The wheezy infant: A viewpoint from low-middle income countries.

OBJECTIVE: To review the recent evidence in the literature of various aspects of recurrent/severe wheezing in children under 3 in low-middle income countries [LMICS]. SOURCES: A non-systematic review including articles in English. We mainly selected publications from the last 5 years. Studies on epidemiology, aetiology, diagnosis, treatment, and prevention were included in the search. We reviewed differential diagnoses of wheezing that focused on LMICS. We also reviewed aspects of prevention. SUMMARY OF THE FINDINGS: Many epidemiological studies have shown a variable but significant number of wheezy infants [WI] cases in LMICS when compared to other countries. The differential diagnosis of causes of wheezing in this age group is mandatory, taking into account local facilities. Few treatment options have been well studied for this age group. In LMICS, a pragmatic approach could be considered, as described in the article. It is difficult to study primary prevention for WI and secondary prevention (mainly environmental) may have some impact. A schematic approach for recurrent wheezers is presented, which takes into account settings with limited resources. CONCLUSION: Severely or recurrently wheezy children under 3 is a common clinical issue in LMICS. Studies on this age group are needed to reduce the significant morbidity. It may be possible to lower the high burden of wheezing in this age group by selecting the phenotype which may respond to inhaled steroids.

Cystic fibrosis in low and middle-income countries (LMIC): A view from four different regions of the world.

Cystic fibrosis (CF) has been shown to affect people all over the world. While life expectancy for people with CF has increased substantially, CF is still associated with death in infants and young children in many regions, particularly in low and middle-income countries (LMIC). These countries face significant challenges to promote CF diagnosis and improvements to CF care due to financial constraints and a significant burden of other diseases. In this review, we describe the status of CF diagnosis and care in different LMIC settings, from four different parts of the world (Brazil, South Africa, Israel and India). We highlight challenges and opportunities for CF practitioners in LMIC to improve CF care and outcomes. While early CF diagnosis is the key to optimising outcomes, newborn screening may not be feasible for countries with lower CF incidence and higher birth rates, such as India or South Africa. CF therapies and care in LMIC need to be adapted to available resources of these countries. Collaboration initiatives of the global CF community with LMIC may improve CF care in these countries. Most individuals with CF in LMIC are not benefiting from CFTR modulator treatments due to the prohibitive cost of these drugs.

Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country.

BACKGROUND: The Brazilian population has a tri-hybrid composition with a high degree of ethnic admixture. We hypothesized that Brazilian individuals with CF from different Brazilian regions have a specific distribution of CFTR variants. METHODS: Individuals with CF with data available in the Patient Registry and without an established genotype were submitted to CFTR sequencing by Next Generation Sequencing (NGS) methodology, and results were anonymously incorporated to the Registry Database. Genotyping results were expressed as 'positive', 'inconclusive' or 'negative'. Logistic regression models were performed to investigate the association between demographic/clinical variables and genotyping results. Mediation analysis was conducted to estimate direct and indirect effects of Brazilian region on a binary positive genotyping response. RESULTS: In October 2017, data from 4,654 individuals with CF were available, and 3,104(66.7%) of them had a genotyping result. A total of 236 variants (114 new variants) were identified, with F508del identified in 46% of the alleles tested. Genotyping revealed 2,002(64.5%) individuals positive, 757(24.4%) inconclusive and 345(11.1%) negative. Distribution of genotype categories was markedly different across Brazilian Regions, with greater proportions of negative individuals in the North (45%) and Northeast (26%) regions. Newborn screening (CF-NBS) and age at diagnosis were identified as mediators of the effect of Brazilian region on a positive genotyping result. CONCLUSIONS: This large initiative of CFTR genotyping showed significant regional discrepancies in Brazil, probably related to socio-economic conditions, lack of adequate CF-NBS and poor access to reliable sweat testing. These results may be useful to indicate Regions where CF care demands more attention.

Primary Ciliary Dyskinesia as a Cause of Repeating Atelectasis in the Neonatal Period.

BACKGROUND Primary ciliary dyskinesia (PCD) is a disease characterized by motor ciliary dysfunction, which leads to the accumulation of secretions in the lower airways and, consequently, to atelectasis and repeated infections. During the neonatal period, diagnosis can be difficult because the symptoms are frequently associated with other respiratory diseases common in neonates. The laterality defects should warn the clinician of the need for further investigation using clinical criteria, but the confirmation depends on a genetic test. CASE REPORT The objective of this report is to present a case of PCD manifesting in the neonatal period that was diagnosed due to respiratory failure associated with recurrent atelectasis and situs inversus totalis. CONCLUSIONS This disease is not well known by neonatologists, but early diagnosis decreases morbidity and improves patient quality of life.

Typical epidemiology of respiratory virus infections in a Brazilian slum.

Host population size, density, immune status, age structure, and contact rates are critical elements of virus epidemiology. Slum populations stand out from other settings and may present differences in the epidemiology of acute viral infections. We collected nasopharyngeal specimens from 282 children aged ≤5 years with acute respiratory tract infection (ARI) during 2005 to 2006 in one of the largest Brazilian slums. We conducted real-time reverse transcription-polymerase chain reaction (RT-PCR) for 16 respiratory viruses, nested RT-PCR-based typing of rhinoviruses (HRVs), and collected clinical symptoms. Viruses were common causes of respiratory disease; with ≥1 virus being detected in 65.2% of patients. We detected 15 different viruses during 1 year with a predominance of HRV (33.0%) and human respiratory syncytial virus (hRSV, 12.1%) infections, and a high rate of viral coinfections (28.3%). We observed seasonality of hRSV, HRV and human coronavirus infections, more severe symptoms in hRSV and influenza virus (FLU) infections and prolonged circulation of seven HRV clusters likely representing distinct serotypes according to genomic sequence distances. Potentially unusual findings included the absence of human metapneumovirus detections and lack of typical FLU seasonal patterns, which may be linked to the population size and density of the slum. Nonetheless, most epidemiological patterns were similar to other studies globally, suggesting surprising similarities of virus-associated ARI across highly diverse settings and a complex impact of population characteristics on respiratory virus epidemiology.

Cystic fibrosis carriership and tuberculosis: hints toward an evolutionary selective advantage based on data from the Brazilian territory.

BACKGROUND: The reason why Cystic Fibrosis (CF) is the most common fatal genetic disease among Caucasians has been incompletely studied. We aimed at deepening the hypothesis that CF carriers have a relative protection against Mycobacterium tuberculosis (Mtb) infection. METHODS: Applying spatial epidemiology, we studied the link between CF carriership rate and tuberculosis (TB) incidence in Brazil. We corrected for 5 potential environmental and 2 immunological confounders in this relation: monthly income, sanitary provisions, literacy rates, racial composition and population density along with AIDS incidence rates and diabetes mellitus type 2. Smoking data were incomplete and not available for analysis. RESULTS: A significant, negative correlation between CF carriership rate and TB incidence, independent of any of the seven confounders was found. CONCLUSION: We provide exploratory support for the hypothesis that carrying a single CFTR mutation arms against Mtb infections.

Albuterol via metered-dose inhaler in children: Lower doses are effective, and higher doses are safe.

BACKGROUND: The ideal dosing of albuterol via metered-dose inhalers for acute childhood asthma is not well established. We hypothesized that greater doses of albuterol would result in less time in the hospital and lower admission rates. METHODS: This was a randomized controlled double-blind multicenter study, conducted in emergency rooms (ER). We included patients with 2-17 years old with moderate to severe acute asthma (Pediatric Respiratory Assessment Measure, PRAM, score ≥5). Dosages administered during the first hour included: 6 (up to 25 kg) or 12 puffs (>25 kg) in the control group and 9 (up to 15 kg), 12 (>15-20 kg), 15 (>20-25 kg), or 18 puffs (>25 kg) in the study group. Several efficacy (changes in PRAM score, pulse oximetry, and FEV1 , length of stay, and admission rates) and safety (albuterol plasma levels, heart rate, serum potassium, glucose and bicarbonate levels, EKG, and tremor rates) outcome measures were assessed. RESULTS: We included 119 patients with similar baseline conditions, and no significant differences were observed between groups in the length of stay (P = 0.48) or admission rate (P = 0.55). No significant differences were observed in FEV1 , PRAM score, and pulse oximetry changes after 1 hr and at discharge or admission. No significant differences were observed in safety outcomes between groups. CONCLUSIONS: Higher albuterol dosage regimens did not result in lower admission rate or shorter length of stay in the ER, but showed similar safety profile for children with moderate to severe acute asthma. Pediatr Pulmonol. 2016;51:1122-1130. © 2016 Wiley Periodicals, Inc.

Evidence for an Ancestral Association of Human Coronavirus 229E with Bats.

