WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Treatment of varicose tributaries with sclerotherapy with polidocanol 0.5 % foam.

BACKGROUND: Although foam sclerotherapy of varicose tributaries is common in daily practice, scientific evidence for the optimal sclerosant-concentration and session-frequency is still low. This study aimed to increase the knowledge on foam sclerotherapy of varicose tributaries and to evaluate the efficacy and safety of foam sclerotherapy with 0.5 % polidocanol in tributaries with 3-6 mm in diameter. PATIENTS AND METHODS: Analysis of 110 legs in 76 patients. Injections were given every second or third day. A maximum of 1 injection / leg and a volume of 2 ml / injection were administered per session. Controls were performed approximately 6 months and 12 months after the start of therapy. RESULTS: 110 legs (CEAP C2-C4) were followed up for a period of 14.2 +/- 4.2 months. Reflux was eliminated after 3.4 +/- 2.7 injections per leg. Insufficient tributaries were detected in 23.2 % after 6.2 +/- 0.9 months and in 48.2 % after 14.2 +/- 4.2 months, respectively. Only 30.9 % (34 / 110) of the legs required additional therapy. In 6.4 % vein surgery was performed, in 24.5 % similar sclerotherapy was repeated. Significantly fewer sclerotherapy-sessions were required compared to the initial treatment (mean: 2.3 +/- 1.4, p = 0.0054). During the whole study period thrombophlebitis (8.2 %), hyperpigmentation (14.5 %), induration in the treated region (9.1 %), pain in the treated leg (7.3 %) and migraine (0.9 %) occurred. One patient with a history of thrombosis developed thrombosis of a muscle vein (0.9 %). After one year there were just hyperpigmentation (8.2 %) and induration (1.8 %) left. No severe adverse effect occurred. CONCLUSIONS: Foam sclerotherapy with injections of 0.5 % polidocanol every 2nd or 3rd day, is a safe procedure for varicose tributaries. The evaluation of efficacy is difficult, as it can hardly be said whether the detected tributaries in the controls are recurrent veins or have recently developed in the follow-up period. The low number of retreated legs indicates a high efficacy and satisfaction of the patients.

Results of a tuberculosis-specific IFN-gamma assay in children at high risk for tuberculosis infection.

The specificity of the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) is adversely affected by bacille Calmette-Guérin (BCG) vaccination and infection with non-tuberculous mycobacteria. Interferon-gamma release assays (IGRAs) using TB-specific antigens promise higher specificity. We compared a new IGRA and TST in 184 schoolchildren at high risk for LTBI. The IGRA and TST were positive in 33.2% and 43.5% of the children, respectively (P < 0.001). If studies confirm that this difference is due to higher specificity of this IGRA, it may have an important role to play in the diagnosis of LTBI and identification of children at true risk for TB.

Risk factors associated with default from multidrug-resistant tuberculosis treatment, South Africa, 1999-2001.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) treatment centers in five provinces, South Africa. OBJECTIVES: To estimate the mortality and evaluate risk factors associated with default from MDR-TB treatment. DESIGN: Using registries and a standardized questionnaire, we conducted a case-control study among patients diagnosed and treated for MDR-TB. Cases were defined as patients who began MDR-TB treatment between 1 October 1999 and 30 September 2001 and defaulted from treatment for more than 2 months; controls were defined as patients who began MDR-TB treatment during the same time and were cured, completed or failed. RESULTS: After initial identification and reclassification, 269 cases and 401 controls were confirmed eligible for interview. Further investigation revealed that 74 (27%) cases and 44 (10%) controls had died. Among 96 cases located who consented and were interviewed, 70% had defaulted after receiving at least 6 months of treatment. In a multivariate model, the strongest individual risk factors for default included reporting smoking marijuana or mandrax during treatment, and having an unsatisfactory opinion about the attitude of health care workers. CONCLUSION: Mortality among MDR-TB defaulters was high. Interventions to reduce default from MDR-TB treatment should center on substance abuse treatment, patient education and support and improving provider-patient relationships.

Current tools available for the diagnosis of drug-resistant tuberculosis.

Drug-resistant tuberculosis (DR-TB) poses a major threat to control of tuberculosis worldwide. Diagnosis and treatment of DR-TB are considerably more difficult than for drug-susceptible tuberculosis (TB) and require higher level infrastructure and proficiency from laboratory specialists and clinicians. The World Health Organization (WHO) End TB Strategy calls for early diagnosis and initiation of appropriate treatment of all persons of all ages with any form of drug-susceptible TB or DR-TB. This requires ensuring access to WHO-recommended rapid diagnostics and universal drug susceptibility testing (DST) for all persons with signs and symptoms of TB. There are a number of laboratory tools available for diagnosis of DR-TB, including phenotypic culture-based DST as well as molecular methods. Optimal and complementary use of the available diagnostic tools at the different levels of the tiered network of TB laboratories, as well as correct interpretation of the diagnostic results provided by them is critical for accurate and timely diagnosis of DR-TB thus enabling effective treatment and care of patients.

Conservation in sequence and affinity of human and rodent PDGF ligands and receptors.

Platelet-derived growth factor (PDGF) consists of two chains, PDGF-A and -B, which activate as homo- or heterodimers two receptors, alpha and beta. To test PDGF function in vivo we have generated neutralizing monoclonal antibodies. When analyzed with rat PDGFs only antibodies raised against human PDGF-AA showed cross-species activity. This correlated with complete amino acid sequence conservation of PDGF-A whereas rat PDGF-B differed in six positions when cloned rat PDGF cDNAs were compared with their human homologs within the receptor binding region. Extracellular domains of cloned rat PDGF alpha- and beta-receptor cDNAs did not reflect this difference in cross-species ligand conservation. When rat extracellular domains were expressed as soluble proteins they bound human PDGF-BB with high affinity after immobilization of the purified proteins on solid phase. Dissociation constants were identical to those of their human homologs. Thus, high affinity binding of human PDGF-BB to extracellular domains does not depend on species origin but only on receptor type.

Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis.

SETTING: Globally it is estimated that 273000 new cases of multidrug-resistant tuberculosis (MDR-TB, resistance to isoniazid and rifampicin) occurred in 2000. To address MDR-TB management in the context of the DOTS strategy, the World Health Organization and partners have been promoting an expanded treatment strategy called DOTS-Plus. However, standard definitions for MDR-TB patient registration and treatment outcomes do not exist. OBJECTIVE: To propose a standardized set of case registration groups and treatment outcome definitions for MDR-TB and procedures for conducting cohort analyses under the DOTS-Plus strategy. DESIGN: Using published definitions for drug-susceptible TB as a guide, a 2-year-long series of meetings, conferences, and correspondence was undertaken to review published literature and country-specific program experience, and to develop international agreement. RESULTS: Definitions were designed for MDR-TB patient categorization, smear and culture conversion, and treatment outcomes (cure, treatment completion, death, default, failure, transfer out). Standards for conducting outcome analyses were developed to ensure comparability between programs. CONCLUSION: Optimal management strategies for MDR-TB have not been evaluated in controlled clinical trials. Standardized definitions and cohort analyses will facilitate assessment and comparison of program performance. These data will contribute to the evidence base to inform decision makers on approaches to MDR-TB control.

Capacity building for international tuberculosis control through operations research training.

SETTING: In resource-poor countries, few tuberculosis (TB) program staff at the national, provincial, and even district levels have the basic analytical and epidemiological skills necessary for collecting and analyzing quality data pertaining to national TB control program (NTP) improvements. This includes setting program priorities, operations planning, and implementing and evaluating program activities. OBJECTIVES: To present a model course for building capacity in basic epidemiology and operations research (OR). DESIGN: A combination of didactic lectures and applied field exercises were used to achieve the main objectives of the 6-day OR course. These were to increase the understanding of quantitative and qualitative research concepts, study design, and analytic methods, and to increase awareness of how these methods apply to the epidemiology and control of TB; and to demonstrate the potential uses of OR in answering practical questions on NTP effectiveness. As a final outcome, course participants develop OR proposals that are funded and later implemented. RESULTS: Since 1997, this OR course has been conducted nine times in five countries; 149 key NTP and laboratory staff have been trained in OR methods, and 44 OR protocols have been completed or are underway. CONCLUSION: This low-cost model course can be adapted to a wide range of public health issues.

Differentiation of primary and secondary cutaneous B-cell lymphoma by Southern blot analysis.

Malignant B-cell lymphomas represent a heterogenous group of lymphoreticular disorders that involve the skin in about 20% of reported cases. Skin involvement may be primary or secondary (ie, the result of hematogenous spread). Primary cutaneous B-cell lymphomas (PCBCLs) are thought to take a comparatively favorable course, respond readily to nonaggressive treatment, and lack evidence of extracutaneous spread. Nine primary B-cell lymphomas (7 centrocytic or centroblastic follicular, 1 immunoblastic, 1 centroblastic), three secondary (follicular) cutaneous B-cell lymphomas (SCBCLs) and two pseudolymphomas were studied. Staging revealed that bone marrow was involved only in SCBCLs. Centrocytes were detected in blood smear preparations of all SCBCLs. All lymphomas were treated with local irradiation. Patients with primary centroblastic and immunoblastic cutaneous lymphomas and those with secondary lymphomas received additional chemotherapy. Pseudolymphomas were treated by simple excision. Patients were monitored on average for 55 months. During this period, no patients with PCBCLs exhibited cutaneous relapses or hematogenous spread. In contrast, all patients with SCBCLs experienced cutaneous relapses. Peripheral blood, bone marrow, and skin samples from all patients were subjected to Southern blot analysis using a JH probe. Clonal rearrangement was found in all skin samples investigated except specimens from pseudolymphomas. Peripheral blood and bone marrow samples were positive in SCBCLs (the rearrangement pattern was different from that of the skin samples for two of the three patients), whereas it was negative in all PCBCLs and pseudolymphomas. In conclusion, Southern blot analysis of peripheral blood may be useful in differential diagnosis of PCBCLs and SCBCLs and a prognostic marker. Furthermore, these data confirm the comparatively favorable clinical course of PCBCLs and suggest that in these cases, local irradiation can be considered adequate treatment, whereas SCBCLs require additional systemic therapy.

Mycobacterium bovis as a zoonosis in the Kruger National Park, South Africa.

SETTING: The Kruger National Park (KNP), Mpumalanga Province, South Africa. OBJECTIVE: The prevalence of tuberculosis caused by Mycobacterium bovis exceeds 70% in African buffalo in the southern region of the KNP. Inter-species transmission (lion, cheetah, baboon, antelope) has also been confirmed. Regular culling of emaciated buffalo and processing of meat and hides constitute routine control policy. Following extensive media coverage of the problem, public health concerns about the transmission of M. bovis to humans, including visitors to the KNP, prompted this investigation. DESIGN: The study was designed to determine the prevalence of infection and/or active disease due to M. bovis among KNP employees selected from three defined risk groups based on occupation category. RESULTS: Of 206 persons screened for active disease by sputum bacteriology, two persons with disease due to M. tuberculosis were identified. No isolate of M. bovis was found. Differential skin testing using three antigens failed to show any degree of M. bovis infection risk, even among high risk occupations. Reasons for these results are discussed. CONCLUSIONS: Bovine tuberculosis was not indicated as an occupational zoonosis in the KNP, nor was aerosol transmission implicated as a mechanism for human infection. Concerns about the public health implications of tuberculosis in buffalo in the KNP have therefore not been validated.

Universal pattern of RpoB gene mutations among multidrug-resistant isolates of Mycobacterium tuberculosis complex from Africa.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) presents an increasing burden in Southern Africa. Rapid diagnostic tests for drug resistance to rifampicin have been developed based on mutation analysis of the rpoB gene. However, geographic differences of underlying mutations have recently been suggested. OBJECTIVE: Drug-resistant strains of Mycobacterium tuberculosis complex from Africa were analysed for geographic differences in frequency and location of rpoB mutations. DESIGN: A random sample of rifampicin-resistant strains was collected from 87 patients with pulmonary MDR-TB treated in 12 hospitals from six different regions of South Africa. In addition, 18 isolates of M. tuberculosis complex from Namibia, Sierra Leone, and Uganda, including 13 isolates of M. africanum, were analyzed. Point mutations were detected by direct sequence analysis of the rpoB gene. RESULTS: Missense mutations were identified for 91 isolates (87%). Double mutations were present in eight (8%) MDR-TB isolates, two of which carried one mutation outside a previously described diagnostic region. We found no geographic differences regarding the frequency and pattern of single rpoB gene mutations. CONCLUSION: Our results confirm that molecular genetic analysis of rifampicin resistance based on a core region within the rpoB gene is universally applicable to strains of M. tuberculosis complex from different geographic regions.

Determinants of drug-resistant tuberculosis: analysis of 11 countries.

