Abrogation of neutrophil inflammatory pathways and potential reduction of neutrophil-related factors in COVID-19 by intravenous immunoglobulin.

Pathogenesis of lung injury in COVID-19 is not completely understood, leaving gaps in understanding how current treatments modulate the course of COVID-19. Neutrophil numbers and activation state in circulation have been found to correlate with COVID-19 severity, and neutrophil extracellular traps (NETs) have been found in the lung parenchyma of patients with acute respiratory distress syndrome (ARDS) in COVID-19. Targeting the pro-inflammatory functions of neutrophils may diminish lung injury in COVID-19 and ARDS. Neutrophils were isolated from peripheral blood of healthy donors, treated ex vivo with dexamethasone, tocilizumab and intravenous immunoglobulin (IVIG) and NET formation, oxidative burst, and phagocytosis were assessed. Plasma from critically ill COVID-19 patients before and after clinical treatment with IVIG and from healthy donors was assessed for neutrophil activation-related proteins. While dexamethasone and tocilizumab did not affect PMA- and nigericin-induced NET production ex vivo, IVIG induced a dose-dependent abrogation of NET production in both activation models. IVIG also reduced PMA-elicited reactive oxygen species production, but did not alter phagocytosis. COVID-19 patients were found to have elevated levels of cell-free DNA, neutrophil elastase and IL-8 as compared to healthy controls. Levels of both cell-free DNA and neutrophil elastase were lower 5 days after 4 days of daily treatment with IVIG. The lack of impact of dexamethasone or tocilizumab on these neutrophil functions suggests that these therapeutic agents may not act through suppression of neutrophil functions, indicating that the door might still be open for the addition of a neutrophil modulator to the COVID-19 therapeutic repertoire.

Abrogation of neutrophil inflammatory pathways and potential reduction of neutrophil-related factors in COVID-19 by intravenous immunoglobulin

Pathogenesis of lung injury in COVID-19 is not completely understood, leaving gaps in understanding how current treatments modulate the course of COVID-19. Neutrophil numbers and activation state in circulation have been found to correlate with COVID-19 severity, and neutrophil extracellular traps (NETs) have been found in the lung parenchyma of patients with acute respiratory distress syndrome (ARDS) in COVID-19. Targeting the pro-inflammatory functions of neutrophils may diminish lung injury in COVID-19 and ARDS. Neutrophils were isolated from peripheral blood of healthy donors, treated ex vivo with dexamethasone, tocilizumab and intravenous immunoglobulin (IVIG) and NET formation, oxidative burst, and phagocytosis were assessed. Plasma from critically ill COVID-19 patients before and after clinical treatment with IVIG and from healthy donors was assessed for neutrophil activation-related proteins. While dexamethasone and tocilizumab did not affect PMA- and nigericin-induced NET production ex vivo, IVIG induced a dose-dependent abrogation of NET production in both activation models. IVIG also reduced PMA-elicited reactive oxygen species production, but did not alter phagocytosis. COVID-19 patients were found to have elevated levels of cell-free DNA, neutrophil elastase and IL-8 as compared to healthy controls. Levels of both cell-free DNA and neutrophil elastase were lower 5 days after 4 days of daily treatment with IVIG. The lack of impact of dexamethasone or tocilizumab on these neutrophil functions suggests that these therapeutic agents may not act through suppression of neutrophil functions, indicating that the door might still be open for the addition of a neutrophil modulator to the COVID-19 therapeutic repertoire.

Case Series of Successful Intravenous Immunoglobulin (IVIG) Treatment in 4 Pregnant Patients with Severe COVID-19-Induced Hypoxia.

