Publications

BACKGROUND

Although World Health Organization guidelines recommend clinical judgment and chest radiography for diagnosing tuberculosis in HIV-infected adults with unexplained cough and negative sputum smears for acid-fast bacilli, the diagnostic performance of this approach is unknown. Therefore, we sought to assess the accuracy of symptoms, physical signs, and radiographic findings for diagnosing tuberculosis in this population in a low-income country with a high incidence of tuberculosis.

METHODOLOGY

We performed a cross-sectional study enrolling consecutive HIV-infected inpatients with unexplained cough and negative sputum smears for acid-fast bacilli at Mulago Hospital in Kampala, Uganda. Trained medical officers prospectively collected data on standard symptoms and signs of systemic respiratory illness, and two radiologists interpreted chest radiographs in a standardized fashion. We calculated positive- and negative-likelihood ratios of these factors for diagnosing pulmonary tuberculosis (defined when mycobacterial cultures of sputum or bronchoalveolar lavage fluid were positive). We used both conventional and novel regression techniques to develop multivariable prediction models for pulmonary tuberculosis.

PRINCIPAL FINDINGS

Among 202 enrolled HIV-infected adults with negative sputum smears for acid-fast bacilli, 72 (36%) had culture-positive pulmonary tuberculosis. No single factor, including respiratory symptoms, physical findings, CD4+ T-cell count, or chest radiographic abnormalities, substantially increased or decreased the likelihood of pulmonary tuberculosis. After exhaustive testing, we were also unable to identify any combination of factors which reliably predicted bacteriologically confirmed tuberculosis.

CONCLUSIONS AND SIGNIFICANCE

Clinical and radiographic criteria did not help diagnose smear-negative pulmonary tuberculosis among HIV-infected patients with unexplained cough in a low-income setting. Enhanced diagnostic methods for smear-negative tuberculosis are urgently needed.

The kinase-phosphatase pair Csk and CD45 reciprocally regulate phosphorylation of the inhibitory tyrosine of the Src family kinases Lck and Fyn. T cell receptor (TCR) signaling and thymic development require CD45 expression but proceed constitutively in the absence of Csk. Here, we show that relative titration of CD45 and Csk expression reveals distinct regulation of basal and inducible TCR signaling during thymic development. Low CD45 expression is sufficient to rescue inducible TCR signaling and positive selection, whereas high expression is required to reconstitute basal TCR signaling and beta selection. CD45 has a dual positive and negative regulatory role during inducible but not basal TCR signaling. By contrast, Csk titration regulates basal but not inducible signaling. High physiologic expression of CD45 is thus required for two reasons-to downmodulate inducible TCR signaling during positive selection and to counteract Csk during basal TCR signaling.