Bromhexine Hydrochloride Prophylaxis of COVID-19 for Medical Personnel: A Randomized Open-Label Study.

BACKGROUND: Bromhexine hydrochloride has been suggested as a TMPRSS2 protease blocker that precludes the penetration of SARS-CoV-2 into cells. We aimed to assess the preventive potential of regular bromhexine hydrochloride intake for COVID-19 risk reduction in medical staff actively involved in the evaluation and treatment of patients with confirmed or suspected SARS-CoV-2 infection. METHODS: In a single-centre randomized open-label study, medical staff managing patients with suspected and confirmed COVID-19 were enrolled and followed up for 8 weeks. The study began at the initiation of COVID-19 management in the clinic. The study was prematurely terminated after the enrollment of 50 participants without a history of SARS-CoV-2 infection: 25 were assigned to bromhexine hydrochloride treatment (8 mg 3 times per day), and 25 were controls. The composite primary endpoint was a positive nasopharyngeal swab polymerase chain reaction (PCR) test for SARS-CoV-2 or signs of clinical infection within 28 days and at week 8. Secondary endpoints included time from the first contact with a person with COVID-19 to the appearance of respiratory infection symptoms; the number of days before a first positive SARS-CoV-2 test; the number of asymptomatic participants with a positive nasopharyngeal swab test; the number of symptomatic COVID-19 cases; and adverse events. RESULTS: The rate of the combined primary endpoint did not differ significantly between the active treatment group (2/25 [8%]) and control group (7/25 [28%]); P=0.07. A fewer number of participants developed symptomatic COVID-19 in the treatment group compared to controls (0/25 vs. 5/25; P=0.02). CONCLUSION: Although the study was underpowered, it showed that Bromhexine hydrochloride prophylaxis was associated with a reduced rate of symptomatic COVID-19. The prophylactic treatment was not associated with a lower combined primary endpoint rate, a positive swab PCR test, or COVID-19 (ClinicalTrials.gov number, NCT04405999).

Cytokine Storm Signature in Patients with Moderate and Severe COVID-19.

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1ß, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19.

Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study.

Recent studies showed that a low 25-hydroxyvitamin D (25(OH)D) level was associated with a higher risk of morbidity and severe course of COVID-19. Our study aimed to evaluate the effects of cholecalciferol supplementation on the clinical features and inflammatory markers in patients with COVID-19. A serum 25(OH)D level was determined in 311 COVID-19 patients. Among them, 129 patients were then randomized into two groups with similar concomitant medication. Group I (n = 56) received a bolus of cholecalciferol at a dose of 50,000 IU on the first and the eighth days of hospitalization. Patients from Group II (n = 54) did not receive the supplementation. We found significant differences between groups with the preferential increase in serum 25(OH)D level and Δ 25(OH)D in Group I on the ninth day of hospitalization (p < 0.001). The serum 25(OH)D level on the ninth day was negatively associated with the number of bed days (r = -0.23, p = 0.006); we did not observe other clinical benefits in patients receiving an oral bolus of cholecalciferol. Moreover, in Group I, neutrophil and lymphocyte counts were significantly higher (p = 0.04; p = 0.02), while the C-reactive protein level was significantly lower on the ninth day of hospitalization (p = 0.02). Patients with supplementation of 100,000 IU of cholecalciferol, compared to those without supplementation, showed a decrease in the frequencies of CD38++CD27 transitional and CD27-CD38+ mature naive B cells (p = 0.006 and p = 0.02) and an increase in the level of CD27-CD38- DN B cells (p = 0.02). Thus, the rise in serum 25(OH)D level caused by vitamin D supplementation in vitamin D insufficient and deficient patients may positively affect immune status and hence the course of COVID-19.

Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19.

