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BACKGROUND: Recommended by the World Health Organization as an initial diagnostic test for TB in children, Xpert® MTB/RIF is widely implemented in many countries, including Kenya.METHODS: Three hundred HIV-positive and negative children (RESULTS: Of 32 children with bacteriologically confirmed TB, 27 had positive Xpert results. Of these, 3/27 (11%, 95% CI 4–28) had RIF resistance detected on Xpert, but not by phenotypic DST, line-probe assay, or sequencing. For these three children, five Xpert tests showed RIF resistance; all five tests had semi-quantitative “very low” results and delay or absence of probe D signal, whereas no Xpert results with higher semi-quantitative results showed RIF resistance. All three children responded well to standard TB treatment.CONCLUSIONS: False RIF resistance may be detected in pediatric specimens. Further study is needed to determine if false RIF resistance is associated with low bacterial load.

Background Pediatric tuberculosis (TB) remains a critical public health concern, yet bacteriologic confirmation of TB in children is challenging. Clinical, demographic, and radiological factors associated with a positive Mycobacterium tuberculosis specimen in young children (≤5 years) are poorly understood. Methods We conducted a prospective cohort study of young children with presumptive TB and examined clinical, demographic, and radiologic factors associated with invasive and noninvasive specimen collection techniques (gastric aspirate, induced sputum, nasopharyngeal aspirate, stool, and string test); up to 2 samples were taken per child, per technique. We estimated associations between these factors and a positive specimen for each technique using generalized estimating equations (GEEs) and logistic regression. Results A median (range) of 544 (507–566) samples were obtained for each specimen collection technique from 300 enrolled children; bacteriologic yield was low across all collection techniques (range, 1%–7% from Xpert MTB/RIF or culture), except for lymph node fine needle aspiration (29%) taken for children with cervical lymphadenopathy. Factors associated with positive M. tuberculosis samples across all techniques included prolonged lethargy (median [range] adjusted odds ratio [aOR], 8.1 [3.9–10.1]), history of exposure with a TB case (median [range] aOR, 6.1 [2.9–9.0]), immunologic evidence of M. tuberculosis infection (median [range] aOR, 4.6 [3.7–9.2]), large airway compression (median [range] aOR, 6.7 [4.7–9.5]), and hilar/mediastinal density (median [range] aOR, 2.9 [1.7–3.2]). Conclusions Identifying factors that lead to a positive M. tuberculosis specimen in very young children can inform clinical management and increase the efficiency of diagnostic testing in children being assessed for TB.

Diagnosis of tuberculosis (TB) among young children (M. tuberculosis in young children using simply defined features and increase the bacteriologic yield in diagnostic cohorts. These findings may facilitate clinical decision making and guide clinical research into novel biomarkers of TB disease in young children.

Setting Fifteen human immunodeficiency virus (HIV) clinics in Nyanza Region, Western Kenya. Objective To describe routine tuberculosis (TB) screening and diagnostic practices among newly enrolled people living with HIV (PLHIV) prior to the implementation of World Health Organization recommended TB intensified case finding. Design Retrospective chart abstraction of PLHIV aged ⩾7 years who were newly enrolled in HIV care in July and August 2009, and who had not received antiretroviral treatment in the preceding 2 years or been diagnosed with TB in the previous year. Factors associated with evidence of TB diagnostic evaluation among symptomatic PLHIV were assessed. Results Of 1020 patients included in the analysis, 995 (98%) were screened for TB at enrolment and 613 (62%) reported TB symptoms. Ninety-six (16%) patients with symptoms had evidence of referral for TB diagnostic evaluation, including patients at large clinics, those with advanced HIV disease and those reporting multiple TB symptoms. Among the 43 (45%) with documented evaluation results, 26 (60%) were diagnosed with TB. Conclusion Although most PLHIV were screened for TB, very few underwent an evaluation, and the proportion diagnosed with TB was very low. Efforts to improve TB screening should focus on standardizing the intensified case finding algorithm and linkage to, and adequate infrastructure for, TB diagnostic evaluation.

