Pulmonary Mycobacterium avium complex infection associated with the IVS8-T5 allele of the CFTR gene.

BACKGROUND: The T5 allele in intron 8 (IVS8) on specific haplotype backgrounds (e.g., long TG repeats) causes abnormal splicing in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is also known to be associated with chronic airway diseases. OBJECTIVE: To investigate the role of CFTR variations for susceptibility to pulmonary Mycobacterium avium complex (MAC) infection. PARTICIPANTS: Three hundred patients with pulmonary MAC infection (72 males, 228 females; mean age at onset 61.6 + or - 12.4 years) took part in this study. Diagnosis of MAC infection was based on American Thoracic Society criteria. Clinical profiles were collected and blood samples were genotyped for TG repeats, poly-T and M470V polymorphisms. RESULTS: We found significantly higher T5 frequency in MAC patients than in healthy controls from our own study (0.035 and 0.005, respectively, P = 0.023) and other reports. Homozygote for the T5 allele was found in two MAC patients. All T5 alleles were associated with longer TG repeats, the TG12 or TG13 allele. Seventeen of the 21 T5 alleles appeared to be associated with the V470 allele. Other polymorphisms did not show any significant differences in frequency. CONCLUSIONS: These findings suggest that the IVS8 5T allele might be involved in susceptibility to pulmonary MAC infection.

[Pulmonary Mycobacterium Kansasii infection in the southern area of Fukuoka prefecture].

Cases of pulmonary infection caused by Mycobacterium kansasii (Mk) in our hospital located at the mid-northern area of the Kyushu district, which is in the southern part of Fukuoka prefecture were evaluated. Mk infection is not so rare in other areas of Japan, such as Tokyo and Kinki district, however, there has been no published report on the disease from the Kyusyu district. Therefore, the frequency and the clinical features of our cases of Mk infection were analyzed. During 17 years from 1982 to 1998, there were 14 patients of Mk infection out of 241 nontuberculous mycobacteriosis (NTM). There were 595 patients of culture-positive pulmonary tuberculosis without prior treatment (Tbc). The proportion of Mk/Tbc was 2.4% and that of Mk/NTM was 5.8%. During the period A (from 1982 to 1994) the ratio of Mk/Tbc was 5/462 (1.1%), while on the other side that of Mk/Tbc during the period B (from 1995 to 1998), it was 9/133 (6.8%), which was significantly (P < 0.01) higher compared with that in the period A. Although the patients of Mk infection in our hospital had been rare until 1994, from the results mentioned above, it was considered that the frequency of Mk infection in our hospital has increased to some extent since 1995. One of the characteristics in our cases was that the ratio of female (42.9%) was relatively high. All the female patients were considered to be compromised hosts. The results of the drug resistance tests were consistent with the other reports in our country. By the combination treatment including rifampicin as the major drug, the negative conversion of culture were obtained within 2 months in all our cases.

[Comparison of chest CT findings between suspected and definite cases of primary pulmonary M. avium complex infection].

It is very difficult to treat pulmonary infection with MAC, because we have few effective drugs against this organism. In this situation, an early diagnosis and treatment are very important to manage this disease. We evaluated chest CT scans of the primary pulmonary MAC infection which had no underlying lung diseases and no immunocompromised diseases such as HIV infection. We defined suspected cases of pulmonary MAC infection as cases in which abnormal features of chest CT scans were recognized but frequency of detection of organisms of MAC did not fulfil the diagnostic criteria for atypical mycobacteriosis according to Japanese Mycobacteriosis Research Group of the National Chest Hospitals. CT scans of suspected cases were compared with the definite cases. Results obtained were as follows: 1. In classification by CT scans of primary pulmonary MAC infection, the proportion of localized type and diffuse type was the same both in suspected and definite cases. In localized type, more tuberculosis-like pattern was seen in definite cases. 2. In suspected cases, characteristic features of CT scans of primary pulmonary MAC infection were recognized in the same frequency as in definite cases. 3. In pulmonary tuberculosis-like type, definite cases showed more cavitary lesions than suspected cases. These results showed that a careful long term follow-up of suspected cases with frequent bacteriological tests of sputum and chest CT scannings was important for early diagnosis of primary pulmonary MAC infection.

