Overall Enrollment & Baseline Characteristics
A total of 383 patients were enrolled and received at least three doses (50 mg) of NaIHS (Figure 1); 253 from multiple hospitals in Cordoba Province, 95 from a single hospital in Buenos Aires and 35 from multiple hospitals in Mendoza Province. At Baseline (before initiation of NaIHS therapy) 327 were not receiving mechanical ventilation (MV) while 56 patients (14.6%) were receiving MV. Outcome measures are presented for these two aggregate groups separately. Among patients not receiving MV at baseline (n=327), mean age was 59 and the majority (62.5%) were male (Table 1). Prior diagnoses of diabetes, cardiovascular disease including hypertension, and chronic lung disease were noted in 22%, 44% and 14% of patients, respectively. Baseline SpO2 was 91%, with 75% of patients on supplemental oxygen at the time of measurement (baseline). The mean and median NEWS 2 score at baseline for this group was 7.0.
Among patients receiving MV at baseline (n-56), mean age was 60.6 and the majority were male (Table 1). Prior diagnoses of diabetes, cardiovascular disease including hypertension and chronic lung disease was noted in 28.6%, 46.6% and 23.2% of patients, respectively. Baseline SpO2 was 90±0.8, and 100% were on supplemental oxygen at the time of measurement (baseline). The mean and median NEWS 2 score at baseline for this group was 8.7 and 8.0.
NEWS 2 Scores: The mean daily NEWS 2 score for patients not on MV at Baseline is presented in Figure 2. Progressive improvement over Days 1 through 6 to a mean NEWS2 score of <4 is evident in the group as a whole. For a subset of patients (n=60), NEWS 2 scores were available for a time period of 1 to 3 days prior to initiation of NaIHS therapy. Strikingly, this subgroup of patients demonstrated progressive clinical deterioration indicated by worsening NEWS2 scores prior to initiation of NaIHS therapy, with peak NEWS 2 score evident on the day of (but prior to) therapy initiation. This clinical course reversed dramatically coinciding with initiation of NaIHS therapy. In Figure 2, data for patients enrolled from each province are graphed separately demonstrating a range in baseline disease severity.
The mean daily respiratory rate (RR) for patients not on MV at baseline are presented in Figure 3A. Consistent with the observation of NEWS2 scores over time, following initiation of NaIHS there was steady improvement in mean RR for this group, and for the subset with pre-ibuprofen therapy data collection, a trend of increasing (worsening) RR despite the addition of supplemental oxygen is clear, with immediate improvement after NaIHS initiation. Overall, mean RR for the entire group had normalized (≤ 20 breaths/minute) by Day-6, with decreasing numbers of patients on supplemental oxygen during this time period.
Oxygen Saturation: Mean daily pulse oximetry oxygen saturation for patients not on MV at Baseline is presented in Figure 3B. As was observed with RR and NEWS2 scores, among patients with available data prior to initiation of therapy with NaIHS, there was daily deterioration in oxygen saturation (despite increasing use of supplemental oxygen), which reversed acutely with initiation of therapy. By Day 6, mean SpO2 was >94%, remaining at this level with decreasing numbers of patients on supplemental oxygen and discharge from hospital of increasing numbers of patients. Importantly, this figure reflects the SpO2 status of patients still hospitalized; as patients improved, they were discharged, creating a data bias towards flattening of the improvement curve (or worsening). Indeed, this phenomenon was observed in the Cordoba subset of patients at Days 9-10, but for the entire study population, stable improvement of oxygenation is observed.
Length of Hospital Stay (LOS) & Duration of Therapy (DOT): Among patients not on MV at baseline, the average LOS was 11.5±0.3 days (Table 1), with DOT of 9.0±0.2 days. In this group, 25 patients never required oxygen supplementation; among those receiving oxygen therapy (n=302), the mean duration of oxygen supplementation was 6 days, with a median duration of 5 days. For the 35 patients who progressed to death (10.7%), the average LOS was 13±1.2 days. Among patients on MV at baseline, the average LOS was 15.5±1.4 days (Table 2), with DOT of 10.5±0.7 days. For the 11 patients who progressed to death in hospital (19.6%), the ALOS was 13.5±3.3 days.
In Hospital Mortality Rates: Overall in-hospital mortality among patients receiving NaIHS was 12.0% (46/383). At the time of data collection 28 patients remained in hospital (some for social reasons despite returning to clinical stability). Mortality among patients not on MV at baseline was 10.7%, and for those on MV at baseline, 19.6% (Figure 1). For the subset of patients not on MV at baseline (n=327), mortality rates were influenced by age and baseline oxygenation status (Tables 2 and 3). Among patients of age ≤ 60 (Table 2), overall mortality was 3.4% (6/174), occurring in 5 patients who presented with baseline SpO2 ≤ 90%, and in 1 who presented with normal oxygenation but died with sepsis (an immunosuppressed renal transplant recipient). Among patients > age 60 (Table 3), overall mortality was 19.0% (29/153), the majority of deaths occurring in patients presenting with SpO2 <90% (19/29, 66%).
Concomitant medications: SOC medications administered to the majority of patients included: dexamethasone 6 mg qd, (79.4%), enoxaparin 40 mg sc qd (81.2%), and the combination of clarithromycin 500 mg bid and ampicillin-sulbactam 3.0 gr tid (63.2 %). A small number of patients received convalescent plasma, ivermectin or hydroxychloroquine.
Adverse Events: No serious AE events were considered directly related to NaIHS. Patients reported mild to moderate cough during the first doses of NaIHS and salty taste. Bradycardia associated with improved SpO2 was observed in some patients. Three episodes of epistaxis were reported. One patient reported ibuprofen allergy, another claustrophobic reaction due to the hood and another patient developed a cough that was considered secondary to nebulization therapy, these three discontinued the medication permanently.