New diagnostics are needed to improve clinicians’ ability to detect tuberculosis (TB) disease in key populations such as children and persons living with HIV and to rapidly detect drug resistance. Circulating cell-free DNA (ccfDNA) in plasma is a diagnostic target in new obstetric and oncologic applications, but its utility for diagnosing TB is not known. Here we show that Mycobacterium tuberculosis complex DNA can be detected in plasma of persons with sputum smear-positive TB, even in the absence of mycobacteremia. Among 40 participants with bacteriologically-confirmed smear-positive TB disease who had plasma tested by quantitative PCR (qPCR), 18/40 (45%) had a positive result on at least one triplicate reaction. Our results suggest that plasma DNA may be a useful target for improving clinicians’ ability to diagnose TB. We anticipate these findings to be the starting point for optimized methods of TB ccfDNA testing and sequence-based diagnostic applications such as molecular detection of drug resistance.

We implemented a quality management system (QMS) and documented our improvements in a tuberculosis (TB) laboratory in Kisumu, Kenya. After implementation of the QMS, a sustained reduction in culture contamination rates for solid (from 15.4% to 5.3%) and liquid media (from 15.2% to 9.3%) was observed, and waste from product expiry was reduced significantly. External quality assurance (EQA) results were satisfactory before and after QMS implementation, and a client survey after implementation revealed 98% satisfaction. The laboratory attained ISO 15189 accreditation in October 2013. The implementation of QMS facilitated the attainment of target quality indicators, reduced waste due to expiry and led to high client satisfaction.

BACKGROUND Delayed diagnosis of tuberculosis (TB) increases mortality. OBJECTIVE To evaluate whether stool culture improves the diagnosis of TB in people living with the human immunodeficiency virus (PLHIV). DESIGN We analysed cross-sectional data of TB diagnosis in PLHIV in Cambodia, Thailand and Viet Nam. Logistic regression was used to assess the association between positive stool culture and TB, and to calculate the incremental yield of stool culture. RESULTS A total of 1693 PLHIV were enrolled with a stool culture result. Of 228 PLHIV with culture-confirmed TB from any site, 101 (44%) had a positive stool culture; of these, 91 (90%) had pulmonary TB (PTB). After adjusting for confounding factors, a positive stool culture was associated with smear-negative (odds ratio [OR] 26, 95% confidence interval [CI] 12-58), moderately smear-positive (OR 60, 95%CI 23-159) and highly smear-positive (OR 179, 95%CI 59-546) PTB compared with no PTB. No statistically significant association existed with extra-pulmonary TB compared with no extra-pulmonary TB (OR 2, 95%CI 1-5). The incremental yield of one stool culture above two sputum cultures (5%, 95%CI 3-8) was comparable to an additional sputum culture (7%, 95%CI 4-11). CONCLUSION Nearly half of the PLHIV with TB had a positive stool culture that was strongly associated with PTB. Stool cultures may be used to diagnose TB in PLHIV.

Bloodstream infections (BSIs) are a major cause of illness in HIV-infected persons. To evaluate prevalence of and risk factors for BSIs in 2,009 HIV-infected outpatients in Cambodia, Thailand, and Vietnam, we performed a single Myco/F Lytic blood culture. Fifty-eight (2.9%) had a clinically significant BSI (i.e., a blood culture positive for an organism known to be a pathogen). Mycobacterium tuberculosis accounted for 31 (54%) of all BSIs, followed by fungi (13 [22%]) and bacteria (9 [16%]). Of patients for whom data were recorded about antiretroviral therapy, 0 of 119 who had received antiretroviral therapy for >/=14 days had a BSI, compared with 3% of 1,801 patients who had not. In multivariate analysis, factors consistently associated with BSI were fever, low CD4+ T-lymphocyte count, abnormalities on chest radiograph, and signs or symptoms of abdominal illness. For HIV-infected outpatients with these risk factors, clinicians should place their highest priority on diagnosing tuberculosis

BACKGROUND Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

OBJECTIVE To measure the burden and improve management of tuberculosis (TB), HIV-associated TB and MDR TB in Tak Province, Thailand, which borders Myanmar. METHODS From September 2006 to August 2007, we collected uniform data about TB cases and enhanced human immunodeficiency virus (HIV) counselling and testing. We provided mycobacterial culture and drug-susceptibility testing in public or non-governmental organization facilities. Patients were classified by nationality and, for non-Thais, by migration status. RESULTS Of 1662 TB cases in the 12-month period, 1087 (65%) occurred in non-Thais. Of non-Thais, 415 (38%) lived in Myanmar but crossed the border for healthcare. HIV infection was diagnosed in 18% of Thais compared with 12% of non-Thais (P < 0.01); HIV status was unknown for 22% of Thais and 27% of non-Thais (P = 0.02). Overall, multidrug-resistant (MDR) TB was diagnosed in 27 patients, 19 (70%) in non-Thais. Among TB cases never previously treated for TB, no MDR cases were diagnosed in Thais or in Myanmar refugees, but six cases were diagnosed in migrants from Myanmar. CONCLUSIONS In Thailand, TB, HIV-associated TB and MDR TB in migrants from Myanmar are important public health problems; they need to be resolved in both the countries.

