Gregory J. Fox

Contact investigation for tuberculosis: a systematic review and meta-analysis

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines. We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB. After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies. Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.

Epidemiology of Tuberculosis Immunology

Immunological impairment plays a major role in the epidemiology of TB. Globally, the most common causes of immunological impairment are malnutrition, diabetes, HIV/AIDS, aging, and smoking. With the notable exception of HIV, each factor leads to relatively mild immunological impairment in individuals. However, as these conditions affect a significant proportion of the population, they contribute substantially to the incidence of TB at a global scale. Understanding immunological impairment is central to understanding the global TB pandemic, and vital to the development of effective disease control strategies.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis

BACKGROUND Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Preventive therapy for latent tuberculosis infection—the promise and the challenges

Around one third of the worlds population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed.

Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis

RATIONALE Fluoroquinolone (FQN) therapy of latent tuberculosis infection among contacts of individuals with multidrug-resistant tuberculosis (MDR-TB) is controversial. OBJECTIVES To determine the potential benefits, risks (including acquired FQN resistance), and cost-effectiveness of FQN therapy to prevent TB in contacts of individuals with MDR-TB. METHODS We used decision analysis to estimate costs and outcomes associated with no therapy compared with a 6-month course of daily FQN therapy to treat latent TB infection in contacts of individuals with MDR-TB. Outcomes modeled were the incidence of MDR-TB, MDR-TB with FQN resistance, TB-related death, quality-adjusted life years, and health system costs. MEASUREMENTS AND MAIN RESULTS FQN preventive therapy resulted in health system savings, lower incidence of MDR-TB, and lower mortality than no treatment. We found the incidence of MDR-TB with acquired FQN resistance would also be lower with FQN therapy of infected contacts. CONCLUSIONS In our model, FQN preventive therapy resulted in substantial health system savings and in reduced mortality, incidence of MDR-TB, and incidence of acquired FQN-resistant disease as well as improved quality of life. FQN therapy remained cost saving with improved outcomes even if the effectiveness of therapy in preventing MDR-TB was as low as 10%.

Tuberculosis in Newborns: The Lessons of the “Lübeck Disaster” (1929–1933)

In an accident later known as the Lübeck disaster, 251 neonates were orally given three doses of the new Bacille Calmette–Guérin (BCG) antituberculosis (TB) vaccine contaminated with Mycobacterium tuberculosis. A total of 173 infants developed clinical or radiological signs of TB but survived the infection, while 72 died from TB. While some blamed the accident on BCG itself by postulating reversion to full virulence, such a possibility was conclusively disproven. Rather, by combining clinical, microbiological, and epidemiological data, the chief public health investigator Dr. A. Moegling concluded that the BCG vaccine had been contaminated with variable amounts of fully virulent M. tuberculosis. Here, we summarize the conclusions drawn by Moegling and point out three lessons that can be learned. First, while mortality was high (approximately 29%), the majority of neonates inoculated with M. tuberculosis eventually overcame TB disease. This shows the high constitutional resistance of humans to the bacillus. Second, four semiquantitative levels of contamination were deduced by Moegling from the available data. While at low levels of M. tuberculosis there was a large spread of clinical phenotypes reflecting a good degree of innate resistance to TB, at the highest dose, the majority of neonates were highly susceptible to TB. This shows the dominating role of dose for innate resistance to TB. Third, two infants inoculated with the lowest dose nevertheless died of TB, and their median time from inoculation to death was substantially shorter than for those who died after inoculation with higher doses. This suggests that infants who developed disease after low dose inoculation are those who are most susceptible to the disease. We discuss some implications of these lessons for current study of genetic susceptibility to TB.

The impact of sputum quality on tuberculosis diagnosis: a systematic review.