BACKGROUND Despite unprecedented speed in the execution of the COVID-19 vaccine and therapeutic clinical trials, pregnant patients have been largely excluded from initial studies. In addition, pregnant patients who are unvaccinated against SARS-CoV-2 have greater morbidity risk with severe COVID-19 disease as compared to patients of similar age and comorbidity status. Intravenous immunoglobulin (IVIG) has been deemed safe in pregnancy in other diseases. Prior data demonstrate the possible benefit of utilizing IVIG for the treatment in hospitalized patients with severe respiratory symptoms associated with COVID-19 active infections when administered within 14 days of COVID symptom onset. CASE REPORT We administered IVIG (Privigen®, CSL Behring) 0.5 g/kg daily for 3 consecutive days to 4 pregnant patients (ages 24-34 years of age) who were hospitalized with moderate-to-severe COVID-19 and not vaccinated against SARS-CoV-2. All patients received concomitant glucocorticoid therapy. Gestational ages were 26, 17, 35, and 35 weeks. All patients were discharged home breathing room air after a mean hospital stay of 15 days. Two patients had uncomplicated cesarean section at 35 weeks during the hospitalization. The pre-term pregnancies at 17 and 26 weeks were intact at hospital discharge and resulted in normal vaginal deliveries at term. All 4 patients consented to participate in this case series report. CONCLUSIONS IVIG may be a safe treatment consideration in pregnant women with severe COVID-19 to avoid pregnancy complications. Its use warrants further study in pregnancy acute respiratory distress syndrome (ARDS) due to SARS-CoV-2, influenza, and other respiratory viruses to which pregnant patients are vulnerable.

Azithromycin: An Underappreciated Quinolone-Sparing Oral Treatment for Pseudomonas aeruginosa Infections.

Outpatient treatment of Pseudomonas aeruginosa infections is challenged by increasing rates of resistance to fluoroquinolones, the only class of antibiotics which offers an established oral route of administration against this organism. Azithromycin does not demonstrate activity against P. aeruginosa when evaluated under standard methods of susceptibility testing with bacteriologic media. However, growing evidence shows that azithromycin is very active against P. aeruginosa when using physiologic media that recapitulate the in vivo milieu and is supported by animal models of infection and various clinical settings, including cystic fibrosis. We present three cases of outpatient management of P. aeruginosa otolaryngological infections successfully treated with oral azithromycin, 500 mg daily ranging from 3-8 weeks, where use of fluoroquinolones was not possible due to either resistance or patient intolerance. We review the previous data supporting this clinical approach, in the hope that this will alert clinicians to this treatment option and to inspire a more thorough clinical trial evaluation of azithromycin in this environment of growing medical need.

Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report.

Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis has been reported after SARS-CoV-2 infection, but not after SARS-CoV-2 vaccination. We report the first known case of anti-NMDAR encephalitis after SARS-CoV-2 immunization in a young female presenting with acute psychosis, highlighting a rare potential immunological complication of vaccination against SARS-CoV-2 that is currently being distributed worldwide. The patient presented initially with anxiety and hypochondriacal delusions which progressed to psychosis and catatonia but returned to baseline with aggressive immunomodulatory therapy consisting of intravenous immunoglobulin, high-dose glucocorticoids, and rituximab. This study highlights that the workup of acute psychosis should include establishing a history of recent vaccination followed by a thorough neurological assessment, including for anti-NMDAR antibodies in blood and cerebrospinal fluid.

Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia.

INTRODUCTION: Despite considerable scientific debate, there have been no prospective clinical studies on the effects of angiotensin II receptor blockers (ARBs) on the course of COVID-19 infection. Losartan is the ARB that was chosen to be tested in this study. METHODS: Patients with COVID-19 and mild hypoxia (receipt of ≤ 3 L/min O2 by nasal cannula) admitted to three hospitals were randomized in a 1:1 ratio within 72 h of SARS-CoV-2 nucleic acid testing confirmation to prospectively receive standard of care (SOC) alone or SOC plus losartan 12.5 mg orally every 12 h for 10 days or until hospital discharge, with the option to titrate upward dependent on blood pressure tolerability. Primary composite endpoint was receipt of mechanical ventilation or death before receiving ventilation. Subjects were followed until discharge to home or until an endpoint was met in the hospital. RESULTS: Sixteen subjects received an ARB plus SOC and 15 subjects received SOC alone. The median age was 53 years for both groups. Median time from hospital admission to study enrollment was 2 days (range 1-6) for the ARB group and 2 days (range 1-4) for the SOC group. Mean Charlson comorbidity index was 2 for both groups. One subject in each group achieved the composite endpoint. CONCLUSION: This small prospective randomized open-label study showed no clinically significant impacts of ARB therapy in mildly hypoxemic patients hospitalized with COVID-19 early in the pandemic. A larger prospective randomized placebo-controlled trial would be needed to confirm these findings or capture less pronounced effects and probably should focus on outpatients earlier in disease course. TRIAL REGISTRATION: clinicaltrials.gov; March 27, 2020; NCT04340557.

