Luis E. Cuevas

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

Lactobacillus GG promotes recovery from acute nonbloody diarrhea in Pakistan.

A prospective, placebo-controlled, triple blind clinical trial was carried out in Pakistan to determine the effect of Lactobacillus GG on the course of acute diarrhea in hospitalized children. Forty children (mean age, 13 months) were enrolled and after rehydration received either oral Lactobacillus GG (n = 21) or placebo (n = 19) twice daily for 2 days, in addition to the usual diet. The clinical course of diarrhea was followed during the treatment period. Features on admission into the study groups were similar and were characterized by severe diarrhea, malnutrition and inappropriate management before presentation. Response was evident on Day 2 when the frequency of both vomiting and diarrhea was less in the Lactobacillus group. In those who had presented with acute nonbloody diarrhea (n = 32), the percentage of children with persistent watery diarrhea at 48 hours was significantly less in the Lactobacillus group: 31% vs. 75% (P < 0.01). No significant difference was observed by 48 hours in those presenting with bloody diarrhea. The relevance of this finding to the management of diarrhea in the tropics is discussed.

Lactobacillus GG and Acute Diarrhoea in Young Children in the Tropics

A prospective, placebo controlled, triple blind clinical trial was undertaken in Thailand to determine the effect of Lactobacillus GG on recovery from acute diarrhoea in children. Thirty-nine children (mean age = 8 months) were enrolled and following rehydration received either oral Lactobacillus GG (n = 20) as a freeze-dried preparation or placebo (n = 19) twice daily for 2 days. The clinical characteristics of the study groups were similar. There was no significant difference overall in clinical response detected between the study groups. When only those with acute non-bloody diarrhoea (n = 26) were considered, the mean duration of diarrhoea was significantly shorter in the lactobacillus group (1.9 days) than in the placebo group (3.3 days) (P < 0.055). Stool frequency was less on the second day in the lactobacillus group (P < 0.05). The results suggest that Lactobacillus GG accelerates recovery from acute watery diarrhoea in young children in a tropical setting.

Incidence of Rotavirus and All-Cause Diarrhea in Northeast Brazil Following the Introduction of a National Vaccination Program

BACKGROUND & AIMS Rotavirus vaccines were introduced in Brazil in 2006; we evaluated their effects in the state of Sergipe, Brazil. METHODS We performed a cross-sectional survey of children with diarrhea attending emergency services in Aracaju, Brazil, between October 2006 and April 2008 and a cluster sampling survey to assess vaccination coverage. Vaccine efficacy was assessed using the screening method. Diarrhea consultation and hospitalization data (2003-2007) were obtained from state and national surveillance systems. RESULTS Rotavirus was detected in 59 of 534 stool samples (11%) from children attending emergency services. The number of rotavirus-positive samples decreased from 18 of 74 (24%) in 2006 to 31 of 321 (9.5%) in 2007 and 10 of 136 (7.4%) in 2008 (P < .01). Diarrhea severity was greater in children with rotavirus (P < .01) but decreased over time (P < .001). Of the rotaviruses detected, 56 of 59 (95%) were P[4]G2 genotype, 1 was P[4]G-non-typeable (NT), 1 was P[NT]G2, and 1 was P[NT]GNT. Diarrhea consultations decreased from 3020 in 2004 to 604 in 2007; reductions were greatest among children under 5 years old. Diarrhea hospitalizations decreased from 2121 in 2003 to 1176 in 2007. Vaccine coverage was 90.3%. Vaccines were highly effective against the strain P[8]G1; efficacy against P[4]G2 genotype was 89% (95% confidence interval: 0.87-0.92) in Aracaju and 95% in Sergipe. CONCLUSIONS Since vaccines were introduced in 2006, there has been an overall reduction in diarrhea consultations and hospitalizations in northeast Brazil, with the greatest reductions in young children. This might have resulted from vaccination and improved sanitation. Although a single rotavirus genotype (P[4]G2) was recovered, vaccine efficacy was high against this genotype.

Respiratory syncytial virus and metapneumovirus in children over two seasons with a high incidence of respiratory infections in Brazil

Abstract Acute respiratory infections (ARI) are one of the most important causes of death in children. Human metapneumovirus (HMPV), a virus first described in 2001, has now been detected in almost all continents. HMPV causes bronchiolitis and pneumonia with a clinical spectrum similar to respiratory syncytial virus (RSV). We describe the incidence of HMPV and RSV during two consecutive seasons with a high incidence of ARI in Aracaju, Brazil. HMPV was responsible for 24% of cases of bronchiolitis in the 1st season (April–May 2002) but was not found in the 2nd year (April–May 2003). RSV was recovered from 61 (55%) children with ARI in 2002 and from 72 (68%) in 2003. Children with RSV bronchiolitis in 2002 had more hypoxia but less wheezing than in 2003. The incidence of HMPV and RSV genotypes causing bronchiolitis varied between the years. Long-term prospective studies are required to better describe the epidemiology of these viruses in children.

