[Strategies for Mycobacterium avium complex infection control in Japan: how do they improve the present situation?].

Mycobacterium avium complex (MAC) were the most frequently isolated (about 80%) and most common cause of lung nontuberculosis. Its rate of infection is globally increasing, especially in Japan. In this situation, it is urgently needed to provide scientific evidences and develop therapeutic interventions in MAC infections. Recently, more and more patients are elderly women with no history of smoking, and they have reticulonodular infiltrates and patchy bilateral bronchiectasis. However the prognostic and intractable factors of MAC infections are poorly known. In this symposium, we address five novel strategies for MAC infection, concerning the more accurate incidence and prevalence rates compared with other countries, host defense associated with Th1/Th17 balance, route of MAC infection related soil exposure, MAC IgA antibody as a diagnosis maker, and improved chemotherapy including aminoglycoside or new quinolone. Appropriate clinical intervention may help to reduce the prolongation of MAC infection or enhance the activity of chemotherapy for the improved control of MAC. Below are the abstracts for each of the five speakers. 1. Review of current epidemiological study of pulmonary nontuberculous mycobacterial disease in Japan and the rest of the world: Kozo MORIMOTO (Respiratory Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association) The studies on pulmonary nontuberculous mycobacterial (NTM) disease prevalence were started in early 1970s in Japan by the Mycobacteriosis Research Group of National Chest Hospitals. They were followed by a questionnaire survey in 1990s, by the National Tuberculosis and NTM Survey in late 1990s, and recently by the questionnaire surveys conducted by the NTM Disease Research Committee. The latest data in Japan (from 2007) indicated a morbidity rate of 5.7 per 100,000 population. Deaths from NTM disease were reported for the first time in 1970 and showed a marked, steady increase until 2007, with 912 deaths in that year. We estimated NTM prevalence in our country in 2005 to be 33-65/100,000 using death number and the 1-2% fatality rate obtained from in our hospital. Epidemiologic study conducted by some regions, states and countries estimated the incidence or prevalence of NTM by unique methods in each. Although the microbiologic criteria of diagnosis is attractive to get information of prevalence, we think the most reliable method is to use the health insurance claims that should be done in future in Japan. 2. The elucidation of the pathogenesis of pulmonary MAC disease by using gene modified mice: Masashi MATSUYAMA, Yukio ISHII, Nobuyuki HIZAWA (Division of Respiratory Medicine, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba), Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Thl immune responses are associated with protective immunity to intracellular pathogens. T-bet is the master regulator for Thl cell differentiation. We therefore investigated the role of T-bet in the host defense against pulmonary MAC infection using T-bet knockout (T-bet-/-) mice and T-bet overexpressing (T-bet tg/tg) mice. Pulmonary MAC infection was induced by intratracheal instillation with 1 X 10(7) CFU of Mycobacterium avium subsp. hominissuis. The degrees of pulmonary inflammation and the number of organisms were much enhanced in T-bet-/- mice than in wild-type mice and T-bet tg/tg mice after MAC infection. A significant decrease in Th1 cytokines and increase in Th17 cytokines were observed in the lungs of T-bett-/-mice, compared with wild-type mice and T-bet tg/tg mice. Interestingly, however, the level of Th2 cytokines was not different among mice genotypes in response to MAC. These findings indicate that T-bet plays a central role in controlling MAC disease progression, through the regulation of both Th1 and Th17, but not Th2 responses. 3. Route of infection in Mycobacterium avium-intracellulare complex disease: Yutaka ITO (Department of Respiratory Medicine, Department of Infection Control and Prevention, Kyoto University) Environmental exposure is considered to be the primary route for Mycobacterium avium-intracellulare complex (MAC) infection. MAC is isolated from drinking water distribution systems, bathroom and showerheads and the genetic relatedness of clinical isolates from MAC patients with water isolates have been reported. We reported that patients with pulmonary MAC disease had significantly more soil exposure (>2 per week) than noninfected control patients after adjustments for the potential confounding diseases and conditions in pulmonary MAC disease. Moreover, we found six pairs of clinical isolates and corresponding soil isolates with identical variable numbers of tandem repeats profiles among patients with high soil exposure, suggesting that residential soils are a likely source of pulmonary MAC infection. 4. Clinical data analysis of Mycobacterium avium complex serodiagnosis kit: Yuta HAYASHI (Department of Respiratory Medicine, National Hospital Organization Higashi Nagoya National Hospital), Taku NAKAGAWA, Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Mycobacterium avium complex (MAC) serodiagnosis kit was covered by health insurance in August 2011 in Japan, but experience with this kit in daily clinical practice is still scarce. We analyzed the clinical data of MAC serum diagnostic kit in our hospital. Considering the high diagnostic performance of this kit (specificity 92.9%), that can also be incorporated into the diagnostic criteria. However it should be noted that there can be false-negative even in patients with active pulmonary MAC. Although this test is also expected usefulness as a marker of disease activity, at the present time should be kept for reference. 5. Clinical effect of combined chemotherapy containing aminoglycoside or new quinolone antibiotics for Mycobacterium avium complex disease: Yosihiro KOBASHI, Mikio OKA (Department of Respiratory Medicine, Kawasaki Medical School) Because it was possible to administrate CAM 800 mg/day for the treatment of Mycobacterium avium complex (MAC) disease after 2008, we compared the clinical effect of combined chemotherapy (RFP, EB, CAM 800 mg/day) containing aminoglycoside (SM) and combined chemotherapy (RFP, EB, CAM 400 mg/day or 600 mg/day) containing SM before 2007. Subsequently, the latter treatment was significantly better in the sputum conversion rate and clinical improvement such as clinical symptoms or radiological findings than the former treatment. Concerning the side effects or abnormal laboratory findings, although gastrointestinal symptoms were frequently appeared in the latter period, there was no significant difference between both periods.

