Michael K. Leonard

Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children

Background. Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods. A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results. Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions. These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.

Tuberculosis of the Pancreas: Report of Two Cases and Review of the Literature

Tuberculosis of the pancreas is a clinical entity rarely described in the literature. The pancreas is biologically protected from infection by Mycobacterium tuberculosis, probably because of the presence of pancreatic enzymes that interfere with the seeding of M. tuberculosis. However, when pathogens are able to overcome the resistance, they can have diverse presentations, such as pancreatic masses that can mimic carcinoma, obstructive jaundice, pancreatitis, and gastrointestinal bleeding. Herein we describe 2 cases of pancreatic tuberculosis that presented as multicystic masses, and we review the literature to describe the diverse clinical manifestations of this condition.

Site of Extrapulmonary Tuberculosis is Associated with HIV Infection

BACKGROUND In the United States, the proportion of patients with extrapulmonary tuberculosis (EPTB) has increased relative to cases of pulmonary tuberculosis. Patients with central nervous system (CNS)/meningeal and disseminated EPTB and those with human immunodeficiency virus (HIV)/AIDS have increased mortality. The purpose of our study was to determine risk factors associated with particular types of EPTB. METHODS We retrospectively reviewed 320 cases of EPTB from 1995-2007 at a single urban US public hospital. Medical records were reviewed to determine site of EPTB and patient demographic and clinical characteristics. Multivariable logistic regression analyses were performed to determine independent associations between patient characteristics and site of disease. RESULTS Patients were predominantly male (67%), African American (82%), and US-born (76%). Mean age was 40 years (range 18-89). The most common sites of EPTB were lymphatic (28%), disseminated (23%), and CNS/meningeal (22%) disease. One hundred fifty-four (48.1%) were HIV-infected, 40% had concomitant pulmonary tuberculosis, and 14.7% died within 12 months of EPTB diagnosis. Multivariable analysis demonstrated that HIV-infected patients were less likely to have pleural (adjusted odds ratio [AOR] 0.3; 95% confidence interval [CI] .2, .6) as site of EPTB disease than HIV-uninfected patients. Among patients with EPTB and HIV-infection, patients with CD4 lymphocyte cell count <100 were more likely to have severe forms of EPTB (CNS/meningeal and/or disseminated) (AOR 1.6; 95% CI, 1.0, 2.4). CONCLUSIONS Among patients hospitalized with EPTB, patients coinfected with HIV and low CD4 counts were more likely to have CNS/meningeal and disseminated disease. Care for similar patients should include consideration of these forms of EPTB since they carry a high risk of death.

Acute forms of tuberculosis in adults.

Although typically considered a chronic disease, tuberculosis (TB) has protean acute manifestations, the major forms of which are reviewed in this article. The pathogenesis of acute TB, although still incompletely understood, may be related to both epidemiologic and genetic host factors. Miliary TB manifests as a nonspecific clinical syndrome with a high mortality rate. The most well-known form of acute TB is meningitis, characterized by fever, nuchal rigidity, and a lymphocytic pleocytosis of the cerebrospinal fluid. Acute abdominal TB may present with obstruction or less commonly as perforated viscus or peritonitis. Critically ill patients may have acute respiratory distress syndrome, shock, or disseminated intravascular coagulopathy. The spectrum of disease makes diagnosis of acute TB difficult unless clinical suspicion of disease is high, but the high mortality mandates its consideration. Early initiation of therapy is crucial to optimize clinical outcome.

Use of a Molecular Diagnostic Test in AFB Smear Positive Tuberculosis Suspects Greatly Reduces Time to Detection of Multidrug Resistant Tuberculosis

Background The WHO has recommended the implementation of rapid diagnostic tests to detect and help combat M/XDR tuberculosis (TB). There are limited data on the performance and impact of these tests in field settings. Methods The performance of the commercially available Genotype MTBDRplus molecular assay was compared to conventional methods including AFB smear, culture and drug susceptibility testing (DST) using both an absolute concentration method on Löwenstein-Jensen media and broth-based method using the MGIT 960 system. Sputum specimens were obtained from TB suspects in the country of Georgia who received care through the National TB Program. Results Among 500 AFB smear-positive sputum specimens, 458 (91.6%) had both a positive sputum culture for Mycobacterium tuberculosis and a valid MTBDRplus assay result. The MTBDRplus assay detected isoniazid (INH) resistance directly from the sputum specimen in 159 (89.8%) of 177 specimens and MDR-TB in 109 (95.6%) of 114 specimens compared to conventional methods. There was high agreement between the MTBDRplus assay and conventional DST results in detecting MDR-TB (kappa = 0.95, p<0.01). The most prevalent INH resistance mutation was S315T (78%) in the katG codon and the most common rifampicin resistance mutation was S531L (68%) in the rpoB codon. Among 13 specimens from TB suspects with negative sputum cultures, 7 had a positive MTBDRplus assay (3 with MDR-TB). The time to detection of MDR-TB was significantly less using the MTBDRplus assay (4.2 days) compared to the use of standard phenotypic tests (67.3 days with solid media and 21.6 days with broth-based media). Conclusions Compared to conventional methods, the MTBDRplus assay had high accuracy and significantly reduced time to detection of MDR-TB in an area with high MDR-TB prevalence. The use of rapid molecular diagnostic tests for TB and drug resistance should increase the proportion of patients promptly placed on appropriate therapy.

