key: cord-0940895-p2pl2edr authors: Lior, Yotam; Yatzkan, Noga; Brami, Ido; Yogev, Yuval; Riff, Reut; Hekselman, Idan; Fremder, Moran; Freixo-Lima, Gabriella; Be'er, Moria; Amirav, Israel; Lavie, Moran title: Fractional exhaled Nitric Oxide (FeNO) level as a predictor of COVID-19 disease severity date: 2022-05-18 journal: Nitric Oxide DOI: 10.1016/j.niox.2022.05.002 sha: 787ab9c96875632d2b7fda63f700d6ec535464c8 doc_id: 940895 cord_uid: p2pl2edr OBJECTIVE: To assess the feasibility of Fractional exhaled Nitric Oxide (FeNO) as a simple, non-invasive, cost-effective and portable biomarker and decision support tool for risk stratification of COVID-19 patients. METHODS: We conducted a single-center prospective cohort study of COVID-19 patients whose FeNO levels were measured upon ward admission by the Vivatmo-me handheld device. Demographics, COVID-19 symptoms, and relevant hospitalization details were retrieved from the hospital databases. The patients were divided into those discharged to recover at home and those who died during hospitalization or required admission to an intensive care unit, internal medicine ward, or dedicated facility (severe outcomes group). RESULTS: Fifty-six patients were enrolled. The only significant demographic difference between the severe outcomes patients (n = 14) and the home discharge patients (n = 42) was age (64.21 ± 13.97 vs. 53.98 ± 15.57 years, respectively, P = .04). The admission FeNO measurement was significantly lower in the former group compared with the latter group (15.86 ± 14.74 vs. 25.77 ± 13.79, parts per billion [PPB], respectively, P = .008). Time to severe outcome among patients with FeNO measurements ≤11.8 PPB was significantly shorter compared with patients whose FeNO measured >11.8 PPB (19.25 ± 2.96 vs. 24.41 ± 1.09 days, respectively, 95% confidence interval [CI] 1.06 to 4.25). An admission FeNO ≤11.8 PPB was a significant risk factor for severe outcomes (odds ratio = 12.8, 95% CI: 2.78 to 58.88, P = .001), with a receiver operating characteristics curve of 0.752. CONCLUSIONS: FeNO measurements by the Vivatmo-me handheld device can serve as a biomarker and COVID-19 support tool for medical teams. These easy-to-use, portable, and noninvasive devices may serve as valuable ED bedside tools during a pandemic. Fractional exhaled Nitric Oxide (FeNO) is an easily achievable, noninvasive measurement of 1 exhaled air that is to known to be associated with respiratory dynamics in the clinical setting. 2 For instance, it was shown to be effective in monitoring asthma exacerbations and in 3 assessing the clinical course of various respiratory viral infections [9] [10] [11] [12] [13] . FeNO is produced 4 in airway epithelial and inflammatory cells mainly by the enzyme inducible nitric oxide 5 synthase (iNOS). Angiotensin-converting enzyme 2 (ACE2) was shown to be involved in 6 airway NO production via downstream effects on iNOS, [14] [15] [16] [17] and to be a significant 7 airway and vascular regulator [18, 19] . Much like its counterpart SARS-CoV-1, SARS-CoV-8 2 was shown to invade respiratory epithelial cells via the ACE2 receptor. Interestingly, ACE2 9 was shown to be downregulated during a SARS-CoV-1 infection [20] . It is therefore logical 10 to assume the existence of a negative correlation between SARS-CoV-2 infection burden and 11 ACE2 airway expression, representing a correlation that could affect downstream airway NO 12 production and therefore FeNO measurements. Thus, FeNO may serve as an indirect 13 predictor of COVID-19 disease burden, allowing risk stratification and medical decision-14 making regarding COVID-19 patients. The purpose of this study was to assess the potential 15 use of FeNO as a prognostic biomarker of outcome severity and its application as a tool for 16 risk stratification for supporting management decision-making of COVID-19 patients at 17 admission to the emergency department (ED). This was a single-center, prospective cohort study whose aim was to assess the 4 applicability of admission FeNO levels as a biomarker for hospitalization outcome of 5 COVID-19 patients. 