Induction of persistent in vivo resistance to Mycobacterium avium infection in BALB/c mice injected with interleukin-18-secreting fibroblasts.

Interferon-gamma (IFN-gamma) is closely associated with the generation of cell-mediated immunity and resistance to intracellular parasites. Interleukin-18 (IL-18) is known to strongly induce IFN-gamma production by T cells and natural killer (NK) cells. To determine whether the paracrine secretion of IL-18 can efficiently stimulate the resistance to Mycobacterium avium complex (MAC) infection, 3T3 fibroblasts were stably transfected to secrete bioactive IL-18 and their effects on MAC infection were investigated in genetically susceptible BALB/c mice, compared with that of free recombinant IL-18. Immunization with IL-18-secreting fibroblasts (3T3/IL-18) during intranasal infection with MAC resulted in a significant decrease in bacterial load of lung during the entire 8-week observation period, while rIL-18 reduced the bacterial load at initial 1 week but not by 8 weeks postinfection. Immunization with the 3T3/IL-18 cells induced and maintained significantly higher levels of cytotoxic activity and nitric oxide production by lung cells than those of rIL-18 immunization. Furthermore, lung cells in mice injected with the 3T3/IL-18 cells showed persistent production of IFN-gamma throughout the 8-week period, suggesting that the 3T3/IL-18 cells induced the resistance to MAC infection via IFN-gamma production. This work suggests that IL-18-secreting fibroblasts may serve as a vehicle for paracrine secretion of IL-18 in immunotherapy of MAC infection.

Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion.

Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4+ cell counts of <50 cells/mm3, followed by a sustained increase to > or =100 cells/mm3 after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4+ cell count was 226 cells/mm3 at entry and 358 cells/mm3 at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4+ cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P=.009) and mumps skin test antigen (29% vs. 17%; P=.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk.

Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America.

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.

Discontinuation of secondary prophylaxis against disseminated Mycobacterium avium complex infection and toxoplasmic encephalitis.

We retrospectively studied outcomes for patients infected with human immunodeficiency virus who received highly active antiretroviral therapy (HAART) and had stopped receiving secondary prophylaxis against toxoplasmic encephalitis (TE) or disseminated Mycobacterium avium complex (MAC) infection. Nineteen patients had a history of TE, and 26 had a history of disseminated MAC infection. The median duration of secondary prophylaxis was 27 months, and the median duration of HAART before discontinuation of secondary prophylaxis was 22 months. Median CD4(+) cell counts at the time of cessation of secondary prophylaxis against TE or disseminated MAC infection were 404 and 105 cells/mm(3), respectively. Plasma virus load was undetectable in 68% of the patients who had a history of TE and in 31% of patients who had a history of disseminated MAC infection. Patients were followed up for a median of 29 months after discontinuation of secondary prophylaxis; no relapses occurred in patients with a history of TE, and 3 relapses occurred in patients with a history of disseminated MAC infection (incidence, 4 relapses per 100 person-years).

Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America.

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.

Serum interleukin-6 (IL-6), IL-10, tumor necrosis factor (TNF) alpha, soluble type II TNF receptor, and transforming growth factor beta levels in human immunodeficiency virus type 1-infected individuals with Mycobacterium avium complex disease.

To characterize changes in serum cytokine levels in human immunodeficiency virus type 1 (HIV-1)-infected persons with Mycobacterium avium complex (MAC) bacteremia, the levels of IL-1alpha (interleukin-1alpha), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), soluble type II TNF receptor (sTNF-RII), and transforming growth factor beta (TGF-beta) in serum were measured in two cohorts of HIV-1-infected persons with MAC bacteremia. The first cohort was part of a MAC prophylaxis study. Patients with bacteremia were matched with controls without bacteremia. Elevated IL-6, IL-10, TNF-alpha, sTNF-RII, and TGF-beta levels were noted at baseline for all subjects, a result consistent with advanced HIV-1 disease. IL-1alpha was not detected. No differences in cytokine levels in serum were noted at baseline and at the time of bacteremia between patients with MAC and controls. In the second cohort, subjects had serum samples collected at the time of MAC bacteremia and thereafter while on macrolide therapy. Serum samples at time of bacteremia were collected from HIV-1-infected persons at a time when neither highly active antiretroviral therapy (HAART) nor MAC prophylaxis was used routinely. MAC treatment resulted in decreased levels of IL-6 and TNF-alpha in serum, which were evident for IL-6 by 4 to 6 weeks and for TNF-alpha by 8 to 16 weeks. Thus, antibiotic treatment for MAC results in decreased levels of IL-6 and TNF-alpha in serum in HIV-1-infected persons who are not on HAART.