[Diagnostic usefulness of the tuberculin reaction by PPD-B in Mycobacterium avium complex disease].

This study was carried out to clarify the diagnostic usefulness of the skin tests of purified protein derivatives from M. intracellulare (PPD-B) and M. tuberculosis (PPDs). Study subjects consisted of 41 patients with primary infection type of M. avium complex (MAC) disease, 36 patients with pulmonary tuberculosis (TB) and 29 patients with other bacterial respiratory infections including COPD (OB). The patients were sorted out to middle (50-69 y.o.) and old (70-89 y.o.) age groups of each disease. The size of skin redness elicited 48 hours after the PPD-B and PPDs intradermal injections were compared among them. The results were as follows. 1) Both PPD-B and PPDs skin reactions were larger in the middle age group than in the old one for each disease. 2) In PPDs skin tests, the reaction of TB group was the largest among the three diseases. In PPD-B skin tests, that of MAC was the largest. 3) In TB group, PPDs skin reaction was significantly larger than that of PPD-B, while in MAC and OB groups there was no significant difference between the skin reactions of PPDs and PPD-B. 4) Defining significant positive reaction to PPD-B as PPD-B skin reaction exceeding 10 mm and larger than that of PPDs skin reaction, the rate of significant positive reaction to PPD-B was significantly higher in MAC than TB in both age groups. These results showed that the simultaneous skin tests of PPD-B and PPDs were a useful aid in the diagnosis of MAC infection disease when mycobacterial infection diseases were clinically suspected by bacteriological or chest radiographic examinations.

[A study of sialylated carbohydrate antigen in patients with benign bronchopulmonary disease].

We studied the levels of carbohydrate antigen (CA 19-9, SLX, CA 50, Span-1, and Dupan-2) in serum, bronchoalveolar lavage fluid, and tissue from patients with benign bronchopulmonary disease. Patients had bronchiectasis, healed pulmonary tuberculosis, pulmonary fibrosis, or other diseases. Bronchoalveolar lavage fluid levels and immunohistochemical findings for lung tissue samples, in the absence of digestive and other diseases, suggested that elevated serum sialylated Lewis(A) (CA 19-9, CA 50, and Span-1) and Lewis(X) (SLX) antigen in patients with benign broncho-pulmonary disease are due to marked production of sialylated carbohydrate antigen in respiratory bronchioles. Common features of patients with benign bronchopulmonary disease include elevated serum carbohydrate antigen levels and bronchiectasis.

[Tracheobronchopathia osteoplastica with "rock garden" findings on bronchoscopy].

We encountered a 65-year-old man with tracheobronchopathia osteoplastica with "rock garden" findings on fiberoptic bronchoscopy. Many nodular elevated lesions were seen on all sides of the trachea and main bronchi except the membranous portion. The diagnosis was confirmed by examination of a biopsy specimen.

[The distribution and the characteristics in computed tomography (CT) of the lungs in primary Mycobacterium avium complex (MAC) infection].

