Nasopharyngeal SARS-CoV-2 Load at Hospital Admission as a Predictor of Mortality

to the editor—We read with interest the article by Bhargava et al [1] that was recently published in the Journal, which significantly contributes to the definition of clinical risk factors for severe coronavirus disease 2019 (COVID-19) manifestations. However, despite the comprehensive analysis of multiple clinical and laboratory parameters, the virus is still a poorly represented piece of this puzzle. During the severe acute respiratory syndrome coronavirus (SARSCoV-1) epidemic, higher viral loads were strongly correlated with disease severity and death [2]. Similarly, the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrated a strikingly fast, and intense, replication kinetics, whose contribution to the clinical evolution of COVID-19 is starting to be investigated [3–6]. The nasopharyngeal SARS-CoV-2 load expressed by cycle thresholds (Cts) of real-time polymerase chain reaction (RT-PCR), the standard-of-care for COVID-19 molecular diagnosis [7, 8], is a widely available parameter to be correlated with the severity of COVID-19. To prove this hypothesis, we investigated the correlation between the initial nasopharyngeal SARS-CoV-2 loads and 30-day in-hospital mortality in 206 consecutive adult patients with a laboratoryconfirmed SARS-CoV-2 infection, admitted to Niguarda Hospital (Milan, Italy) since 5 March, and who have either died or been discharged by 23 April 2020 (study protocol: 92-15032020). Dynamic ranges of categorized Ct values of viral RdRp, E, and N genes were assessed by quantitative droplet-digital PCR. The median (interquartile range) time from symptom onset to hospital admission was 6 (4–9) days. By then, 188 of 206 (91.3%) patients presented an interstitial pneumonia with groundglass opacities. Survivors (n = 153) and nonsurvivors (n = 53) significantly differed in several anamnestic, clinical, virological, and laboratory characteristics (Supplementary Appendix). These included both the mean and the absolute Ct values of RdRp, N, and E genes that were significantly lower in nonsurvivors compared with survivors (P = .001), reflecting higher viral loads in the nasal/throat compartment of the former patients. Of note, 20.7% of nonsurvivors had initial Cts less than 20 (viral loads ≥107 copies/mL) versus only 5.3% of survivors (P < .001). Kaplan-Meier curves showed a progressive increase in 30-day mortality, by increase in nasopharyngeal SARS-CoV-2 load (Figure 1). Thirty days after disease onset, the survival rate dropped to 35.3% in patients with Cts less than 20 (viral loads ≥10 copies/mL) versus 81.0% in patients with Cts greater than 35 (viral loads <10 copies/mL) (P = .001).

a single pharmacist leader is responsible for improving antibiotic use [6].
We agree with Bland and Jones that given their consistent presence and existing role within ASPs, pharmacists could greatly expand the accessibility of inpatient penicillin allergy assessments [7]. In our study, just 6 sites (13%, 5 academic medical centers and 1 community hospital), indicated that pharmacists were performing PST. While scope of practice limitations may be limiting pharmacists from performing PST in some US states, pharmacists have led programs addressing penicillin allergies with a variety of activities beyond performing skin testing: allergy history reconciliation, screening for PST, patient/provider education about penicillin allergy, protocol development for test doses/ drug challenges, penicillin allergy delabeling, and penicillin allergy relabeling monitoring [3].
While there are still barriers to widespread pharmacist penicillin allergy assessments, such as lack of "full provider" status in many states and lack of standardized drug allergy education and credentialing [8,9], we agree that pharmacists are ideal champions for inpatient β-lactam allergy programs and critical allies for allergists and infectious diseases doctors engaged in delabeling efforts [10]. manifestations. However, despite the comprehensive analysis of multiple clinical and laboratory parameters, the virus is still a poorly represented piece of this puzzle. During the severe acute respiratory syndrome coronavirus (SARS-CoV-1) epidemic, higher viral loads were strongly correlated with disease severity and death [2]. Similarly, the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrated a strikingly fast, and intense, replication kinetics, whose contribution to the clinical evolution of COVID-19 is starting to be investigated [3][4][5][6]. The nasopharyngeal SARS-CoV-2 load expressed by cycle thresholds (Cts) of real-time polymerase chain reaction (RT-PCR), the standard-of-care for COVID-19 molecular diagnosis [7,8], is a widely available parameter to be correlated with the severity of COVID-19. To prove this hypothesis, we investigated the correlation between the initial nasopharyngeal SARS-CoV-2 loads and 30-day in-hospital mortality in 206 consecutive adult patients with a laboratoryconfirmed SARS-CoV-2 infection, admitted to Niguarda Hospital (Milan, Italy) since 5 March, and who have either died or been discharged by 23 April 2020 (study protocol: 92-15032020). Dynamic ranges of categorized Ct values of viral RdRp, E, and N genes were assessed by quantitative droplet-digital PCR.
The median (interquartile range) time from symptom onset to hospital admission was 6 (4-9) days. By then, 188 of 206 (91.3%) patients presented an interstitial pneumonia with groundglass opacities. Survivors (n = 153) and nonsurvivors (n = 53) significantly differed in several anamnestic, clinical, virological, and laboratory characteristics (Supplementary Appendix). These included both the mean and the absolute Ct values of RdRp, N, and E genes that were significantly lower in nonsurvivors compared with survivors (P = .001), reflecting higher viral loads in the nasal/throat compartment of the former patients. Of note, 20.7% of nonsurvivors had initial Cts less than 20 (viral loads ≥10 7 copies/mL) versus only 5.3% of survivors (P < .001).
Kaplan-Meier curves showed a progressive increase in 30-day mortality, by increase in nasopharyngeal SARS-CoV-2 load (Figure 1). Thirty days after disease onset, the survival rate dropped to 35.3% in patients with Cts less than 20 (viral loads ≥10 7 copies/mL) versus 81.0% in patients with Cts greater than 35 (viral loads <10 3 copies/mL) (P = .001). Notably, the 36.4% of patients with initial Cts of less than 20 died within 7 days versus 14.3% and 0.0% of patients with initial Cts of 20-24.9 and higher (Cts >25) (P = .006).
Overall, we identified the high initial nasopharyngeal viral load as an independent risk factor for in-hospital mortality, and for a significantly faster worsening of clinical conditions towards death. These results strengthen the recently reported correlation between viral load and severe disease [5,6] and provide initial evidence of a role for viral load in influencing the definitive outcome. As RT-PCR on nasopharyngeal swabs is used worldwide, clinically validated Ct cutoffs (ie, <20) represent a ready-touse prognostic marker to help stratify patients for risk of in-hospital death, and to consequently implement appropriate measures to contain fatalities.  report; or in the decision to submit the paper for publication.
Financial support. This work was supported by the Italian Ministero dell'Istruzione · Ministero dell'Università e della Ricerca (MIUR), Ministry of Education, University and Research (PRIN grant number 20179JKAMZ).
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have