[Lessons learned from tuberculosis outbreak cases].

Most TB outbreaks were caused by exposure of many people to tuberculosis bacilli due to delayed detection of initial cases who had long-lasting severe coughs and excretion of massive tuberculosis bacilli. They were also affected by several other factors, such as socio-environmental factors of the initial case; time and place of infection; and host factors of the infected persons such as immune status, infectivity, and/or pathogenicity of the bacilli. In this symposium, we learned the seriousness of infection and disease among immune-suppressed groups, special environmental factors with regard to the spread of infection, disease after treatment of latent tuberculosis infection, diagnostic specification of IGRA, and bacteriological features including genotyping of the bacilli. We reaffirmed that countermeasures for the case are important, but outbreaks can provide excellent opportunities to learn important information about infection, disease progression, etc. 1. Tuberculosis outbreak in a cancer ward: Katsuhiro KUWABARA (Division of Respiratory Diseases, National Hospital Organization Nishi-Niigata Chuo National Hospital) There was an outbreak of tuberculosis in a cancer ward of a highly specialized medical center. Outbreak cases included eight hospitalized patients and two medical staff members over a 1.5-year observation period after initial contact. Three immune-compromised patients including the index patent died of cancer and tuberculosis. Community hospitals and highly specialized medical centers, such as cancer centers, should carefully prepare a proper system to prevent nosocomial transmission of tuberculosis. 2. Sixty-one cases of TB exposures in hospital settings and contact investigations of the hospital staff, with special reference to the application of QFT: Hiroko Yoshikawa NIGORIKAWA (The Division of Infectious Diseases, Tokyo Metropolitan Health and Medical Treatment Corporation, Toshima Hospital; present: Division of Infectious Diseases, Tokyo Teishin Hospital), Toru MORI (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The index case was a patient who was admitted to a general hospital where she was treated with pulsed corticosteroid therapy and then put on a respirator. Soon after, she developed tuberculosis (TB) and died. Immediately after her death, the healthcare workers who had close contact with the index case were given the QuantiFERON TB Gold (QFT) test, which indicated that all staff except one were negative. However, a QFT test administered eight weeks later had a positive rate of 18.6%. Subsequently, a total of five workers, including a doctor, nurses, and radiology technicians, developed TB. The bacterial isolates from five of them exhibited an RFLP pattern identical to that of the index case. These secondary cases of TB included a case who had contact of less than 5 minutes, a case whose QFT was negative ("doubtful" in the Japanese criterion of the QFT), and a case who was QFT-positive but declined to be treated for latent TB infection (LTBI). No other workers nor hospitalized patients developed TB. The healthcare worker contacts were further examined with the QFT 6, 9 and 12 months after the contact. The QFT results revealed four additional positive reactors and four "doubtful" reactors who were indicated for LTBI treatment. Among them were seven subjects who turned positive six months after the contact. TB prevention in hospital settings and contact investigations were discussed with the hospital staff, with special reference to the application of QFT. 3. Summary and issues of concern relating to a tuberculosis outbreak in a prison: Mitsunobu HOMMA, Takefumi ITOH (Department of Respiratory Medicine, Akita City Hospital) We report a tuberculosis outbreak that occurred in a prison in the spring of 2011, resulting in 11 cases of active disease and 40 cases of infection. The primary cause of the outbreak is thought to be the delay in identifying the index case, where the screening result interpretation might have contributed to the delay. However, we also speculate that environmental factors, such as occurrence in the closed space of a prison, inmates spending long periods living together, inmates staying in their rooms due to the cold winter, and poor ventilation in the prison factory, all contributed to accelerating the spread of the infection. Both the QuantiFERON TB-2G (QFT)-positive rate and disease incidence were higher among the close contact group, and there were no cases of tuberculosis among QFT-negative individuals, proving the utility of QFT screening in contact surveys. Genetic testing for Mycobacterium tuberculosis is a useful method for studying outbreak cases. In the present case, it led to the discovery of an unexpected route of infection, reaffirming its importance. This outbreak occurred among a particular population with whom it was difficult to deal and it occurred under unique circumstances. In fact, there were various obstacles to overcome, the most important of which was to ensure the three organizations involved (prisons, health centers, and hospitals) worked together closely, sharing accurate, real-time information. 4. Environmental factors, treatment for latent tuberculosis infection and molecular epidemiology relating to an outbreak of tuberculosis: Makoto TOYOTA (Kochi City Public Health Center), Seiya KATO (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association). The ventilation rate within the room of a junior high school was analyzed using sulfur hexafluoride (SF6) as the tracer gas. Low ventilation of the room contributed to the massive outbreak. The risk of active tuberculosis was reduced by 81.0% with treatment for latent tuberculosis infection, compared with that without treatment. Delayed reactivation of tuberculosis was observed among patients treated with isoniazid for latent tuberculosis infection. Molecular epidemiology can provide insights into the process of tuberculosis transmission, which may otherwise go unrecognized by conventional contact investigations. Additionally, it can play an important role in identifying places of tuberculosis outbreaks and routes of transmission in a contact investigation.

[Anti-tuberculosis chemotherapy and management of adverse reactions].

Six-month regimen consisting of two-month initial intensive phase of isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA) and ethambutol, (or streptomycin) and four-month maintenance phase of INH and RFP has been established as the global standard. Alternatively, 9-month regimen without PZA is acceptable for patients like elderly persons. Standard regimen is well tolerated in most patients. However some patients have adverse reactions. The frequent and serious reaction is hepatic toxicity caused by INH and PZA. Close monitoring of serum aminotransferase at every two weeks of initial treatment phase is recommended. Hypersensitivity to INH and RFP is common reaction seen in 4-5 percent of the general population. About 60-80% patients who had hypersensitivity can continue the standard regimen by desensitization therapy.

Anti-interferon-gamma autoantibody in a patient with disseminated Mycobacterium avium complex.

We report the case of a 44-year-old woman with disseminated Mycobacterium avium complex (MAC) infection involving multiple bone lesions despite a normal healthy status until 6 months previously. Because she was suspected to have acquired immunodeficiency, we tested interferon (IFN)-gamma production by peripheral blood mononuclear cells (PBMC) after phytohemagglutinin (PHA) or anti-CD3 stimulation, and found that these cells produced no, or undetectable, levels of IFN-gamma in the presence of the patient's plasma, but produced nearly normal levels of IFN-gamma in the presence of healthy donor plasma. Since the IgG fraction of the patient's plasma was capable of blocking in vitro responses to IFN-gamma, the cause of disseminated MAC infection in this case appeared to be anti-IFN-gamma autoantibodies. To reduce the titer of anti-IFN-gamma autoantibodies, the patient received intravenous immunoglobulin (IVIG). However, titer of autoantibodies changed little compared to that before IVIG administration. According to our literature search, this is only the second case of disseminated MAC infection associated with anti-IFN-gamma autoantibodies in Japan.

[Clinical features and treatment history of clarithromycin resistance in M. avium-intracellulare complex pulmonary disease patients].

Effective antimicrobial treatment of Mycobacterium avium-intracellulare complex (MAC) has not been established. Clarithromycin (CAM) is an extremely important drug in treatment regimens of MAC diseases. Except for monotherapy, the clinical features of CAM resistance are not clear. We investigated the clinical background of CAM resistance of pulmonary MAC disease patients. Minimum inhibitory concentrations (MICs) of CAM to 283 strains of M. avium and 58 strains of M. intracellulare were determined by drug susceptibility test using BrothMIC NTM. All 243 M. avium isolates from untreated patients except one isolate were susceptible to CAM. We also examined CAM susceptibility of 40 pulmonary disease patients who received chemotherapy including CAM during a period of over 6 months. Seventeen patients (43%) were resistant to CAM. All (17/17) resistant patients were treated with CAM monotherapy. However 8 of the 23 (35%) susceptible patients were also treated with monotherapy. Many resistant patients were treated with high dose CAM monotherapy and were classified as the non-nodular bronchiectasis type. However 7 of 8 susceptible patients despite long-term monotherapy were the nodular bronchiectasis type. High dose CAM monotherapy and non-nodular bronchiectasis subtype were considered to be risk factors for CAM resistance.

[Molecular epidemiological analysis by IS1245-based restriction fragment length polymorphism typing on cases with pulmonary Mycobacterium avium disease observed in the same family].

INTRODUCTION: Mycobacterium avium-intracellulare complex (MAC) has become one of major human pathogens, however, its routes of transmission and environmental reservoirs causing human infection were not yet elucidated. We reported three families affected by pulmonary Mycobacterium avium (M. avium) disease. Previous reports on MAC diseases observed in the same family were very rare. The purposes of this study were to investigate whether the infected M. avium was the same strain among cases in the same family and to examine the possibility of human-to-human transmission, or infection from exposure to a common environmental reservoir. METHODS: M. avium isolates from nine cases of three families were examined by DNA polymorphism based typing technique, restriction fragment length polymorphism (RFLP) analysis using insertion sequence IS1245 as a probe, to type the strains. Some isolates were subcultured to a single clone. RESULTS: All strains isolated from cases in the same family showed different patterns by the RFLP analysis. And not only simultaneous polyclonal infection but also repeated polyclonal infections were observed in some patients. DISCUSSION: The results suggest importance of underlying anti-mycobacterial immunological impairment and defects of local defense rather than virulence of infected strains as the pathogenesis of pulmonary M. avium disease.

