Upper Respiratory Tract Research Articles

Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial

BackgroundPreclinical Alzheimer’s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer’s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.ObjectivesTo report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.DesignPhase 3, 4.5-year, multicenter, placebo-controlled trial.SettingPlacebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study.ParticipantsEnrolled participants were aged 65–85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 2–-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6–18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.MeasurementsStudy participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).ResultsIn total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2–0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2–0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4–12.5), fall (incidence rate=7.7; 95% confidence interval=6.6–9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8–6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0–2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3–1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6–494.4; adjusted p<0.001).ConclusionSafety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer’s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer’s disease.

Human coronavirus OC43 infection remodels connexin 43-mediated gap junction intercellular communication in vitro.

β-coronaviruses cause acute infection in the upper respiratory tract, resulting in various symptoms and clinical manifestations. OC43 is a human β-coronavirus that induces mild clinical symptoms and can be safely studied in the BSL2 laboratory. Due to its low risk, OC43 can be a valuable and accessible model for understanding β-coronavirus pathogenesis. One potential target for limiting virus infectivity could be gap junction-mediated communication. This study aims to unveil the status of cell-to-cell communications through gap junctions in human β-coronavirus infection. Infection with OC43 leads to reduced expression of Cx43 in A549, a lung epithelial carcinoma cell line. Infection with this virus also shows a significant ER and oxidative stress increase. Internal localization of Cx43 is observed post-OC43 infection in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) region, which impairs the gap junction communication between two adjacent cells, confirmed by Lucifer yellow dye transfer assay. It also affects hemichannel formation, as depicted by the EtBr uptake assay. Impairment of Cx43 trafficking and the ability to form hemichannels and functional GJIC are hampered by virus-induced Golgi apparatus disruption. Altogether, these results suggest that several physiological changes accompany OC43 infection in A549 cells and can be considered an appropriate model system for understanding the differences in gap junction communication post-viral infections. This model system can provide valuable insights for developing therapies against human β-coronavirus infections.IMPORTANCEThe enduring impact of the recent SARS-CoV-2 pandemic underscores the importance of studying human β-coronaviruses, advancing our preparedness for future coronavirus infections. As SARS-CoV-2 is highly infectious, another human β-coronavirus OC43 can be considered an experimental model. One of the crucial pathways that can be considered is gap junction communication, as it is vital for cellular homeostasis. Our study seeks to understand the changes in Cx43-mediated cell-to-cell communication during human β-coronavirus OC43 infection. In vitro studies showed downregulation of the gap junction protein Cx43 and upregulation of the endoplasmic reticulum and oxidative stress markers post-OC43 infection. Furthermore, HCoV-OC43 infection causes reduced Cx43 trafficking, causing impairment of functional hemichannel and GJIC formation by virus-mediated Golgi apparatus disruption. Overall, this study infers that OC43 infection reshapes intercellular communication, suggesting that this pathway may be a promising target for designing highly effective therapeutics against human coronaviruses by regulating Cx43 expression.

Bimekizumab Safety and Tolerability in Moderate to Severe Plaque Psoriasis: Pooled Analysis from Up to 4 Years of Treatment in 5 Phase 3/3b Clinical Trials