6 7 Adult patients hospitalized between December 2020 and March 2021 in dedicated 9 COVID-19 wards in the Tel Aviv Medical Center (TLVMC), a major tertiary hospital in 10 central Israel, were prospectively enrolled in this study. Inclusion criteria were a positive 11 oropharyngeal and nasopharyngeal swab SARS-CoV-2 PCR test and the ability to perform 12 the FeNO test. Patients unable or unwilling to sign an informed consent or to undergo the 13 FeNO measurement procedure were excluded from the study. This study was approved by the 14 TLVMC institutional ethics committee (IEC, 0355-20-TLV). 15 16 Following enrolment, the study patients were given a short explanation of the 18 exhalation procedure and requested to perform the FeNO measurements. In order to optimize 19 the chances for successful measurement, each participant was requested to perform 3 FeNO 20 measurements, which were later averaged to represent the enrolment FeNO. They were then 21 requested to respond to a questionnaire on demographics (age, sex, and comorbidities), 22 COVID-19 symptoms (fever, fatigue, cough, myalgia, nasal congestion, sore throat, diarrhea, 23 and dyspnea), and onset dates. Further clinical data were obtained from electronic medical 24 files, including vital signs (temperature, heart rate, blood pressure, and O2 saturation), 25 laboratory evaluations (complete blood counts, coagulation tests, biochemistry tests, 1 inflammatory markers, such as C-reactive protein [CRP], troponin, and venous blood gas 2 analysis) on admission and before discharge, length of stay, treatment, and clinical outcomes 3 (e.g., home discharge, transfer to an internal medicine ward, or transfer to the ICU, or death). 4 Follow-up telephone calls to the study participants were made 14 and 28 days after 5 hospital discharge. They were queried about the above-cited COVID-19 symptoms and 6 further need of medical attention. Hospital readmission and mortality during the 28 days post-7 discharge were assessed via the TLVMC electronic medical files. 8 The cohort of patients was divided into 2 groups comprised of those who were 9 discharged home with no required additional medical attention (the "home discharge" group), 10 and those with subsequent complications/severe outcomes, including death, admission to the 11 ICU, mortality, or transfer to a non-COVID-19 internal medicine ward or a dedicated 12 COVID-19 medical ward for continuous medical treatment (the "severe outcome" group). 13 14 Tests were executed by means of the Bosch's handheld Vivatmo-me device (Bosch 16 Healthcare Solutions, Waiblingen, Germany) for FeNO measurements [21] . The Vivatmo-me 17 is a handheld device utilizing a single-use mouthpiece and a chemical field-effect transistor, 8 screen. In order to minimize possible cross-contamination s, the study personnel were 1 properly protected with full personal protective equipment (PPE), and the Vivatmo-me device 2 was thoroughly sanitized between uses together with single-use mouthpiece replacements. 3 4 Statistical analyses were performed with IBM SPSS, and graphic representation with 6 GraphPad Prism software. Given the small sample size of the severe outcomes group, all of 7 the continuous variables were analyzed by means of a non-parametric approach which 8 included the Mann-Whitney U test. Categorical variables were tested with Pearson's χ2 test 9 for contingency tables or Fisher Exact test, as appropriate. Correlation analyses were 10 performed with Spearman rho (ρ) tests. Survival analysis was by Kaplan-Meier survival plots 11 with group comparisons assessed by the log-rank test. A univariate binary logistic model was 12 used for evaluation of the association between FeNO and severe outcomes. The 13 discriminative capability of the model was assessed by a receiver operating characteristics 14 (ROC) curve. All statistical tests and/or confidence intervals were performed at α=0.05 (2-15 sided). All P-values were rounded off to 2 decimal places. 16 1 3. RESULTS 2 Fifty-six patients (mean age±standard deviation [SD] 56.5±17.2 years, 51.8% females) 4 were enrolled in the study. Table 1 describes their basic demographic characteristics. Only 5 the variable of age was significantly different between the 2 groups, with the home-6 discharged patients being younger than the severe outcome patients (54±15.6 vs. 64.2±14 7 years, respectively, P=.04). 