[A DRG/PPS simulation in the medical care of tuberculosis].

PURPOSE: To study the expected usefulness of the introduction of the DRG-PPS (Diagnosis-Related Group/Prospective Payment System, in which an insurer pays a fixed medical fee per hospitalization) into the current medical care of tuberculosis (TB) in Japan. METHOD: The medical fees were reviewed for all TB inpatients at 19 hospitals under the National Hospital Organization who were discharged in either June 2007 or February 2008. The sum of the fixed fee by the DRG was assumed based on the bivariate regression analysis of each patient's hospital days and his or her total actual fees during the hospital stay under the current (fee for care) system, since it was difficult to directly calculate the daily fees for every patient that would be the basis of DRG-PPS. RESULTS: Linear regression analysis estimated that the medical fees (including fees for the medical examinations and the treatments) for a hospital stay of 60 days, which is the standard for TB treatment, was 1,192,470 yen (19,870 yen per person per day) in June 2007, and 1,167,600 yen (19,460 yen per person per day) in February 2008. DISCUSSION: If we assume an average medical fee of about Y1.1-1.2 million yen for the standard hospital care of TB, the economic balance of the hospitals is negative, with a deficit of 0.6-0.7 million yen, given the estimated expenses of 1.8 million yen (i.e., 30,000 yen per person per day x 60 days). CONCLUSION: If the DRG-PPS is to be implemented based on the current medical fee rating system, the hospital administrators could not accept its introduction to the TB medical care service as it is, because it may undermine the economic management of hospitals.

[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.

[Exogenous re-infection in tuberculosis].

Patients infected by tuberculosis (TB) had been thought to never experience exogenous re-infection. However, exogenous re-infection in HIV-positive patients is well known. Thanks to the introduction of histopathological examination, analysis of similarities in drug-resistance patterns and epidemiological surveys of genetic phage typing for TB infection, we have begun to understand that even people with a normal immune system can experience re-infection. Recent advances in the techniques of restriction fragment length polymorphism (RFLP) and spoligotyping allow determination of similarities in tubercle bacilli, revealing a high ratio of exogenous re-infection. In this mini-symposium, Dr. Kazunari Tsuyuguchi reported cases of nosocomial multidrug-resistant tuberculosis (MDRTB) infection, as exogenous re-infection, at 3 tuberculosis hospitals in the Osaka area. Although the virulence of MDRTB as a variant strain has generally been regarded as weaker than that of drug-sensitive strains, he reported even non-Beijing strain MDRTB, which displays strong virulence, could possess possible infectiosity with a 42% ratio of clustering formation and 2 of 8 patients with MDRTB exhibiting exogenous re-infection, as analyzed by RFLP. Dr. Hideo Ogata reported the actual condition of exogenous re-infection, having cited a large number of reports at home and abroad. In his report he indicated that even among hosts without serious hypoimmunity, re-infection rate is high in high-prevalence countries. Conversely, endogenous TB reactivation is high in low-prevalence countries. As Japan has become a low-prevalence country, endogenous reactivation might be seen in TB wards. Dr. Katsuhiro Kuwabara reported on his study about exogenous re-infection of Mycobacterium avium, which represented resident flora in the environment, using IS1245 RFLP analysis. He demonstrated that re-infection and multiple infections were frequently observed in M. avium infection. Dr. Tomoshige Matsumoto finally added that about 90% of patients with recurrence in the Osaka area exhibit endogenous reactivation, as found using molecular epidemiologic analysis of bacterial strains from initially treated and retreated patients. Compared with reports from other countries, the ratio of exogenous re-infection in Japan is lower than elsewhere. Thanks to the public health service about TB, sources of TB infection are not present, so patients with TB do not experience exogenous re-infection, he concluded. He also discussed the variable number of tandem repeats (VNTR)-typing method that has been taking the place of the IS6110 RFLP. In this mini-symposium referring to molecular epidemiological analyses and reports from Japan and overseas, we showed that depending on factors involving hosts, parasites and the density of TB re-exposure, the possibility of universal exogenous nosocomial re-infection exists. Each presenter alerted us to the fact that as exogenous re-infection occurs mainly in TB inpatient wards, prevention of TB infection is crucial for inpatients and medical staff in Japan as a low-prevalence country. (1) Exogenous re-infection by multidrug-resistant tuberculosis: Kazunari TSUYUGUCHI, Shiomi YOSHIDA, Katsuhiro SUZUKI, Masaji OKADA, Mitsunori SAKATANI (NHO Kinki-chuo Chest Medical Center) We describe three recurrent cases of multidrug-resistant (MDR) tuberculosis (TB) nosocomially re-infected with MDRTB strain during treatment for drug-sensitive TB. The first and the second patients, both of whom were middle-aged heavy smoker men, were associated with the outbreak caused by non-Beijing MDRTB strain. The third patient was a immunocompetent young man and the isolated strain was Beijing MDRTB strain. All the patients were HIV-seronegative. We conclude that exogenous re-infection by MDRTB can occur on various situations. These results underscore the importance of placing MDRTB patients separately from drug-sensitive TB patients. (2) Reviews of the exogenous re-infection in tuberculosis: Hideo OGATA (Fukujuji Hospital, JATA) In Japan, they have thought that a tubercular relapse is based on endogenous reactivation in almost all cases. However, there are many studies which prove exogenous re-infection using tuberculin test or drug susceptibility test. The technique of developed strain typing contributed exogenous re-infection to clarifying greatly in a real proof and its frequency in recent years. (3) Multiple and repeated polyclonal infections in patients with Mycobacterium avium lung diseases: Katsuhiro KUWABARA (NHO Nishi-Niigata Chuo National Hospital) The routes of transmission and environmental reservoirs of Mycobacterium avium infections have been unclear. IS1245 based RFLP analysis showed genetic diversity of Mycobacterium avium clinical isolates and the relation between clinical subtype and polyclonal infection. Our study demonstrates that polyclonal infections are common in Mycobacterium avium lung diseases, especially nodular bronchiectasis type. In addition, not only simultaneous polyclonal infections but also repeated polyclonal infections were observed in some patients. The knowledge of polyclonal infection will lead to better understanding of Mycobacteriuim avium pathogenesis and epidemiology. SPECIAL COMMENTARIES: Consideration of exogenous re-infection of tuberculosis in Osaka. Japan, by using molecular epidemiologic tools: Tomoshige MATSUMOTO (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) By using IS6110 RFLP, we showed that 9.5% of TB recurrence was caused by re-infection in the middle-eastern area of Osaka Prefecture, Japan. The molecular typing tools are now being applicable not only to epidemiological but also to clinical fields by an introduction of PCR-based method, such as Variable Numbers of Tandem Repeats (VNTR) typing. We showed some examples about usefulness of the clinical application of molecular epidemiology, using VNTR.