Introduction: Psoriasis is a chronic condition requiring long-term management; evaluating long-term safety of treatments is important. We report the first 4-year (yr) safety data for bimekizumab (BKZ) in patients with moderate to severe plaque psoriasis. Methods: Data were pooled from 5 trials: BE SURE/BE VIVID/BE READY, their open-label extension (OLE) BE BRIGHT (4‑yr data; cut-off 14Nov2022), and BE RADIANT (3‑yr data; cut‑off 6May2022).1-5 Patients received BKZ 320mg every 4 weeks (wks)(Q4W) or Q8W; all received Q8W from Wk64 (BE RADIANT)/OLE Wk48 (BE BRIGHT) or next scheduled visit. Treatment-emergent adverse events (TEAEs) are presented as exposure-adjusted incidence rates (EAIRs)/100 patient‑yrs (PY) for all patients who received ≥1 BKZ dose, and evaluated separately for Yr1/Yr2/Yr3/Yr4 (Wks0-52/52-104/104-156/156-208) of treatment. Results: Total BKZ exposure was 6,324.3PY (N=2,186) (Yr1: 2,053.3PY [n=2,186]; Yr2: 1,904.3PY [n=2,013]; Yr3: 1,521.1PY [n=1,803]; Yr4: 819.5PY [n=1,309]). Overall, TEAEs occurred at an EAIR of 170.5/100PY (Yr1, Yr2, Yr3, Yr4: 230.9/100PY, 137.7/100PY, 107.1/100PY, 99.9/100PY), serious TEAEs at 5.5/100PY (6.5/100PY, 5.9/100PY, 5.8/100PY; 5.6/100PY), and TEAEs leading to discontinuation at 2.9/100PY (4.6/100PY, 2.3/100PY, 2.3/100PY, 1.1/100PY). The most common TEAEs were nasopharyngitis at 12.7/100PY (25.8/100PY, 13.2/100PY, 5.4/100PY, 5.9/100PY), oral candidiasis at 8.9/100PY (18.9/100PY, 10.7/100PY, 6.8/100PY, 5.4/100PY), and upper respiratory tract infection at 5.7/100PY (10.4/100PY, 5.7/100PY, 3.7/100PY, 3.9/100PY). Throughout, fewer TEAEs occurred with BKZ Q8W vs Q4W (115.4/100PY vs 224.4/100PY), including for oral candidiasis (6.5/100PY vs 16.7/100PY). Conclusions: BKZ demonstrated good tolerability and a consistent safety profile over 4 yrs in patients with plaque psoriasis. EAIRs of TEAEs remained consistent/decreased with longer BKZ exposure; no new safety findings were identified.

An Exploratory Randomized Controlled Study to Investigate Concentration-Dependence of Green Tea Catechin Gargling on Acute Upper Respiratory Tract Infections.

Green tea (GT) catechins exhibit antiviral effects in experimental studies. However, we lack clinical evidence on the preventive effects of catechin concentrations in gargling against acute upper respiratory tract infections (URTIs). Therefore, we aimed to investigate the concentration-dependence of GT catechins in gargling on the incidence of URTIs. We conducted an open-label randomized study. The target population consisted of 209 students from the University of Shizuoka and Meiji University, who were randomly assigned to high-catechin (approximate catechin concentration: 76.4 mg/dL), low-catechin (approximate catechin concentration: 30.8 mg/dL), and a control water gargling (catechin concentration: 0 mg/dL) group. All participants gargled water or GT daily for 12 weeks. The symptoms of URTIs were recorded on a daily survey form by participants. The incidences of URTIs occurred in 6 (9.1%), 7 (10.8%), and 11 (15.7%) participants in the high-catechin, low-catechin, and water groups, respectively. Cox proportional hazards analysis, using background factors and prevention status as covariates, revealed a hazard ratio of 0.57 (95% Confidence Interval (CI): 0.21-1.55, p = 0.261) for the high-catechin vs. water group and 0.54 (95% CI: 0.20-1.50, p = 0.341) for the low-catechin vs. water group. Our findings showed the incidence of URTIs in a concentration-dependent GT gargling was not significantly different, partly owing to the low event rates caused by intense precautions against the coronavirus disease 2019 pandemic. Our study would serve as a foundation for the development of an advanced protocol with optimal concentrations and a larger number of participants.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

A monoclonal antibody called mirikizumab is used to treat ulcerative colitis. It is marketed under the Omvoh brand. It is intended to bind to interleukin-23 (IL-23) and obstruct its function. Upper respiratory tract (nose and throat) infections, headaches, rashes, and injection site responses (when administered by subcutaneous injection) are the most frequent adverse effects. In the United States in October 2023 and the European Union in May 2023, mirikizumab was authorized for medicinal use. For the treatment of people with moderately to highly active ulcerative colitis who have not responded well to, have lost responsiveness to, or are intolerant to either biologic therapy or conventional therapy, mirikizumab is suggested. A subset of people with ulcerative colitis (UC) do not react to currently available medications, despite advancements in UC medical therapy. Many innovative medications have recently acquired regulatory approval for use in UC, or are in the latter stages of development. The novel antibody mirikizumab, which is given intravenously (IV), binds to the inflammatory protein interleukin 23 and inhibits its function, preventing inflammation from being triggered. For individuals with moderately to highly active UC, mirikizumab would therefore provide an additional therapy choice if legalized.

