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Contact investigation is a key component of tuberculosis (TB) control in developed, but not developing, countries. We aimed to measure the prevalence of TB among household contacts of sputum-smear-positive TB cases in The Gambia and to assess the sensitivity of an enzyme-linked immunospot (ELISPOT) assay in this regard. Household contacts of adult smear-positive TB patients were assessed by questionnaire, purified protein derivative (PPD) skin test, ELISPOT assay, physical examination, chest X-ray and sputum/gastric aspirate. Thirty-three TB cases were identified from 2174 of 2381 contacts of 317 adult smear-positive pulmonary TB patients, giving a prevalence of 1518/100000. The cases identified tended to have milder disease than those passively detected. The sensitivity of ESAT-6/CFP-10 ELISPOT test as a screening test for TB disease was estimated as 71%. Fifty-six per cent of contacts with a PPD skin test result >= 10 mm induration had detectable responses to ESAT-6/CFP-10 by ELISPOT, 11% with a negative PPD skin test (

The immaturity of the neonatal immune system in mice is associated with defective IFN-gamma production and Th2-biased immune responses. In this study, infants vaccinated at birth with BCG produced similar concentrations of IFN-gamma in response to PPD and showed similar frequencies of IFN-gamma-producing lymphocytes as compared to immune adults. Infants and adults produced only low concentrations of IL-4 and IL-5. CD4+ T lymphocytes were the main source of IFN-gamma. Similar proportions of Th1 and Th0 PPD-specific T cell clones were observed in infants and adults. This study demonstrates that the human neonatal immune response to BCG is not biased towards Th2 and is characterized by the predominant production of IFN-gamma by CD4+ T lymphocytes.

Data obtained in animals indicate that neonatal immune responses are biased toward Th2. This could reduce the efficacy of vaccines against viral and mycobacterial diseases. The ability of human newborns to develop a Th1 immune response upon immunization has not been studied. Since the vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) triggers a Th1-type response in adults, we investigated whether it induces a similar response in newborns and whether age at vaccination influences immunogenicity. We found that BCG vaccination at birth induces a memory Th1-type response of similar magnitude to that when given later in life. This study demonstrates that human newborns can be immunized against pathogens controlled by a Th1 immune response.

C-reactive protein (CRP) is a major acute phase protein of man, with serum concentrations increasing dramatically following stimulation of hepatocytes by inflammatory cytokines. However, the role of CRP in inflammation and resistance to infection is still poorly understood. Here, the specificity of CRP binding to the surface of Leishmania donovani, an obligate intracellular parasite of mononuclear phagocytes, is described. CRP is shown to bind to promastigotes at the infectious metacyclic stage of development, at concentrations found in normal human serum. The presence of CRP on the surface of promastigotes substantially increases uptake into human monocyte-derived macrophages. Unusually, CRP does not bind via its characteristic ligand, phosphorylcholine. We show that CRP binds to the lipophosphoglycan (LPG) component of the promastigote cell surface, a molecule implicated in both uptake and survival of these parasites within the macrophage, and also to the major secreted protein of promastigotes, secreted acid phosphatase. Using mAb to LPG with known ligand specificities, we define a novel ligand for CRP as the repeating phosphorylated disaccharide units that form the backbone of LPG.

Sixteen out of 45 (36%) leprosy patients with clinical features of acute erythema nodosum leprosum (ENL) did not show the characteristic presence of neutrophils (polymorphs) in histology of the ENL lesion. The acute-phase reactants, serum amyloid A (SAA) and C-reactive protein (CRP) which are systemic markers of inflammation, and IgM and IgG antibody to Mycobacterium leprae were determined in these patients in order to understand the differences in histological diagnosis. Both SAA and CRP were elevated in ENL patients, irrespective of the presence of polymorph infiltrates, as compared to nonreactional lepromatous patients, patients with histologically confirmed reversal reactions and endemic controls, indicating that all clinically diagnosed ENL patients had ongoing inflammatory reactions. On the other hand, IgM and IgG antibodies were significantly lower (70%) in ENL patients as compared to nonreactional lepromatous patients. When the two ENL groups [ENL-PMN+ve (positive for neutrophils) and ENL-PMN-ve (negative for neutrophils)] were compared, there were no significant differences in the mean SAA, IgM or IgG antibody concentrations, but CRP was eightfold lower in ENL-PMN-ve as compared to the ENL-PMN+ve group. This may indicate that the timing or modulation of the reaction was different in the two ENL groups. Thus, measurement of the acute-phase response and the ratio of SAA/CRP in particular are helpful in the clinical diagnosis of ENL reactions in leprosy.

Rural and urban health centres in The Gambia, West Africa.To estimate the time delay between onset of symptoms and initiation of treatment and identify the risk factors influencing the delay in patients with tuberculosis (TB).Structured interviews with newly diagnosed TB patients aged over 15 years presenting to TB control staff in four health centres.A total of 152 TB patients were interviewed. The median delay from onset of symptoms to commencement of treatment was 8.6 weeks (range 5-17). Delay to treatment was independent of sex, but was shorter in young TB patients. The median delay was longer in rural than in urban areas (12 weeks [range 8.5-17] vs. 8 [4-12], P0.01) and in those who did not attend school, but this effect disappeared after adjusting for age and area of residence. Patients who reported haemoptysis as one of their initial symptoms had shorter delays to treatment. There was no relation between duration of delay to treatment and cure rate, but longer delay did increase the risk of death.Starting TB patients on treatment as early as possible plays a major role in reducing disease transmission in the community. Key to this is increasing awareness of the signs and symptoms of TB and ensuring easy access to diagnostic facilities and treatment.

The sera of 187 patients from across the leprosy spectrum were screened for the expression of the PR4 idiotype, which was first identified on a human hybridoma-derived monoclonal antibody from a patient with leprosy and found to react with the Mycobacterium leprae phenolic glycolipid and a variety of polynucleotides. Sixty per cent (51 out of 85) of patients with lepromatous leprosy (LL), 66% (33 out of 49) with borderline lepromatous (BL) disease, 47% (14 out of 30) with borderline tuberculoid (BT) leprosy, and 56% (13 out of 23) of tuberculoid (TT) patients were found to have significantly elevated titres of the PR4 idiotype in their sera compared with endemic controls, irrespective of the presence or absence of endemic malaria. Sera from 52 patients with tuberculosis were also screened as a control for mycobacterial infection. The PR4 idiotype was significantly elevated in 37% (19 out of 52) of these patients. No correlation between idiotype and serum immunoglobulins IgG and IgM was found, indicating that the concentrations of idiotype levels in sera were not merely a reflection of changes in serum immunoglobulin levels. It is hypothesized that the expression of the PR4 idiotype is due to certain germline genes preferentially expressed rather than being the result of polyclonal B cell activation.

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.