Given the rapid evolution of SARS-CoV-2, changes in virus pathogenicity, and variations in the severity of the conditions among patients admitted to the hospital, even a difference of just 1 month could determine a significant difference in mortality rates. Furthermore, patients enrolled in our study had a lower disease severity at entry and were hospitalized, possibly benefiting from a larger number of drugs recommended in the guidelines. Finally, we cannot rule out that our cohort represents a selected population of individuals who survived long enough after hospital admission to be treated with CAS/IMV.

Contrary to what was previously described, only cardiac insufficiency [and not diabetes or hypertension, for example (19–22)] showed an association with the risk of outcomes after controlling for sex and age. However, this association did not persist after further controlling for other factors included in the score.

The patients who underwent MV or died and the controls differed significantly in age, PaO²/FiO² ratio, LDH, and platelet count, all factors that characterized severe COVID-19 since the beginning of the pandemic and were included in similar predictive algorithms. However, it was important to confirm that they are still strong predictors of outcomes in our specific setting.

Prediction accuracy of the derived score was high (84% in the toughest external validation) and did not vary by the endpoint chosen. If anything, the score derived on the composite endpoint was even more predictive when applied to the secondary endpoint of death alone. The score also showed good calibration, a metric which is often neglected when evaluating the performance of a score in addition to discrimination (23). A well-discriminating model similar to our model (i.e., with a c-statistic >0.8) may be useless if the decision threshold for clinical decisions is outside the range of predictions provided by the model. Importantly, good calibration was retained in the test set.

Our study has several limitations; first, CAS/IMV are not currently used in clinical practice as they are considered to be not active against the new omicron VoC and therefore it is unlikely that the score could be used in clinical practice for this particular combination. However, monoclonal antibodies are still in development and are tailored to the fast-evolving virus. Some of these new compounds might be re-introduced for the treatment of hospitalized patients as well. Second, it is a retrospective cohort; therefore, data collection was not complete for some biomarkers, and we performed a complete case analysis excluding those with missing laboratory data. Third, we constructed a simple model based on a linear predictor. We cannot rule out that a full machine learning approach with a larger number of variables as well as their interactions could have led to better values for the AUC in validation and test. For example, the score does not account for time-varying data including medical interventions received post hospitalization. Fourth, the sample size of the test cohort was relatively small including approximately 150 participants. However, the AUC in external validation test for both endpoints remained >80% which is considerably above the minimum for a good discrimination.

The main strength of our analysis is that it is the first score derived for hospitalized patients treated with CAS/IMV. In addition, it is very easy to use in practice, uses a small number of routinely collected features, and is calculable without having to input patients' data into a website or a similar graphic user interface (24).

In conclusion, although CAS/IMV is no longer routinely used in clinical practice, our newly developed score might help in identifying at hospital admission which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions.

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 the Institutional Ethics Committee of Area Vasta Emilia Nord. The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants' legal guardians/next of kin because Due to the observational nature of the study, written informed consent was not required.

AC-L: Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing, Formal analysis. VB: Writing – original draft. SR: Writing – original draft. BM: Writing – original draft. AF: Writing – original draft. CD: Writing – original draft. FB: Writing – original draft. PC: Writing – original draft. PM: Writing – original draft. CTo: Writing – original draft. AC: Writing – original draft. GC: Writing – original draft. MB: Writing – original draft. CTa: Writing – original draft. GP: Writing – original draft. SC: Writing – original draft. AG: Writing – original draft. GM: Data curation, Writing – original draft. ML: Writing – original draft. LC: Writing – original draft. CS: Writing – original draft. AD'A: Writing – original draft. VM: Writing – original draft. GG: Data curation, Writing – original draft. EF: Data curation, Writing – review & editing. MM: Writing – original draft. LS: Writing – review & editing. AA: Writing – original draft. EN: Writing – review & editing. CM: Writing – review & editing, Conceptualization, Methodology, Supervision, Writing – original draft.