A low 25-hydroxyvitamin D (25(OH)D) level is considered as an independent risk factor for COVID-19 severity. However, the association between vitamin D status and outcomes in COVID-19 is controversial. In the present study we investigate the association between the serum 25(OH)D level, immune response, and clinical disease course in patients with COVID-19. A total of 311 patients hospitalized with COVID-19 were enrolled. For patients with a vitamin D deficiency/insufficiency, the prevalence of severe COVID-19 was higher than in those with a normal 25(OH)D level (p < 0.001). The threshold of 25(OH)D level associated with mortality was 11.4 ng/mL (p = 0.003, ROC analysis). The frequency of CD3+CD4+ T helper (Th) cells was decreased in patients with 25(OH)D level ≤ 11.4 ng/mL, compared to healthy controls (HCs). There were no differences in the frequency of naive, central memory (CM), effector memory (EM), and terminally differentiated effector memory Th cells in patients with COVID-19 compared to HCs. The frequency of T-follicular helpers was decreased both in patients with 25(OH)D level > 11.4 ng/mL (p < 0.001) and 25(OH)D level ≤ 11.4 ng/mL (p = 0.003) compared to HCs. Patients with 25(OH)D level > 11.4 ng/mL had an increased frequency of Th2 CM (p = 0.010) and decreased Th17 CM (p < 0.001). While the frequency of Th2 EM was significantly increased, the frequency of Th17 EM was significantly decreased in both groups compared to HCs. Thus, 25(OH)D level is an independent risk factor for the disease severity and mortality in patients with COVID-19. We demonstrate that the serum 25(OH)D level ≤ 11.4 ng/mL is associated with the stimulation of Th2 and the downregulation of Th17 cell polarization of the adaptive immunity in patients with COVID-19.

Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers.

In the last 2 years, observational studies have shown that a low 25-hydroxyvitamin D (25(OH)D) level affected the severity of infection with the novel coronavirus (COVID-19). This study aimed to analyze the potential effect of vitamin D supplementation in reducing SARS-CoV-2 infection morbidity and severity in health care workers. Of 128 health care workers, 91 (consisting of 38 medical doctors (42%), 38 nurses (42%), and 15 medical attendants (16%)) were randomized into two groups receiving vitamin D supplementation. Participants of group I (n = 45) received water-soluble cholecalciferol at a dose of 50,000 IU/week for 2 consecutive weeks, followed by 5000 IU/day for the rest of the study. Participants of group II (n = 46) received water-soluble cholecalciferol at a dose of 2000 IU/day. For both groups, treatment lasted 3 months. Baseline serum 25(OH)D level in health care workers varied from 3.0 to 65.1 ng/mL (median, 17.7 (interquartile range, 12.2; 24.7) ng/mL). Vitamin D deficiency, insufficiency, and normal vitamin D status were diagnosed in 60%, 30%, and 10%, respectively. Only 78 subjects completed the study. Vitamin D supplementation was associated with an increase in serum 25(OH)D level, but only intake of 5000 IU/day was accompanied by normalization of serum 25(OH)D level, which occurred in 53% of cases. Neither vitamin D intake nor vitamin D deficiency/insufficiency were associated with a decrease in SARS-CoV-2 morbidity (odds ratio = 2.27; 95% confidence interval, 0.72 to 7.12). However, subjects receiving high-dose vitamin D had only asymptomatic SARS-CoV-2 in 10 (26%) cases; at the same time, participants who received 2000 IU/day showed twice as many SARS-CoV-2 cases, with mild clinical features in half of them.

Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19.

We evaluated associations between serum 25-hydroxyvitamin D [25(OH)D] level and severity of new coronavirus infection (COVID-19) in hospitalized patients. We assessed serum 25(OH)D level in 133 patients aged 21-93 years. Twenty-five (19%) patients had severe disease, 108 patients (81%) had moderate disease, and 18 (14%) patients died. 25(OH)D level ranged from 3.0 to 97.0 ng/mL (median, 13.5 [25%; 75%, 9.6; 23.3] ng/mL). Vitamin D deficiency was diagnosed in 90 patients, including 37 with severe deficiency. In patients with severe course of disease, 25(OH)D level was lower (median, 9.7 [25%; 75%, 6.0; 14.9] ng/mL), and vitamin D deficiency was more common than in patients with moderate course (median, 14.6 [25%; 75%, 10.6; 24.4] ng/mL, p = 0.003). In patients who died, 25(OH)D was 9.6 [25%; 75%, 6.0; 11.5] ng/mL, compared with 14.8 [25%; 75%, 10.1; 24.3] ng/mL in discharged patients (p = 0.001). Severe vitamin D deficiency was associated with increased risk of COVID-19 severity and fatal outcome. The threshold for 25(OH)D level associated with increased risk of severe course was 11.7 ng/mL. Approximately the same 25(OH)D level, 10.9 ng/mL, was associated with increased risk of mortality. Thus, most COVID-19 patients have vitamin D deficiency; severe vitamin D deficiency is associated with increased risk of COVID-19 severity and fatal outcome.