UNLABELLED: We previously showed that close relatives of human coronavirus 229E (HCoV-229E) exist in African bats. The small sample and limited genomic characterizations have prevented further analyses so far. Here, we tested 2,087 fecal specimens from 11 bat species sampled in Ghana for HCoV-229E-related viruses by reverse transcription-PCR (RT-PCR). Only hipposiderid bats tested positive. To compare the genetic diversity of bat viruses and HCoV-229E, we tested historical isolates and diagnostic specimens sampled globally over 10 years. Bat viruses were 5- and 6-fold more diversified than HCoV-229E in the RNA-dependent RNA polymerase (RdRp) and spike genes. In phylogenetic analyses, HCoV-229E strains were monophyletic and not intermixed with animal viruses. Bat viruses formed three large clades in close and more distant sister relationships. A recently described 229E-related alpaca virus occupied an intermediate phylogenetic position between bat and human viruses. According to taxonomic criteria, human, alpaca, and bat viruses form a single CoV species showing evidence for multiple recombination events. HCoV-229E and the alpaca virus showed a major deletion in the spike S1 region compared to all bat viruses. Analyses of four full genomes from 229E-related bat CoVs revealed an eighth open reading frame (ORF8) located at the genomic 3' end. ORF8 also existed in the 229E-related alpaca virus. Reanalysis of HCoV-229E sequences showed a conserved transcription regulatory sequence preceding remnants of this ORF, suggesting its loss after acquisition of a 229E-related CoV by humans. These data suggested an evolutionary origin of 229E-related CoVs in hipposiderid bats, hypothetically with camelids as intermediate hosts preceding the establishment of HCoV-229E. IMPORTANCE: The ancestral origins of major human coronaviruses (HCoVs) likely involve bat hosts. Here, we provide conclusive genetic evidence for an evolutionary origin of the common cold virus HCoV-229E in hipposiderid bats by analyzing a large sample of African bats and characterizing several bat viruses on a full-genome level. Our evolutionary analyses show that animal and human viruses are genetically closely related, can exchange genetic material, and form a single viral species. We show that the putative host switches leading to the formation of HCoV-229E were accompanied by major genomic changes, including deletions in the viral spike glycoprotein gene and loss of an open reading frame. We reanalyze a previously described genetically related alpaca virus and discuss the role of camelids as potential intermediate hosts between bat and human viruses. The evolutionary history of HCoV-229E likely shares important characteristics with that of the recently emerged highly pathogenic Middle East respiratory syndrome (MERS) coronavirus.

Follow-up on pediatric patients with bronchiolitis obliterans treated with corticosteroid pulse therapy.

BACKGROUND: Bronchiolitis obliterans (BO) is a rare but severe disease in children. Currently, there is no consensus on the treatment for BO with respect to the systemic use of corticosteroids. Here we report on the follow-up of children with a diagnosis of BO who were treated with corticosteroid pulse therapy. METHODS: Forty patients fulfilling the BO diagnosis criteria were treated with methylprednisolone pulse therapy in monthly cycles until clinical improvement. After the pulse therapy began, we analyzed the clinical and laboratory data at intervals. Statistical analyses were performed using non-parametric tests to compare repeated measures (Friedman, Wilcoxon) or paired nominal data (McNemar) (α = 5%). RESULTS: The frequency of wheezing exacerbations and hospitalizations was reduced (p = 0.0042 and p < 0.0001, respectively) and oxygen saturation improved (p = 0.0002) in the pulse therapy-treated patients. Prolonged oral corticosteroid therapy was discontinued in 83% of these patients. The mean Z-score length for age improved from -1.08 to -0.63, and the mean Z-score weight for age improved from -0.91 to -0.59. The adverse effects during the infusion were temporary and none were serious. CONCLUSIONS: Our data suggest that pulse corticotherapy could be a safe alternative to prolonged systemic oral corticotherapy in children with BO, thus minimizing the adverse effects of the oral therapy. New prospective controlled studies are required to confirm this proposition.

The differential clinical impact of human coronavirus species in children with cystic fibrosis.

We investigated the clinical impact of human coronaviruses (HCoV) OC43, 229E, HKU1 and NL63 in pediatric patients with cystic fibrosis (CF) during routine and exacerbation visits. A total of 408 nasopharyngeal aspirate samples were obtained from 103 patients over a 1-year period. Samples positive for HCoV were submitted for nucleotide sequencing to determine the species. Nineteen samples (4.65%) were positive for HCoV, of which 8 were positive for NL63, 6 for OC43, 4 for HKU1, and 1 for 229E. Identification of HCoV was not associated with an increased rate of respiratory exacerbations, but NL63-positive patients had higher exacerbation rates than patients who were positive for other HCoV species.