Bronchiolitis: Increased severity in the post-COVID-19 era.

INTRODUCTION: Acute bronchiolitis is a pressing public health concern, leading to numerous infant hospitalizations worldwide annually. The notable decrease in bronchiolitis hospitalizations during the COVID-19 pandemic sparked concerns about a potential resurgence post-pandemic. Questions also arose about the severity of post-pandemic cases compared to prepandemic ones. This study aimed to compare bronchiolitis severity before and after the COVID-19 pandemic, alongside changes in the epidemiology of bronchiolitis viral agents. MATERIAL AND METHODS: We conducted a retrospective analysis of medical records concerning infants under 12 months hospitalized for acute bronchiolitis in our pediatric pulmonology department over a period of 5 years: 2 pre-COVID years (2018-2020), the COVID year (2020), and 2 post-COVID years (2021-2023). Clinical and laboratory data were collected using standardized forms. RESULTS: Hospital admissions exhibited comparable rates pre- and post-COVID but witnessed a decline during the COVID period. Post-COVID, bronchiolitis severity increased, with longer hospitalization durations (p < 0.001) and increased oxygen therapy (p = 0.04), coinciding with a surge in the prevalence of RSV infections (p = 0.01). Patients testing positive for RSV were significantly younger (p = 0.005) and exhibited more severe symptoms. DISCUSSION AND CONCLUSION: This study reveals a significant increase in bronchiolitis severity and a rise in RSV cases following the COVID pandemic. The implementation of preventive measures such as nirsevimab is crucial to alleviate the burden of respiratory illnesses in vulnerable populations. Continued vigilance and research are needed to address the evolving challenges of bronchiolitis in the post-COVID era.

Non-invasive respiratory support in children and young adults with complex medical conditions in pediatric palliative care.

OBJECTIVE: Dyspnoea and sleep-disordered breathing (SDB) are common in children with life-limiting conditions but studies on treatment with non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) are scarce. The aim of the study was to describe children treated with long-term NIV/CPAP within a paediatric palliative care programme in France. METHODS: Cross-sectional survey on children and young adults with complex medical conditions treated within the French paediatric NIV network with long-term NIV/CPAP. Characteristics of the patients were analysed and patient-related outcome measures of NIV/CPAP benefit were reported. RESULTS: The data of 50 patients (68% boys), median age 12 (0.4-21) years were analysed. Twenty-three (46%) patients had a disorder of the central nervous system and 5 (10%) a chromosomal anomaly. Thirty-two (64%) patients were treated with NIV and 18 (36%) with CPAP. NIV/CPAP was initiated on an abnormal Apnoea-Hypopnoea Index in 18 (36%) of the patients, an abnormal nocturnal gas exchange alone in 28 (56%), and after an acute respiratory failure in 11 (22%) of the patients. Mean objective NIV/CPAP adherence was 9.3±3.7 hours/night. NIV/CPAP was associated with a decrease in dyspnoea in 60% of patients, an increase in sleep duration in 60% and in sleep quality in 74%, and an improvement in parents' sleep in 40%. CONCLUSIONS: In children with life-limiting conditions, long-term NIV/CPAP may be associated with relief of dyspnoea, an improvement of SDB and an improvement in parents' sleep.

Pulmonary mucoepidermoid carcinoma in a 7-year-old child.

A 7-year-old boy presented with exertional dyspnea and cough, initially misdiagnosed as asthma. Imaging revealed a mass obstructing the left main bronchus, later identified as a pulmonary mucoepidermoid carcinoma (MEC). Following surgical sleeve resection, complete tumor removal occurred without malignancy in surrounding lymph nodes, resulting in symptom resolution without additional therapy. Pulmonary MEC, uncommon in pediatric patients, poses diagnostic challenges due to nonspecific symptoms, resulting in delayed diagnosis. Typically managed via complete surgical resection, MEC offers a favorable prognosis, primarily affecting central airways and requiring conservative surgical approaches to preserve lung tissue. This case underscores the diagnostic challenges of primary pulmonary MEC in pediatric patients. It stresses the need to consider unusual causes in pediatric respiratory symptoms and highlights the critical role of precise diagnostic methods and personalized surgical strategies in managing such rare pulmonary malignancies for optimal outcomes.

Pulmonary cystic echinococcosis in a child.

