Classical Tuberculosis Symptoms Research Articles

A clinical score for identifying active tuberculosis while awaiting microbiological results: Development and validation of a multivariable prediction model in sub-Saharan Africa.

In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and >14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high.

Optimizing Tuberculosis Diagnosis in Human Immunodeficiency Virus-Infected Inpatients Meeting the Criteria of Seriously Ill in the World Health Organization Algorithm.

The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill human immunodeficiency virus (HIV)-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard. A priori selected variables were assessed for univariate associations with tuberculosis. The most predictive variables were assessed in a multivariate logistic regression model and used to establish a clinical prediction rule for diagnosing tuberculosis. We enrolled 484 participants. The median age was 36 years, 65.5% were female, the median CD4 count was 89 cells/µL, and 35.3% were on antiretroviral therapy. Tuberculosis was diagnosed in 52.7% of participants. The c-statistic of our clinical prediction rule (variables: cough ≥14 days, unable to walk unaided, temperature >39°C, chest radiograph assessment, hemoglobin, and white cell count) was 0.811 (95% confidence interval, .802-.819). The classic tuberculosis symptoms (fever, night sweats, weight loss) added no discriminatory value in diagnosing tuberculosis. Xpert MTB/RIF assay sensitivity was 86.3% and specificity was 96.1%. Our clinical prediction rule had good diagnostic utility for tuberculosis among seriously ill HIV-infected inpatients. Xpert MTB/RIF assay, incorporated into the updated 2016 WHO algorithm, had high sensitivity and specificity in this population. Our findings could facilitate improved diagnosis of tuberculosis among seriously ill HIV-infected inpatients in resource-constrained settings.

National tuberculosis prevalence surveys in Asia, 1990-2012: an overview of results and lessons learned.

In many countries, national tuberculosis (TB) prevalence surveys are the only way to reliably measure the burden of TB disease and monitor trends. They can also provide evidence about the current performance of TB care and control and how this could be improved. We developed an inventory of Asian surveys from 1953 to 2012 and then compiled and analysed a standard set of data for all national surveys implemented between 1990 (the baseline year for 2015 global TB targets) and 2012. There were 21 surveys in 12 countries between 1990 and 2012; published results were available for 18. The participation rate was at least 80% and often much higher except for two surveys in Thailand. The prevalence of bacteriologically-positive TB disease among adults aged ≥15years varied widely among countries (1.2 per 1000 population in China in 2010 to 15 per 1000 population in Cambodia in 2002), but age and sex distribution patterns were consistent with a progressive increase in rates of disease by age, and men accounting for 66-75% of prevalent cases. A high proportion of cases (40-79% across all surveys) did not report TB symptoms that met screening criteria (generally cough of 2-3weeks or more, and blood in the sputum) and were only detected due to chest X-ray screening of all survey participants; this proportion increased over time in countries with repeat survey data. The ratio of prevalent cases to cases notified to national TB programmes was typically around two, but was as high as three in Lao PDR and Pakistan even after the internationally recommended TB control strategy had been implemented nationwide for several years. Four countries (China, Cambodia, the Republic of Korea and the Philippines demonstrated declines in smear or culture-positive pulmonary TB prevalence of approximately 50% over 10years. National TB prevalence surveys in Asia show that large reductions in the prevalence of TB disease can be achieved within a decade, that men bear much more of the burden than women and that the epidemic is ageing. Comparisons among countries show that more can be achieved in TB control in some countries with existing strategies and technologies. However, with many prevalent cases not reporting classic TB symptoms, all countries face the challenge of defining and implementing strategies that will result in earlier detection and treatment of cases.

Clinical presentation of children with pulmonary tuberculosis: 25 years of experience in Lima, Peru.

