Association of respiratory virus types with clinical features in bronchiolitis: Implications for virus testing strategies. A systematic review and meta-analysis.

BACKGROUND: Bronchiolitis is a leading cause of infant hospitalization, linked to respiratory syncytial virus (RSV) and rhinovirus (RV). Guidelines lack specific viral testing for bronchiolitis management. To establish effective management strategies, it is crucial to assess whether specific respiratory virus types are correlated with distinct examination features. METHODS: Through a systematic search of three databases, 21 studies were qualitatively analyzed, with 18 used for meta-analysis. Various outcomes like wheezing on auscultation, fever, atopic traits, and infection severity were evaluated. RESULTS: RSV-positive bronchiolitis was associated with a higher need for oxygen supplementation (OR 1.78, 95% CI 1.04-3.02) in 5 studies, while RV-positive bronchiolitis was more frequently linked to personal history of eczema (OR 0.60, 95% CI 0.41-0.88) in 6 studies. No significant differences were observed in the other outcomes examined. CONCLUSIONS: Bronchiolitis caused by RSV or RV presents with similar clinical features. Despite the associations between RSV-positive bronchiolitis and need for oxygen supplementation, and RV-positive bronchiolitis and a history of eczema, our study shows that viral etiology of bronchiolitis cannot be determined solely based on clinical presentation. Tailored management strategies, informed by accurate viral testing, seem crucial in clinical practice for enhancing patient outcomes in severe bronchiolitis.

Respiratory syncytial virus shedding by children hospitalized with lower respiratory tract infection.

Children with respiratory syncytial virus (RSV) infection shed virus for variable periods. The aim of this study was to quantify the viral load in nasopharyngeal aspirates of children with RSV throughout their hospitalization. This study included 37 children who were admitted with a diagnosis of RSV infection based on a positive rapid diagnostic test. Nasopharyngeal aspirates were collected from patients every day, from admission to discharge. Viral detection and quantification were performed using quantitative real-time PCR. Of the 37 patients, RSV-A was detected in 29 and RSV-B in 6. Two patients were PCR-negative for any type of RSV. RSV-A was detected in 12 of 16 patients (75%) 6 days after admission. These patients shed detectable virus from days 1 to 12, and for a significantly longer period (mean 5.7 days) than RSV-B (mean 3.8 days) patients. Half of the RSV-A patients were also positive on day 14 following onset. RSV-A was detected in patients <12 months of age for significantly longer periods after onset than in patients ≥12 months of age. RSV-A viral load was negatively correlated with days from admission and days from onset. Because RSV shedding was frequently prolonged, the hospitalized children may have contracted RSV as a nosocomial infection. To prevent nosocomial RSV infections in hospital wards, healthcare workers must take appropriate infection control measures and provide adequate guidance on hand washing to the family of the patient.

Influenza viral load and peramivir kinetics after single administration and proposal of regimens for peramivir administration against resistant variants.

We estimated the efficacy of the current single administration of peramivir on the basis of peramivir pharmacokinetics in the upper respiratory tract (URT) and determined the predictive peramivir concentration-time curve to assess its efficacy against viruses with decreased susceptibility to neuraminidase inhibitors. Serum, nasal swab, or aspiration samples were collected from 28 patients treated with 10 mg/kg body weight peramivir. The sequential influenza viral RNA load and susceptibility after peramivir administration were measured using a quantitative real-time reverse transcription-PCR and neuraminidase inhibition assay. The peramivir concentrations in the serum and URT after a single administration at 10 mg/kg were measured, and the predictive blood and URT peramivir concentration-time curves were determined to assess various administration regimens against resistant variants. The peramivir concentration decreased to <0.1% of the maximum concentration of drug in serum (Cmax) at 24 h after administration. Rapid elimination of peramivir from the URT by 48 h after administration may contribute to an increase in the influenza A viral load after day 3 but not to a decrease in the influenza B viral load, despite the absence of a decrease in the susceptibility to peramivir. A longer maintenance of a high level of peramivir in the URT is expected by divided administration rather than once-daily administration. When no clinical improvement is observed in patients with normal susceptibility influenza A and B, peramivir readministration should be considered. In severe cases caused by resistant variants, better inhibitory effectiveness and less frequent adverse events are expected by divided administration rather than once-daily administration with an increased dosage.

Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years.

UNLABELLED: Most wheezing episodes in infants are caused and exacerbated by virus-induced lower respiratory tract infections. However, there are few reports of epidemiologic and clinical virus-specific research with a focus on virus-induced wheezing. The purpose of the current study was to characterize the clinical presentation of virus-induced wheezing in pediatric patients <3 years of age who were hospitalized with lower respiratory tract infections. Of the 412 patients in the study, 216 were followed for 3 years. Nasopharyngeal aspirates collected from the patients at the time of admission were examined for the presence of respiratory syncytial virus (RSV), rhinovirus (RV), parainfluenza-3 virus (PIV-3), human metapneumovirus (hMPV), and influenza virus (Flu) using reverse-transcription polymerase chain reaction and rapid diagnostic tests. Clinical signs were assessed using a severity scoring system. In patients with wheezing at the time of admission, RSV, RV, RSV+RV, Flu, PIV-3, and hMPV were detected in 33, 14, 8, 8, 5, and 3 % of samples, respectively. There were no differences in age and severity scores between patients harboring more prevalent viruses (RSV and RV) and those with less common infections. Patients with wheezing and RV-positive aspirates at the time of admission were more likely to develop subsequent wheezing during the following 3 years. CONCLUSION: RSV and RV infections are factors in the development and exacerbation of wheezing after virus-induced lower respiratory tract infections. Moreover, RV-induced wheezing may be associated with subsequent recurrent wheezing and the development of asthma.

