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The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcomes

Background. Individualized treatment for multidrug-resistant (MDR) tuberculosis and extensively drug-resistant (XDR) tuberculosis depends upon reliable and valid drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line tuberculosis drugs. However, the reliability of these tests is uncertain, due to unresolved methodological issues. We estimated the association of DST results for pyrazinamide, ethambutol, and second-line drugs with treatment outcomes in patients with MDR tuberculosis and XDR tuberculosis.Methods. We conducted an analysis of individual patient data assembled from 31 previously published cohort studies of patients with MDR and XDR tuberculosis. We used data on patients' clinical characteristics including DST results, treatment received, outcomes, and laboratory methods in each center.Results. DST methods and treatment regimens used in different centers varied considerably. Among 8955 analyzed patients, in vitro susceptibility to individual drugs was consistently and significantly associated with higher odds of treatment success (compared with resistance to the drug), if that drug was used in the treatment regimen. Various adjusted and sensitivity analyses suggest that this was not explained by confounding. The adjusted odds of treatment success for ethambutol, pyrazinamide, and the group 4 drugs ranged from 1.7 to 2.3, whereas for second-line injectables and fluoroquinolones, odds ranged from 2.4 to 4.6.Conclusions. DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.

The inherited disorders of human haemoglobin are very common in some populations. Relative protection afforded to heterozygous carriers of these conditions against P. falciparum malaria is a likely cause for these high gene frequencies. However, very little is known at the cellular level of how this protective effect works. As an approach to this problem, an in vitro culture technique was developed in order to examine the factors which might modify the interaction of P. falciparum with human red cells. Fetal haemoglobin was of particular interest as a means of protection, since young infants, who are known to have high levels of this haemoglobin, are relatively resistant to P. falciparum. Furthermore, there is increasing evidence that infants heterozygous for thalassaemia and other haemoglobinopathies have higher levels of fetal haemoglobin than expected during the first year of life. A paucity of parasites was observed in the fetal haemoglobin-containing cells in young infants but this was shown to be due to the predilection of the parasite for metabolically young cells. Fetal haemoglobin was shown to have no effect on the rates of invasion of parasites into cells from a variety of conditions. However fetal haemoglobin caused significant retardation of growth once the parasite had entered the cell. This effect was independent of cell age. Further findings indicated that in the sickling disorders and glucose-6-phosphate dehydrogenase deficiency the red cell provided an unfavourable environment for the development of P. falciparum. This was not the case in thalassaemia and haemoglobin C and E traits. It was therefore suggested that these latter disorders have maintained their high frequencies due to the relatively high level of fetal haemoglobin which occurs in heterozygous carriers at an early stage in life, and protects them at an age when mortality from falciparum malaria is at its highest.

Background\ud \ud An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum.\ud \ud Methods\ud \ud In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries.\ud \ud Results\ud \ud Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6.4–8.5, p

The wide spectrum of clinical outcomes following infection with Mycobacterium tuberculosis is largely determined by the host immune response; therefore, we studied several clinically defined groups of individuals (n = 120) that differ in their ability to contain the bacillus. To quantitate M. tuberculosis-specific T cells directly ex vivo, we enumerated IFN-gamma-secreting CD4 T cells specific for ESAT-6, a secreted Ag that is highly specific for M. tuberculosis, and a target of protective immune responses in animal models. We found that frequencies of circulating ESAT-6 peptide-specific IFN-gamma-secreting CD4 T cells were higher in latently infected healthy contacts and subjects with minimal disease and low bacterial burdens than in patients with culture-positive active pulmonary tuberculosis (p = 0.009 and p = 0.002, respectively). Importantly, the frequency of these Ag-specific CD4 T cells fell progressively in all groups with treatment (p = 0.005), suggesting that the lower responses in patients with more extensive disease were not due to tuberculosis-induced immune suppression. This population of M. tuberculosis Ag-specific Th1-type CD4 T cells appears to correlate with clinical phenotype and declines during successful therapy; these features are consistent with a role for these T cells in the containment of M. tuberculosis in vivo. Such findings may assist in the design and evaluation of novel tuberculosis vaccine candidates.