[Relations between clinical subtypes of Mycobacterium avium pulmonary disease and polyclonal infections detected by IS1245 based restriction fragment length polymorphism analysis].

INTRODUCTION: The epidemiology of Mycobacterium avium-intracellulare (MAC) infections has not been completely defined. Recently some reports presented polyclonal MAC infections. The purpose of this study was to reveal the clonal diversity of Mycobacterium avium isolates and the relation between clinical subtype of lung disease and polyclonal infection. METHODS: We categorized pulmonary Mycobacterium avium infection to three clinical subtypes, tuberculosis like type, bronchiectasis with preexisting tuberculosis type and nodular bronchiectasis type. Mycobacterium avium isolates of 11 patients were studied for their heterogeneity using IS1245 based RFLP analysis. The insertion sequence IS1245 is repetitive element identified only in Mycobacterium avium. Standard method of IS1245 based RFLP analysis has been proposed as a suitable technique for typing of Mycobacterium avium isolates for epidemiological and taxonomic studies. At least three distinct colonies were subcultured to single clone. The subclones of the isolates were analyzed by IS1245 based RFLP technique and some subclones were also examined by antimicrobial susceptibility test. RESULTS: Two of three patients of tuberculosis like type were considered to be monoclonal infection because only a single genotype was identified. And only one of four patients of bronchiectasis with preexisting tuberculosis type was considered to be polyclonal infection despite of long-term observation. Although isolates were collected in two or more occasions in clinical course over one year period, only a single genotype was observed in two patients. In contrast, three of four patients of nodular bronchiectasis type had multiple genotypes. Isolates recovered from patients with monoclonal infection pattern following long-term treatment with clarithromycin monotherapy became resistant to clarithromycin. In contrast, three strains derived from one nodular bronchiectasis patient were susceptible to clarithromycin despite of long-term chemotherapy including clarithromycin. The susceptibility patterns of the other drugs were also apparently different. Strain conversion due to repeated polyclonal infection was considered. These results of the antimicrobial susceptibility test supported clonal diversity of the Mycobacterium avium infection. DISCUSSION: IS1245 based RFLP analysis possesses a discriminatory power between the isolates on clonal level. This study demonstrates that polyclonal infections are common in nodular bronchiectasis type and monoclonal infections are common in tuberculosis like type and bronchiectasis with preexisting tuberculosis type. And not only simultaneous polyclonal infection but also repeated polyclonal infection were observed in a nodular bronchiectasis type patient. Drug susceptibility test showed long-term chemotherapy including clarithromycin could change the susceptibility of clarithromycin to resistant in patients with monoclonal infection. In contrast patients with repeated polyclonal infection pattern would avoid drug resistance because of strain conversion. This multiple susceptibility patterns identified in this study would not have been detected by the standard susceptibility test without subculture. And we also need the treatment strategy considering the polyclonal infection. CONCLUSIONS: Polyclonal infections are considered to be common in pulmonary Mycobacterium avium infection, especially nodular bronchiectasis type. Clonal diversity of Mycobacterium avium infection is an important factor to perform chemotherapy and drug susceptibility test.

[An outbreak of pulmonary tuberculosis probably due to exogenous reinfection at a nursing home for the elderly].

In Japan and other countries where tuberculosis is not so common, people who were once infected with tuberculosis are thought to rarely suffer from the disease again due to exogenous reinfection. We experienced a mass outbreak of tuberculosis with 27 patients (including the source of infection) at a nursing home for the elderly. Epidemiological investigation suggested that the source of infection was an 82-year-old woman resident. For about 2 years before this outbreak, she had complained of a productive cough. At the time of the diagnosis of tuberculosis, chest radiography revealed a cavitary lesion and a smear of her sputum revealed organisms rated as Gaffky No. 8. Sputum culture was also positive (++++). Of the 27 patients, 19 (including the source) underwent restriction fragment length polymorphism (RFLP) analysis of isolates from the sputum. Eighteen patients showed an identical RFLP pattern, indicating that the infection had arisen from one source. Out of all patients, the source case of infection, 9 others with the same RFLP pattern, and other 3 who did not undergo RFLP analysis were admitted to our hospital. In 12 patients (3 men and 9 women excluding the source case) aged 80.6 years (range: 67-89 years), chest radiography disclosed tuberculous lesions, and smears, the polymerase chain reaction, and culture of sputum demonstrated Mycobacterium tuberculosis. As the prevalence of tuberculosis infection in Japanese aged 80 years at the time of the mass outbreak (1995) was presumed to be about 80%, the disease seemed to be caused by exogenous reinfection in most of these patients. All of the patients had senile dementia and other complications, and they were bedridden and undernourished. Anemia, hypoalbuminemia and lymphocytopenia were also observed in most of the cases. Malnutrition due to these complications appeared to be a possible risk factor of tuberculosis caused by exogenous reinfection.