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group.

OBJECTIVE: To examine the effects of antiretroviral therapy (ART) and opportunistic illness chemoprophylaxis on the survival of persons with AIDS and survival time based on year of AIDS diagnosis. DESIGN: Longitudinal medical record review. SETTING: Ninety-three hospitals and clinics in nine cities in the USA. PATIENTS: We observed 19,565 persons with AIDS from 1990 through January 1998. INTERVENTIONS: Prescribed use of antiretroviral monotherapy, dual- and triple-combination therapies, primary prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium complex, and pneumococcal vaccine. MAIN OUTCOME MEASURES: Time from AIDS diagnosis to death in the presence and absence of ART. Survival curves were compared of AIDS cases diagnosed during 1990-1992 and 1993-1995. RESULTS: Triple ART had the greatest effect on the risk of death [relative risk (RR), 0.15; 95% confidence limit (CL), 0.12, 0.17], followed by dual ART (RR, 0.24; 95% CL, 0.22, 0.26), and monotherapy (RR, 0.38; 95% CL, 0.36, 0.40). Risk of death was decreased among persons receiving Pneumocystis carinii pneumonia prophylaxis (RR, 0.79; 95% CL, 0.70, 0.89) and Mycobacterium avium complex prophylaxis (RR, 0.76; 95% CL, 0.68, 0.86). Median survival increased from 31 months [95% confidence interval (CI), 30-32 months] for AIDS cases diagnosed during 1990-1992 to 35 months (95% CI, 35-38 months) for cases diagnosed during 1993-1995. CONCLUSIONS: The risk of death was decreased for persons receiving triple ART compared with persons receiving dual therapy and persons receiving monotherapy. Increased use of ART and improved ART regimens probably contributed to prolonged survival of persons whose diagnosis was made during 1993-1995 compared with persons whose diagnosis was made during 1990-1992.

MAC prophylaxis in the era of polypharmacy.

In the advanced stages of AIDS, patients are increasingly susceptible to disseminated Mycobacterium avium-intracellulare (MAC) infection, causing significant morbidity and mortality. It has been shown that prophylaxis against this infection is effective in reducing the incidence as well as the symptoms of MAC. Although chemoprophylaxis against MAC is a standard recommendation, it is not always carried out due to a variety of reasons. Several agents are now approved for this purpose, adding to the complexity of the decision to start the prophylaxis. This article reviews the need for prophylaxis against MAC, and considers the different agents available, with the aim of helping readers come to an informed decision about starting MAC prophylaxis in their patients. This issue will be of rising importance with the effective prevention of other opportunistic infections in patients with advancing immune deficiency.

Adherence to guidelines for antiretroviral therapy and for preventing opportunistic infections in HIV-infected adults and adolescents in Ryan White-funded facilities in the United States.

To determine adherence by health care providers to guidelines for antiretroviral therapy and for prevention of opportunistic infections (OIs) in adults with HIV infection in federally funded facilities in the United States, we reviewed records of HIV-infected adults (>13 years) in 11 Ryan White Title III facilities in four states for information on eight standard-of-care recommendations during November 1996 through September 1997. Eligibility required a visit to the facility within 6 months before record abstraction and a lowest CD4+ lymphocyte count <500 cells/microl. Reviews were completed for 148 patients in Maryland, 355 in New York, 370 in Georgia, and 538 in Illinois. Adherence to prevention measures by health care providers was >85% for HIV plasma RNA testing, prescription of antiretroviral therapy, Pneumocystis carinii pneumonia (PCP) prophylaxis, anti-Toxoplasma antibody testing, and obtaining Papanicolaou (Pap) smears but lower (69%-80%) for Mycobacterium avium complex (MAC) prophylaxis, tuberculin skin testing (TST), and pneumococcal vaccination. Adherence was similar by patient age, gender, racial/ethnic group, urban versus rural, and hospital versus clinic setting but was generally lower for injecting drug users (IDUs) than for patients with other HIV exposures (p < .05 by multivariate analysis for TST, anti-Toxoplasma antibody testing, Pap smear, and measurement of HIV plasma RNA). Adherence by health care providers to guidelines for preventing OIs in these federally funded facilities is generally high but could be improved for some prevention measures, for instance, MAC prophylaxis, TST, and pneumococcal vaccination, especially for IDUs.

OIs and cancers.

AIDS: A study presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) demonstrates that Kaposi's sarcoma herpesvirus (KSHV) can be transmitted via saliva in deep oral kissing. Results of multivariate analysis showed that KSHV positivity was associated with deep oral kissing with HIV-positive persons, the use of amyl nitrates during sex, and sex with a person who has KSHV.^ieng