We investigated the distribution and the characteristics of the lung lesions of patients with primary Mycobacterium avium complex (MAC) infections mainly by computed tomography (CT). They admitted to our hospital during the period from 1984 to 1995 and none of them had a medical history of tuberculosis or other lung diseases. The subjects consisted of fifty patients: fourteen male (average age +/- SD was 66.4 +/- 14.0 year old) and thirty six female (69.0 +/- 11.9 year old). Of 50 patients 24 were M. intracellulare infection, 10 were M. avium infection and others were not identified. First, by using the ratio of slices with lesions on CT to all CT slices from the apex to the base of the lungs, all the patients were divided into two groups; a slight group with less than 15.0% (n = 19) and a severe group with 15.0% or more (n = 31). Next, the density of abnormal shadows in each segment as divided into 5 grades; none (-), minimal (+/-), slight (+), moderate (+2) and severe (+3). The grading was done by taking into account the grade of distribution, density of lesions and destruction of lung parenchym found mainly on CT, and in addition by a standard roentogenographic and tomographic features supplemental. The characteristics frequently observed findings on CT in primary MAC infection patients were nodular (94%), cavitary (74%), bronchiectatic (62%), infiltrative (74%), atelectatic (56%), and pleural-thickened (36%) shadows. Comparing the incidence of segmental lesions in MAC infection patients by segment, it was higher in right and in left lung, but the difference was statistically not significant. As to the number of segments with lesions graded from (+/-) to (+3), many segments were infected unexpectedly: the mean value was 7.7 +/- 1.5 even in the slight group. The proportion of segments with relatively severe lesions graded from (+2) to (+3) in each segment was observed, and the rate in the slight group was 52.6% in S5, 28.9% in S4, 16.7% in S1 (S1 + 2a, b), and 16.7% in S2 (S1 + 2c). In severe group, it was 54.8% in S5, 45.2% in S4, 46.8% in S1 (S1 + 2a, b) 54% in S2 (S1 + 2c), 27.4% in S3 and 26.2% in S6, respectively. The rate of segments with lesions in the lower lobes were less frequent especially in the slight group while it was slightly higher in the severe group. Speculating the initial lesions in the slight group, it was assumed that there might be two types of foci; the one is relatively localized in the beginning and the other is a diffuse type with lesions in many segments even from its early stage. As to the location of initial lesions, the middle lobe and lingula were the most important sites, and the right upper lobe and the left upper division were the next.

[A case of pulmonary hyalinizing granuloma with its occupational history of dust exposure].

Multiple pulmonary nodules were found in a patient who had an occupational history of coal mining for eleven years and road construction for fifteen years. An open lung biopsy was performed, because nodules had increased in size compared to previous ones and a trasbronchial biopsy was not diagnostic. The nodules were composed of dense concentric lamellar collagenous structures with a serpentine pattern surrounded by an infiltration of histiocytes, lymphocytes and plasma cells with Russel bodies. These findings are compatible with pulmonary hyalinizing granuloma (PHG) named by Liebow A. A. The etiopathogenetic mechanism and the difference between PHG and silicotic nodule is discussed.

[An investigation on risk factors relating to the treatment difficulty in originally treated pulmonary tuberculosis cases].

In order to investigate whether so-called risk factors relating to treatment difficulty are true risk or not, treatment results of 520 in-patients originally treated for pulmonary tuberculosis during 12 years' period from 1980 to 1991 in our hospital were analyzed. The proportion of cases with so-called risk factors among total 520 cases was as follows: Aged patients (70 years of age and over) 31.5%. Cases discharging abundant bacilli in sputum (Gaffky scale VII or above or culture, +3 positive) 29.4%. Adverse reactions to drugs 18.1%. Far advanced cavitary lesions (GAKKAI Classification I or II3) 15.6%. Relative risk of various risk factors in cases of group A (died of tuberculosis), group B (showed delay in the negative conversion of bacilli; namely, cases converted to negative only 4th month of treatment or later) and group C (cases of groups A and B) were calculated comparing with cases of the control group (pretreatment negative bacilli cases or cases converted to negative within 3 months). In cases of group A died of tuberculosis, the results were as follows; pretreatment abundant bacilli discharge 3.1, far advanced cavitary lesions 4.6, emaciation and/or malnutrition 5.1. Other risk factors identified were the following; unhealthy life style 4.0, severe gastrointestinal tract disease 3.9, impaired pulmonary function 3.3, complicated infections 3.2, cerebrovascular injuries including psychosis and nervous system diseases 2.3, diabetes mellitus 2.0, and the adverse reactions to drugs 1.9. In cases of group B showing delay in the negative conversion of bacilli, significant risk factors were pretreatment abundant bacilli discharge, far advanced cavitary lesions, emaciation and/or malnutrition and diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of hypogamma-globulinemia with thymoma (Good's syndrome) follow-up for 8 years].