Intranasal adenovirus-vectored Omicron vaccine induced nasal immunoglobulin A has superior neutralizing potency than serum antibodies

The upper respiratory tract is the initial site of SARS-CoV-2 infection. Nasal spike-specific secretory immunoglobulin A (sIgA) correlates with protection against Omicron breakthrough infection. We report that intranasal vaccination using human adenovirus serotype 5 (Ad5) vectored Omicron spike in people who previously vaccinated with ancestral vaccine could induce robust neutralizing sIgA in the nasal passage. Nasal sIgA was predominantly present in dimeric and multimeric forms and accounted for nearly 40% of total proteins in nasal mucosal lining fluids (NMLFs). A low-level IgG could also be detected in NMLFs but not IgM, IgD, and IgE. After a complete nasal wash, sIgA in the nasal passage could be replenished rapidly within a few hours. A comparison of purified paired serum IgA, serum IgG, and nasal sIgA from the same individuals showed that sIgA was up to 3-logs more potent than serum antibodies in binding to spikes and in neutralizing Omicron subvariants. Serum IgG and IgA failed to neutralize XBB and BA.2.86, while nasal sIgA retained potent neutralization against these newly emerged variants. Further analysis showed that sIgA was more effective than IgG or IgA in blocking spike-mediated cell-to-cell transmission and protecting hACE2 mice from XBB challenge. Using a sIgA monoclonal antibody as a reference, we estimated that the total nasal sIgA contains about 2.6–3.9% spike-specific sIgA in NMLFs collected approximately one month after intranasal vaccination. Our study provided insights for developing intranasal vaccines that can induce sIgA to build an effective and mutation-resistant first-line immune barrier against constantly emerging variants.

Pharmacokinetics and Safety of Spesolimab in Healthy Chinese Subjects: An Open-Label, Phase I Study.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects. In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45years received a single spesolimab dose by intravenous infusion (IV; 450mg, 900mg, or 1200mg) or subcutaneous (SC) administration (300mg or 600mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs). Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved. Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects. Clinicaltrials.gov registration: NCT04390568.

Long-term efficacy, safety, and patient-reported outcomes of apitegromab in patients with spinal muscular atrophy: results from the 36-month TOPAZ study.

At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months. Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%). The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings.

Pre-septal and Orbital Cellulitis: A Retrospective Analysis of Manifestations and Outcomes of a Tertiary Center in Kuwait.

Introduction Orbital cellulitis is an infectious condition that presents a gap in the literature in regard to its manifestations in the Middle East. A retrospective investigation was undertaken at one tertiary care facility in Kuwait, aiming to augment regional insights into the etiological factors and subsequent outcomes associated with this condition. Methods A retrospective review collected data from 92 patients in a tertiary care center in Kuwait for patients admitted with pre-septal and orbital cellulitis between January 2013 and June 2023. Primary outcomes assessed the resolution of symptoms, categorized as "completely resolved" and "resolved with complications". Secondary outcome measures included patients' ages, microbiology, laboratory, and radiological findings. Gender, predisposing conditions, surgical status, and orbital involvement were additionally extracted and analyzed descriptively. Results Data of n=92 (56 males and 36 females) were extracted. Ages ranged from 20 days to 18 years, the mean being seven years. Additionally, 52.2% (n=48) were diagnosed with orbital cellulitis, and 42.4% (n=39) were diagnosed with pre-septal cellulitis on admission. Cultures were available for n=60. Specifically, 52.1% (n=48) received CT scans; 6.5% (n=6) MRI scans; and 98.9% (n=91) received antibiotics (microbiology investigated: n=83). Ceftriaxone was used in 82.6% (n=76); 20.6% (n=19) received surgical interventions, and incision and drainage (I&D) were done on 15.2% (n=14). Visual acuity was assessed in 59.7% (n=55) patients. Five (5.43%) reported visual deterioration, and 87 (94.6%) of the outcomes were classified as "completely resolved". Conclusion Upper respiratory tract infections were the most common documented predisposing risk factor in the development of pre-septal and orbital cellulitis. Adverse outcomes in vision were documented in 5.43% of patients. A paucity of regional data highlights the importance of conducting further studies locally.

The Green Solution: In-Vitro and In-Silico Screening of Fagonia cretica and Berberis lyceum Phytochemicals against Haemophilus influenzae

Haemophilus influenzae (family Pasteurellaceae) is a coccobacillus, which is a non-spore-forming, non-motile, and non-acid-fast Gram-negative bacteria, present in upper respiratory tract causing epiglottitis, chronic bronchitis, meningitis, sinusitis, and community-acquired pneumonia. H. influenzae is resistant to certain antibiotics; novel drug discoveries are needed. In the present study, B. lyceum and F. cretica plant phytochemicals were tested in vitro against H. influenzae. Zones of inhibition were measured after the crude extract was tested using a well diffusion method against H. influenzae cultured on chocolate agar. Methanolic crude extract from B. lyceum showed a maximum zone of inhibition (32 mm) followed by ethanolic extract (30 mm). Similarly, methanolic extract from F. cretica showed maximum zone of inhibition (29 mm) followed by ethanolic extract (27.5 mm). Cytotoxic factor outer membrane protein (OMP) from H. influenzae was docked with the previously identified phytochemicals of these plants. In silico analysis shows that phytic acid from these plants is the most potent inhibitor of outer membrane protein (P6) followed by sindamine and karakuramine. The present study recommends that B. lyceum phytochemicals can be synergistically used as a potential drug against H. influenzae.

SARS-CoV-2 Vaccines: The Advantage of Mucosal Vaccine Delivery and Local Immunity.

Immunity against respiratory pathogens is often short-term, and, consequently, there is an unmet need for the effective prevention of such infections. One such infectious disease is coronavirus disease 19 (COVID-19), which is caused by the novel Beta coronavirus SARS-CoV-2 that emerged around the end of 2019. The World Health Organization declared the illness a pandemic on 11 March 2020, and since then it has killed or sickened millions of people globally. The development of COVID-19 systemic vaccines, which impressively led to a significant reduction in disease severity, hospitalization, and mortality, contained the pandemic's expansion. However, these vaccines have not been able to stop the virus from spreading because of the restricted development of mucosal immunity. As a result, breakthrough infections have frequently occurred, and new strains of the virus have been emerging. Furthermore, SARS-CoV-2 will likely continue to circulate and, like the influenza virus, co-exist with humans. The upper respiratory tract and nasal cavity are the primary sites of SARS-CoV-2 infection and, thus, a mucosal/nasal vaccination to induce a mucosal response and stop the virus' transmission is warranted. In this review, we present the status of the systemic vaccines, both the approved mucosal vaccines and those under evaluation in clinical trials. Furthermore, we present our approach of a B-cell peptide-based vaccination applied by a prime-boost schedule to elicit both systemic and mucosal immunity.

Effects of Chronic Barley Consumption on Upper Respiratory Tract Symptoms in Japanese Healthy Adults: A Randomized, Parallel-Group, Controlled Trial.

β-(1,3/1,4)-glucan is a major component of cereal grains, such as oats and barley. In this study, we investigated the effects of cooked waxy barley, which contains β-(1,3/1,4)-glucan, on upper respiratory tract physical symptoms and mood status by performing a randomized, parallel-group, comparative trial. The primary outcome was assessed using the Wisconsin Upper Respiratory Symptom Survey-21 and Profile of Mood States second edition. Twenty-seven healthy Japanese adult participants were supplemented with 100 g of cooked waxy barley (containing 1.8 g of β-glucan) or 100 g of cooked white rice daily for 8 weeks. Participants receiving cooked waxy barley reported a reduction in cumulative days of sneezing (p < 0.05) and feeling tired (p < 0.0001) compared with the control group. After the intervention period, there were significantly less severe nasal symptoms, such as runny nose, plugged nose, and sneezing (p < 0.05), and a significantly greater reduction of the Tension-Anguish score (p < 0.05) in the barley group than in the control group. This study suggests that supplementation of cooked waxy barley containing β-(1,3/1,4)-glucan prevents or alleviates nasal upper respiratory tract symptoms and improves mood status. The findings of this study should be confirmed by double-blind trials with a larger number of participants.

Early Childhood Onset Vanishing White Matter Disease with Multiple Cranial Nerve Enhancement: A New Consensus Criteria?

Vanishing White Matter Disease (VWM), also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH), although a rare neurological condition, is a prevalent hereditary leukoencephalopathy with a characteristic phenotype of gradual neurologic deterioration with ataxia being a prominent feature. It is characterized by a wide range of onset, from antenatal and infantile periods to early childhood and later adulthood periods. The early childhood form is considered the prevailing form, characterized by a preceding phase of normal development until the second or 3rd year of life, followed by progressive neurologic deterioration, accentuated by certain stressors, such as infections or minor trauma. Diagnosis is achieved based on the clinical pretext combined with distinctive MRI brain features, confirmed by DNA analysis detection of elf2B mutation. Our case is a healthy 18-month-old male who after a preceding upper respiratory tract infection, developed an ataxic gait, encephalopathy, and recurrent generalized seizures. Physical assessment revealed signs of generalized spasticity and hyperreflexia. Neuroimaging revealed diffuse symmetric supratentorial and infratentorial diffuse white matter hypomyelination. Interestingly, there was notable enhancement of the 3rd and 5th cranial nerves. Differential diagnosis included acute demyelinating leukoencephalopathies; and neuromatobolic disorders with acute presentations (including leukodystrophies, hypomyelinating disorders, and mitochondrial encephalopathies). In the early course of his management, he received immunomodulatory therapy in the form of pulse steroids, intravenous immunoglobulins, and oral tapering course of steroids. He had limited response to these interventions. Whole exome sequencing yielded a homozygous mutation in EIF2B3, confirming the diagnosis of VWMD/CACH. The presence of enhancing cranial neuropathies represent an atypical phenotype reported in other case reports and should alert the physician to avoid unnecessary intervention with immunosuppressive therapies.

Detection of pathogenic bacteria and biomarkers in lung specimens from cystic fibrosis patients

Diagnosing lung infections is often challenging because of the lack of a high-quality specimen from the diseased lung. Since persons with cystic fibrosis are subject to chronic lung infection, there is frequently a need for a lung specimen. In this small, proof of principle study, we determined that PneumoniaCheckTM, a non-invasive device that captures coughed droplets from the lung on a filter, might help meet this need. We obtained 10 PneumoniaCheckTM coughed specimens and 2 sputum specimens from adult CF patients hospitalized with an exacerbation of their illness. We detected amylase (upper respiratory tract) with an enzymatic assay, surfactant A (lower respiratory tract) with an immunoassay, pathogenic bacteria by PCR, and markers of inflammation by a Luminex multiplex immunoassay. The amylase and surfactant A levels suggested that 9/10 coughed specimens were from lower respiratory tract with minimal upper respiratory contamination. The PCR assays detected pathogenic bacteria in 7 of 9 specimens and multiplex Luminex assay detected a variety of cytokines or chemokines. These data indicate that the PneumoniaCheckTM coughed specimens can capture good quality lower respiratory tract specimens that have the potential to help in diagnosis, management and understanding of CF exacerbations and other lung disease.

Predictors of radiographic pneumonia in febrile children with cancer presenting to the emergency department

BackgroundFever is a common presenting complaint to the pediatric emergency department (PED), especially among oncology patients. While bacteremia has been extensively studied in this population, pneumonia has not. Some studies suggest that chest X-ray (CXR) does not have a role in the investigation of neutropenic fever in the absence of respiratory symptoms, yet non-neutropenic pediatric oncology patients were excluded from these studies. ObjectiveWe aimed to determine the incidence of CXRs ordered for febrile pediatric oncology patients, irrespective of their absolute neutrophil count (ANC), and to evaluate the rates of radiographic pneumonia as well as predictors of the latter in this group. MethodThis study was conducted in the PED at the American University of Beirut Medical Center (AUBMC), an Eastern Mediterranean tertiary-care hospital. We conducted a retrospective cohort study of acutely febrile pediatric cancer patients, younger than 18 years, presenting to a tertiary center from 2014 to 2018. We included one randomly selected febrile visit per patient. Fever was defined as a single oral temperature ≥38 °C within 24 h of presentation. We collected data on patient characteristics and outcomes. Our primary outcome was radiographic pneumonia; our secondary outcome was whether a CXR was done or not. We defined radiographic pneumonia as a consolidation, pleural effusion, infiltrate, pneumonia, “infiltrate vs. atelectasis,” or possible pneumonia mentioned by the radiologist. SPSS was used for the statistical analysis. ResultsWe reviewed a total of 664 medical charts and included data from 342 febrile pediatric patients in our analysis. Of these, 64 (18.7%) had a CXR performed. Overall, 16 (25%) had radiographic pneumonia while 48 (75%) did not. Patients were significantly more likely to have a CXR performed if they presented with upper respiratory tract symptoms, cough (p < 0.001 for both), or abnormal lung auscultation at the bedside (p = 0.004). Patients were also less likely to have a CXR done if they were asymptomatic upon admission to the PED (p < 0.001). However, neither cough nor shortness of breath nor abnormal lung examinations were significant predictors of a positive CXR (p = 0.17, 0.43, and 0.669, respectively). Patients with radiographic pneumonia were found to be significantly younger (4.29 vs. 6 years, p = 0.03), with a longer time since their last chemotherapy (15 vs. 7 days, p = 0.005), and were given intravenous (IV) bolus in the PED (87.5% vs. 56.3%, p = 0.02). Interestingly, patients with higher white blood cell (WBC) counts were more likely to have radiographic pneumonia (4850 vs. 1750, p = 0.01). Having a cough and an abnormal lung examination on presentation increased the odds of having a CXR (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI]: 3.4–12.8 and aOR: 4.5; 95% CI: 1.1–18.3, respectively). Returning to the PED for the same complaint within 2 weeks was associated with lower odds of a CXR at the index visit (aOR: 0.3; 95% CI: 0.1–0.6). For every year the child is older, the odds of having radiographic pneumonia decreased by 0.8 (95% CI: 0.6–0.98). However, for every day since the last chemotherapy session, the odds increased by 1.1 (95% CI: 1.01–1.12). ConclusionIn our sample, CXR was not commonly performed in the initial assessment of febrile cancer patients in the PED, unless respiratory symptoms or an abnormal lung examination was noted. However, these were not significant predictors of radiographic pneumonia. Further studies are needed to identify better predictors of pneumonia in this high-risk population.

