Health worker views on pre-treatment loss to follow-up in adults with pulmonary TB in Western Kenya.

SETTING: County referral hospital in Western Kenya. OBJECTIVES: To explore factors contributing to pre-treatment loss to follow-up (PTLFU) in adults with pulmonary TB and propose solutions to address PTLFU from healthcare worker (HCW) perspectives. DESIGN: This was an exploratory qualitative study using thematic analysis. RESULTS: We conducted 19 key informant interviews with HCWs representing laboratory, clinical care, management and the community. Participant age ranged from 26 to 62 years; 14 (74%) were females; and most (74%) had worked in TB care for ⩽5 years. They reported that patients experienced stigma and had misconceptions about TB that contributed to PTLFU. HCWs were hesitant to work in the TB clinic, which contributed to suboptimal patient care, leading to PTLFU. Unclear linkage between laboratory and clinician, and limited financial resources to track patients were among the healthcare system factors that led to PTLFU. HCWs suggested having proper patient preparation, assigning resources to track patients and holding regular interdisciplinary meetings as practical solutions to address PTLFU. CONCLUSION: HCWs reported multiple factors that may influence PTLFU and recommended various solutions to address these. Knowledge of TB management, patient preparation, resources to track patients and multidisciplinary meetings will be central to addressing PTLFU.

CONTEXTE: Hôpital de référence du comté dans l'ouest du Kenya. OBJECTIFS: Explorer les facteurs contribuant à la perte de suivi avant traitement (PTLFU) chez les adultes atteints de TB pulmonaire et proposer des solutions pour traiter la PTLFU du point de vue des travailleurs de la santé (HCW). MÉTHODE: Il s'agit d'une étude qualitative exploratoire utilisant l'analyse thématique. RÉSULTATS: Nous avons mené 19 entretiens avec des informateurs clés représentant les laboratoires, les soins cliniques, la gestion et la communauté. Les participants étaient âgés de 26 à 62 ans, 14 (74%) étaient des femmes et la plupart (74%) travaillaient dans le domaine de la TB depuis ⩽5 ans. Ils ont indiqué que les patients étaient stigmatisés et avaient des idées fausses sur la TB, ce qui contribuait à la PTLFU. Les HCW hésitaient à travailler dans la clinique de la TB, ce qui a contribué à une prise en charge sous-optimale des patients, conduisant à la PTLFU. Le manque de clarté du lien entre le laboratoire et le clinicien et les ressources financières limitées pour suivre les patients font partie des facteurs du système de santé qui ont conduit à la PTLFU. Les HCW ont suggéré de préparer correctement les patients, d'affecter des ressources au suivi des patients et d'organiser des réunions interdisciplinaires régulières comme solutions pratiques pour remédier à la PTLFU. CONCLUSION: Les HCW ont fait état de multiples facteurs susceptibles d'influencer la PTLFU et ont recommandé diverses solutions pour y remédier. La connaissance de la prise en charge de la TB, la préparation des patients, les ressources pour suivre les patients et les réunions multidisciplinaires seront essentielles pour traiter la PTLFU.

Commercial products to preserve specimens for tuberculosis diagnosis: a systematic review.

SETTING: Eliminating tuberculosis in high-burden settings requires improved diagnostic capacity. Important tests such as Xpert® MTB/RIF and culture are often performed at centralised laboratories that are geographically distant from the point of specimen collection. Preserving specimen integrity during transportation, which could affect test performance, is challenging. OBJECTIVE: To conduct a systematic review of commercial products for specimen preservation for a World Health Organization technical consultation. DESIGN: Databases were searched up to January 2018. Methodological quality was assessed using Quality Assessment of Technical Studies, a new technical study quality-appraisal tool, and Quality Assessment of Diagnostic Accuracy Studies-2. Studies were analysed descriptively in terms of the different products, study designs and diagnostic strategies used. RESULTS: Four products were identified from 16 studies: PrimeStore-Molecular-Transport-Medium (PS-MTM), FTA card, GENO•CARD (all for nucleic acid amplification tests [NAATs]) and OMNIgene•SPUTUM (OMS; culture, NAATs). PS-MTM, but not FTA card or GENO•CARD, rendered Mycobacterium tuberculosis non-culturable. OMS reduced Löwenstein-Jensen but not MGIT™ 960™ contamination, led to delayed MGIT time-to-positivity, resulted in Xpert performance similar to cold chain-transported untreated specimens, and obviated the need for N-acetyl-L-cysteine-sodium hydroxide decontamination. Data from paucibacillary specimens were limited. Evidence that a cold chain improves culture was mixed and absent for Xpert. The effect of the product alone could be discerned in only four studies. CONCLUSION: Limited evidence suggests that transport products result in test performance comparable to that seen in cold chain-transported specimens.

