Impact of Penicillin Allergy Label on Clinical Outcomes of Pneumonia in Children.

BACKGROUND: Penicillin (PCN) allergy label, reported in approximately 5% of children, influences antibiotic choice and prolongs hospital stay. To our knowledge, the impact of PCN allergy label on clinical outcomes of pneumonia in children is not well characterized. OBJECTIVES: To investigate the impact of PCN allergy label on clinical outcomes of pneumonia in children. METHODS: In this propensity score-matched cohort study, we used the TriNetX research network, a population-based database, to compare the 30-day risk of hospitalization, need for intensive level of care, and acute respiratory failure from pneumonia between pediatric patients (aged 1-17 years) with and without a PCN allergy label after matching the 2 cohorts for demographic and medical comorbidities. Antibiotic prescription patterns were also contrasted. RESULTS: When comparing 3793 pediatric patients with pneumonia labeled with a PCN allergy with matched children without a PCN allergy label, PCN allergy label was associated with a higher risk of hospitalization (relative risk [RR], 1.15; 95% confidence interval [CI], 1.07-1.23), acute respiratory failure (RR, 1.27; 95% CI, 1.17-1.39), and need for intensive level of care (RR, 1.46; 95% CI, 1.15-1.84). PCN allergy label resulted in overutilization of broader-spectrum antibiotics and increased complications including cutaneous drug reactions (RR, 2.43; 95% CI, 1.31-4.52) and Clostridioides difficile infection (RR, 2.25; 95% CI, 1.14-4.44). CONCLUSION: Children with a PCN allergy label are more likely to be hospitalized, receive broader-spectrum antibiotics, and develop acute respiratory failure from pneumonia. Delabeling may offer a way to lessen morbidity from pneumonia in children.

Penicillin Allergy Label Is Associated With Worse Clinical Outcomes in Bacterial Pneumonia.

BACKGROUND: Penicillins (PCNs) are a first-line treatment option for bacterial pneumonia. PCN allergy label can delay antimicrobial treatment and result in the use of alternative antibiotic regimens risking an inadequate response to treatment and potentially increased adverse drug reactions. OBJECTIVE: To investigate the impact of PCN allergy label on clinical outcomes of bacterial pneumonia. METHODS: This retrospective cohort study used TriNetX, a web-based tool for population cohort research, to identify adult patients with and without PCN allergy label diagnosed with bacterial pneumonia. Cohorts were matched for baseline demographics and chronic medical conditions. The 30-day risks of hospitalization, acute respiratory failure, intubation, need for intensive level of care, and mortality were compared. Antibiotics used and their possible adverse reactions were explored. RESULTS: After matching, there were 68,748 patients in each cohort. Patients with bacterial pneumonia with PCN allergy label had higher risks of hospitalization (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.22-1.24), acute respiratory failure (RR, 1.14; 95% CI, 1.12-1.15), intubation (RR, 1.18; 95% CI, 1.13-1.22), intensive level of care (RR, 1.11; 95% CI, 1.08-1.14), and mortality (RR, 1.08; 95% CI, 1.04-1.13) compared with patients without PCN allergy label. Patients with PCN allergy label had decreased use of PCNs and cephalosporins and increased utilization of other antibiotic classes compared with patients without PCN allergy label. PCN allergy label was also associated with increased risk of adverse drug reactions. CONCLUSION: PCN allergy label is associated with worse clinical outcomes in bacterial pneumonia, and risk mitigation strategies should be considered.

IL-1ß and the Intestinal Epithelial Tight Junction Barrier.

The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn's disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1ß (IL-1ß), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1ß-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1ß-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1ß on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1ß modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.

