LAUSR

In this issue of Bone Marrow Transplantation, Ogimi and colleagues report on a large cohort of 1027 allogeneic hematopoietic cell transplant (HCT) recipients from a single center infected with respiratory viruses (excluding severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) to identify risk factors for progression to lower respiratory tract infection (LRTI). The authors evaluated in their cohort the use of the Immunodeficiency Scoring Index (ISI) [1], a combination of different predictors of LRTI, in addition to risk factors such as hyperglycemia and hypoalbuminemia. Prior studies identified lymphopenia, neutropenia, age, time from transplantation, exposure to steroids, graftversus-host disease, prior autologous HCT, smoking history, and type of transplant as risk factors for progression to an LRTI [2]. Our group developed the ISI for respiratory syncytial virus (RSV) that combines seven major risk factors to predict the rate of LRTI in allogeneic HCT recipients in a large cohort (n= 237) [1]. The ISI assigns a weighted score to each risk factor based on its adjusted hazard ratio. These factors include neutropenia (absolute neutrophil count <500/μl), lymphocytopenia (absolute lymphocyte count <200/μl), patient age of at least 40 years, use of a myeloablative conditioning regimen, acute or chronic graftversus-host disease, use of corticosteroids within 30 days of RSV infection, and transplantation within 30 days of or in the preengraftment period during RSV infection [1]. This quantifiable ISI stratifies patients into low-risk (0–2), moderate-risk [3–6], and high-risk (≥7) categories regarding progression or death. Studies have validated the ISI for different respiratory viral infections in allogeneic and autologous HCT recipients at multiple centers with varying success [2–6]. In addition to a high ISI score (≥7), Ogimi and colleagues identified factors not reported before in multivariate models, such as hypoalbuminemia (<3 g/dL), more than one HCT prior to infection, and hyperglycemia (peak glucose level >200 mg/dl), with the highest risk for progression to LRTI in patients with RSV and metapneumovirus infections. Notably, some of these factors are potentially modifiable, such as hyperglycemia and hypoalbuminemia. Not surprisingly, influenza infection was not associated with significant progression to LRTI in their analysis, as therapy with a neuraminidase inhibitor such as oseltamivir may have altered the course of the infection. In a previous study, we showed that early therapy (within 48 h of symptom onset) with oseltamivir was associated with decreased rates of LRTI and death regardless of the ISI score [7]. Influenza vaccines in allogeneic HCT recipients may also impact outcomes, but this remains to be determined in future studies [7]. The variable definitions in this study were consistent with those in prior studies by their group and others [6, 8, 9], including LRTI and lymphopenia. The Use of consistent variable definitions across studies increases the reliability of quantitative models like the ISI score in predicting outcomes from respiratory viral infections, which will lead to better design and planning of future clinical trials in this patient population. Ogimi and colleagues did not analyze mortality or risk factors for mortality in their study. We believe this information may be of great value to better delineate strategies to prevent this outcome. The ISI was intended to predict mortality in allogeneic HCT recipients with RSV, with 0%, 3%, and 29% rates of 90-day mortality due to RSV associated with low, moderate, and high ISI scores, respectively (p < 0.0001) [1]. Our group validated the association of a high ISI score with 30and 90-day overall mortality in RSV-infected HCT recipients in another study [10]. Preventing progression to LRTI would reduce mortality rates, and strategies such as early therapy or “pre-emptive therapy” at the upper respiratory tract infection phase and vaccination prior to infection are strongly recommended in allogeneic HCT recipients. Vaccination to prevent these complications is limited to influenza and Coronavirus disease 2019 (COVID-19) vaccines at this time, however. In nontransplant patients, early treatment of influenza infection with oseltamivir [11, 12] and of COVID-19 with molnupiravir [13] was effective in preventing poor outcomes, such as hospitalization or even death. However, conducting large clinical trials in allogeneic HCT recipients with infection with a respiratory virus is challenging at best because of the seasonality of many of these infections and a limited number of transplant recipients affected. High-risk allogeneic HCT recipients who would benefit the most from therapeutic intervention should be the targeted patient population for inclusion in clinical trials for respiratory viral infections. In a recent trial assessing the efficacy of molnupiravir in preventing hospitalization and death in patients with COVID-19, Bernal et al. [13] selected a population at high risk for