How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis?

SETTING: The diagnosis of tuberculosis (TB) may be rejected in the absence of symptoms such as fever, sweats or weight loss. OBJECTIVES: To determine how frequently these features and blood test evidence of inflammation were absent in individuals with TB. METHODS: Prospective cohort study of 175 unselected subjects diagnosed with TB at a UK TB service between 2003 and 2006. RESULTS: Eight (5%) subjects identified by screening and 24 (14%) without culture confirmation were excluded. Of the remaining 143, fever, sweats or weight loss were absent in respectively 37%, 39% and 38%. All three symptoms were absent in 25%. In 88 subjects with pulmonary disease, all three symptoms were absent in 20% (10% of smear-positive cases). Overall, C-reactive protein was normal in 15%, erythrocyte sedimentation rate in 21% and lactate dehydrogenase in 55%. In a multivariable model, factors associated with absent symptoms included drug-resistant TB (adjusted odds ratio [aOR] 3.58, P = 0.004) and female sex (aOR 3.15, P = 0.004). CONCLUSIONS: In our population, TB, including pulmonary disease, frequently presented without fever, sweats or weight loss and with normal blood inflammatory markers. This information is of as much relevance to policy makers seeking to improve active case detection as to clinicians and the general public.

Clinical application of a rapid lung-orientated immunoassay in individuals with possible tuberculosis.

BACKGROUND: Immunological ex vivo assays to diagnose tuberculosis (TB) have great potential but have largely been blood-based and poorly evaluated in active TB. Lung sampling enables combined microbiological and immunological testing and uses higher frequency antigen-specific responses than in blood. METHODS: A prospective evaluation was undertaken of a flow cytometric assay measuring the percentage of interferon-gamma synthetic CD4+ lymphocytes following stimulation with purified protein derivative of Mycobacterium tuberculosis (PPD) in bronchoalveolar lavage fluid from 250 sputum smear-negative individuals with possible TB. A positive assay was defined as >1.5%. RESULTS: Of those who underwent lavage and were diagnosed with active TB, 95% (106/111) had a positive immunoassay (95% CI 89% to 98%). In 139 individuals deemed not to have active TB, 105 (76%) were immunoassay negative (95% CI 68% to 82%). Of the remaining 24% (34 cases) with a positive immunoassay, a substantial proportion had evidence of untreated TB; in two of these active TB was subsequently diagnosed. Assay performance was unaffected by HIV status, disease site or BCG vaccination. In culture-positive pulmonary cases, response to PPD was more sensitive than nucleic acid amplification testing (94% vs 73%). The use of early secretory antigen target-6 (ESAT-6) responses in 71 subjects was no better than PPD, and 19% of those with culture-confirmed TB and a positive PPD immunoassay had no detectable response to ESAT-6. CONCLUSIONS: These findings suggest that lung-orientated immunological investigation is a potentially powerful tool in diagnosing individuals with sputum smear-negative active TB, regardless of HIV serostatus.

Montelukast in the treatment of HIV associated immune reconstitution disease.

The pathogenesis of immune reconstitution disease (IRD) is not well understood and it can be difficult to manage. Leukotrienes exert proinflammatory effects, have an important role in the innate immune response, and are relatively deficient in HIV infection. Montelukast is a leukotriene receptor antagonist (LTRA) currently licensed for the treatment of asthma. We report a series of three patients with severe HIV associated IRD (cases 1 and 2 associated with starting HAART and unresponsive to steroids), who obtained clinically dramatic responses to treatment with montelukast. The first case is of IRD to secondary syphilis and the second and third to tuberculosis. Cases 1 and 3 both relapsed after a temporary break from montelukast and resolved on restarting. Montelukast should be considered in HIV associated IRD as an alternative to steroids and where these are not effective. Leukotriene overactivity may be implicated in IRD.

Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection.

BACKGROUND: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy. METHODS: The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV. RESULTS: 111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment. CONCLUSION: Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.

Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection.

BACKGROUND: It has been suggested that deterioration of tuberculosis (TB) during appropriate treatment, termed a paradoxical reaction (PR), is more common and severe in HIV positive individuals on highly active antiretroviral therapy (HAART). METHOD: A study was undertaken to determine the frequency of PR and its associated features in a population of HIV+TB+ patients and a similar sized group of HIV-TB+ individuals. RESULTS: PR occurred in 28% of 50 HIV+TB+ patients and 10% of 50 HIV-TB+ patients. Disseminated TB was present in eight of 13 HIV+TB+ patients and four of five HIV-TB+ patients with PR. In 28 HIV+TB+ patients starting HAART, PR was significantly associated with commencing HAART within 6 weeks of starting antituberculosis treatment (p = 0.03) and was more common in those with disseminated TB (p = 0.09). No association was found between development of PR and baseline CD4 count or CD4 response to HAART. CONCLUSIONS: PR is common in HIV infected and uninfected individuals with TB. Early introduction of HAART and the presence of disseminated TB appear to be important in co-infected patients.