Penicillin Allergy Label Increases Risk of Worse Clinical Outcomes in COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) ranges from asymptomatic to severe. Several comorbidities are associated with worse clinical outcomes. Antibiotic use is common in COVID-19 and penicillin (PCN) allergy can affect antibiotic choice and may influence COVID-19 outcomes. OBJECTIVE: To investigate the impact of PCN allergy label on COVID-19 outcomes. METHODS: For this retrospective, cohort study, a Web-based tool for population cohort research, TriNetX, was used to identify adult COVID-19 patients with and without PCN allergy label. The two cohorts were matched using 1:1 propensity score matching for baseline demographics and conditions associated with risk for severe COVID-19. The 30-day risks for hospitalization, acute respiratory failure, intensive care unit requirement, mechanical ventilation requirement, and mortality were then compared between groups. Because bacterial infection can drive alternative antibiotic regimens, additional analyses focused on patients without bacterial infection. RESULTS: After propensity score matching, each cohort consisted of 13,183 patients. COVID-19 patients with PCN allergy had higher risks for hospitalization (risk ratio [RR] = 1.46; 95% confidence interval [CI], 1.41-1.52) acute respiratory failure (RR = 1.25; 95% CI, 1.19-1.31), intensive care unit requirement (RR = 1.20; 95% CI, 1.08-1.34), and mechanical ventilation (RR = 1.17; 95% CI 1.03-1.32) compared with patients without PCN allergy; however, there was no mortality difference (RR = 1.09; 95% CI, 0.96-1.23). Although the bacterial infection risk was higher in PCN allergic COVID-19 patients, exclusion of patients with bacterial infections yielded similar results. CONCLUSIONS: Penicillin allergic patients have higher risk for worse COVID-19 outcomes and should be considered for risk mitigation strategies.

Use of omalizumab for management of idiopathic anaphylaxis: A systematic review and retrospective case series.

BACKGROUND: Patients with idiopathic anaphylaxis (IA) may fail to respond to a combination of high-dose H1 and H2 antihistamines and mast cell stabilizers. Treatment options for these patients are currently limited. OBJECTIVE: To describe the clinical experience of omalizumab use for the treatment of patients with IA with no evidence of underlying clonal mast cell disorders. METHODS: We performed a retrospective review at 2 separate institutions of medical records of patients with a diagnosis of IA without evidence of mast cell clonality who had received treatment with omalizumab. We searched PubMed for studies describing omalizumab use in similar patients. Information on symptoms and omalizumab therapy was compiled, and response pattern of anaphylaxis was determined. RESULTS: A total of 35 patients with IA and no evidence of mast cell clonality who received omalizumab were identified. The median age was 36 years at the start of omalizumab (range, 11-54 years; n = 29). The frequency of anaphylaxis episodes before omalizumab treatment varied from 2 total episodes to several episodes per month. The most often used initial omalizumab dose was 300 mg every 4 weeks (n = 16). Most patients ultimately achieved clinical response after starting omalizumab: complete response (63%, n = 22), partial response (28.5%, n = 10), with 3 nonresponders. CONCLUSION: Omalizumab may be an effective treatment option for patients with IA who do not have evidence of mast cell clonality and fail to respond to antihistamines and mast cell stabilizers.

Multiple doses of icatibant used during pregnancy.

BACKGROUND: Hereditary angioedema (HAE) is a life-long disease that often manifests by puberty. Treatment of attacks is essential to improve quality of life and to decrease morbidity and mortality. During pregnancy, treatment is limited because multiple treatment options, including icatibant, are not approved for use during pregnancy. OBJECTIVE: We report the outcomes of three pregnancies during which icatibant was used by a patient with HAE with normal C1-inhibitor for treatment of attacks. We also reviewed the literature for reports of icatibant use during pregnancy for outcomes and adverse events. METHODS: We report on a patient who treated herself with icatibant during three separate pregnancies. Postpartum follow-up verified the health of the mother and children. We also performed a complete literature search of medical literature data bases on icatibant use during pregnancy. RESULTS: The patient in our report administered multiple doses of icatibant during three pregnancies. The child born from the first pregnancy and the child from the third pregnancy were born at term and without congenital anomalies. The child from the second pregnancy was 1-month preterm. All three children were developmentally normal. The literature search identified two case reports and one abstract of limited icatibant use without adverse events during pregnancy in patients with HAE. These pregnancies resulted in the births of healthy infants. CONCLUSION: From a search of the literature, three cases of icatibant use during pregnancy resulted in healthy infants. In addition, we report that from icatibant use in three separate pregnancies, one infant was born prematurely, but there were no birth defects. From follow-up, the children continued meeting developmental milestones. This report adds to the acquisition of knowledge for drug adverse events during postmarketing surveillance for icatibant use during pregnancy.