This case report describes the presentation, diagnosis, and treatment of a 13-year-old boy with pulmonary cystic echinococcosis. The patient presented with low-volume hemoptysis, and lung imaging revealed a large cystic mass, as well as smaller pseudo-nodular lesions, suggesting a large intrathoracic hydatid cyst and ruptured cysts. The diagnosis was confirmed by a positive echinococcosis Western Blot assay, despite equivocal serology. The treatment consisted of surgical removal of the large cyst using thoracoscopy, along with a two-week course of albendazole and praziquantel, followed by albendazole alone for two years. Analysis of the cyst membrane revealed an Echinococcus granulosus protoscolex. The patient had a successful recovery.

Binding of heparan sulfate to human cystatin C modulates inhibition of cathepsin L: Putative consequences in mucopolysaccharidosis.

Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases characterized by glycosaminoglycan (GAG) accumulation causing progressive multi-organs dysfunction and ultimately severe cardio-respiratory damages. Human cystatin C (hCC), a potent inhibitor of cysteine cathepsins, plays an important role in respiratory diseases. However, its regulation remained unknown in MPS. Herein, elevated hCC levels were measured in respiratory specimens from MPS-I, -II, and -III patients and were significantly correlated with severe respiratory symptoms (rs = 0.7173). Heparan sulfate (HS), a prominent GAG, dampened its inhibitory activity toward cathepsin L in a dose-dependent manner. HS and HS-oligosaccharides bound tightly hCC, in combination with a secondary structure rearrangement. Molecular modeling studies identified three HS binding regions in hCC, including the N-terminus, which is crucial in the inhibition of cathepsins. Impairment of inhibitory potential of hCC may reflect abnormal regulation of proteolytic activity of cathepsin L in lung, ultimately contributing to the severity of MPS.

Recommended respiratory tests are not routinely performed for mucopolysaccharidosis patients.

Recommended respiratory tests used as major outcomes in clinical trials for MPS treatment cannot be routinely performed in everyday practice because neurocognitive impairment and motor skill difficulties affect compliance for most MPS patients https://bit.ly/3G4qp8U.

Outcome analysis of a conservative approach to diaphragmatic paralysis following congenital cardiac surgery in neonates and infants: a bicentric retrospective study.

OBJECTIVES: Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy. METHODS: This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery. RESULTS: Fifty-one neonates and infants were included in the analysis. Patients' median age was 12.0 days at cardiac surgery (5.0-82.0), and median weight was 3.5 kg (2.8-4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients' characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29-37.3); P = 0.024 and OR 6.0 (1.4-24.7); P = 0.013, respectively]. CONCLUSIONS: The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy's failure.

The abnormal accumulation of heparan sulfate in patients with mucopolysaccharidosis prevents the elastolytic activity of cathepsin V.

Mucopolysaccharidosis (MPS) are rare inherited diseases characterized by accumulation of lysosomal glycosaminoglycans, including heparan sulfate (HS). Patients exhibit progressive multi-visceral dysfunction and shortened lifespan mainly due to a severe cardiac/respiratory decline. Cathepsin V (CatV) is a potent elastolytic protease implicated in extracellular matrix (ECM) remodeling. Whether CatV is inactivated by HS in lungs from MPS patients remained unknown. Herein, CatV colocalized with HS in MPS bronchial epithelial cells. HS level correlated positively with the severity of respiratory symptoms and negatively to the overall endopeptidase activity of cysteine cathepsins. HS bound tightly to CatV and impaired its activity. Withdrawal of HS by glycosidases preserved exogenous CatV activity, while addition of Surfen, a HS antagonist, restored elastolytic CatV-like activity in MPS samples. Our data suggest that the pathophysiological accumulation of HS may be deleterious for CatV-mediated ECM remodeling and for lung tissue homeostasis, thus contributing to respiratory disorders associated to MPS diseases.

Subcellular mechanisms involved in apoptosis induced by aminoglycoside antibiotics: Insights on p53, proteasome and endoplasmic reticulum.