To describe clinical presentation across age groups in 2855 children with pulmonary tuberculosis (TB) attending the Children's Hospital, Lima, Peru, to improve the diagnosis, treatment and care of childhood TB. Children aged 0-14 years admitted between 1 January 1973 and 31 December 1997 with active pulmonary TB were enrolled. Demographic information, history, physical examination data, laboratory and microbiological results, chest radiograph data, disease classification, treatment and adverse effect data, and outcome at the time of discharge were recorded by pulmonologists using detailed chart abstractions. Of the 2855 enrollees, 47% were malnourished and 56% had a household contact. Older children presented with classic TB symptoms, while weight loss and anorexia were rare in children aged <5 years. Microbiological or pathologic confirmation was obtained in 71% of children aged 10-14 years compared with 34% of children aged <2 years; however, severe extra-pulmonary TB was most common among children aged <2 years (41%). Classic TB symptoms should be considered when making a diagnosis; however, systematic symptoms among young children are also important. In high-burden settings, clinicians should have a low threshold to diagnose and treat children for TB across all ages, even in the context of a negative tuberculin skin test result and lack of micro-pathological confirmation.

Patients treated with a tumor necrosis factor-α inhibitor are more likely to develop extrapulmonary tuberculosis

See Article on Page 174-179 Tumor necrosis factor (TNF) and TNF receptors play a key role in mediating immune responses in acute and chronic inflammation. Over the past decade, TNF inhibitors have become invaluable in the treatment of chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, and inflammatory bowel disease [1]. The United States Food and Drug Administration (FDA) approved infliximab, a humanized monoclonal antibody against TNF-α, for use in patients with Crohn's disease in 1998, and in those with rheumatoid arthritis in 1999. Although only one case of tuberculosis after infliximab therapy was reported in a clinical trial [2], 70 cases were detected through the MedWatch spontaneous reporting system of the FDA within 3 years of approval [3]. Subsequent studies revealed that the relative risk for tuberculosis is increased 1.6 to 25.1 times following TNF-α inhibitor therapy, depending on the clinical setting and the TNF-α inhibitor used [1]. Therefore, recent guidelines recommend that all patients undergoing TNF-α inhibitor therapy should be screened for tuberculosis, and that patients with latent tuberculosis infection (LTBI) receive preventive chemotherapy [1]. The role of TNF-α in the human immune response to tuberculosis remains unclear. Antibodies against TNF-α caused a reactivation of tuberculosis in a mouse model of LTBI [4]. TNF-α inhibitors have been used in South Korea since 2001. Screening and preventive chemotherapy for LTBI would seem to be essential before commencing TNF-α inhibitor therapy in South Korea, a country with an intermediate tuberculosis burden. Seong et al. [5] reported that the risk of tuberculosis is 9-fold higher in Korean patients with rheumatoid arthritis and 30-fold higher in rheumatoid arthritis patients treated with infliximab, compared with the general Korean population [5]. In this report, only 193 patients treated with TNF-α inhibitors were identified, two of whom developed tuberculosis during the study period [5]. In the current issue of The Korean Journal of Internal Medicine, Chung et al. [6] described the clinical characteristics and treatment responses of seven patients with tuberculosis among 457 treated with a TNF-α inhibitor. The incidences of tuberculosis after TNF-α inhibitor therapy were not significantly different between the reports of Seong et al. [5] and Chung et al. [6] (2/193, 1.0% [95% confidence interval (CI), 0.04% to 3.9%] vs. 7/457, 1.5% [95% CI, 0.7% to 3.2%]). According to an official report of the Korean National Tuberculosis Association (http://www.knta.or.kr), the proportion of extrapulmonary tuberculosis among newly reported cases in Korea is less than 24%. Extrapulmonary involvement was common (57%) among TNF-α inhibitor users who developed tuberculosis according to Chung et al. [6]. This finding is comparable with the results of previous studies which included TNF-α inhibitor users [3] and solid organ transplant recipients [7,8]. In data from the FDA reporting system, the majority of the patients (56%) had extrapulmonary tuberculosis, and 24% had disseminated disease [3]. These patterns are similar to those of solid organ transplant recipients. Among kidney and liver transplant recipients who developed tuberculosis, extrapulmonary involvement was common (67%), including cases of disseminated disease (27% to 31%) [7,8]. Furthermore, classic symptoms of tuberculosis, such as fever, night sweats, and weight loss, may not be present [3,7]. This unusual manifestation of tuberculosis may make diagnosis uncertain. Therefore, the diagnosis of tuberculosis requires a high index of suspicion in patients treated with TNF-α inhibitors. Diagnostic invasive procedures such as tissue biopsy or aspiration of body fluids and abscesses are often required. In the report by Chung et al. [6], most patients were not screened for LTBI, because the study was performed before the publication of official Korean guidelines for TNF-α inhibitor users. To diagnose LTBI, all patients undergoing TNF-α inhibitor therapy should be screened for a history of untreated or inadequately treated tuberculosis, and/or for recent contact with an active tuberculosis patient. In addition to the patient history, a tuberculin skin test must be included in LTBI screening. The prevalence of LTBI, determined by a tuberculin skin test (diameter of induration, > 10 mm), is estimated to be 37% in Korean patients treated with TNF-α inhibitors [9]. The ability of the tuberculin skin test to diagnose LTBI in patients with rheumatologic disease might be suboptimal, due to anergy to skin test antigens and to the effects of immunosuppressive drugs [9]. These shortcomings of tuberculin skin tests have generated interest in interferon-γ release assays [10]. However, further studies are awaited to determine whether the ability of interferon-γ release assays for LTBI can better predict the development of tuberculosis in TNF-α inhibitor users.