A systemic macrophage response is required to contain a peripheral poxvirus infection.

The goal of the innate immune system is to reduce pathogen spread prior to the initiation of an effective adaptive immune response. Following an infection at a peripheral site, virus typically drains through the lymph to the lymph node prior to entering the blood stream and being systemically disseminated. Therefore, there are three distinct spatial checkpoints at which intervention to prevent systemic spread of virus can occur, namely: 1) the site of infection, 2) the draining lymph node via filtration of lymph or 3) the systemic level via organs that filter the blood. We have previously shown that systemic depletion of phagocytic cells allows viral spread after dermal infection with Vaccinia virus (VACV), which infects naturally through the skin. Here we use multiple depletion methodologies to define both the spatial checkpoint and the identity of the cells that prevent systemic spread of VACV. Subcapsular sinus macrophages of the draining lymph node have been implicated as critical effectors in clearance of lymph borne viruses following peripheral infection. We find that monocyte populations recruited to the site of VACV infection play a critical role in control of local pathogenesis and tissue damage, but do not prevent dissemination of virus. Following infection with virulent VACV, the subcapsular sinus macrophages within the draining lymph node become infected, but are not exclusively required to prevent systemic spread. Rather, small doses of VACV enter the bloodstream and the function of systemic macrophages, but not dendritic cells, is required to prevent further spread. The results illustrate that a systemic innate response to a peripheral virus infection may be required to prevent widespread infection and pathology following infection with virulent viruses, such as poxviruses.

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection.

UNLABELLED: Viruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8α(+) DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8α(+) DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection. IMPORTANCE: Prior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design.

Peptide-MHC-I from Endogenous Antigen Outnumber Those from Exogenous Antigen, Irrespective of APC Phenotype or Activation.

Naïve anti-viral CD8+ T cells (TCD8+) are activated by the presence of peptide-MHC Class I complexes (pMHC-I) on the surface of professional antigen presenting cells (pAPC). Increasing the number of pMHC-I in vivo can increase the number of responding TCD8+. Antigen can be presented directly or indirectly (cross presentation) from virus-infected and uninfected cells, respectively. Here we determined the relative importance of these two antigen presenting pathways in mousepox, a natural disease of the mouse caused by the poxvirus, ectromelia (ECTV). We demonstrated that ECTV infected several pAPC types (macrophages, B cells, and dendritic cells (DC), including DC subsets), which directly presented pMHC-I to naïve TCD8+ with similar efficiencies in vitro. We also provided evidence that these same cell-types presented antigen in vivo, as they form contacts with antigen-specific TCD8+. Importantly, the number of pMHC-I on infected pAPC (direct presentation) vastly outnumbered those on uninfected cells (cross presentation), where presentation only occurred in a specialized subset of DC. In addition, prior maturation of DC failed to enhance antigen presentation, but markedly inhibited ECTV infection of DC. These results suggest that direct antigen presentation is the dominant pathway in mice during mousepox. In a broader context, these findings indicate that if a virus infects a pAPC then the presentation by that cell is likely to dominate over cross presentation as the most effective mode of generating large quantities of pMHC-I is on the surface of pAPC that endogenously express antigens. Recent trends in vaccine design have focused upon the introduction of exogenous antigens into the MHC Class I processing pathway (cross presentation) in specific pAPC populations. However, use of a pantropic viral vector that targets pAPC to express antigen endogenously likely represents a more effective vaccine strategy than the targeting of exogenous antigen to a limiting pAPC subpopulation.