Rhinovirus load and disease severity in children with lower respiratory tract infections.

It has not been clarified if there is a correlation between rhinovirus (RV) load and disease severity in the lower respiratory tract infections of hospitalized children. This study was undertaken to elucidate the contribution of the viral load to the development of disease severity in 412 children ≤3 years of age who were hospitalized with lower respiratory tract infections. The RV load in nasopharyngeal aspirates obtained from the patients at the time of admission was measured by real-time quantitative reverse-transcription polymerase chain reaction (PCR), and the clinical symptoms of the patients were assessed using a severity scoring system. Of the 412 patients, 43 (10.4%) were diagnosed with RV infections only, and 15 were determined to have high severity scores. When all patients infected with RV were assessed, there was no correlation between the viral load and the disease severity. However, there was a significant negative correlation between the disease severity and age among children <11 months of age (n = 15, ρ = -0.677, P = 0.006) and a significant positive correlation between the viral load and the disease severity among children ≥11 months of age (n = 28, ρ = 0.407, P = 0.032). Among the patients infected with RV <11 months of age, the disease severity may be associated with an immature immune response and the small diameter of their airways rather than viral load. By contrast, in the patients ≥11 months of age, viral load may contribute to the development of disease severity.

Megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells.

Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.

Clinical course and background of nasopharyngeal antibiotic-resistant bacteria carriers among preschool children hospitalized for lower respiratory tract infection.

AbstractWe investigated the nasopharyngeal microbiota in preschool patients hospitalized with lower respiratory tract infection to clarify the relationships between culturable nasopharyngeal bacteria and prognosis. From 2016 to 2018, nasopharyngeal culture was performed on inpatients under 6 years of age with a lower respiratory tract infection. Among the 1,056 study patients, 1,046 provided nasopharyngeal samples that yielded positive cultures, yielding 1,676 isolated strains. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, were isolated in 25%, 27%, and 31% of the samples, respectively, and were the major causes of respiratory tract infection in these children. The only factor associated with the isolation of antibiotic-resistant strains from the nasopharynx was daycare attendance, which did not affect clinical severity, such as duration of fever and hospitalization. This study demonstrated that resistant bacteria in the nasopharynx did not affect the severity of lower respiratory tract infection and supports the use of narrow-spectrum antimicrobial agents in accordance with published guidelines when initiating therapy for pediatric patients with community-acquired pneumonia.

The trend of drug-resistant Streptococcus pneumoniae from nasopharynx of children.

We investigated the trend of the carriage of drug-resistant Streptococcus pneumoniae in nasopharynx of children. The 202 isolates from pediatric outpatients and their previous antibiotic use was investigated from 2004 to 2006. The total rate of patients medicated with antibiotics was 47.5%, a 6.9% decrease compared with our previous study performed from 2001 to 2003. There were 56 (27.7%) penicillin-susceptible, 83 (41.1%) penicillin-intermediate, and 63 (31.2%) penicillin-resistant strains by the susceptibility breakpoints used during the previous study period. There were 196 (97%) susceptible, 5 (2.5%) intermediate, and 1 (0.5%) resistant strains by breakpoints in this study, which were introduced in 2008 by the Clinical Laboratory and Standards Institute. The rate of strains with a single altered pbp gene was 21.8% (44), with 2 altered pbp genes was 21.8% (31), and with 3 altered pbp genes was 53.5% (108). The total rate of strains with altered pbp gene(s) was 90.1% (183). We found the emergence of strains with pbp1a and 2b and the higher rate of strains with pbp2x. There was obvious association between amoxicillin use and the carriage of altered pbp gene(s). These results might suggest that amoxicillin was not a safe alternative to prevent the emergence of resistant strains. We need to reassess a beneficial approach for the treatment of pediatric outpatients.

Non-antibiotic treatment for pediatric outpatients with common cold inhibits the emergence of drug resistant pneumococci.

The occurrence of drug resistant Streptococcus pneurmoniae (S. pneumoniae) is very high in Japan. Unnecessary use of antibiotics had been thought to cause this problem but previous studies had not clearly showed that the decreasing rate of antibiotic use had been related to the reduction of the prevalence of resistant strains. In this study, we tried to prove that non-antibiotic treatment for common cold would reduce the antibiotic resistant S. pneumoniae in nasopharynx in children. Forty-five children with the common cold were randomly selected from pediatric patients who had taken antibiotics within the past three months. We collected nasopharyngeal swabs from all of the participants and once again after a period of 2 to 3 months without using any antibiotics. Twenty-four of these patients had the S. pneumoniae strains isolated. Then these strains were undergone a susceptibility test and drug-resistant gene detection. The susceptibility test reveled that patients with penicillin-resistant strains decreased from 17 to 7 (p < 0.01). The test also reveled that the decreased number of patients had strains that were resistant to cefditren. The gene detection revealed that none of the patients acquired a higher resistance to penicillin. Our study suggests that the treatment without antibiotics reduces the drug-resistant S. pneumoniae. Controlled antibiotic use in children might prevent children from carrying the antibiotic resistant S. pneumoniae.

Regulation of megalin expression in cultured proximal tubule cells by angiotensin II type 1A receptor- and insulin-mediated signaling cross talk.

Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3-kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs.