Paediatric tuberculosis (TB) represents a major public health concern worldwide. About 1 million children aged less than 15 years develop TB each year, contributing to 3-25% of the total TB caseload. The aim of this review is to evaluate national and international guidelines concerning tuberculosis in childhood and compare them in terms of diagnosis and treatment strategies.
A literature search of the Pubmed database was performed from January 2000 to August 2013, using the terms “tuberculosis” and “children”. The search was limited to guidelines and consensus conferences, human species and full text availability, with no language restrictions.
Twenty-seven national and international guidelines are identified. Several discrepancies on the diagnosis workup of TB are underlined. The main points of disagreement are represented by the interpretation of tuberculin skin test (TST) result and the recommendations on the use of TST and/or interferon-gamma release assay (IGRA) for the diagnosis of TB infection. Otherwise, all guidelines are in agreement that a microbiological confirmation should always be sought. Similarly, susceptibility drug testing and genotyping should be performed whenever it is possible on the basis of resources availability. On the contrary, the use of nucleic acid amplification tests (NAATs) for the M. tuberculosis detection is still controversial. A general consensus exists, otherwise, on TB treatment and only minor discrepancies are evidenced, such as the recommendations on daily or intermittent treatment regimens.
Despite advances in TB diagnostic tools have been reached during the last decade, a lack of uniformity in their availability, indication and interpretation has relevant consequences for clinical practice. Further studies need to be performed to clarify this issue and identify a reliable and reproducible diagnostic workup. Moreover, future studies should analyze the drug metabolism and the efficacy of intermittent dosing regimes in childhood, as well as new treatment regimens in order to improve the therapy compliance.
The ongoing spread of tuberculosis (TB) in poor resource countries and the recently increasing incidence in high resource countries lead to the need of updated knowledge for clinicians, particularly for pediatricians. The purpose of this article is to provide an overview on the most important peculiarities of TB in children. Children are less contagious than adults, but the risk of progression to active disease is higher in infants and children as compared to the subsequent ages. Diagnosis of TB in children is more difficult than in adults, because few signs are associated with primary infection, interferon-gamma release assays and tuberculin skin test are less reliable in younger children, M. tuberculosis is more rarely detected in gastric aspirates than in smears in adults and radiological findings are often not specific. Treatment of latent TB is always necessary in young children, whereas it is recommended in older children, as well as in adults, only in particular conditions. Antimycobacterial drugs are generally better tolerated in children as compared to adults, but off-label use of second-line antimycobacterial drugs is increasing, because of spreading of multidrug resistant TB worldwide. Given that TB is a disease which often involves more than one member in a family, a closer collaboration is needed between pediatricians and clinicians who take care of adults.
Many and large dumps exist in our knowledge about Mycobacterium tuberculosis infection and disease in infants and children. We still do not understand why some individuals do acquire and others do not acquire the infection in the presence of the same risk factors. We do not understand why some individuals convert from latent to active tuberculosis and why other individuals convert from active to inactive tuberculosis even without treatment.
As a matter of fact the immune system mounts a bouncing, robust and polyedral defence against Mycobacterium tuberculosis, but the bacillus is so much artful and dextrous that it has ahead from this immunological fierce accoutrements. Mycobacterium tuberculosis survival, multiplication, and transmission are largely favoured by the immune mechanisms. The granuloma itself is more bacillus- than host-protective.
These abilities make Mycobacterium tuberculosis one of more successful human pathogens, but dumps in our knowledge and the counterproductive immunity hinder development of new diagnostics, therapies and vaccines. This occurs in front of an infection which engages one third of the world population and a disease which kills in a year about 1.5 million individuals worldwide.
Understanding mechanisms and meaning of immune response in tuberculosis marks out the foundations of strategies with a view to prepare effective vaccines and reliable diagnostic tools as well as to build up therapeutic weapons. To gain these objectives is vital and urgent considering that tuberculosis is a common cause of morbidity and is a leading cause of death.
one of the World Health Organization Millennium Development Goal is to reduce tuberculosis incidence by 2015. However, more of 8.5 million tuberculosis cases have been reported in 2011, with an increase of multidrug-resistant strains. Therefore, the World Health Organization target cannot be reach without the help of a vaccine able to limit the spread of tuberculosis. Nowadays, bacille Calmette-Guérin is the only vaccine available against tuberculosis. It prevents against meningeal and disseminated tuberculosis in children, but its effectiveness against pulmonary form in adolescents and adults is argued.
a systematic review was performed by searches of Pubmed, references of the relevant articles and Aeras and ClinicalTrial.gov websites.