Etiology of Neonatal Blood Stream Infections in Tbilisi, Republic of Georgia

BACKGROUND Neonatal blood stream infections (BSI) are a major cause of morbidity and mortality in developing countries. It is crucial to continuously monitor the local epidemiology of neonatal BSI to detect any changes in patterns of infection and susceptibility to various antibiotics. OBJECTIVES To examine the etiology of BSI in two neonatal intensive care units (NICUs) in the Republic of Georgia, a resource-poor country, and to determine antibiotic susceptibility of the isolated organisms. METHODS A cross-sectional study of all septic infants was conducted in the NICUs of two pediatric hospitals in Tbilisi between September 2003 and September 2004. RESULTS A total of 200 infants with clinical signs of sepsis were admitted to two NICUs. Of these, 126 (63%) had confirmed bacteremia. The mortality rate was 34%. A total of 98 (78%) of 126 recovered isolates were Gram-negative organisms and 28 (22%) were Gram-positive. Klebsiella pneumoniae was the most common pathogen, accounting for 36 (29%) of 126 isolates, followed by Enterobacter cloacae accounting for 19 (15%) and Staphylococcus aureus accounting for 15 (12%). The Gram-negative organisms showed a high degree of resistance to commonly used antibiotics such as ampicillin and amoxicillin/clavulanate, and comparatively low resistance to amikacin, ciprofloxacin, carbapenems, and gentamicin; 40% of S. aureus isolates were methicillin-resistant (MRSA). In multivariate analysis only umbilical discharge was a significant risk factor for having a positive blood culture at admission to NICU (prevalence ratio = 2.25, 95% confidence interval 1.82-2.77). CONCLUSIONS Neonatal BSI was mainly caused by Gram-negative organisms, which are developing resistance to commonly used antibiotics. Understanding the local epidemiology of neonatal BSI can lead to the development of better medical practices, especially more appropriate choices for empiric antibiotic therapy, and may contribute to improvement of infection control practices.

Extensively drug-resistant tuberculosis: are we learning from history or repeating it?

Tuberculosis (TB) is an enormous global public health problem. Cases of extensively drug-resistant TB (XDR-TB) are being reported in increasing numbers across the globe. A large outbreak of XDR-TB associated with rapid and nearly universal mortality has been reported among patients with human immunodeficiency virus infection or acquired immunodeficiency disease in South Africa who have been receiving standard TB therapy and antiretrovirals. Epidemiologic features of this outbreak make it highly suspicious for health care-associated transmission. We urge the Infectious Diseases Society of America and its members to increase involvement in ongoing international TB prevention and treatment efforts and to develop a registry of experts in infection control and laboratory and disease management. We urge advocacy for increased funding for domestic and global TB control programs, including expanded access to sputum culture and drug susceptibility testing, as well as funding for TB clinical trials and research capacity. We believe that substandard TB diagnostic tests are not acceptable for TB control in resource-poor countries. We urge the development of shorter, less toxic TB treatment and prevention regimens. Funding of TB control and research should be reassessed to prevent budget cuts at a time when the disease is killing as many as 2 million people a year.

Salmonella Meningitis in Adults Infected with HIV: Case Report and Review of the Literature

&NA; We report a case of Salmonella infantis meningitis in a patient infected with HIV who was successfully treated with 4 weeks of therapy and has had no relapses after 12 months of follow‐up. Only 10 episodes of Salmonella species meningitis in patients infected with HIV are reported in the literature.

Vitamin D as adjunctive therapy in refractory pulmonary tuberculosis: a case report.

Vitamin D regulates calcium homeostasis in the body and may play a major role in regulating immune responses to tuberculosis (TB). Pilot studies suggest that vitamin D supplementation may improve outcomes in pulmonary TB (PTB), but clinical evidence using vitamin D in TB treatment is limited. We present a case of vitamin D deficiency in a woman with refractory drug-susceptible PTB. Antituberculous therapy and the correction of vitamin D deficiency resulted in clinical and microbiologic improvement at month 13 of her treatment. The basis for vitamin D/TB interactions and a brief literature review are discussed. Data from controlled trials are needed to evaluate the efficacy of vitamin D as adjunctive TB therapy.

Cost analysis of a nucleic acid amplification test in the diagnosis of pulmonary tuberculosis at an urban hospital with a high prevalence of TB/HIV.

Introduction The Centers for Disease Control and Prevention has recommended using a nucleic acid amplification test (NAAT) for diagnosing pulmonary tuberculosis (TB) but there is a lack of data on NAAT cost-effectiveness. Methods We conducted a prospective cohort study that included all patients with an AFB smear-positive respiratory specimen at Grady Memorial Hospital in Atlanta, GA, USA between January 2002 and June 2008. We determined the sensitivity, specificity, and positive and negative predictive value of a commercially available and FDA-approved NAAT (amplified MTD, Gen-Probe) compared to the gold standard of culture. A cost analysis was performed and included costs related to laboratory tests, hospital charges, anti-TB medications, and contact investigations. Average cost per patient was calculated under two conditions: (1) using a NAAT on all AFB smear-postive respiratory specimens and (2) not using a NAAT. One-way sensitivity analyses were conducted to determine sensitivity of cost difference to reasonable ranges of model inputs. Results During a 6 1/2 year study period, there were 1,009 patients with an AFB smear-positive respiratory specimen at our public urban hospital. We found the NAAT to be highly sensitive (99.6%) and specific (99.1%) on AFB smear-positive specimens compared to culture. Overall, the positive predictive value (PPV) of an AFB smear-positive respiratory specimen for culture-confirmed TB was 27%. The PPV of an AFB smear-positive respiratory specimen for culture-confirmed TB was significantly higher for HIV-uninfected persons compared to those who were HIV-seropositive (152/271 [56%] vs. 85/445 [19%]; RR = 2.94, 95% CI 2.36–3.65, p<0.001). The cost savings of using the NAAT was