De-implementation strategy to reduce unnecessary antibiotic prescriptions for ambulatory HIV-infected patients with upper respiratory tract infections in Mozambique: a study protocol of a cluster randomized controlled trial

BackgroundAntibiotics are globally overprescribed for the treatment of upper respiratory tract infections (URTI), especially in persons living with HIV. However, most URTIs are caused by viruses, and antibiotics are not indicated. De-implementation is perceived as an important area of research that can lead to reductions in unnecessary, wasteful, or harmful practices, such as excessive or inappropriate antibiotic use for URTI, through the employment of evidence-based interventions to reduce these practices. Research into strategies that lead to successful de-implementation of unnecessary antibiotic prescriptions within the primary health care setting is limited in Mozambique. In this study, we propose a protocol designed to evaluate the use of a clinical decision support algorithm (CDSA) for promoting the de-implementation of unnecessary antibiotic prescriptions for URTI among ambulatory HIV-infected adult patients in primary healthcare settings.MethodsThis study is a multicenter, two-arm, cluster randomized controlled trial, involving six primary health care facilities in Maputo and Matola municipalities in Mozambique, guided by an innovative implementation science framework, the Dynamic Adaption Process. In total, 380 HIV-infected patients with URTI symptoms will be enrolled, with 190 patients assigned to both the intervention and control arms. For intervention sites, the CDSAs will be posted on either the exam room wall or on the clinician´s exam room desk for ease of reference during clinical visits. Our sample size is powered to detect a reduction in antibiotic use by 15%. We will evaluate the effectiveness and implementation outcomes and examine the effect of multi-level (sites and patients) factors in promoting the de-implementation of unnecessary antibiotic prescriptions. The effectiveness and implementation of our antibiotic de-implementation strategy are the primary outcomes, whereas the clinical endpoints are the secondary outcomes.DiscussionThis research will provide evidence on the effectiveness of the use of the CDSA in promoting the de-implementation of unnecessary antibiotic prescribing in treating acute URTI, among ambulatory HIV-infected patients. Findings will bring evidence for the need to scale up strategies for the de-implementation of unnecessary antibiotic prescription practices in additional healthcare sites within the country.Trial registrationISRCTN, ISRCTN88272350. Registered 16 May 2024, https://www.isrctn.com/ISRCTN88272350

The Assessment and Efficiency of Cefixime in Upper Respiratory Tract Infections: Insights and Perspectives.