Systematic review and meta-analysis of antigen detection tests for the diagnosis of tuberculosis.

Tests that detect Mycobacterium tuberculosis antigens in clinical specimens could provide rapid direct evidence of active disease. We performed a systematic review to assess the diagnostic accuracy of antigen detection tests for active tuberculosis (TB) according to standard methods and summarized test performance using bivariate random effects meta-analysis. Overall, study quality was a concern. For pulmonary TB (47 studies, 5,036 participants), sensitivity estimates ranged from 2% to 100% and specificity from 33% to 100%. Lipoarabinomannan (LAM) was the antigen most frequently targeted (23 studies, 49%). The pooled sensitivity of urine LAM was higher in HIV-infected than HIV-uninfected individuals (47%; 95% confidence interval [CI], 26 to 68% versus 14%; 95% CI, 4 to 38%); pooled specificity estimates were similar: 96%; 95% CI, 81 to 100% and 97%; 95% CI, 86 to 100%, respectively. For extrapulmonary TB (21 studies, 1,616 participants), sensitivity estimates ranged from 0% to 100% and specificity estimates from 62% to 100%. Five studies targeting LAM, ESAT-6, Ag85 complex, and the 65-kDa antigen in cerebrospinal fluid, when pooled, yielded the highest sensitivity (87%; 95% CI, 61 to 98%), but low specificity (84%; 95% CI, 60 to 95%). Because of the limited number of studies targeting any specific antigen other than LAM, we could not draw firm conclusions about the overall clinical usefulness of these tests. Further studies are warranted to determine the value of LAM detection for TB meningitis in high-HIV-prevalence settings. Considering that antigen detection tests could be translated into rapid point-of-care tests, research to improve their performance is urgently needed.

Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review.

OBJECTIVE: To provide a descriptive synthesis of the evidence assessing the efficacy and safety of higher doses of rifampin (RMP) for the treatment of pulmonary tuberculosis (TB). METHODS: Systematic review of randomized controlled trials that evaluate a range of RMP doses, including doses higher than standard (>10 mg/kg or >600 mg), used as part of combination drug therapies for pulmonary TB. Two reviewers applied inclusion criteria, assessed trial quality and extracted data. Inclusion criteria were smear- or culture-confirmed pulmonary TB, and English and French language articles. Exclusion criteria were RMP monotherapy and smear-negative TB. Outcomes included were sputum culture conversion, treatment failure, recurrence and adverse events, including hepatotoxicity and flu-like syndrome. RESULTS: Of 14 trials (4256 participants) identified, 12 were conducted before 1980. Four trials were considered high quality according to published guidelines. Study characteristics, including history of prior TB treatment, dose of RMP, duration of treatment, timing of introduction of intervention treatment, concomitant drugs, and duration of follow-up, varied, making synthesis of efficacy data challenging. Several trials suggested an advantage in terms of likelihood of culture conversion among patients receiving at least 900 mg RMP. However, an increased incidence of flu-like syndrome was seen when RMP doses of 900 mg and higher were given intermittently. CONCLUSION: Historical trials suggest that higher than standard RMP dosing results in improved culture conversion rates. Phase 2 and 3 clinical trials evaluating higher doses of RMP and other rifamycins are needed to confirm efficacy and assure tolerability. Pharmacokinetic studies will be needed to inform the development of such trials.

Translating tuberculosis research into global policies: the example of an international collaboration on diagnostics.

Using the example of an international collaboration on tuberculosis (TB) diagnostics, we mapped the key stages and stakeholders involved in translating research into global policies. In our experience, the process begins with advocacy for high-quality, policy-relevant research and appropriate funding. Following the assessment of current policy and the identification of key study areas, policy-relevant research questions need to be formulated and prioritised. It is important that a framework for translating evidence into policy at the target policymaking level, in this case global, is available to researchers. This ensures that research questions, study designs and research standards are appropriate to the type and quality of evidence required. The framework may evolve during the period of research and, as evidence requirements may change, vigilance is required. Formal and informal multi-stakeholder partnerships, as well as information sharing through extensive networking, facilitate efficient building of a broad evidence base. Coordination of activities by an international, neutral body with strong convening powers is important, as is regular interaction with policy makers. It is recognised that studies on diagnostic accuracy provide weak evidence that a new diagnostic will improve patient care when implemented to scale in routine settings. This may be one reason why there has been poor uptake of new tools by national TB control programmes despite global policy recommendations. Stronger engagement with national policy makers and donors during the research-intopolicy process may be needed to ensure that their evidence requirements are met and that global policies translate into national policies. National policies are central to translating global policies into practice.

Does bleach processing increase the accuracy of sputum smear microscopy for diagnosing pulmonary tuberculosis?

Bleach digestion of sputum prior to smear preparation has been reported to increase the yield of microscopy for diagnosing pulmonary tuberculosis, even in high-HIV-prevalence settings. To determine the diagnostic accuracy of bleach microscopy, we updated a systematic review published in 2006 and applied the Grading of Recommendations Assessment, Development, and Evaluation framework to rate the overall quality of the evidence. We searched multiple databases (as of January 2009) for primary studies in all languages comparing bleach and direct microscopy. We assessed study quality using a validated tool and heterogeneity by standard methods. We used hierarchical summary receiver operating characteristic (HSROC) analysis to calculate summary estimates of diagnostic accuracy and random-effects meta-analysis to pool sensitivity and specificity differences. Of 14 studies (11 papers) included, 9 evaluated bleach centrifugation and 5 evaluated bleach sedimentation. Overall, examination of bleach-processed versus direct smears led to small increases in sensitivity (for bleach centrifugation, 6% [95% confidence interval [CI] = 3 to 10%, P = 0.001]; for bleach sedimentation, 9% [95% CI = 4 to 14%, P = 0.001]) and small decreases in specificity (for bleach centrifugation, -3% [95% CI = -4% to -1%, P = 0.004]; for bleach sedimentation, -2% [95% CI = -5% to 0%, P = 0.05]). Similarly, analysis of HSROC curves suggested little or no improvement in diagnostic accuracy. The quality of evidence was rated very low for both bleach centrifugation and bleach sedimentation. This updated systematic review suggests that the benefits of bleach processing are less than those described previously. Further research should focus on alternative approaches to optimizing smear microscopy, such as light-emitting diode fluorescence microscopy and same-day sputum collection strategies.

Transmission of measles virus in healthcare settings during a communitywide outbreak.

OBJECTIVE: To describe the epidemiology of measles in medical settings and to evaluate the implementation and effectiveness of the 1989 Advisory Committee on Immunization Practices (ACIP) guidelines for measles immunization in healthcare workers (HCWs). DESIGN: Confirmed cases of measles reported in Clark County, Washington, from March 14 to June 2, 1996, were analyzed for characteristics of cases occurring in medical settings. A questionnaire was used to assess employee immunization (95% response rate). SETTING AND PARTICIPANTS: Reported measles cases and HCWs at community hospitals, primary-care medical facilities, a health-maintenance organization, and a multispecialty group practice. RESULTS: Of 31 cases of measles, 8 (26%) occurred in HCWs, and 5 (16%) occurred in patients or visitors to medical facilities. Cases of measles occurred in HCWs who were not required to have proof of measles immunity as defined by the 1989 ACIP guidelines. The relative risk of measles in HCWs compared to Clark County adults was 18.6 (95% confidence interval, 7.4-45.8; P<.001). A survey of medical facilities revealed that 47% had an employee measles immunization policy; only 21% met ACIP recommendations and enforced their policies. CONCLUSIONS: HCWs were at higher risk of measles than the adult population. Transmission of measles in medical settings was related to both deficiencies in, and lack of implementation of, the ACIP guidelines.

Tobacco smoke as a risk factor for meningococcal disease.

