Reduced control of SARS-CoV-2 infection associates with lower mucosal antibody responses in pregnancy.

Pregnant patients are at greater risk of hospitalization with severe COVID-19 than non-pregnant people. This was a retrospective observational cohort study of remnant clinical specimens from patients who visited acute care hospitals within the Johns Hopkins Health System in the Baltimore, MD-Washington DC, area between October 2020 and May 2022. Participants included confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant people and matched non-pregnant people (the matching criteria included age, race/ethnicity, area deprivation index, insurance status, and vaccination status to ensure matched demographics). The primary dependent measures were clinical COVID-19 outcomes, infectious virus recovery, viral RNA levels, and mucosal anti-spike (S) IgG titers from upper respiratory tract samples. A total of 452 individuals (117 pregnant and 335 non-pregnant) were included in the study, with both vaccinated and unvaccinated individuals represented. Pregnant patients were at increased risk of hospitalization (odds ratio [OR] = 4.2; confidence interval [CI] = 2.0-8.6), intensive care unit admittance (OR = 4.5; CI = 1.2-14.2), and being placed on supplemental oxygen therapy (OR = 3.1; CI = 1.3-6.9). Individuals infected during their third trimester had higher mucosal anti-S IgG titers and lower viral RNA levels (P < 0.05) than those infected during their first or second trimesters. Pregnant individuals experiencing breakthrough infections due to the Omicron variant had reduced anti-S IgG compared to non-pregnant patients (P < 0.05). The observed increased severity of COVID-19 and reduced mucosal antibody responses particularly among pregnant participants infected with the Omicron variant suggest that maintaining high levels of SARS-CoV-2 immunity through booster vaccines may be important for the protection of this at-risk population.IMPORTANCEIn this retrospective observational cohort study, we analyzed remnant clinical samples from non-pregnant and pregnant individuals with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who visited the Johns Hopkins Hospital System between October 2020 and May 2022. Disease severity, including intensive care unit admission, was greater among pregnant than non-pregnant patients. Vaccination reduced recovery of infectious virus and viral RNA levels in non-pregnant patients, but not in pregnant patients. In pregnant patients, increased nasopharyngeal viral RNA levels and recovery of infectious virus were associated with reduced mucosal IgG antibody responses, especially among women in their first trimester of pregnancy or experiencing breakthrough infections from Omicron variants. Taken together, this study provides insights into how pregnant patients are at greater risk of severe COVID-19. The novelty of this study is that it focuses on the relationship between the mucosal antibody response and its association with virus load and disease outcomes in pregnant people, whereas previous studies have focused on serological immunity. Vaccination status, gestational age, and SARS-CoV-2 omicron variant impact mucosal antibody responses and recovery of infectious virus from pregnant patients.

Sex-related difference analyses of efficacy and safety in clinical trials of direct-acting antivirals to treat chronic HCV genotype 1 and 3 infections.

This study aims to identify clinically meaningful sex differences in efficacy and selected safety adverse events for the treatment of chronic hepatitis C virus infection (HCV) or HIV/HCV co-infection in those receiving combination direct-acting antiviral (DAA) regimens. Our assessment was based on adult trial participants treated at the approved DAA dosage and treatment duration from 40 phase 3 clinical trials submitted to the FDA. Female enrollment ranged from 11% to 54% (overall mean 38%). Females with HCV genotype (GT) 1 or 3 infection had statistically significant higher unadjusted or covariant-adjusted odds of achieving sustained virologic response at post-treatment Week 12 (SVR12) compared with males. Odds ratios favouring females were observed among Whites and those ≥40 years of age with HCV GT1 or 3 infections, and among those ≥50 years of age, non-cirrhotic and those with HCV GT3 infection who were treatment-experienced. These differences were not clinically relevant due to the high SVR12 rate achieved by females and males, overall or in subgroups. No differences were observed in SVR12 rates between HCV GT1 mono-infected and HCV GT1/ HIV-1 co-infected participants. Numerically, more females reported headache, fatigue and nausea compared to males, but the differences were small and predominately Grade 1 or 2 severity. Discontinuation rates for any reason or due to an adverse event were low and similar between the sexes. Our study demonstrated females successfully complete DAA regimens and achieve high SVR12 rates despite numerically higher adverse events for certain commonly reported events.

Reduced control of SARS-CoV-2 infection is associated with lower mucosal antibody responses in pregnant women.

