Donald A. Enarson

Exogenous Reinfection as a Cause of Recurrent Tuberculosis after Curative Treatment

BACKGROUND For decades it has been assumed that postprimary tuberculosis is usually caused by reactivation of endogenous infection rather than by a new, exogenous infection. METHODS We performed DNA fingerprinting with restriction-fragment-length polymorphism analysis on pairs of isolates of Mycobacterium tuberculosis from 16 compliant patients who had a relapse of pulmonary tuberculosis after curative treatment of postprimary tuberculosis. The patients lived in areas of South Africa where tuberculosis is endemic. Medical records were reviewed for clinical data. RESULTS For 12 of the 16 patients, the restriction-fragment-length polymorphism banding patterns for the isolates obtained after the relapse were different from those for the isolates from the initial tuberculous disease. This finding indicates that reinfection was the cause of the recurrence of tuberculosis after curative treatment. Two patients had reinfections with a multidrug-resistant strain. All 15 patients who were tested for the human immunodeficiency virus were seronegative. CONCLUSIONS Exogenous reinfection appears to be a major cause of postprimary tuberculosis after a previous cure in an area with a high incidence of this disease. This finding emphasizes the importance of achieving cures and of preventing anyone with infectious tuberculosis from exposing others to the disease.

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial

BACKGROUND A WHO-recommended 8-month regimen based on ethambutol and isoniazid was evaluated in a randomised clinical trial against a 6-month standard regimen. METHODS 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly assigned one of three regimens: daily ethambutol, isoniazid, rifampicin, and pyrazinamide for 2 months, followed by ethambutol and isoniazid for 6 months (2EHRZ/6HE); the same drugs but given three times weekly in the initial intensive phase (2[EHRZ]3/6HE); or the same initial intensive phase as the first regimen, followed by 4 months of daily rifampicin and isoniazid (2EHRZ/4HR). Follow-up was to 30 months after the start of chemotherapy. Sputum was regularly examined by microscopy and culture. Unfavourable outcome was defined as failure during treatment or relapse afterwards. Analyses were by intention to treat. FINDINGS At 2 months, a significantly higher proportion of patients assigned the daily intensive phase than of those assigned the three-times-weekly regimen were culture negative (700/828 [85%] vs 333/433 [77%], p=0.001). 12 months after the end of chemotherapy, the proportions of unfavourable outcomes were 36 of 346 (10%) with 2EHRZ/6HE, 48 of 351 (14%) with 2(EHRZ)3/6HE, and 17 of 347 (5%) with 2EHRZ/4HR. Both 8-month regimens were significantly inferior to the control 6-month standard regimen (difference between control and 2EHRZ/6HE 5.5% [95% CI 1.6 to 9.4]; between control and 2(EHRZ)3/6HE 8.8% [4.5 to 13.0]). Adverse effects leading to interruption of treatment for 7 days or longer occurred in 28 patients (12 2EHRZ/6HE, five 2[EHRZ]3/6HE, 11 2EHRZ/4HR). INTERPRETATION The results of this study must be taken into account in recommendations on management of new cases of smear-positive tuberculosis.

Analysis for a Limited Number of Gene Codons Can Predict Drug Resistance of Mycobacterium tuberculosis in a High-Incidence Community

ABSTRACT Correct and rapid diagnosis is essential in the management of multidrug-resistant tuberculosis (MDR-TB). In this population-based study of 61 patients with drug-resistant tuberculosis, we evaluated the frequency of mutations and compared the performance of genotypic (mutation analysis by dot blot hybridization) and phenotypic (indirect proportion method) drug resistance tests. Three selected codons (rpoB531, rpoB526, and katG315) allowed identification of 90% of MDR-TB cases. Ninety percent of rifampin, streptomycin, and ethambutol resistance and 75% of isoniazid resistance were detected by screening for six codons: rpoB531, rpoB526, rrs-513, rpsL43, embB306, and katG315. The performance (reproducibility, sensitivity, and specificity) of the genotypic method was superior to that of the routine phenotypic method, with the exception of sensitivity for isoniazid resistance. A commercialized molecular genetic test for a limited number of target loci might be a good alternative for a drug resistance screening test in the context of an MDR “DOTS-plus” strategy.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Chronic respiratory diseases in developing countries: the burden and strategies for prevention and management

