Resurgence of tuberculosis in children†

Updated data on epidemiology of tuberculosis are needed in Italy. The aim of this study is to evaluate trends in incidence and associated lethality of tuberculosis in immigrants compared with Italians.

All tuberculosis cases diagnosed from 2000 to 2018 in 31 Tuscan hospitals were retrospectively identified.

In 10,827 tuberculosis cases 6715 were males (62%), 4312 (60%) were Italian-born. Hospitalization rate was 15.37/100,000 population/year. The most common comorbidity were liver disease (832/10,827; 7.7%), COPD (675/10,827; 6.2%), cancer (614/10,827; 5.7%). HIV was more frequent in the immigrants (p < 0.001). Extra-pulmonary tuberculosis cases (EPTB) were mainly localized in pleura (740/3,894, 19%) and lymph nodes (449/3,894, 11,5%). HIV was associated with an increased risk of EPTB (OR 3.51 95% CI 2.92–4.23, p < 0.0001). EPTB risk was increased in South Asian-born patients (OR 1.77, 95% CI 1.46–2.15, p < 0.0001) as well in African-born patients (OR 1.13, 95% CI 1.03–1.24, p = 0.0091), who were at risk for gastroenteric tuberculosis (OR 3.74, 95% CI 2.69–5.22, p < 0.0001). Overall mortality rate was 0.006 per 1000. Most of death cases (89%) were Italians (p < 0.02) and mainly affected by pulmonary tuberculosis (PTB).

In Tuscany, tuberculosis is still a health concern in terms of both morbidity and mortality.

Although tuberculosis (TB) is one of the most common causes of morbidity and mortality in humans worldwide and diagnostic methods have been in place for more than 100 years, diagnosis remains a challenge. The main problems with diagnosis relate to the time needed to obtain a definitive result, difficulty in obtaining sputum, the primary clinical material used, and the ability of the causative agent, Mycobacterium tuberculosis, to cause disease in nearly any tissue within the body. In order to decrease incidence of TB, discovery of a novel interventions will be required, since current technologies have only been able to control numbers of infections, not reduce them. Diagnostic innovation is particularly needed because there are no effective pediatric or extrapulmonary TB diagnostic methods and multiple-drug resistance is only identified in less than 25% of those patients that are thought to have it. The most common diagnostic method worldwide remains acid-fast stain on sputum, with a threshold of ∼10,000 bacteria/ml that is only reached ∼5–6 months after development of symptoms. In order to obtain definitive diagnostic results earlier during the disease process, we have developed a diagnostic method designated reporter enzyme fluorescence (REF) that utilizes BlaC produced by M. tuberculosis and custom substrates to produce a specific fluorescent signal with as few as 10 bacteria/ml in clinical samples. We believe that the unique biology of the REF technique will allow it to contribute new diagnostic information that is complementary to all existing diagnostic tests as well as those currently known to be in development.

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis, is one of the major public health problems worldwide. Cure rates of >95% can be achieved with modern anti-TB treatment, which comprises short-course chemotherapy regimens containing isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) for patients with drug-susceptible TB strains. Despite the availability of potent drugs, some patients do not respond to treatment or develop serious adverse effects.

Although many nongenetic factors influence the effects of medications, interindividual differences in drug response have been linked to sequence variants in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets. Pharmacogenomic studies of drugs used in the treatment of TB can promote understanding of intersubject variations in treatment response. In this chapter, we look at pharmacogenomic data on anti-TB drugs from different settings to provide better insight into the role of pharmacogenomics in the treatment of TB, thereby enhancing efficacy and limiting toxicity of existing anti-TB medications.

A review of different studies has established the importance of pharmacogenomics in TB. Studies from different settings show that pharmacogenomics plays a significant role in INH metabolism, affecting both treatment efficacy and ADR frequency. There are limited data on single-nucleotide polymorphisms that influence plasma RMP concentrations. No data are available on the other first-line drugs, EMB and PZA. It would be useful for treating physicians to incorporate pharmacogenomics in clinical TB trials to understand the factors that influence therapeutic success and the occurrence of adverse drug reactions.

The immune regulatory mechanisms involved in the acquisition of Mycobacterium tuberculosis infection in children are largely unknown. We investigated the influence of parasitic infections, malnutrition and plasma cytokine profiles on tuberculin skin test (TST) positivity in Warao Amerindians in Venezuela. Pediatric household contacts of sputum smear-positive tuberculosis (TB) cases were enrolled for TST, chest radiograph, plasma cytokine analyses, QuantiFERON-TB Gold In-Tube (QFT-GIT) testing and stool examinations. Factors associated with TST positivity were studied using generalized estimation equations logistic regression models. Of the 141 asymptomatic contacts, 39% was TST-positive. After adjusting for age, gender and nutritional status, TST positivity was associated with Trichuris trichiura infections (OR 3.5, 95% CI 1.1–11.6) and low circulating levels of T helper 1 (Th1) cytokines (OR 0.51, 95% CI 0.33–0.79). Ascaris lumbricoides infections in interaction with Th2- and interleukin (IL)-10-dominated cytokine profiles were positively associated with TST positivity (OR 3.1, 95% CI 1.1–8.9 and OR 2.4, 95% CI 1.04–5.7, respectively). A negative correlation of QFT-GIT mitogen responses with Th1 and Th2 levels and a positive correlation with age were observed (all p < 0.01). We conclude that helminth infections and low Th1 cytokine plasma levels are significantly associated with TST positivity in indigenous Venezuelan pediatric TB contacts.