100 articles were included in this review. Three viral vectored booster vaccines, five protein adjuvant booster vaccines, two priming vaccines and two therapeutic vaccines have been analyzed.
Several vaccines are in the pipeline, but further studies on basic research, clinical trial and mass vaccination campaigns are needed to achieve the TB eradication target by 2050.
HIV is the top and tuberculosis is the second leading cause of death from infectious disease worldwide, with an estimated 8.7 million incident cases of tuberculosis and 2.5 million new HIV infections annually. The World Health Organization estimates that HIV prevalence among children with tuberculosis, in countries with moderate to high prevalence, ranges from 10 to 60%. The mechanisms promoting susceptibility of people with HIV to tuberculosis disease are incompletely understood, being likely caused by multifactorial processes.
Paediatric tuberculosis and HIV have overlapping clinical manifestations, which could lead to missed or late diagnosis. Although every effort should be made to obtain a microbiologically-confirmed diagnosis in children with tuberculosis, in reality this may only be achieved in a minority, reflecting their paucibacillary nature and the difficulties in obtain samples. Rapid polymerase chain reaction tests, such as Xpert MTB/RIF assay, are increasingly used in children. The use of less or non invasive methods of sample collection, such as naso-pharyngeal aspirates and stool samples for a polymerase chain reaction-based diagnostic test tests and mycobacterial cultures is promising technique in HIV negative and HIV positive children. Anti-tuberculosis treatment should be started immediately at diagnosis with a four drug regimen, irrespective of the disease severity. Moreover, tuberculosis disease in an HIV infected child is considered to be a clinical indication for initiation of antiretroviral treatment. The World Health Organization recommends starting antiretroviral treatment in children as soon as anti-tuberculosis treatment is tolerated and within 2- 8 weeks after initiating it. The treatment of choice depends on the child’s age and availability of age-appropriate formulations, and potential drug interactions and resistance. Treatment of multi-drug resistant tuberculosis in HIV-infected children follows same principles as for HIV uninfected children. There are conflicting results on effectiveness of isoniazid preventive therapy in reducing incidence of tuberculosis disease in children with HIV.
Data on HIV/TB co-infection in children are still lacking. There are on-going large clinical trials on the prevention and treatment of TB/HIV infection in children that hopefully will help to guide an evidence-based clinical practice in both resource-rich and resource-limited settings.
Previous meta-analyses regarding the performance of interferon-gamma release assays (IGRAs) for tuberculosis diagnosis in children yielded contrasting results, probably due to different inclusion/exclusion criteria.
We systematically searched PubMed, EMBASE and Cochrane databases and calculated pooled estimates of sensitivities and specificities of QuantiFERON-TB Gold In Tube (QFT-G-IT), T-SPOT.TB, and tuberculin skin test (TST). Several sub-analysis were performed: stratification by background (low income vs. high income countries); including only microbiological confirmed TB cases; including only studies performing a simultaneous three-way comparison of the three tests, and including immunocompromised children.
Overall, 31 studies (6183 children) for QFT-G-IT, 14 studies (2518 children) for T-SPOT.TB and 34 studies (6439 children) for TST were included in the analyses. In high income countries QFT-G-IT sensitivity was 0.79 (95%IC: 0.75-0.82) considering all the studies, 0.78 (95%CI:0.70-0.84) including only studies performing a simultaneous three-way comparison and 0.86 (95%IC 0.81-0.90) considering only microbiologically confirmed studies. In the same analyses T-SPOT.TB sensitivity was 0.67 (95%IC 0.62-0.73); 0.76 (95%CI: 0.68 to 0.83); and 0.79 (95%IC 0.69-0.87), respectively. In low income countries QFT-G-IT pooled sensitivity was significantly lower: 0.57 (95%IC:0.52-0.61), considering all the studies, and 0.66 (95%IC 0.55-0.76) considering only microbiologically confirmed cases; while T-SPOT.TB sensitivity was 0.61 (95%IC 0.57-0.65) overall, but reached 0.80 (95%IC 0.73-0.86) in microbiologically confirmed cases. In microbiologically confirmed cases TST sensitivity was similar: 0.86 (95%IC 0.79-0.91) in high income countries, and 0.74 (95%IC 0.68-0.80) in low income countries. Higher IGRAs specificity with respect to TST was observed in high income countries (97-98% vs. 92%) but not in low income countries (85-93% vs. 90%).
Both IGRAs showed no better performance than TST in low income countries.
Persistent digestive disorders account for considerable disease burden in the tropics. Despite advances in understanding acute gastrointestinal infections, important issues concerning epidemiology, diagnosis, treatment and control of most persistent digestive symptomatologies remain to be elucidated. Helminths and intestinal protozoa are considered to play major roles, but the full extent of the aetiologic spectrum is still unclear. We provide an overview of pathogens causing digestive disorders in the tropics and evaluate available reference tests.