Use of Intravenous Immunoglobulin (Prevagen or Octagam) for the Treatment of COVID-19: Retrospective Case Series.

Treatment with immunomodulators, such as intravenous immunoglobulin (IVIG), may attenuate inflammatory responses observed in the severe stages of acute respiratory distress syndrome (ARDS) caused by coronavirus disease 19 (COVID-19). We retrospectively evaluated the clinical courses of 12 COVID-19 patients who received IVIG at various stages of their illness, including within the first 72 h of clinical presentation, after initiation of mechanical ventilation, and after prolonged ventilation and ICU stay. The patients included 9 men and 3 women with a median age of 50 years (range 23-74), median Charlson Comorbidity Score of 2 (range 0-7), and median Acute Physiology and Chronic Health Evaluation Score of 13 (range 5-33) at the time of IVIG. The IVIG total dose ranged from 0.5 to 2.0 g/kg (median 1.25 g/kg) distributed over 1-4 daily doses. The most common regimen received was 0.5 g/kg daily for 3 days. The median time to IVIG administration was 9 days (range 0-48 days) after admission. The median time from first IVIG dose administration to hospital discharge was 14 days (range 3-48). The 5 patients who received IVIG ≤4 days of admission demonstrated a significantly shorter length of hospital stay after treatment (median 7 days, range 3-14 days) than the 7 patients who received it >7 days after admission (median 33 days, range 8-48 days, p = 0.03, Mann-Whitney U test). These cases demonstrate that IVIG may improve the clinical state of patients with moderate to severe COVID-19 infection. Despite very high illness severity scores, all patients survived hospital discharge. No thrombotic events occurred and IVIG was well tolerated, despite most cases demonstrating very elevated D-dimer suggestive of active intravascular fibrinolysis. We believe that IVIG warrants immediate clinical trial evaluation in COVID-19 to confirm its role as a mainstay treatment of moderate to severe COVID-19 infection as a means to reduce hospital stay and utilization of ICU resources, including mechanical ventilation, and potentially reduce mortality.

Intravenous Immunoglobulin Plus Methylprednisolone Mitigate Respiratory Morbidity in Coronavirus Disease 2019.

Dysregulated neutrophil and platelet interactions mediate immunothrombosis and cause lung injury in coronavirus disease 2019. IV immunoglobulin modulates neutrophil activation through FcγRIII binding. We hypothesized that early therapy with IV immunoglobulin would abrogate immunothrombosis and improve oxygenation and reduce progression to mechanical ventilation in coronavirus disease 2019 pneumonia. DESIGN: Prospective randomized open label. SETTING: Inpatient hospital. PATIENTS AND INTERVENTION: Hypoxic subjects with coronavirus disease 2019 pneumonia were randomized 1:1 to receive standard of care plus IV immunoglobulin 0.5 g/kg/d with methylprednisolone 40 mg 30 minutes before infusion for 3 days versus standard of care alone. MAIN RESULTS: Sixteen subjects received IV immunoglobulin and 17 standard of care. Median ages were 51 and 58 years for standard of care and IV immunoglobulin, respectively. Acute Physiology and Chronic Health Evaluation II and Charlson comorbidity scores were similar for IV immunoglobulin and standard of care. Seven standard of care versus two IV immunoglobulin subjects required mechanical ventilation (p = 0.12, Fisher exact test). Among subjects with A-a gradient of greater than 200 mm Hg at enrollment, the IV immunoglobulin group showed: 1) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p = 0.038 Fisher exact test), 2) shorter median hospital length of stay (11 vs 19 d, p = 0.01 Mann Whitney U test), 3) shorter median ICU stay (2.5 vs 12.5 d, p = 0.006 Mann Whitey U test), and 4) greater improvement in Pao2/Fio2 at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44·5 [-115 to +157], p = 0.01, Mann Whitney U test) than standard of care. Pao2/Fio2 improvement at day 7 was significantly less for the standard of care patients who received glucocorticoid therapy than those in the IV immunoglobulin arm (p = 0.0057, Mann Whiney U test). CONCLUSIONS: This pilot study showed that IV immunoglobulin significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in coronavirus disease 2019 patients with A-a gradient greater than 200 mm Hg. A phase 3 multicenter randomized double-blinded clinical trial is under way to validate these findings.