Marc Tebruegge

Pneumonia in severely malnourished children in developing countries - mortality risk, aetiology and validity of WHO clinical signs: a systematic review

Objectives  To quantify the degree by which moderate and severe degrees of malnutrition increase the mortality risk in pneumonia, to identify potential differences in the aetiology of pneumonia between children with and without severe malnutrition, and to evaluate the validity of WHO‐recommended clinical signs (age‐specific fast breathing and chest wall indrawing) for the diagnosis of pneumonia in severely malnourished children.

Epidemiology, Etiology, Pathogenesis, and Diagnosis of Recurrent Bacterial Meningitis

SUMMARY Recurrent bacterial meningitis is a rare phenomenon and generally poses a considerable diagnostic challenge to the clinician. Ultimately, a structured approach and early diagnosis of any underlying pathology are crucial to prevent further episodes and improve the overall outcome for the affected individual. In this article, we are reviewing the existing literature on this topic over the last two decades, encompassing 363 cases of recurrent bacterial meningitis described in 144 publications. Of these cases, 214 (59%) were related to anatomical problems, 132 (36%) were related to immunodeficiencies, and 17 (5%) were related to parameningeal infections. The review includes a detailed discussion of the underlying pathologies and microbiological aspects as well as recommendations for appropriate diagnostic pathways for investigating this unusual entity.

The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial.

RATIONALE Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient. OBJECTIVES To compare the immune response to three different BCG vaccine strains given to infants at birth. METHODS Newborn infants in a tertiary womens hospital were immunized at birth with one of three BCG vaccine strains. A stratified randomization according to the mothers region of birth was used. MEASUREMENTS AND MAIN RESULTS The presence of mycobacterial-specific polyfunctional CD4 T cells measured by flow cytometry 10 weeks after immunization. Of the 209 infants immunized, data from 164 infants were included in the final analysis (BCG-Denmark, n = 54; BCG-Japan, n = 54; BCG-Russia, n = 57). The proportion of polyfunctional CD4 T cells was significantly higher in infants immunized with BCG-Denmark (0.013%) or BCG-Japan (0.016%) than with BCG-Russia (0.007%) (P = 0.018 and P = 0.003, respectively). Infants immunized with BCG-Japan had higher concentrations of secreted Th1 cytokines; infants immunized with BCG-Denmark had higher proportions of CD107-expressing cytotoxic CD4 T cells. CONCLUSIONS There are significant differences in the immune response induced by different BCG vaccine strains in newborn infants. Immunization with BCG-Denmark or BCG-Japan induced higher frequencies of mycobacterial-specific polyfunctional and cytotoxic T cells and higher concentrations of Th1 cytokines. These findings have potentially important implications for global antituberculosis immunization policies and future tuberculosis vaccine trials.

Susceptibility of Mycobacterium bovis BCG vaccine strains to antituberculous antibiotics.

ABSTRACT Mycobacterium bovis BCG is one of the most commonly administered vaccines. Complications, including disseminated BCG disease, are rare but increasingly reported in immunodeficient children. There is growing recognition of the importance of differences between BCG vaccine strains. We determined the susceptibilities of five genetically distinct BCG vaccine strains to 12 antituberculous drugs.

Indeterminate Interferon-γ Release Assay Results in Children

To the Editors: We read with interest the recent report by Haustein et al entitled “The likelihood of an indeterminate test result from a whole-blood interferonrelease assay for the diagnosis of Mycobacterium tuberculosis infection in children correlates with age and immune status.” This report adds to recent publications that question the performance of current interferon(IFN) release assays (IGRA) for the diagnosis of tuberculosis (TB) in routine pediatric clinical practice. The retrospective study by Haustein et al in 237 children highlights the high proportion of indeterminate test results obtained with the QuantiFERON-TB (QFT) Gold In-Tube assay (35% of the study population). Notably, indeterminate test results were over-represented in children younger than 5 years of age, and those with immunodeficiencies or medical conditions associated with immunosuppression. Importantly, these groups represent children most at risk for disease progression after exposure to M. tuberculosis.

Mycobacteria-Specific Cytokine Responses Detect Tuberculosis Infection and Distinguish Latent from Active Tuberculosis.

RATIONALE Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management. OBJECTIVES To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB. METHODS A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays. MEASUREMENTS AND MAIN RESULTS IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively. CONCLUSIONS We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.

Extremes of Age Are Associated with Indeterminate QuantiFERON-TB Gold Assay Results

ABSTRACT Results from 3,263 QuantiFERON-TB Gold in-tube (QFT-GIT) assays were analyzed to determine the impact of age on test performance. The proportion of indeterminate results was significantly higher in pediatric and elderly (9.1% and 7.4%, respectively) than in adult (2.6%; chi-square test, P < 0.0001) patients. A detailed analysis of indeterminate QFT-GIT assay results is presented.

Nontuberculous Mycobacterial Disease in Children – Epidemiology, Diagnosis & Management at a Tertiary Center

Background There are limited data on the epidemiology, diagnosis and optimal management of nontuberculous mycobacterial (NTM) disease in children. Methods Retrospective cohort study of NTM cases over a 10-year-period at a tertiary referral hospital in Australia. Results A total of 140 children with NTM disease, including 107 with lymphadenitis and 25 with skin and soft tissue infections (SSTIs), were identified. The estimated incidence of NTM disease was 0.6–1.6 cases / 100,000 children / year; no increasing trend was observed over the study period. Temporal analyses revealed a seasonal incidence cycle around 12 months, with peaks in late winter/spring and troughs in autumn. Mycobacterium-avium-complex accounted for most cases (77.8%), followed by Mycobacterium ulcerans (14.4%) and Mycobacterium marinum (3.3%). Polymerase chain reaction testing had higher sensitivity than culture and microscopy for acid-fast bacilli (92.0%, 67.2% and 35.7%, respectively). The majority of lymphadenitis cases underwent surgical excision (97.2%); multiple recurrences in this group were less common in cases treated with clarithromycin and rifampicin compared with clarithromycin alone or no anti-mycobacterial drugs (0% versus 7.1%; OR:0.73). SSTI recurrences were also less common in cases treated with two anti-mycobacterial drugs compared with one or none (10.5% versus 33.3%; OR:0.23). Conclusions There was seasonal variation in the incidence of NTM disease, analogous to recently published observations in tuberculosis, which have been linked to seasonal variation in vitamin D. Our finding that anti-mycobacterial combination therapy was associated with a reduced risk of recurrences in patients with NTM lymphadenitis or SSTI requires further confirmation in prospective trials.

Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. The World Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and stakeholders in childhood DR-TB. An early priority was to establish standardized definitions for key parameters in order to facilitate study comparisons and the development of an evidence base to guide future clinical management. This consensus statement proposes standardized definitions to be used in research. In particular, it suggests consistent terminology, as well as definitions for measures of exposure, drug resistance testing, previous episodes and treatment, certainty of diagnosis, site and severity of disease, adverse events, and treatment outcome.

What's bugging you? An update on the treatment of head lice infestation

Head lice infestation (pediculosis capitis) is a common problem in paediatric practice. It can cause considerable distress to children and their families and may lead to bullying and social stigmatisation. Therapy with “conventional” topical pediculicides with neurotoxic mode of action—such as malathion, permethrin, phenothrin and carbaryl—is increasingly associated with treatment failure as a result of the emergence of resistance within the parasite population. This review provides an overview of the natural history, clinical symptoms and diagnosis of head lice infestation. It also discusses general management principles and summarises the current data on novel treatment strategies, including wet combing, dimeticone, isopropyl myristate, benzyl alcohol, plant-based compounds and oral medication.