We searched the literature to identify pathogens that might give rise to persistent diarrhoea, chronic abdominal pain and/or blood in the stool. We reviewed existing laboratory diagnostic methods for each pathogen and stratified them by (i) microscopy; (ii) culture techniques; (iii) immunological tests; and (iv) molecular methods. Pathogen-specific reference tests providing highest diagnostic accuracy are described in greater detail.
Over 30 pathogens may cause persistent digestive disorders. Bacteria, viruses and parasites are important aetiologic agents of acute and long-lasting symptomatologies. An integrated approach, consisting of stool culture, microscopy and/or specific immunological techniques for toxin, antigen and antibody detection, is required for accurate diagnosis of bacteria and parasites. Molecular techniques are essential for sensitive diagnosis of many viruses, bacteria and intestinal protozoa, and are increasingly utilised as adjuncts for helminth identification.
Diagnosis of the broad spectrum of intestinal pathogens is often cumbersome. There is a need for rapid diagnostic tests that are simple and affordable for resource-constrained settings, so that the management of patients suffering from persistent digestive disorders can be improved.
Bacteria; Clinical microbiology; Diagnosis; Digestive disorders; Gastroenterology; Helminths; Intestinal protozoa; Persistent diarrhoea; Virus
The epidemiological status of HCV in Europe, and in particular in Mediterranean countries, is continuously evolving. The genotype distribution is related to improvement of healthcare conditions, expansion of intravenous drug use and immigration. We review and characterize the epidemiology of the distribution of HCV genotypes within Calabria, an area of Southern Italy. We focus on the pattern of distinct HCV genotype changes over the last 16 years; particularly subtype 1b and genotype 4. We collected data by evaluating a hospital-based cohort of chronic hepatitis C patients; in addition, we report an update including new patients enrolled during last eight months.
A major goal of modern medicine is the application of personalized therapies, consisting of decisions and practices tailored to the individual patient. Information about genetic variants, either mutant or polymorphic, represents the basis for the development of this clinical approach. Recently, several independent genome-wide association studies (GWAS) have identified two single nucleotide polymorphisms (SNPs) on the IL28B locus associated with HCV containment, spontaneous clearance, treatment response, and disease progression. In this minireview we will concisely discuss some critical genetic concepts that may have possible implications for clinical decisions in the treatment of HCV infection.
The SINERGIE (South Italian Network for Rational Guidelines and International Epidemiology) project is intended to set up a collaborative network comprising virologists, clinicians and public health officials dealing with patients affected by HCV disease in the Calabria Region. A prospective observational data-base of HCV infection will be developed and used for studies on HCV natural history, response to treatment, pharmaco-economics, disease complications, and HCV epidemiology (including phylogenetic analysis). With this approach, we aim at improving the identification and care of patients, focusing on upcoming research questions. The final objective is to assist in improving care delivery and inform Public Health Authorities on how to optimize resource allocation in this area.
Hepatitis C virus (HCV), first recognized as a cause of transfusion-associated acute and chronic hepatitis in 1989, plays a major role as a cause of chronic liver injury, with potential for neoplastic degeneration. It is mainly transmitted by the parenteral route. However, although with lower efficiency, it may be also transmitted by sexual intercourses and by the mother-to-child route. Epidemiological evidence shows that a wave of infection occurred in the 1945-65 period (baby boomers) in western countries. After acute infection, as many as 50-85% of the patients fail to clear the virus resulting in chronic liver infection and/or disease. It is estimated that, on a global scale, about 170 million people are chronically infected with HCV, leading to about 350.000 deaths yearly. Among western countries southern Europe, and particularly Italy, is among the most affected areas. The impact on the public health systems is noteworthy, with high number of hospitalizations due to chronic liver disease, cirrhosis or hepatocellular carcinoma. While waiting for a safe and effective vaccine to be made available, new promising direct-acting antiviral (DAA) drugs offer a better therapeutic scenario than in the past even for the poor responder genotypes 1 and 4, provided that effective screening and care is offered. However, the long and aspecific prodromic period before clinical symptoms develop is a major obstacle to early detection and treatment. Effective screening strategies may target at-risk groups or age specific groups, as recently recommended by the CDC.
The advent of triple therapy (TT) with first-generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) in addition to pegylated interferon and ribavirin resulted in a significant gain in terms of sustained virological response (SVR) when treating naive or previous treated patients with genotype 1 (G1) chronic hepatitis C (CHC). This gain is partly balanced by the increased complexity of treatment and by the raised costs and risks of therapy, making necessary to optimize the indication to TT.