Importance: Pregnant women are at increased risk of severe COVID-19, but the contribution of viral RNA load, the presence of infectious virus, and mucosal antibody responses remain understudied. Objective: To evaluate the association of COVID-19 outcomes following confirmed infection with vaccination status, mucosal antibody responses, infectious virus recovery and viral RNA levels in pregnant compared with non-pregnant women. Design: A retrospective observational cohort study of remnant clinical specimens from SARS-CoV-2 infected patients between October 2020-May 2022. Setting: Five acute care hospitals within the Johns Hopkins Health System (JHHS) in the Baltimore, MD-Washington, DC area. Participants: Participants included confirmed SARS-CoV-2 infected pregnant women and matched non-pregnant women (matching criteria included age, race/ethnicity, and vaccination status). Exposure: SARS-CoV-2 infection, with documentation of SARS-CoV-2 mRNA vaccination. Main Outcomes: The primary dependent measures were clinical COVID-19 outcomes, infectious virus recovery, viral RNA levels, and mucosal anti-spike (S) IgG titers from upper respiratory tract samples. Clinical outcomes were compared using odds ratios (OR), and measures of virus and antibody were compared using either Fisher's exact test, two-way ANOVA, or regression analyses. Results were stratified according to pregnancy, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant. Resultss: A total of 452 individuals (117 pregnant and 335 non-pregnant) were included in the study, with both vaccinated and unvaccinated individuals represented. Pregnant women were at increased risk of hospitalization (OR = 4.2; CI = 2.0-8.6), ICU admittance, (OR = 4.5; CI = 1.2-14.2), and of being placed on supplemental oxygen therapy (OR = 3.1; CI =13-6.9). An age-associated decrease in anti-S IgG titer and corresponding increase in viral RNA levels (P< 0.001) was observed in vaccinated pregnant, but not non-pregnant, women. Individuals in their 3rd trimester had higher anti-S IgG titers and lower viral RNA levels (P< 0.05) than those in their 1st or 2nd trimesters. Pregnant individuals experiencing breakthrough infections due to the omicron variant had reduced anti-S IgG compared to non-pregnant women (P< 0.05). Conclusions and Relevance: In this cohort study, vaccination status, maternal age, trimester of pregnancy, and infecting SARS-CoV-2 variant were each identified as drivers of differences in mucosal anti-S IgG responses in pregnant compared with non-pregnant women. Observed increased severity of COVID-19 and reduced mucosal antibody responses particularly among pregnant participants infected with the Omicron variant suggest that maintaining high levels of SARS-CoV-2 immunity may be important for protection of this at-risk population.

Participation of HIV-1 infected treatment-naive females in clinical trials and sex differences in efficacy and safety outcomes.

OBJECTIVES: To examine female participation and the observed efficacy and safety by sex from phase 3 HIV-1 trials submitted to the United States Food and Drug Administration (FDA) to support approval or a major labeling change. DESIGN: Our analyses were based on phase 3 trials in HIV-1 infected treatment-naive adults submitted to FDA since 2010. METHODS: We evaluated enrollment of treatment-naive females in 18 clinical trials for HIV-1. Participation to prevalence ratio (PPR) was calculated as the percentage of females among trial participants divided by the percentage of females in the disease population. PPR between 0.8 and 1.2 reflects similar representation of females in the trial and the disease population. Sex differences in efficacy (virologic response rates) and selected safety events were evaluated. RESULTS: United States (US) females, particularly US Black females were not adequately represented in clinical trials. The PPR for US females overall was 0.59 and for US Black females was 0.63. Statistically significant sex differences favoring males were observed for efficacy outcomes in both the global population and US participants. Statistically significant sex differences were observed for some safety outcomes. CONCLUSIONS: US females are underrepresented in phase 3 HIV-1 clinical trials. Underrepresentation was not likely due to enrollment criteria. Statistically significant sex differences were noted for efficacy and selected safety outcomes; however, some differences were not clinically relevant. The ability to detect sex differences was hindered by low numbers of female participants overall and within subgroups. Additional research into innovative approaches to recruit and retain females in clinical trials should continue.

Fatal neutropenic enterocolitis associated with docetaxel use: A review of cases reported to the United States Food and Drug Administration Adverse Event Reporting System.

Docetaxel is a microtubule inhibitor indicated for the treatment of multiple cancers as a single agent or in combination with other antineoplastics. The U.S. Food and Drug Administration (FDA) conducted a postmarketing review of fatal neutropenic enterocolitis cases reported with docetaxel using the FDA Adverse Event Reporting System (FAERS) and literature to determine whether the drug was a potential cause. We searched FAERS and the literature for reports of fatal neutropenic enterocolitis with docetaxel-based treatment reported between 14 May 1996 and 13 March 2017. We characterized the clinical course and severity of neutropenic enterocolitis and utilized the World Health Organization-Uppsala Monitoring Centre rubric to assess drug causality. We identified 41 fatal cases of neutropenic enterocolitis with docetaxel from FAERS and the literature. The median time to onset of neutropenic enterocolitis from last docetaxel dose was seven days (range 2-13 days), and median time to death was nine days (range 3-23 days). The cause of death in 83% (34/41) of patients was neutropenic enterocolitis. We determined the drug-event association as probable in seven cases. Neutropenic enterocolitis with docetaxel monotherapy occurred in six cases; however, in 85% (35/41) of cases, neutropenic enterocolitis occurred when docetaxel was used in combination with other cytotoxic chemotherapy. In some cases, neutropenic enterocolitis occurred despite use of granulocyte colony-stimulating factors. Neutropenic enterocolitis is a severe and potentially fatal complication of docetaxel-based treatment, especially when combined with other antineoplastic treatments known to cause neutropenia. Practitioners should be aware of this safety risk to promptly recognize and manage patients.

Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases.

Background: Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors has been associated with Fournier gangrene (FG), a rare urologic emergency characterized by necrotizing infection of the external genitalia, perineum, and perianal region. Objective: To describe and compare reported cases of FG in diabetic adults receiving treatment with SGLT2 inhibitors or other antiglycemic agents. Design: Descriptive case series. Setting: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and published case reports. Patients: Adults receiving SGLT2 inhibitors or other antiglycemic agents. Measurements: Clinical and laboratory data. Results: The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019. The patients ranged in age from 33 to 87 years; 39 were men, and 16 were women. Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill. Reported complications included diabetic ketoacidosis (n = 8), sepsis or septic shock (n = 9), and acute kidney injury (n = 4). Eight patients had fecal diversion surgery, 2 patients developed necrotizing fasciitis of a lower extremity that required amputation, and 1 patient required a lower-extremity bypass procedure because of gangrenous toes. Three patients died. For comparison, the FDA identified 19 FG cases associated with other antiglycemic agents between 1984 and 31 January 2019: metformin (n = 8), insulin glargine (n = 6), short-acting insulin (n = 2), sitagliptin plus metformin (n = 2), and dulaglutide (n = 1). These patients ranged in age from 42 to 79 years; 12 were men, and 7 were women. Two patients died. Limitation: Inability to establish causality or incidence, variable quality of reports, possible underreporting, and confounding by indication. Conclusion: FG is a newly identified safety concern in patients receiving SGLT2 inhibitors. Physicians prescribing these agents should be aware of this possible complication and have a high index of suspicion to recognize it in its early stages. Primary Funding Source: None.

Unusual Neisseria species as a cause of infection in patients taking eculizumab.

BACKGROUND: Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. METHODS: We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. RESULTS: We identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. CONCLUSIONS: Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.

Disseminated Gonococcal Infections in Patients Receiving Eculizumab: A Case Series.

BACKGROUND: Gonorrhea is the second most commonly reported notifiable condition in the United States. Infrequently, Neisseria gonorrhoeae can cause disseminated gonococcal infection (DGI). Eculizumab, a monoclonal antibody, inhibits terminal complement activation, which impairs the ability of the immune system to respond effectively to Neisseria infections. This series describes cases of N. gonorrhoeae infection among patients receiving eculizumab. METHODS: Pre- and postmarketing safety reports of N. gonorrhoeae infection in patients receiving eculizumab worldwide were obtained from US Food and Drug Administration safety databases and the medical literature, including reports from the start of pivotal clinical trials in 2004 through 31 December 2017. Included patients had at least 1 eculizumab dose within the 3 months prior to N. gonorrhoeae infection. RESULTS: Nine cases of N. gonorrhoeae infection were identified; 8 were classified as disseminated (89%). Of the disseminated cases, 8 patients required hospitalization, 7 had positive blood cultures, and 2 required vasopressor support. One patient required mechanical ventilation. Neisseria gonorrhoeae may have contributed to complications prior to death in 1 patient; however, the fatality was attributed to underlying disease per the reporter. CONCLUSIONS: Patients receiving eculizumab may be at higher risk for DGI than the general population. Prescribers are encouraged to educate patients receiving eculizumab on their risk for serious gonococcal infections and perform screening for sexually transmitted diseases (STDs) per the Centers for Disease Control and Prevention STD treatment guidelines or in suspected cases. If antimicrobial prophylaxis is used during eculizumab therapy, prescribers should consider trends in gonococcal antimicrobial susceptibility due to emerging resistance concerns.

Hepatitis B Virus Reactivation Associated With Direct-Acting Antiviral Therapy for Chronic Hepatitis C Virus: A Review of Cases Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: Direct-acting antiviral agents (DAAs) are used increasingly to treat hepatitis C virus (HCV) infection. Reports were published recently on hepatitis B virus (HBV) reactivation (HBV-R) in patients with HBV-HCV co-infection. Hepatitis B virus reactivation, defined as an abrupt increase in HBV replication in patients with inactive or resolved HBV infection, may result in clinically significant hepatitis. OBJECTIVE: To assess whether HBV-R is a safety concern in patients receiving HCV DAAs. DESIGN: Descriptive case series. SETTING: U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). PATIENTS: 29 patients with HBV-R receiving HCV DAAs. MEASUREMENTS: Clinical and laboratory data. RESULTS: The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom HBV-R developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others. LIMITATIONS: The quality of information varied among reports. Because reporting is voluntary, HBV-R associated with DAAs likely is underreported. CONCLUSION: Hepatitis B virus reactivation is a newly identified safety concern in patients with HBV-HCV co-infection treated with DAAs. Patients with a history of HBV require clinical monitoring while receiving DAA therapy. Studies would help determine the risk factors for HBV-R, define monitoring frequency, and identify patients who may benefit from HBV prophylaxis and treatment. DAAs remain a safe and highly effective treatment for the management of HCV infection. PRIMARY FUNDING SOURCE: None.