Sluggish glucose tolerance in tuberculosis patients.

To examine glucose tolerance in sputum-positive non-treated pulmonary tuberculosis (TB) patients as part of a general metabolic profile. Subjects. Sixty-three sputum-positive non-treated patients (male and female) attending the pulmonary clinic at Mthatha General Hospital in the Eastern Cape and 89 apparently healthy sex and age-matched volunteers. Sixty-three untreated TB patients who came to the Mthatha General Hospital's pulmonary clinic with classic symptoms of TB, confirmed by sputum analysis, were recruited for the study. Eighty-nine apparently healthy sex and age-matched volunteers served as the control group. Anthropometric measurements were taken using an electronic scale. Standard oral glucose tolerance tests (OGTTs) were performed in both groups in the morning after an overnight fast. Anticoagulant-treated blood was analysed for glucose and insulin using Peridochrome Glucose (Boehringer Mannheim, Mannheim, Germany) and radioimmunoassay (RIA) (Diagnostic Products Corporation, Los Angeles, USA) respectively. There was sluggish response to glucose and insulin in the TB patient group compared with the control group. Glucose and insulin levels were significantly higher in patients at 0, 30, 60, 120, and 180 minutes. Analysis of variance gave the following p-values, viz. p = 0.0000, 0.0004, 0.0000, 0.0000 and 0.0000 for glucose, and p = 0.0317, 0.0071, 0.0000, 0.0005 and 0.0000 for insulin respectively. The results of this study suggest an altered glucose/insulin metabolism in TB patients. This might play an important role in the clinical course of the disease.

Tuberculosis mimicking cancer—A reminder

The charts of 26 patients who were referred with a presumptive diagnosis of neoplasms and who were ultimately found to have only tuberculosis were reviewed. Twenty-one patients (81 percent) were born in the United States, and only three patients had a history of exposure to tuberculosis. Most patients had few symptoms, and the average duration of symptoms was 2.8 ± 1.5 months. Classic symptoms of tuberculosis, like fever, hemoptysis, and weight loss, were uncommon. Chest roentgenographic abnormalities were present in 62 percent of the patients. Although some of the patients had undergone nondiagnostic biopsy procedures before referral, none had had skin tests for tuberculosis. Underlying conditions were found in eight patients, and alcoholism was the most common. Laboratory abnormalities were rare with the exception of increased platelet counts, which were found in eight patients. The most common form of tuberculosis was pulmonary (14 patients) followed by lymphadenitis (nine patients). Tuberculosis remains an elusive disease even in countries with advanced medical technology. In some cases, its presentation may suggest the presence of malignancy.