BACKGROUND: Since 1992 the US Pacific Northwest has experienced a substantial increase in the incidence of serogroup B meningococcal disease. The current meningococcal polysaccharide vaccine is poorly immunogenic in young children and does not protect against N. meningitidis serogroup B. Defining alternative approaches to the prevention and control of meningococcal disease is of considerable public health importance. METHODS: We performed a case-control study comparing 129 patients in Oregon and southwest Washington with 274 age- and area-matched controls. We used conditional logistic regression analysis to determine which exposures remained associated with disease after adjusting for other risk factors and confounders and calculated the proportion of disease attributable to modifiable exposures. RESULTS: After adjustment for all other significant exposures identified, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children < 18 years of age [odds ratio (OR), 3.8; 95% confidence interval (CI) 1.6 to 8.9)], with 37% (CI 15 to 65) of all cases in this age group potentially attributable to maternal smoking. Adult patients were more likely than controls to have a chronic underlying illness (OR 10.8, CI 2.7 to 43.3), passive tobacco smoke exposure (OR 2.5, CI 0.9 to 6.9) and to smoke tobacco (OR 2.4, CI 0.9 to 6.6). Dose-response effects were seen for passive smoke exposure and risk of disease in all age groups. CONCLUSION: Tobacco smoke exposure independently increases the risk of developing meningococcal disease.

Determination of measles, mumps, and rubella immunization status using oral fluid samples.

OBJECTIVE: To determine if oral fluid samples can be used to reliably assess protective blood levels of antibodies to measles, mumps, and rubella. DESIGN: A comparison of matched serum and oral fluid samples from asymptomatic subjects in enzyme-linked immunosorbent assays for measles, mumps, and rubella antibodies. A longitudinal study compared matched serum and oral fluid samples from 11 subjects after measles-mumps-rubella vaccination. SETTING: Five US clinical sites with samples tested at the reporting laboratory. PARTICIPANTS: A total of 157 asymptomatic subjects including 55 subjects younger than 18 years. MAIN OUTCOME MEASURES AND RESULTS: The presence of antibodies in oral fluid specimens correlated with that in serum with the following levels of sensitivity and specificity: measles, 97% and 100%, respectively; mumps, 94% and 94%, respectively; rubella, 98% and 98%, respectively. Longitudinal studies of subjects after vaccination showed similar seroconversion profiles in oral fluid and serum samples. CONCLUSION: Protective blood levels of antibodies to measles, mumps, and rubella can be assessed by means of an oral fluid sample with good reliability.

Babesiosis in Washington State: a new species of Babesia?

OBJECTIVE: To characterize the etiologic agent (WA1) of the first reported case of babesiosis acquired in Washington State. DESIGN: Case report, and serologic, molecular, and epizootiologic studies. SETTING: South-central Washington State. PATIENT: A 41-year-old immunocompetent man with an intact spleen who developed a moderately severe case of babesiosis. MEASUREMENTS: Serum specimens from the patient were assayed by indirect immunofluorescent antibody (IFA) testing for reactivity with seven Babesia species and with WA1, which was propagated in hamsters inoculated with his blood. A Babesia-specific, ribosomal-DNA (rDNA) probe was hybridized to Southern blots of restriction-endonuclease-digested preparations of DNA from WA1, Babesia microti, and Babesia gibsoni. Serum specimens from 83 family members and neighbors were assayed for IFA reactivity with WA1 and B. microti. Small mammals and ticks were examined for Babesia infection. RESULTS: The patient's serum had very strong IFA reactivity with WA1, strong reactivity with B. gibsoni (which infects dogs), but only weak reactivity with B. microti. DNA hybridization patterns with the rDNA probe clearly differentiated WA1 from B. gibsoni and B. microti. Four of the patient's neighbors had IFA titers to WA1 of 256. The tick vector and animal reservoir of WA1 have not yet been identified, despite trapping 83 mammals and collecting 235 ticks. CONCLUSIONS: WA1 is morphologically indistinguishable but antigenically and genotypically distinct from B. microti. Some patients elsewhere who were assumed to have been infected with B. microti may have been infected with WA1. Improved serodiagnostic and molecular techniques are needed for characterizing Babesia species and elucidating the epidemiology of babesiosis, an emergent zoonosis.