Rotavirus genotypes circulating in Brazil before national rotavirus vaccination: A review

BACKGROUND Rotavirus vaccine was recently introduced in Brazil, which has the potential to greatly reduce childhood deaths from diarrhoea. To provide baseline data to assess the effect of mass rotavirus vaccination on the ecology of circulating rotavirus strains, we systematically analysed published studies in the pre-vaccine era. AIMS To describe the distribution of rotavirus genotypes in Brazil prior to vaccine introduction. METHODS Systematic literature searches in health-related databases from 1986 to 2006. Information extracted and analysed by time and region. RESULTS 117 studies with 48,401 participants were included. Of these, 3036 were infected with rotavirus. More than 51 genotype combinations were reported, the distribution of which changed over time. P[8]G1 (43%) was the most frequent genotype throughout, followed by P[8]G9 (22%) and P[4]G2 (7%). The detection rate of P[8]G9 increased, while P[4]G2 decreased during the study period. There was a high frequency of G/P combinations between 1995 and 2000 and a low frequency before and after these years. CONCLUSIONS While considerable diversity of rotavirus strains was recognized during the pre-vaccine era, three strains comprised 72% of the total analysed. These data provide a baseline against which any changes in circulating rotavirus strains post-vaccine introduction can be measured.

Carriage of penicillin-resistant pneumococci in Malawian children

In a prospective study of pneumococcal carriage in 200 Malawian children under 5 years of age, 47.5% were carriers. The carriage rate was highest in those aged 3-12 months and did not vary with family size, nor was it higher in those who had recently been admitted to hospital. Nasopharyngeal swabs were significantly more efficient than throat swabs in detecting carriers (p < 0.001) but nasopharyngeal swabs alone would have missed seven (8%) carriers. Pneumococcal isolates from 22% of carriers and from eight cases of meningitis and one of empyema showed intermediate resistance to penicillin (MIC 0.1-1.0 mg/l). All were sensitive to the 3rd-generation cephalosporin cefotaxime but one of the penicillin-resistant pneumococci and two of the clinical isolates had increased MICs of cefuroxime (0.5 mg/l).

Acute diarrhoea in a community cohort of children who received an oral rotavirus vaccine in Northeast Brazil

Rotavirus is an important cause of childhood diarrhoea. A monovalent rotavirus vaccine (Rotarix®) was introduced into the Immunization Program of Brazil in 2006. In this study, we describe the incidence and burden of disease of rotavirus diarrhoea in two cohorts of children (vaccinated and unvaccinated). We followed two groups of 250 children under one year old, who were enrolled in December 2006 from a low-income residential area in Northeast Brazil. The children were monitored every two weeks for two years. Stool samples from children with diarrhoea were examined for the presence of rotavirus. Rotaviruses were genotyped using real time-polymerase chain reaction. The mean numbers of all-cause diarrhoea episodes/child (adjusted for age) in the first year were 0.87 and 0.84, in vaccinated and unvaccinated children, respectively. During the second year, the number of episodes/child decreased to 0.52 and 0.42. Only 16 (4.9%) of 330 stool samples were rotavirus-positive (10 vaccinated and 6 unvaccinated children) and only P[4]G2 rotaviruses were identified. All-cause diarrhoea episodes were more severe in unvaccinated children in the first year of age (p < 0.05), while vaccinated children had more severe episodes 18 months after vaccination. Rotavirus diarrhoea incidence was very low in both groups.

Reply to Holm et al.

TO THE EDITOR—We welcome the feedback provided by Holm et al [1] relating to the application of recently published proposed clinical case definitions for reporting of research findings when evaluating diagnostic tests in young children with suspected intrathoracic tuberculosis. The definitions are intended for research use to evaluate diagnostic assays and strategies under controlled circumstances and not for making individual patient clinical diagnoses for treatment decisions under field conditions. These research case definitions were developed to address the need to standardize reporting for diagnostic studies of tuberculosis in children so that consistency in definitions and methods could allow for more valid comparisons between populations and settings [2]. The need to improve the quantity and quality of diagnostic research in children with suspected tuberculosis is universally recognized, and the opportunity provided by the emergence of novel approaches has made this need stronger. The aim is to strengthen diagnostic research in children, and we hope that these definitions can be revised and improved in the future, informed by data and experience obtained by applying and validating them in real-life studies. We recognize that these definitions have limitations. Although we arrived at these definitions by using formal group consensus rules following careful consideration, not surprisingly agreement was not unanimous for all definitions. There is often a tension between conducting research in locations where there are many eligible children but limited resources and locations with excellent research infrastructure but few eligible children. Similarly, clinical and public health perspectives often apportion different emphasis to the contribution of factors and the level of detail required to make a diagnosis, and there is a lack of data to inform specific definitions. Holm et al [1] highlight some of these limitations, the definition of immunological evidence of infection with Mycobacterium tuberculosis and the definition of treatment response. Another challenge for the panel was to agree on the methodological approach to reading and reporting radiological findings. Chest radiographic findings were considered a critical aspect of the case definition, and the panel applied particular rigor to ensure standard interpreting and reporting of these findings. However, we were aware that the feasibility of this approach might be constrained in the very resource-limited settings where the results of this research need to be applicable. We emphasize the need for rigorous clinical research for pediatric diagnostic studies, while recognizing the tensions of variable levels of resources and pragmatic constraints. Holm et al [1] indicate that a followup period of 2 months might be too short to define treatment response, especially because many children may not have started or may have only recently started anti-tuberculosis therapy at this point. This might be a misunderstanding, as the proposed definitions indicate the follow-up assessment should occur 2 months after initiation of therapy, not from the time of initial assessment or enrollment for suspected disease, which may be considerably earlier. Nonetheless, we accept the inherent potential bias in the classification of children who die or are lost to follow-up before that time, whether receiving anti-tuberculosis therapy or not. These children represent an important high-risk group that should be reported on separately.