A 58-year-old woman, who had a past history of left upper lobectomy with thoracoplasty for pulmonary tuberculosis and resection of thyroid cancer, was diagnosed as having a mediastinal tumor by chest X-ray examination. It was found to be a malignant thymoma (spindle cell type) after resection. The level of serum gammaglobulin, which had been low before resection, progressively decreased. Afterward, she frequently suffered from airway infections which resulted in severe bronchiecatsis. She died due to respiratory failure 8 years later. In the early stage, though the percentage of pan T cells in peripheral blood lymphocyte subsets was normal, CD4 T cells decreased and CD8 T cells increased. A decrease in helper T cells and an increase in cytotoxic T cells were especially marked. In the late stage, all T cells subsets decreased. In particular, naive T (CD45RA* CD3+ T) cells decreased markedly. However, the percentage of B cells remained normal and that of NK cells was elevated. From the findings of lymphocyte subsets and lymphocyte reactivity to PHA stimulation, it is suggested that T cell dysfunction caused hypogrammaglobulinemia in this case.

[Re-evaluation of pyrazinamide].

To re-evaluate pyrazinamide (PZA) which has been a key drug for short course anti-tuberculosis chemotherapy in the world, we started a clinical trial of short course chemotherapy containing PZA (2S (E) HRZ/EHR), and obtained information about the estimation of PZA in the tuberculosis specialists in Japan through a questionnaire. We could not evaluate precisely because of small numbers of registered cases, but the rate of negative conversion by culture was higher at the second months in the PZA group than in the control group. Although the total incidence of the adverse reactions of any kind was higher in the PZA group, the incidence of liver dysfunction was lower in the PZA group. Only about 20% of the tuberculosis specialists choose PZA in the treatment of newly diagnosed tuberculosis patients. The remainder do not choose PZA because they think that; 1) PZA has adverse reactions, 2) PZA is effectless, 3) drugs other than PZA are good enough. Almost half of the tuberculosis specialists continues antituberculosis chemotherapy for more than 9 months. The precise and strict nation-wide co-operative study for PZA should be designed to clarify the usefulness of PZA.

[Two cases of chronic respiratory failure in intravenous methylphenidate (Ritalin) abusers].

Marked obstructive ventilatory impairment and diffusion disturbance were noted in two intravenous methylphenidate (Ritalin) abusers. In one patient, chest radiogram demonstrated pulmonary emphysema accompanied by bullae and atelectasis, and spontaneous pneumothorax was also present. The primary finding in the other patient was interstitial shadows. Both patients began to note dyspnea during exertion after about 10 years of use. Since radiography also disclosed pulmonary emphysema in an ex-companion of Ritalin abuse, and since the onset was at relatively young ages, these pulmonary disorders are considered to have been a result of intravenous Ritalin abuse. Intravenous drug abuse should be considered in patients with precocious emphysema or obstructive ventilatory impairment accompanied by diffusion disturbance.

[Clinico-immunological study of the patients infected with Mycobacterium avium complex (MAC)].

