Jonathan J. Deeks

Diagnosis of tuberculosis in South African children with a T cell-based assay: a prospective cohort study

BACKGROUND Childhood tuberculosis often presents non-specifically and is a common differential diagnosis in high prevalence areas. Current diagnostic tools have poor sensitivity and cannot reliably exclude tuberculosis, so overdiagnosis is common. HIV co-infection exacerbates this problem and accounts for an increasing proportion of paediatric tuberculosis worldwide. METHODS We assessed the usefulness of a T-cell-based rapid blood test for Mycobacterium tuberculosis infection, the enzyme-linked immunospot assay (ELISPOT), in routine clinical practice. We did a prospective blinded study of 293 African children with suspected tuberculosis in kwaZulu-Natal, a region with high HIV prevalence. Children had full clinical assessment, ELISPOT, and a tuberculin skin test. Test results were compared with final clinical and microbiological diagnoses. RESULTS In children with tuberculosis, sensitivity of ELISPOT was 83% (95% CI 75-89, n=133), significantly higher (p<0.001) than the 63% (54-72) sensitivity of tuberculin skin test (n=116). Sensitivity of tuberculin skin test fell significantly in children younger than 3 years (to 51%), with HIV co-infection (36%), or with malnutrition (44%). Sensitivity of ELISPOT, which was not significantly adversely affected by these factors, was 85%, 73%, and 78%, respectively in these subgroups. In 116 children with both test results available, sensitivity of the two tests combined was 91% (85-95). CONCLUSIONS Diagnostic sensitivity of ELISPOT is higher than that of the skin test and is less affected by factors frequently associated with childhood tuberculosis in developing countries. Used together with the skin test, ELISPOT provides a clinically useful diagnostic sensitivity in African children with suspected tuberculosis.

Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study

BACKGROUND Little is known about factors that affect the risk of acquiring infection in children exposed to Mycobacterium tuberculosis. The effect of BCG vaccination has been difficult to ascertain because the tuberculin skin test (TST), until recently the only method for detecting M tuberculosis infection, does not reliably distinguish between tuberculosis infection and BCG vaccination. METHODS We investigated risk factors for tuberculosis infection in 979 child household contacts of 414 adult index patients with sputum smear-positive pulmonary tuberculosis in Istanbul, Turkey. Children were aged up to 16 years (median 7, IQR 3-11) and 770 of 979 (79%) had a BCG scar. A T-cell-based enzyme-linked immunospot assay (ELISpot), which is not confounded by BCG vaccination, and TST were used to assess infection. Independent risk factors for infection were identified through multivariate analysis. FINDINGS Amount of tuberculosis exposure within the household and age (a marker of tuberculosis exposure outside the household) were strongly associated with likelihood of infection as measured by both TST and ELISpot. ELISpot also identified absence of BCG scar as an independent risk factor for infection in tuberculosis-exposed children; BCG-vaccinated children had an odds ratio of 0.60 (95% CI 0.43-0.83, p=0.003) for tuberculosis infection, compared with unvaccinated children. INTERPRETATION Contrary to the prevailing theory that BCG vaccination protects only against tuberculosis disease, our results suggest that the vaccine also protects against tuberculosis infection. This finding has important implications for our understanding of the biology of tuberculosis infection and development of improved tuberculosis vaccines.

Suicide in female nurses in England and Wales.

BACKGROUND Female nurses appear to have an increased risk of suicide but the reasons are unknown. METHOD We have concluded a study of nurse suicides (N = 106) in England and Wales, including a psychological autopsy study (N = 42) and case-control comparison with living nurses (N = 84). RESULTS Nearly three-quarters of the nurse suicides had previous contact with psychiatric services and almost half had been psychiatric in-patients in the past. There were particularly marked differences between the cases and controls for current psychiatric disorder (90.5% v. 7.1%, OR = 68.5), personality disorder (38.1% v. 12%, OR = 32), and history of deliberate self-harm (71.4% v. 2.4%, OR = 58.5). Family background and social factors (especially concerning interpersonal relationships) also distinguished the two groups. Smoking and serious alcohol abuse were much more frequent in the suicides. There was some indication that while many of the suicides were in contact with psychiatric services, care may not have been optimal in some cases. CONCLUSIONS The most important strategies for suicide prevention in nurses are in prevention, detection and management of psychiatric disorders. In assessing suicide risk a history of DSH and the presence of comorbid psychiatric and personality disorders are particularly important.

A Simplified 4-Site Economical Intradermal Post-Exposure Rabies Vaccine Regimen: A Randomised Controlled Comparison with Standard Methods

Background The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Methods Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. Findings All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. Conclusions This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Trial Registration Controlled-Trials.com ISRCTN 30087513