Lipoarabinomannan in sputum to detect bacterial load and treatment response in patients with pulmonary tuberculosis: Analytic validation and evaluation in two cohorts.

BACKGROUND: Lipoarabinomannan (LAM) is a major antigen of Mycobacterium tuberculosis (MTB). In this report, we evaluated the ability of a novel immunoassay to measure concentrations of LAM in sputum as a biomarker of bacterial load prior to and during treatment in pulmonary tuberculosis (TB) patients. METHODS AND FINDINGS: Phage display technology was used to isolate monoclonal antibodies binding to epitopes unique in LAM from MTB and slow-growing nontuberculous mycobacteria (NTM). Using these antibodies, a sandwich enzyme-linked immunosorbent assay (LAM-ELISA) was developed to quantitate LAM concentration. The LAM-ELISA had a lower limit of quantification of 15 pg/mL LAM, corresponding to 121 colony-forming units (CFUs)/mL of MTB strain H37Rv. It detected slow-growing NTMs but without cross-reacting to common oral bacteria. Two clinical studies were performed between the years 2013 and 2016 in Manila, Philippines, in patients without known human immunodeficiency virus (HIV) coinfection. In a case-control cohort diagnostic study, sputum specimens were collected from 308 patients (aged 17-69 years; 62% male) diagnosed as having pulmonary TB diseases or non-TB diseases, but who could expectorate sputum, and were then evaluated by smear microscopy, BACTEC MGIT 960 Mycobacterial Detection System (MGIT) and Lowenstein-Jensen (LJ) culture, and LAM-ELISA. Some sputum specimens were also examined by Xpert MTB/RIF. The LAM-ELISA detected all smear- and MTB-culture-positive samples (n = 70) and 50% (n = 29) of smear-negative but culture-positive samples (n = 58) (versus 79.3%; 46 positive cases by the Xpert MTB/RIF), but none from non-TB patients (n = 56). Among both LAM and MGIT MTB-culture-positive samples, log10-transformed LAM concentration and MGIT time to detection (TTD) showed a good inverse relationship (r = -0.803, p < 0.0001). In a prospective longitudinal cohort study, 40 drug-susceptible pulmonary TB patients (aged 18-69 years; 60% male) were enrolled during the first 56 days of the standard 4-drug therapy. Declines in sputum LAM concentrations correlated with increases of MGIT TTD in individual patients. There was a 1.29 log10 decrease of sputum LAM concentration, corresponding to an increase of 221 hours for MGIT TTD during the first 14 days of treatment, a treatment duration often used in early bactericidal activity (EBA) trials. Major limitations of this study include a relatively small number of patients, treatment duration up to only 56 days, lack of quantitative sputum culture CFU count data, and no examination of the correlation of sputum LAM to clinical cure. CONCLUSIONS: These results indicate that the LAM-ELISA can determine LAM concentration in sputum, and sputum LAM measured by the assay may be used as a biomarker of bacterial load prior to and during TB treatment. Additional studies are needed to examine the predictive value of this novel biomarker on treatment outcomes.

Antibiotic prophylaxis for chemotherapy-induced febrile neutropenia in hematologic and solid organ malignancies

BACKGROUND AND OBJECTIVE: Febrile neutropenia (FN) frequently develops among cancer patients receiving chemotherapy and is associated with significant morbidity and mortality. Although the use of empiric antibiotics has been a standard of care for FN according to the last 2010 Infectious Disease Society of America (IDSA) guidelines, the role of prophylactic antibiotics in patients with high risk features in preventing febrile neutropenia remains to be elucidated. This study aims to investigate the role of antibiotic prophylaxis in preventing post-chemotherapy FN among patients with hematologic and solid organ malignancies. METHODS: A literature search of published English language clinical trials was performed using PubMed, MEDLINE, and the Cochrane Collaboration from January 1980 - October 2015. Four hundred thirty two articles were extracted from our literature search and narrowed down through specified inclusion and exclusion criteria. Results were analyzed based on 1) incidence of FN in post chemotherapy cancer patients, 2) mortality rate, and 3) incidence of FN with different antibiotics. Assessment of methodological quality of each study was done using the Jadad scale. Odds ratios and Forest plots were computed and generated respectively using RevMan 5.2 (© 2013 the Cochrane Collaboration). RESULTS: Antibiotic prophylaxis reduced the incidence of FN (OR 0.59[0.37, 0.91]). Overall effect was significant; Z= 2.35 (p= 0.02). Febrile episodes occurred less frequently in those patients who received prophylactic antibiotic treatment (OR 0.43 [0.34, 0.53]) Z = 7.59 (p CONCLUSION: Antibiotic prophylaxis reduces the incidence of FN among cancer patients treated with cytotoxic chemotherapy, decreases febrile episodes in neutropenic patients, and overall, prevented FN by up to 3.51-fold.