Lymphocyte functions of the peripheral blood in the patients infected with MAC (MAC-pts) were evaluated comparatively with age-matched normal controls by using flow cytometry. The results obtained were as follows: 1) In normal controls, the number of total lymphocytes and the proportion and number of T lymphocyte subsets significantly decreased with age. The proportion of natural killer lymphocytes significantly increased in elder controls. 2) In MAC-pts, the number of total lymphocytes and T lymphocyte subsets were significantly lower and the proportion of natural killer lymphocytes were higher respectively than normal controls. 3) The lymphocyte proliferation induced by PPD-S stimulation in vitro in MAC-pts was significantly lower than the normal controls in both age groups of 50-69 and 70-89 years old. 4) The lymphocyte proliferation induced by PPD-S stimulation in MAC-pts was increased slightly by adding recombinant IL-2 and significantly higher by depletion of monocytes. By combination of both treatments, it recovered to the level of normal controls. From these results, we suggested that the decline of lymphocyte proliferation induced by PPD-S stimulation in MAC-pts was due to the decrease of IL-2 production by antigen committed lymphocytes and suppression by monocytes. 5) Lymphocyte proliferation induced by PHA stimulation in vitro was also significantly depressed in MAC-pts as compared with normal controls.

[A case of psittacosis with migratory infiltrates].

A 56-year-old man with fever, headache, cough and sputum was admitted to another clinic. Chest X-ray examination revealed infiltrates in the upper lobe of the right lung. Cefem and aminoglycoside therapy was not effective, and the infiltrates migrated from the right upper lobe to the right middle and lower lobes and then to the left lung. He was transferred to our clinic, and laboratory data showed that CRP was 6+; ESR, 119 mm/1 h; WBC, 3000/mm3; and CAR, 512. The tentative diagnosis of atypical pneumonia was based on the positive agglutination test for Legionella pneumophila, and treatment with erythromycin, minocycline and rifampicin resulted in alleviation of symptoms and resolution of the infiltrates in the lungs. Complement fixation titer for Chlamydia was 128 at admission and was elevated to 512 after 2 weeks. Indirect fluorescent antibody for Legionella was negative. Transient liver dysfunction was also observed.

Non-Hodgkin's lymphoma of the chest wall developing 37 years after plombage and thoracoplasty.

A 64-year-old man developed non-Hodgkin's lymphoma of the chest wall, 37 yr after left plombage thoracoplasty. Late complications of plombage thoracoplasty are discussed as well as the pathogenesis of chest wall neoplasms.

[A case of sarcoid granulomatous interstitial nephritis improved by steroid therapy].

We report a case of sarcoid granulomatous tubulointerstitial nephritis diagnosed by renal biopsy. A 60-year-old man presented with productive cough, and exertional dyspnea of 3 months duration. A chest X-ray film revealed diffuse reticulonodular infiltrates in both lung fields. A transbronchial lung biopsy specimen showed inflammation of the alveolar septum associated with non-caseating granulomas. The patient also had tubular proteinuria and glucosuria. Ga-scintigraphy demonstrated an abnormal accumulation of gallium in both lungs and kidneys. Renal function tests revealed tubular dysfunction. Tubulointerstitial nephropathy was suspected. A renal biopsy specimen exhibited tubulointerstitial nephritis associated with numerous non-caseating granulomas, similar to the findings of the lung biopsy specimen. No glomerular abnormalities were evident. Later, a scalene node biopsy confirmed the diagnosis of sarcoidosis. Prednisolone therapy yielded a favorable outcome for both the renal and pulmonary involvement. During the corticosteroid therapy, measurement of the urinary beta-2-microglobulin concentration proved a valuable monitoring tool for assessing the recovery of the tubular impairment.

A case of malignant fibrous histiocytoma in the lung--resembling recurrent pulmonary thromboembolism.

Malignant fibrous histiocytoma (MFH) can be classified as a pleomorphic mesenchymal sarcoma which occurs most commonly in the extremities and retroperitoneum. We report a very rare case of MFH presumably originating in the pulmonary artery and resembling recurrent pulmonary thromboembolism. MFH was suggested by transbronchial biopsy and confirmed by open lung biopsy. Obstruction of the right main pulmonary artery and stenosis of the left main pulmonary artery was confirmed by pulmonary angiography.