Neutralizing monoclonal antibodies for early treatment of hospital‐acquired SARS‐CoV‐2 infection in hematologic patients

Abstract Efficacy of early treatment with anti‐SARS‐CoV‐2 spike protein monoclonal antibodies (mAbs) for nosocomial SARS‐CoV‐2 infection in hematologic patients is unknown. Retrospective, cohort study conducted in four Italian teaching hospitals. We included adult patients with hematologic malignancies and hospital‐acquired SARS‐CoV‐2 infection diagnosed between November 2020 and December 2021. The principal exposure variable was administration of mAbs. The primary endpoint was clinical failure dea composite outcome of mortality and/or invasive and noninvasive ventilation within 90 days from infection onset. We included 52 patients with hospital‐acquired SARS‐CoV‐2 infection. Males were 29 (60%), median age was 62 (interquartile range [IQR] 48–70). Forty‐five (86%) patients were on chemotherapy or had received chemotherapy within 30 days. MAbs were administered in 19/52 (36%) patients. Clinical failure occurred in 22 (42%) patients; 21% (4/19) in mAbs group versus 54% (18/33) in non‐mAbs group (p = 0.03). Other predictors of clinical failure were older age (median [IQR] 69 [61–72] versus 58 [46–66], p = 0.001), and higher Charlson comorbidity index (median [IQR], 5 [3.25‐5] versus 3 [2–5], p = 0.002). At multivariable Cox regression model, mAbs were independently associated with a significantly lower rate of clinical failure (HR 0.11, 95% CI 0.01–0.85, p = 0.01), after adjusting for confounders. In conclusion, mAbs are promising for early treatment of hematologic patients with healthcare‐related SARS‐CoV‐2 infection.


Criteria for SARS-CoV-2 screening and definitions
In the participating hospitals routinary screening for SARS-CoV2 was performed in all admitted patients at admission, usually once weekly in asymptomatic patients, in case of other nosocomial cases and in case of symptoms suspicious for COVID-19 using nasal swab for real-time polymerase chain reaction (RT-PCR) assay.

SARS-CoV-2 infection was defined on a new laboratory-positive
infection detected by RT-PCR assay in respiratory specimen. Infection onset was set on the day of first SARS-CoV-2 RT-PCR detection.
Hospital-acquired SARS-CoV-2 infection was defined by a new onset of COVID-19 symptoms, and positive result of SARS-CoV-2 molecular test occurred at least 14 days after hospital admission [9] or 7 days in case of documented in-hospital exposure to another diagnosed case of COVID-19, in patients with one or more negative RT-PCR test performed at hospital admission or afterwards. We considered the time-lapse of 14 days as the maximum estimated period of viral incubation as reported in previous studies [8] and according with last ECDC surveillance definitions [9].
We chose the study population of hematologic cancer patients who acquired SARS-CoV-2 infection during hospitalization because they represent the population most vulnerable to have severe COVID-19.
Moreover, in this way we were able to provide a homogeneous control group of nontreated patients followed from infection onset and excluding outpatients who have generally been tested at different time-points of the course of infection.

Endpoint and exposures
The main exposure variable was administration of mAbs. Choice of mAbs as compound of COVID-19 treatment was basically driven by the availability of the drug at the moment of the infection.  Figure 1A). Results were consistent after excluding patients with baseline positive serum antispike antibodies collected before mAbs administration (log-rank p = 0.06, Figure 1B).
After comparison between patients with and without clinical failure (

Impact of mAbs on 30-day mortality
Overall, 14 (27%) died within 30 days from COVID-19 onset of which three (15%) in the mAbs group and 11 (33%) in the control group, with no statistical differences (log-rank p = 0.18) Figure 2.

DISCUSSION
In this study, we report the clinical features and outcome of 52 hema-

COVID-19 management
Corticosteroids, n (%) 19   Another important finding of our study was that an early use of mAbs was associated with lower rate of critical COVID-19 11 (21% versus 54% in patients treated and not with mAbs, respectively) even after adjustment for potential confounders such as age or comorbidities. Other studies showed that viral shedding in immunocompromised host could be much longer that immunocompetent patients [3,19].
As hematologic treatments are generally interrupted during active infections, shortening of viral shedding with mAbs may allow an early restarting of chemotherapy, which is a determinant factor for survival in patients with HM.
This study has some limitations. First, the small sample size may limit the generalizability of results, but luckily nosocomial cases of SARS-CoV2-infection remain infrequent, and currently most data come from case reports. In addition, typically for SARS-CoV-2 pandemics, patients'

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Open Access funding provided by IRCCS Ospedale Policlinico San
Martino.
[Correction added on 28 November 2022, after first online publication: BIBLIOSAN funding statement has been added.]

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHIC STATEMENT
The study was conducted in accordance with the current version of the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice (ICH-GCP), and national legislation for data protection.