8 further care in an internal medicine ward or in a dedicated medical facility after being 4 discharged from the COVID-19 ward, 6 (42.9%) patients required ICU hospitalization, and 2 5 (14.3%) patients died from COVID-19. 6 Thirty-one home discharge patients (73.8%) and 34 severe outcomes (81%) patients 7 participated in both the 14-and 28-day follow-ups. Loss-to-follow-up rates were higher in the 8 severe outcome group, with only 4 patients (28.6%) responding to the 14-day follow-up call 9 and 5 (35.7%) responding to the 28-day follow-up call, possibly due to continued 10 hospitalization and treatment elsewhere. There were no group differences in COVID-19-11 related symptoms at 14 or 28 days following discharge. According to the TLVMC databases, 12 while no mortality was reported in our cohort during the follow-up period, 2 patients from the 13 home discharge group required hospitalization during the follow-up period at 6 and 11 days 14 post-discharge (data not shown). 15 16 As shown in Figure 1 , the admission FeNO measurements were significantly lower in the 18 severe outcomes group (15.9±14.7 vs. 25.8±13.8 PPB for the home discharge group, P=.008). 19 Inter-variable Spearman's ρ correlation analysis was performed to assess the association of 20 admission FeNO with severe outcomes, length of hospital stay, age, gender and asthma. Of 21 these, enrolment FeNO measurement was found to correlate significantly only with severe In this study, we assessed the efficacy and feasibility of an easily obtained admission 3 FeNO measurement as a biomarker for disease severity trajectory among hospital-admitted 4 COVID-19 patients. In our cohort of 56 patients, that FeNO measurement was significantly 5 lower among patients with severe hospitalization outcomes as determined by death, ICU 6 admission, or hospitalizatiion in a medical facility for continued care, compared with that of 7 patients who were discharged to their homes. Furthermore, an admission FeNO measurement 8 equal to or lower than 11.8 PPB was found to be associated with an earlier occurrence of 9 severe hospitalization outcomes, with an FeNO level ≤11.8 PPB serving as a significant risk 10 factor for these events in a univariate logistic regression model. 11 The FeNO level is a broadly used method for diagnosis and surveillance of various unable to amount such a response, which could suggest an added risk factor, as also 20 suggested by our results. 21 Other clinical scores for the prediction and identification of severe acute COVID-19, 22 such as the neutrophil-lymphocyte ratio (NLR) [27], early CRP [28], and neutrophilia and 23 coagulation dysfunction [3], have been previously described with ORs and hazard ratios 24 ranging from 1.14 to 1.61. Examination of these clinical scores of our cohort failed to reveal 25 a significant difference between the 2 study groups. In comparison, the admission FeNO 1 measurement was found to be a superior tool for the identification of severe acute COVID-19 2 cases, with an OR of 12.8, all the while being an easier, more rapid, noninvasive, and more 3 traceable tool. 4 Some limitations to this study bear mention. In spite of the study team's efforts, 5 recruitment of COVID-19 patients within the wards proved to be difficult, limiting the 6 sample size. The small sample size also limited our ability to relate our results to age 7 differences between the groups, although FeNO measurements reportedly do not seem to 8 differ across different ages in adult populations [29] . Additionally, it took place in a single 9 medical center, and a single Vivatmo-me device was used for all measurements. Lastly, our 10 study population did not include smokers or reported COPD patients, which may limit the 11 applicability of our results to wider populations. At the same time, however, the absence of 12 smokers in this study serves to further strengthen our results by essentially removing that Angiotensin-converting enzyme 2 priming enhances the function of 11 endothelial progenitor cells and their therapeutic efficacy. Hypertension Angiotensin II AT1 receptor alters ACE2 activity CD44-hyaluronan interaction in rats with hypertension and myocardial fibrosis Application of nitric oxide measurements in clinical conditions 17 beyond asthma