SETTING: Eleven countries/territories. OBJECTIVES: Global information on the determinants of drug-resistant tuberculosis (TB) based on representative data is not available. We therefore studied the relationship between demographic characteristics, prior TB treatment, and human immunodeficiency virus (HIV) infection with anti-tuberculosis drug resistance. METHODS: Population-based representative data on new and previously treated patients with TB collected within an international drug resistance surveillance network. RESULTS: Of 9,615 patients, 8,222 (85.5%) were new cases of TB and 1,393 (14.5%) were previously treated cases. Compared with new cases, previously treated cases were significantly more likely to have resistance to one (OR = 2.5,95% CI 2.1-3.0; P < 0.001), two (OR = 4.6, 95%CI 3.7-5.6; P < 0.001), three (OR = 11.5, 95%CI 8.6-15.3; P < 0.001), and four (OR = 18.5, 95% CI 12.0-28.5; P < 0.001) drugs. An approximately linear increase in the likelihood of having multidrug-resistant tuberculosis (MDR-TB) was observed as the total time (measured in months) of prior anti-tuberculosis treatment increased (P < 0.001, chi2 for trend). In multivariate analysis, prior TB treatment for 6-11 months (OR = 7.6, 95% CI 2.6, 22.4; P < 0.001) and > or = 12 months (OR 13.7, 95% CI 4.5-41.6; P < 0.001), but not HIV positivity, was associated with MDR-TB. CONCLUSION: This study shows that prior but ineffective treatment is a strong predictor of drug resistance, and that HIV is not an independent risk factor for MDR-TB. The association between length of treatment and drug resistance may reflect longer treatment as a result of treatment failure in patients with drug resistance; it may also reflect irregular prior treatment for TB, leading to drug resistance.

Immunological aspects of mammary tumors in dogs and cats: a survey including own studies and pertinent literature.

Naturally occurring cancer in companion animals parallels cancer in man more closely than does experimentally induced cancer in inbred laboratory animals. In dogs and cats, as in man, a role for immune responses is indicated in the development of tumors. A survey is presented based on the literature and our own studies concerning the immunological and immunotherapeutic aspects of canine and feline mammary neoplasia. In dogs bearing mammary neoplasms, circulating immune complexes appear to play a negative role in the generation of effective antitumor immune responses. The functional role of peripheral blood lymphocytes and tumor-infiltrating lymphocytes in dogs and cats with mammary tumors is not yet fully established. No tumor antigen responsible for humoral or cellular responses has yet been identified. Extracorporeal perfusion of serum of dogs with mammary tumors and subcutaneous administration of mitomycin- and neuraminidase-treated autologous tumor cells are associated with improved prognosis. The opposite was true for i.v. treatment with BCG or Corynebacterium parvum vaccine in our study, in contrast to a previous report. A number of other treatment modalities in cats and dogs with mammary carcinomas failed to induce tumor regression. Canine and feline mammary carcinomas are good candidates for modern immunotherapeutic approaches.

Drug susceptibility testing proficiency in the network of supranational tuberculosis reference laboratories.

SETTING: The network of supranational tuberculosis reference laboratories (SRLs). OBJECTIVE: To evaluate the annual SRL Rounds 6-14 of proficiency testing for first-line drug susceptibility testing (DST). DESIGN: Panels consisted of 20-30 cultures (including 10 pairs of duplicate strains), aiming at 50% resistance prevalence with a variety of profiles. The 27 SRLs participating in at least one of these rounds were free to use their preferred DST method. A judicial gold standard of at least 80% concordant 'susceptible' or 'resistant' was used to determine sensitivity, specificity and efficiency; otherwise the strain was excluded. RESULTS: Of 600 strains, 10% were excluded from evaluation. The average SRL sensitivity and specificity varied between rounds, without attaining significance or trends. Both sensitivity and specificity remained at >95% for isoniazid (INH), rifampicin (RMP) and streptomycin and at >80% for ethambutol. The 16 SRLs participating in all rounds performed consistently better. CONCLUSION: The rounds succeeded in comparing the proficiency of laboratories, and should be further promoted for DST quality assessment. However, to function with greater precision and to ultimately improve the clinical relevance of DST, the INH and RMP judicial result gold standard also needs to take into account genotypic and treatment outcome information.

Dihydropteroate synthase and novel dihydrofolate reductase gene mutations in strains of Pneumocystis jirovecii from South Africa.

Dihydropteroate synthase (DHPS) gene mutations have raised concerns about emerging sulfonamide resistance in Pneumocystis jirovecii. DHPS and dihydrofolate reductase (DHFR) gene products were amplified in clinical specimens from South African patients. One of 53 DHPS genes sequenced contained the double mutation Thr55Ala Pro57Ser. DHFR gene mutations detected were Ala67Val and the new mutations Arg59Gly and C278T.

Primary and acquired drug resistance in adult black patients with tuberculosis in South Africa: results of a continuous national drug resistance surveillance programme involvement.