In developing countries, chronic respiratory diseases represent a challenge to public health because of their frequency, severity, projected trends, and economic impact. Health care planners, for example, are faced with a dramatic increase in tobacco use and must establish priorities for the allocation of limited resources. Nevertheless, smoking prevention and standardized management programmes for asthma and chronic obstructive pulmonary disease should be implemented in developing countries whenever possible. International measures will be required to reverse tobacco smoking trends, and international agencies could define essential drugs and equipment and encourage the use of generic drugs, particularly for corticosteroids inhaled at high dosages. For such programmes to be effective, producers of high-quality generics will need to be identified, and the medications added to national lists of essential drugs and included in procurement procedures. Other recommendations for alleviating the burden of chronic respiratory diseases in developing countries are: adapting guidelines to local contexts and ensuring their distribution; upgrading equipment at district level; purchasing high-quality drugs at low prices; routine training and supervision of health services personnel; and regular monitoring of performance. Social mobilization by professional societies, nongovernmental organizations, and the mass media will also increase government commitment to tobacco control and standardized case management.

Association between smoking and tuberculosis infection: a population survey in a high tuberculosis incidence area

Background: Associations between smoking and tuberculosis disease including death from tuberculosis have been reported, but there are few reports on the influence of smoking on the risk of developing Mycobacterium tuberculosis infection. The aim of this study was to determine the association between smoking and M tuberculosis infection. Methods: In a cross sectional population survey, data on smoking and tuberculin skin test (TST) results of 2401 adults aged ⩾15 years were compared. Results: A total of 1832 (76%) subjects had a positive TST (⩾10 mm induration). Of 1309 current smokers or ex-smokers, 1070 (82%) had a positive TST. This was significantly higher than for never smokers (unadjusted OR 1.99, 95% confidence interval (CI) 1.62 to 2.45). A positive relationship with pack-years was observed, with those smoking more than 15 pack-years having the highest risk (adjusted OR 1.90, 95% CI 1.28 to 2.81). Conclusion: Smoking may increase the risk of M tuberculosis infection.

The Bacteriologic Yield in Children with Intrathoracic Tuberculosis

This report documents the bacteriologic yield in children who received treatment for intrathoracic tuberculosis in an area where it is highly endemic. A total of 307 children were included in the study, and bacteriologic confirmation was achieved in 122 (62.2%) of 196 children from whom specimens were collected. The lowest bacteriologic yield was recorded for the 69 children with uncomplicated lymph node disease (24 [34.8%] had bacteriologic confirmation). The high overall bacteriologic yield indicates the need to reassess the value of bacteriology-based approaches to diagnosis of intrathoracic tuberculosis in children, particularly in areas of endemicity where they frequently present with advanced disease.

Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study

A retrospective study was performed to determine factors associated with the outcome of pulmonary multidrug-resistant tuberculosis (MDR-TB) in Taipei, Taiwan. All patients newly diagnosed with pulmonary MDR-TB in a referral centre from 1992–1996 were enrolled and their outcome over the subsequent 6 yrs was determined. A total of 299 patients were identified, comprising 215 (71.9%) males and 84 (28.1%) females with a mean age of 47.3 yrs. The patients received a mean of 3.7 effective drugs. Out of the 299 patients, 153 (51.2%) were cured, 31 (10.4%) failed, 28 (9.4%) died and 87 (29.1%) defaulted. Of the 125 patients receiving second-line drugs with ofloxacin, 74 (59.2%) were cured. Those who received ofloxacin had a lower risk of relapse than those receiving only first-line drugs (hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.03–0.81) and a lower risk of TB-related death than those receiving second-line drugs but not ofloxacin (adjusted HR 0.50, 95% CI 0.31–0.82). In conclusion, multidrug-resistant tuberculosis patients who received ofloxacin were more likely to be cured, and were less likely to die, fail or relapse. The utility of new-generation fluoroquinolones, such as moxifloxacin, in the treatment of multidrug-resistant tuberculosis needs to be evaluated. Default from treatment is a major challenge in the treatment of multidrug-resistant tuberculosis.

Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?

Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.