Specifically, the identification of patient needing to TT over DT, the choice of the more correct therapeutic approach according to baseline and on treatment SVR predictors, and the timing of antiviral treatment, appear key issues to evaluate when considering TVR or BOC-based therapies.
Along this line, further efforts aimed to optimize the current TT regimens are still needed, especially in under-represented groups of patients in phase 3 studies such as those with cirrhosis, where post-marketing data are giving interesting evidences.
Hepatitis C virus infection (HCV) is one of the most pressing health emergencies in the world with a global prevalence of about 170 million people chronically infected worldwide. In Europe, Italy has the highest HCV prevalence (3 - 4.4%) with peaks of 12.6 - 26% in Southern regions and the major islands. In Italy HCV genotype 1b prevails, and genotype 4 is mainly found in the south of the country where the prevalence is particularly high in regions such as Calabria.
Phylogenetics analysis is a molecular tool widely used to study rapidly-evolving RNA viruses that establish chronic infections such as HCV. Searching the scientific literature, it was found that thirty-nine genetic studies on HCV genotypes have been carried out in Italy between 1997 to 2012 years. However, phylogenetic analysis was performed only in fourteen out of thirty-nine HCV studies (36%) considered. Monitoring the genetic evolution of HCV is an essential step to control the local as well as global HCV epidemic and to develop efficient preventive and therapeutic strategies.
A significant improvement in the rate of eradication of Hepatitis C Virus Genotype 1 has been achieved with the addition of Boceprevir and Telaprevir to pegylated interferon and ribavirin. These two drugs are the heralds of a new wave of antivirals that will improve the efficacy of pegylated interferon or even will substitute this drug in interferon free combinations. The results of phase II studies in patients naïve to treatment seem to be very promising strongly supporting the possibility of a large success for a first line all oral antiviral combination in interferon naïve. However, data observed in interferon experienced patients are less exciting and probably more complex treatment regimens will be needed to treat this patients’ population.
Since the discovery of HCV, polymerase chain reaction (PCR) has significantly contributed to the understanding of the virus life cycle and its replicative kinetics during anti-viral therapy. Parallel to the progression of dual and triple combination treatment, real-time PCR molecular tests have constantly improved in their ability to monitor viral load and drive personalized management schedules. The current sensitivity, accuracy and dynamic range of the available assays fulfil the requirement of “companion diagnostics” and support the development of new directly acting antiviral (DAA)-based regimens.
Detection of Mycobacterium tuberculosis antigens in urine is attractive as a potential means of diagnosing tuberculosis (TB) regardless of the anatomical site of disease. The most promising candidate antigen is the cell wall lipopolysaccharide antigen lipoarabinomannan (LAM), which has been used to develop commercially available enzyme-linked immunosorbent assays. Although highly variable diagnostic accuracy has been observed in different clinical populations, it is now clear that this assay has useful sensitivity for diagnosis of HIV-associated TB in patients with advanced immunodeficiency and low CD4 cell counts. Thus, this assay is particularly useful when selectively used among patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards. These are the very patients who have the highest mortality risk and who stand to gain the most from rapid diagnosis, permitting immediate initiation of TB treatment. A recently developed low-cost, lateral-flow (urine ‘dip-stick’) format of the assay provides a result within 30 minutes and is potentially a major step forward as it can be used at the point-of-care, making the possibility of immediate diagnosis and treatment a reality. This paper discusses the likely utility of this point-of-care assay and how it might best be used in combination with other diagnostic assays for TB. The many further research studies that are needed on this assay are described. Consideration is particularly given to potential reasons for the variable specificity observed in existing field evaluations of LAM ELISAs. Whether this might be related to the assay itself or to the challenges associated with study design is discussed.
HIV; Tuberculosis; Screening; Diagnosis; Culture; Asymptomatic; Subclinical
Beta-lactamase-producing bacteria (BLPB) can play an important role in polymicrobial infections. They can have a direct pathogenic impact in causing the infection as well as an indirect effect through their ability to produce the enzyme beta-lactamase. BLPB may not only survive penicillin therapy but can also, as was demonstrated in in vitro and in vivo studies, protect other penicillin-susceptible bacteria from penicillin by releasing the free enzyme into their environment. This phenomenon occurs in upper respiratory tract, skin, soft tissue, surgical and other infections. The clinical, in vitro, and in vivo evidence supporting the role of these organisms in the increased failure rate of penicillin in eradication of these infections and the implication of that increased rate on the management of infections is discussed.