BACKGROUND Toxic epidermal necrolysis (TEN) is an exfoliative disorder of the skin usually caused by a drug reaction. The primary goal of wound care for patients with TEN is prevention of further mechanical trauma to the skin, along with management of wound infection. CASE A 77-year-old woman with TEN was successfully managed with a perforated silver soft contact foam and a superabsorbent outer layer. Topical therapy combined nanoparticle silver for management of wound infection and minimized trauma to the skin as only the outer layer needed to be changed. CONCLUSION The silicone foam dressing with silver sulfate epithelialization and reduced pain and trauma associated with dressing changes.

Objective To assess the performance of symptom-based screening for tuberculosis (TB), alone and with chest radiography among people living with HIV (PLHIV), including pregnant women, in Western Kenya. Design Prospective cohort study Methods PLHIV from 15 randomly-selected HIV clinics were screened with three clinical algorithms [World Health Organization (WHO), Ministry of Health (MOH), and “Improving Diagnosis of TB in HIV-infected persons” (ID-TB/HIV) study], underwent chest radiography (unless pregnant), and provided two or more sputum specimens for smear microscopy, liquid culture, and Xpert MTB/RIF. Performance of clinical screening was compared to laboratory results, controlling for the complex design of the survey. Results Overall, 738 (85.6%) of 862 PLHIV enrolled were included in the analysis. Estimated TB prevalence was 11.2% (95% CI, 9.9–12.7). Sensitivity of the three screening algorithms was similar [WHO, 74.1% (95% CI, 64.1–82.2); MOH, 77.5% (95% CI, 68.6–84.5); and ID-TB/HIV, 72.5% (95% CI, 60.9–81.7)]. Sensitivity of the WHO algorithm was significantly lower among HIV-infected pregnant women [28.2% (95% CI, 14.9–46.7)] compared to non-pregnant women [78.3% (95% CI, 67.3–86.4)] and men [77.2% (95% CI, 68.3–84.2)]. Chest radiography increased WHO algorithm sensitivity and negative predictive value to 90.9% (95% CI, 86.4–93.9) and 96.1% (95% CI, 94.4–97.3), respectively, among asymptomatic men and non-pregnant women. Conclusions Clinical screening missed approximately 25% of laboratory-confirmed TB cases among all PLHIV and more than 70% among HIV-infected pregnant women. National HIV programs should evaluate the feasibility of laboratory-based screening for TB, such as a single Xpert MTB/RIF test for all PLHIV, especially pregnant women, at enrollment in HIV services.

Background Diagnosis followed by effective treatment of tuberculosis (TB) reduces transmission and saves lives in persons living with HIV (PLHIV). Sputum smear microscopy is widely used for diagnosis, despite limited sensitivity in PLHIV. Evidence is needed to determine the optimal diagnostic approach for these patients. Methods From May 2011 through June 2012, we recruited PLHIV from 15 HIV treatment centers in western Kenya. We collected up to three sputum specimens for Ziehl-Neelsen (ZN) and fluorescence microscopy (FM), GeneXpert MTB/RIF (Xpert), and culture, regardless of symptoms. We calculated the incremental yield of each test, stratifying results by CD4 cell count and specimen type; data were analyzed to account for complex sampling. Results From 778 enrolled patients, we identified 88 (11.3%) laboratory-confirmed TB cases. Of the 74 cases who submitted 2 specimens for microscopy and Xpert testing, ZN microscopy identified 25 (33.6%); Xpert identified those plus an additional 18 (incremental yield = 24.4%). Xpert testing of spot specimens identified 48 (57.0%) of 84 cases; whereas Xpert testing of morning specimens identified 50 (66.0%) of 76 cases. Two Xpert tests detected 22/24 (92.0%) TB cases with CD4 counts

BACKGROUND: Tuberculin skin test (TST) identifies patients highly likely to benefit from isoniazid preventive therapy and tuberculosis (TB) prevalence may differ by TST status. We evaluated latent and active TB screening and diagnosis strategies among people living with HIV (PLHIV) incorporating TST as the initial screening step. METHODS: PLHIV attending services at the Thai Red Cross Anonymous Clinic during September 2006 to January 2008 were enrolled. TB disease was defined as any positive Mycobacterium tuberculosis (MTB) specimen culture from sputum urine stool lymph node aspiration and blood. The performance of symptom screening (>1 of: any cough any fever night sweats lasting 3 or more weeks in the preceding 4 weeks) and laboratory screening (sputum smear followed by chest radiography and CD4 count) for active TB disease were evaluated according to TST status. RESULTS: We enrolled 604 PLHIV. TST was positive in 151 PLHIV (25.0%). TB disease was diagnosed in 33 PLHIV including 22 (14.6%) TST-positive and 11 (2.4%) TST-negative PLHIV. We found that an approach of performing MTB culture for all TST-positive PLHIV and symptom screening followed by laboratory screening for all TST-negative PLHIV would identify 196 (32.4%) of 604 PLHIV who would need MTB culture to correctly diagnose 29 (87.9%) of 33 active TB cases. CONCLUSIONS: TST can be used as an initial screening test among PLHIV to identify those at highest risk of active TB disease. Access to MTB culture or other sensitive tests to exclude TB disease is urgently needed to improve TB screening and prevention in resource-limited settings.

Background Tuberculosis (TB) is the leading cause of death among people living with HIV and frequently transmitted among this susceptible group. Transmission can be reduced by infection control practices. Simple evidence-based methods to identify patients who should be isolated are not well described in the literature. We sought to identify a simple, sensitive symptom or symptom combination that healthcare providers in resource-limited settings can use to identify and isolate persons living with HIV with highly infectious TB. Methods Participants from 8 outpatient facilities in Cambodia, Thailand, and Vietnam underwent an extensive evaluation for TB. Patients with ≥1 positive sputum smear and Mycobacterium tuberculosis culture growth from a pulmonary site were defined as having highly infectious TB. We calculated sensitivity and prevalence of individual symptoms and >1000 symptom combinations. Results Of 1980 participants, 272 (14%) had TB. Forty percent (n = 109) were highly infectious. Sensitivity for detecting highly infectious TB was highest for having the following symptoms in the past month as follows: weight loss (84%), cough (83%), fever (81%), and fatigue (78%); however, these symptoms were found in 46%-54% of all participants. Having 2 or 3 of 4 symptoms (prevalence, 26%-47%)-weight loss, fever, current cough, and night sweats-was 72%-90% sensitive for highly infectious TB. Conclusions The 2 or 3 of 4 symptom combinations of weight loss, fever, current cough, and night sweats, which are the same symptoms comprising the current World Health Organization-recommended TB diagnostic screen, are sensitive for detecting highly infectious TB in people living with HIV.

Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare.To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia.We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories.In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART.Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Background Over the past several years, new diagnostic techniques have been developed to allow for the rapid detection of multidrug resistant tuberculosis. The GenoType® MTBDRplus test is a deoxyribonucleic acid (DNA) strip assay which uses polymerase chain reaction (PCR) and hybridization to detect genetic mutations in the genes that confer isoniazid (INH) and rifampn (RIF) resistance. This assay has demonstrated good performance and a rapid time to results, making this a promising tool to accelerate MDR-TB diagnosis and improve MDR-TB control. Validation of rapid tests for MDR-TB detection in different settings is needed to ensure acceptable performance, particularly in Asia, which has the largest number of MDR-TB cases in the world but only one previous report, in Vietnam, about the performance of the GenoType® MDRplus assay. Thailand is ranked 18th of 22 "high-burden" TB countries in the world, and there is evidence to suggest that rates of MDR-TB are increasing in Thailand. We compared the performance of the GenoType® MTBDRplus assay to Mycobacterial Growth Indicator Tube for Antimycobacterial Susceptibility Testing (MGIT AST) for detection INH resistance, RIF resistance, and MDR-TB in stored acid-fast bacilli (AFB)-positive sputum specimens and isolates at a Public TB laboratory in Bangkok, Thailand. Methods 50 stored isolates and 164 stored AFB-positive sputum specimens were tested using both the MGIT AST and the GenoType® MTBDRplus assay. Results The GenoType® MTBDRplus assay had a sensitivity of 95.3%, 100%, and 94.4% for INH resistance, RIF resistance, and MDR-TB, respectively. The difference in sensitivity between sputum specimens (93%) and isolates (100%) for INH resistance was not statistically significant (p = 0.08). Specificity was 100% for all resistance patterns and for both specimens and isolates. The laboratory processing time was a median of 25 days for MGIT AST and 5 days for the GenoType® MTBDRplus (p < 0.01). Conclusion The GenoType® MTBDRplus assay has been validated as a rapid and reliable first-line diagnostic test on AFB-positive sputum or MTB isolates for INH resistance, RIF resistance, and MDR-TB in Bangkok, Thailand. Further studies are needed to evaluate its impact on treatment outcome and the feasibility and cost associated with widespread implementation.

The World Health Organization recently revised its recommendations for tuberculosis (TB) diagnosis in people with HIV. Most studies cited to support these policies involved HIV-uninfected patients and only evaluated sputum specimens.To evaluate the performance of acid-fast bacilli smear and mycobacterial culture on sputum and nonsputum specimens for TB diagnosis in a cross-sectional survey of HIV-infected patients.In Thailand and Vietnam, we enrolled people with HIV regardless of signs or symptoms. Enrolled patients provided three sputum, one urine, one stool, one blood, and, for patients with palpable peripheral adenopathy, one lymph node aspirate specimen for acid-fast bacilli microscopy and mycobacterial culture on solid and broth-based media. We classified any patient with at least one specimen culture positive for Mycobacterium tuberculosis as having TB.Of 1,060 patients enrolled, 147 (14%) had TB. Of 126 with pulmonary TB, the incremental yield of performing a third sputum smear over two smears was 2% (95% confidence interval, 0-6), 90 (71%) patients were detected on broth-based culture of the first sputum specimen, and an additional 21 (17%) and 12 (10%) patients were diagnosed with the second and third specimens cultured. Of 82 lymph nodes cultured, 34 (42%) grew M. tuberculosis. In patients with two negative sputum smears, broth-based culture of three sputum specimens had the highest yield of any testing strategy.In people with HIV living in settings where mycobacterial culture is not routinely available to all patients, a third sputum smear adds little to the diagnosis of TB. Broth-based culture of three sputum specimens diagnoses most TB cases, and lymph node aspiration provides the highest incremental yield of any nonpulmonary specimen test for TB.

OBJECTIVES Broth-based culture (BBC) systems are increasingly being used to detect Mycobacterium tuberculosis complex (MTBC) in resource-limited. We evaluated the performance, time to detection and cost of the Capilia TB identification test from broth cultures positive for acid-fast bacilli (AFB) in Thailand. METHODS From October-December 2007, broth cultures that grew AFB from specimens submitted by district TB clinics to the Bangkok city laboratory were tested for MTBC using Capilia TB and standard biochemical tests. Isolates that were identified as MTBC by biochemical tests but not by Capilia TB underwent repeat testing using Capilia TB, Accuprobe (Gen-Probe, San Diego, CA, USA) and sequencing. Costs of time, labour, infrastructure and consumables for all procedures were measured. RESULTS Of 247 isolates evaluated, the sensitivity of Capilia TB was 97% and its true specificity 100% compared with biochemical testing. The median time from specimen receipt to confirmed MTBC identification was 20 days (range 7-53 days) for Capilia TB and 45 days (range 35-79 days) for biochemical testing (P < 0.01). Six isolates that were Capilia TB negative but positive by biochemical testing were confirmed as MTBC and mutations in the mpb64 gene were detected in all. The unit cost of using Capilia TB was 2.67 USD that of biochemical testing was 8.78 USD. CONCLUSIONS In Thailand, Capilia TB had acceptable sensitivity and specificity, was lower in cost and had shorter turn-around times. Laboratories investing in BBC should consider Capilia TB for identification of MTBC, after validation of performance in their setting.

We investigated a cluster of patients with tuberculosis (TB) in North Carolina and determined the extent of transmission of 1 strain of Mycobacterium tuberculosis. A retrospective cohort study was conducted. Homeless shelter attendance and medical records for 1999 and 2000 were reviewed. The period of exposure to M. tuberculosis was determined, and shelter residents were offered TB screening. DNA fingerprinting was performed on 72 M. tuberculosis isolates. In addition to the initial index cluster of 9 patients, another 16 patients were identified. Isolates of M. tuberculosis from all 25 patients shared a matching DNA fingerprint pattern. All but 1 patient was male, 22 (88%) were African American, and 14 (56%) were human immunodeficiency virus-infected. An epidemiological link to a single shelter was identified for all but 1 patient. Earlier recognition of this shelter as a site of M. tuberculosis transmission could have been facilitated through innovative approaches to contact investigation and through genetic typing of isolates.