Drug resistance is a major problem in the treatment of tuberculosis, and monitoring programmes are essential in control of this disease. The extent of primary resistance in a community is an important indication of the effectiveness of treatment schedules. Since 1965 the Tuberculosis Research Institute (TBRI) of the South African Medical Research Council has performed 25 annual surveys of drug resistance in adult black tuberculosis patients where the disease is most prevalent. Methodology for patient selection, specimen collection, laboratory procedures and criteria for drug resistance were strictly adhered to. All specimens were processed in a central laboratory supervised by the same two technologists. Between 1965 and 1988 a total of 33,111 strains of Mycobacterium tuberculosis were isolated from new cases and 19,134 from old cases. Both primary and acquired resistance to the 5 major antituberculosis drugs has decreased dramatically. Sex and age do not influence resistance rates, while patients' ethnic origin and geographical location do. The results indicate that current tuberculosis treatment practices are satisfactory. The prevalence of primary drug resistance in black South Africans is now intermediate between those countries where eradication of tuberculosis is well advanced and those where the disease remains a public health problem. Also, it can be shown that comparable and clinically significant data can be obtained from a central laboratory employing unsophisticated and inexpensive drug susceptibility testing procedures.

[Radiodiagnosis of cerebellopontine-angle tumors (author's transl)]. / Zur radiologischen Diagnostik von Kleinhirnbrückenwinkeltumoren.

The most important radiodiagnostic signs of cerebellopontine-angle tumors are demonstrated. The value of plain films and special projections is discussed. The use of recent diagnostic procedures like scintography, CT and cisternography with oily contrast medium is critically analyzed. The advantage and disadvantages of these procedures are discussed according to their usefullness in evaluating size, route of spread and localisation of cerebellopontine-angle tumors.

Improved biological and transcriptional activity of monopegylated interferon-alpha-2a isomers.

The addition of polyethyleneglycol (PEG) side chains to interferon alpha-2a improves the serum stability and clinical efficacy. Current commercial PEG-INF formulations such as PEGASYS are heterogeneous and contain multiple monopegylated isomers. We have analyzed the activity of nine, purified monopegylated variants in antiproliferative, antiviral and binding assays, together with a global transcriptional analysis using DNA oligonucleotide microarrays. We show a direct correlation between biological and transcriptional activity for all isomers and an inversed correlation between IFN-receptor 2a affinity and signal transduction. Two out of nine positional isomers have a higher specific biological and transcriptional activity than the mixture, which can be explained by unique structural features of interferon signaling, which involves two distinct receptors. The possible clinical implications are discussed, which might guide the development of pegylated interferons with improved pharmacological properties.

Tuberculosis drug resistance in the Western Cape.

OBJECTIVES: Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to determine the prevalence of tuberculosis drug resistance (including multidrug resistance) and to investigate possible relationships between drug resistance and patient demographic characteristics. DESIGN, SETTING, SUBJECTS, OUTCOME MEASURES: During a defined period, all adult (> or = 15 years) patients with pulmonary tuberculosis (confirmed by culture) from all tuberculosis clinics in the Western Cape were included. Previous tuberculosis treatment history was obtained by interviews, utilising a standardised questionnaire. Acquired drug resistance was determined on cultures from patients with a prior history of tuberculosis treatment, while initial resistance was determined from tuberculosis cases with no history of previous treatment. RESULTS: Data from 7,266 patients were analysed. After adjusting for missing information by way of a random sample validation study, 32% of patients were found to have a history of previous treatment, 63% indicated no previous treatment, and in 5% the treatment history was unknown. Rates for initial resistance were found to be low at 3,9% for isoniazid, 1,1% for rifampicin and 0,2% for ethambutol. Combined resistance to isoniazid and rifampicin (multidrug resistance) was found to be 1,1% in patients not treated before. Acquired resistance rates were higher at 10,8% for isoniazid, 4,2% for rifampicin, 0,3% for ethambutol and 4,0% for multidrug resistance. Logistic regression analysis of the data indicated that drug resistance was not influenced by population group, gender or age. Patients with a history of tuberculosis treatment were found to be at an increased risk of developing drug resistance (relative risk 2,6). Some regions in the Western Cape had higher proportions of previously treated patients with consequent higher acquired resistance rates. CONCLUSIONS: Results from this study indicated that drug resistance is currently not a major problem in the Western Cape, rates comparing favourably with those reported from developed countries and being much lower than those for developing countries. Every effort should therefore be made to maintain the status quo and to prevent the emergence of further resistance. The priority for tuberculosis control in the Western Cape should remain to limit transmission of the disease by reducing the infectious pool through improved cure of (especially) smear-positive cases.