Gentamicin, an aminoglycoside used to treat severe bacterial infections, may cause acute renal failure. In the renal cell line LLC-PK1, gentamicin accumulates in lysosomes, induces alterations of their permeability, and triggers the mitochondrial pathway of apoptosis via activation of caspase-9 and -3 and changes in Bcl-2 family proteins. Early ROS production in lysosomes has been associated with gentamicin induced lysosomal membrane permeabilization. In order to better understand the multiple interconnected pathways of gentamicin-induced apoptosis and ensuing renal cell toxicity, we investigated the effect of gentamicin on p53 and p21 levels. We also studied the potential effect of gentamicin on proteasome by measuring the chymotrypsin-, trypsin- and caspase-like activities, and on endoplasmic reticulum by determining phopho-eIF2α, caspase-12 activation and GRP78 and 94. We observed an increase in p53 levels, which was dependent on ROS production. Accumulation of p53 resulted in accumulation of p21 and of phospho-eIF2α. These effects could be related to an impairment of proteasome as we demonstrated an inhibition of trypsin-and caspase-like activities. Moderate endoplasmic reticulum stress could also participate to cellular toxicity induced by gentamicin, with activation of caspase-12 without change in GRP74 and GRP98. All together, these data provide new mechanistic insights into the apoptosis induced by aminoglycoside antibiotics on renal cell lines.

Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells.

The emergence of very multiresistant Gram-negative bacterial strains has reinstated polymyxins (polymyxin B, colistin), pentacationic lipopeptides, in the therapy, in spite of their nephrotoxicity. Extensive tubular reabsorption concentrates polymyxin in proximal tubular cells. The novel polymyxin derivatives NAB739, NAB7061 and NAB741 have their cyclic part identical to that of polymyxin B, but their side chain consists of uncharged octanoyl-threonyl-d-serinyl, octanoyl-threonyl-aminobutyryl, and acetyl-threonyl-D-serinyl respectively. In this study, we compared the toxicities of NAB739, NAB7061 and NAB741 with that of polymyxin B by using the porcine renal proximal tubular cell line LLC-PK1 electroporated or incubated with the selected compound. Both the ability to cause cell necrosis (quantified as the leakage of lactate dehydrogenase) and the ability to cause apoptosis (as quantified by counting apoptotic nuclei) were assessed. In electroporated cells, polymyxin B induced total (>85%) necrosis of the cells at 0.016 mM, whereas an approx. 8-fold concentration of NAB739 and NAB7961 and an approx. 32-fold concentration of NAB741 was required for the same effect. In cells treated without electroporation (incubated), polymyxin B elicited a marked degree (approx. 50%) of necrosis at 0.5mM, whereas the NAB compounds were inert even at 1mM. Neither polymyxin B nor the NAB compounds induced apoptosis.

Role of oxidative stress in lysosomal membrane permeabilization and apoptosis induced by gentamicin, an aminoglycoside antibiotic.

Gentamicin, an aminoglycoside antibiotic used to treat severe bacterial infections, may cause acute renal failure. At therapeutic concentrations, gentamicin accumulates in lysosomes and induces apoptosis in kidney proximal tubular cells. In gentamicin-treated renal LLC-PK1 cells, acridine orange release from lysosomes, previously interpreted as lysosomal membrane permeabilization, precedes the apoptotic cascade that develops during incubation with gentamicin. However, the link between gentamicin lysosomal accumulation and apoptosis remains unclear. We here examined if reactive oxygen species (ROS) production could account for gentamicin-induced acridine orange release and apoptosis, and the implication of iron in these events. We found that gentamicin induced ROS production prior to, and at lower drug concentrations than required for, acridine orange release and apoptosis. ROS antioxidant or scavenger, catalase, and N-acetylcysteine largely prevented these events. Vital confocal imaging revealed that gentamicin-induced ROS production occurs in lysosomes. Deferoxamine, an iron chelator, which is endocytosed and accumulates in lysosomes, largely prevented gentamicin-induced ROS production as well as apoptosis. Direct evidence for gentamicin-induced permeabilization of lysosomal membrane was provided by showing the release into the cytosol of Lucifer yellow, a membrane-impermeant endocytic tracer with a comparable molecular weight as gentamicin. Altogether, our data demonstrate a key role of lysosomal iron and early ROS production in gentamicin-induced lysosomal membrane permeabilization and apoptosis.

Apoptosis induced by aminoglycosides in LLC-PK1 Cells: comparative study of neomycin, gentamicin, amikacin, and isepamicin using electroporation.

Levels of apoptosis induction (4',6'-diamidino-2-phenylindole staining, activation of caspase 3) for aminoglycosides were compared by using renal LLC-PK1 cells. Amikacin caused less apoptosis than gentamicin in incubated cells. In electroporated cells, neomycin B and gentamicin caused apoptosis in the 0.03 to 0.1 mM range, isepamicin required larger concentrations (0.2 mM), and amikacin was without effect.