[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.

Is angiomatosis an intrinsic pathohistological feature of massive osteolysis? Report of an autopsy case and a review of the literature.

We report here an autopsied patient who had died during the clinical course of massive osteolysis (MO), which is a rare chronic disease that begins insidiously and is characterized by progressive regional loss of bone. Since the original description by Gorham and Stout in 1955, vascular proliferation, e.g., hemangiomatosis, has been considered to be the characteristic feature related to the pathogenesis. However, no such vascular changes were observed in the present patient. It was also important to note that a significant number of cases of MO that showed no vascular proliferation have been described previously. Therefore, we consider that vascular proliferation is not always associated with the osteolysis in MO and that the increased vascularity, if any, may be one of the results of the disease rather than the cause.

[A case of mitochondrial myopathy with external ophthalmoplegia and ataxic neuropathy].

We report a 70-year-old woman with bilateral optic atrophy, external ophthalmoplegia, bilateral blepharoptosis, and sensory ataxic neuropathy. She had a visual disturbance since childhood. She had dysarthria and gait disturbance at 28 years old. She had bilateral blepharoptosis, marked gait disturbance and dysphagia at 50. On neurological examination, external ophthalmoplegia, bilateral blepharoptosis, mild weakness and muscular atrophy of promixal muscles, hyporeflexia, positive Romberg sign, glove and stocking type sensory disturbance including hypesthesia, hypalgesia, and bathyhypesthesia were found. She did not show pigmented retinopathy, cognitive dysfunctions, hearing loss, cerebellar ataxia, Hoffman reflex nor Babinski sign. She did not show increased lactic acid nor pyruvic acid in the cerebrospinal fluid but mild increase of pyruvic acid (1.0 mg/dl) in her serum. The conduction velocity and amplitude of CMAP of tibial nerve was 37.4 m/sec and 2.9 mV, respectively. The SNAP of ulner and sural nerve were not evoked. Brain MRI showed no pathological findings. Muscle biopsy from the biceps muscle showed many ragged-red fibers (5.3%) and some fibers with decreased or absent COX activity. Sural nerve biopsy showed a marked loss of large myelinated fibers with thin myelinated fibers, and onion-bulb formation. The clinical findings of our patient is similar to that of SANDO (the triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis), however, large mtDNA deletion reported by Fadic in patients with SANDO was not found in our patient. It might be possible that her mtDNA deletion is small or point mutation is existed.