Upper respiratory tract infections (URTIs) are common in patients of the pediatric age group and often lead to significant morbidity and mortality. Antibiotics such as cefixime have contributed to the management of URTIs, particularly when bacterial etiology is suspected. Several studies have evaluated the effectiveness of cefixime in pediatric URTIs, showing promising results in alleviating symptoms and reducing the duration of illness. Cefixime, a third-generation cephalosporin, exhibits broad-spectrum activity against common pathogens implicated in URTIs, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, which are resistant to hydrolysis by several β-lactamases.Due to itsunique three-hour elimination half-life, cefixime allows for twice-daily or, in most cases, once-daily dosage. As a third-generation cephalosporin, cefixime effectively targets the common bacterial pathogens associated with these infections. Its notable efficacy is coupled with a favorable safety profile, making it a preferred choice for pediatricians and family physicians. The safety profiles of cefixime in children have been extensively studied with generally favorable outcomes. Adverse events are typically mild and infrequent, with gastrointestinal disturbances being most commonly reported. Notably, cefixime has a low propensity to induce bacterial resistance, making it a valuable option in the era of increasing antibiotic resistance. Cefixime may serve as a substitute for penicillin and first-generation cephalosporins in cases of acute upper and lower respiratory tract infections, acute otitis media, and acute uncomplicated urinary tract infections.This review aimed to provide a comprehensive outline of the use of cefixime in the treatment of URTIs in the pediatric population, focusing on its efficacy, safety, and overall clinical applications.

Trametinib for a child with refractory Rosai-Dorfman-Destombes disease harboring a novel somatic mutation in MAP2K1.

Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytosis characterized by accumulation of S100 + , CD68 + , and CD1a- histiocytes, with emperipolesis. It occurs predominantly in black adolescents and young adults, but rarely in Japanese children. Recently, oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes were reported in 30-50% of patients with RDD, and several studies have described treatment of adult patients with MAPK inhibitors. Here, we present the case of a Japanese boy with refractory RDD without signs of cardiofaciocutaneous (CFC) syndrome who harbored MAP2K1 p.Lys59del and responded to trametinib. The patient had lymph node, nasal cavity, kidney, upper respiratory tract, and intracranial involvement. RDD progressed after multi-agent chemotherapy, but responded to trametinib (0.025mg/kg). Trametinib did not eliminate the mass lesions, but trametinib plus minimal prednisolone (0.1mg/kg) resulted in a good outcome for more than 15months, without significant adverse effects. MAP2K1 p.Lys59del has been described as a germline mutation in a patient with CFC syndrome, but not as a somatic mutation in patients with malignancies. Trametinib may be a promising drug for children with RDD that is refractory to multi-agent chemotherapy. Its long-term efficacy and safety alone and in combination with chemotherapy should be investigated.

Human Infant Fecal Microbiota Differentially Influences the Mucosal Immune Pathways Upon Influenza Infection in a Humanized Gnotobiotic Pig Model

In this study, we evaluated the impact of human gut microbiota on the immune pathways in the respiratory tract using a gnotobiotic (Gn) piglet model. We humanized piglets with rural and urban infant fecal microbiota (RIFM and UIFM, respectively) and then infected them with a H1N1 swine influenza virus. We analyzed the microbial diversity and structure of the intestinal and respiratory tracts of the piglets before and after the influenza virus infection and measured the viral load and immune responses. We found that the viral load in the upper respiratory tract of UIFM transplanted piglets was higher than their rural cohorts (RIFM), while virus-specific antibody responses were comparable. The relative cytokine gene expression in the tracheobronchial (respiratory tract) and mesenteric (gastrointestinal) lymph nodes, lungs, blood, and spleen of RIFM and UIFM piglets revealed a trend in reciprocal regulation of proinflammatory, innate, and adaptive immune-associated cytokines as well as the frequency of T-helper/memory cells, cytotoxic T cells, and myeloid immune cell subsets. We also observed different phylum-level shifts of the fecal microbiota in response to influenza virus infection between the two piglet groups, suggesting the potential impact of the gut microbiota on the immune responses to influenza virus infection and lung microbiota. In conclusion, Gn piglets humanized with diverse infant fecal microbiota had differential immune regulation, with UIFM favoring the activation of proinflammatory immune mediators following an influenza virus infection compared to their rural RIFM cohorts. Furthermore, Gn piglets can be a useful model in investigating the impact of diverse human microbiota of the gastrointestinal tract, probably also the respiratory tract, on respiratory health and testing specific probiotic- or prebiotic-based therapeutics.

Reassortment incompetent live attenuated and replicon influenza vaccines provide improved protection against influenza in piglets

Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.