OBJECTIVE To perform a systematic review to evaluate the impact of sputum quality on the yield of tuberculosis (TB) diagnostic tests. METHODS We searched PubMed, EMBASE, LILACS and the Cochrane Database to identify studies that addressed 1) the impact of sputum quality on the proportion of sputum samples with Mycobacterium tuberculosis detected using smear, culture or polymerase chain reaction (PCR); and 2) the impact of pre-sputum collection interventions on sputum quality and M. tuberculosis detection. RESULTS Ten studies met the eligibility criteria for review inclusion. Five studies assessed macroscopic and/or microscopic sputum quality characteristics and M. tuberculosis detection. The other five studies assessed the impact of pre-sputum collection interventions on sputum quality and M. tuberculosis detection. No studies assessed the impact of sputum quality on PCR-based diagnostic tests. CONCLUSION Definitive conclusions about the utility of sputum quality assessments are limited by the paucity of, and heterogeneity within, the available data. Given the potential for sputum quality assessments to enhance diagnostic yield and prevent wasteful laboratory testing, further research into this field is urgently needed.

Contact investigation in households of patients with tuberculosis in Hanoi, Vietnam: a prospective cohort study.

Setting Existing tuberculosis control strategies in Vietnam are based on symptomatic patients attending health services for investigation. This approach has not resulted in substantial reductions in the prevalence of tuberculosis disease, despite the National Tuberculosis Program achieving high treatment completion rates. Alternative approaches are being considered. Objective To determine the feasibility and yield of contact investigation in households of patients with smear positive pulmonary tuberculosis among household members of tuberculosis patients in Hanoi, Vietnam. Methods Household contacts of patients with smear positive pulmonary tuberculosis were recruited at four urban and rural District Tuberculosis Units in Hanoi. Clinical and radiological screening was conducted at baseline, six months and 12 months. Sputum microscopy and culture was performed in contacts suspected of having tuberculosis. MIRU-VNTR molecular testing was used to compare the strains of patients and their contacts with disease. Results Among 545 household contacts of 212 patients, four were diagnosed with tuberculosis at baseline (prevalence 734 cases per 100,000 persons, 95% CI 17–1451) and one was diagnosed with tuberculosis during the subsequent 12 months after initial screening (incidence 180 cases per 100,000 person-years, 95% CI 44–131). Two of these cases were culture positive for M. tuberculosis and both had identical or near-identical MIRU-VNTR strain types. Conclusion Household contacts of patients with potentially infectious forms of tuberculosis have a high prevalence of disease. Household contact investigation is feasible in Vietnam. Further research is required to investigate its effectiveness.

Risk factors for child pneumonia - focus on the Western Pacific Region

Pneumonia is a major cause of disease and death in infants and young children (aged <5 years) globally, as it is in the World Health Organization Western Pacific region. A better understanding of the underlying risk factors associated with child pneumonia is important, since pragmatic primary prevention strategies are likely to achieve major reductions in pneumonia-associated morbidity and mortality in children. This review focuses on risk factors with high relevance to the Western Pacific region, including a lack of exclusive breastfeeding, cigarette smoke and air pollution exposure, malnutrition and conditions of poverty, as well as common co-morbidities. Case management and vaccination coverage have been considered elsewhere.

Preventing the spread of multidrug-resistant tuberculosis and protecting contacts of infectious cases.

Prevention of multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is a top priority for global TB control, given the need to limit epidemic spread and considering the high cost, toxicity and poor treatment outcomes with available therapies. We performed a systematic literature review to evaluate the evidence for strategies to reduce MDR/XDR-TB transmission and disease progression. Rapid detection and timely initiation of effective treatment is critical to rendering MDR/XDR-TB cases non-infectious. The scale-up of rapid molecular testing has transformed the capacity of high-incidence settings to identify and treat patients with MDR/XDR-TB. Optimized infection control measures in hospitals and clinics are critical to protect other patients and healthcare workers, whereas creative measures to reduce transmission within community hotspots require consideration. Targeted screening of high-risk communities may enhance early case-detection and limit the spread of MDR/XDR-TB. Among infected contacts, preventive therapy promises to reduce the risk of disease progression. This is supported by observational cohort studies, but randomized trials are urgently needed to confirm these observations and guide policy formulation. Substantial investment in MDR/XDR-TB prevention and care will be critical if the ambitious global goal of TB elimination is to be realized.