Dendritic cell-based immunization ameliorates pulmonary infection with highly virulent Cryptococcus gattii.

Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection.

[A case of cysticercosis with multiple lesions in the brain and femoral muscles].

A 37-year-old Nepalese man was admitted to Showa University Hospital because of a loss of consciousness and seizures. He had lived in Nepal, Qatar, Singapore, and India before the age of 34 years. He had no history of having eaten raw pork. His physical findings were normal excluding an abnormal visual field, and a positive serum antibody test result for Taenia solium, CT and MRI examinations showed multiple nodular lesions in his brain and thigh. We resected a cyst from his left thigh and diagnosed him as having cysticercosis based on the presence of characteristic hooklets and suckers on a pathological examination. Later, the Asian type of Cysticercus cellulosa was identified using a mitochondrial DNA test. Albendazole (800 mg/day) and prednisolone (60 mg/day) were administered for 14 days. All cysticercus were smaller on Day7 and had almost disappeared on Day 14. No adverse effects from the treatment occurred. Cysticercosis is rare in Japan, and cases requiring treatment for a large number of cysticercus in the brain and thigh are rare. We report a case of neurocysticercosis that had a good clinical course.

Measurement of antifungal drug levels in cerebrospinal fluid for cryptococcal meningoencephalitis.

We report a rare case of cryptococcal meningoencephalitis in which antifungal therapy was monitored by measuring the cerebrospinal fluid (CSF) levels of the antifungal drugs. A 78-year-old man with diabetes mellitus being treated with oral agents. He had no history of human immunodeficiency virus infection. The patient showed abnormal behavior and fever (>38°C) on November 20, 2009, and was admitted for disturbance of consciousness on November 24. CSF examination showed an increased cell count, and a yeast-like fungus, suggesting cryptococcal meningoencephalitis, was observed by India ink staining. Initial treatment was liposomal amphotericin B (L-AMB) plus flucytosine. Cryptococcus neoformans was isolated by CSF culture on day 2. MIC was 0.25 µg/ml for amphotericin B (AMPH-B), 4 µg/ml for flucytosine, 4 µg/ml for fluconazole (FLCZ), and 0.03 µg/ml for voriconazole (VRCZ). Despite treatment, his disturbance of consciousness persisted. The CSF level of AMPH-B was ≤0.05 µg/ml on day 8. Therefore, L-AMB was switched to fosfluconazole. The CSF level of FLCZ was sufficient (22.6 µg/ml) on day 25, but there was a decrease in glucose and the fungus could still be detected in CSF smears. Consequently, FLCZ was switched to VRCZ. On day 47, CSF level of VRCZ was 1.97 µg/ml, exceeding its MIC, so treatment was continued. On day 77, the patient was generally lucid, and CSF smears did not detect any fungi. The patient was then transferred for rehabilitation. On day 84, voriconazole was discontinued, with no evidence of fungal recurrence.

Mold colonization of fiberglass insulation of the air distribution system: effects on patients with hematological malignancies.

We investigated mold colonization of air handling units (AHUs) of heating, ventilating, and air conditioning (HVAC) systems and its effects, including invasive pulmonary mycoses and febrile neutropenia, in patients with hematological malignancies. Sample collection with transparent adhesive tape and culture swabs revealed that AHUs were heavily colonized with molds, including thermotolerant, variously distributed Penicillium spp. Cases of nosocomial invasive pulmonary mycosis were not clustered in specific patient rooms but did occur frequently when the HVAC systems were not in use, prior to intervention (i.e., sealing and disuse of AHUs in private room), and during construction of a new hospital building. Multivariate logistic regression analysis of initial episodes of febrile neutropenia showed that the rate of febrile neutropenia was significantly associated with the duration of neutropenia (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.07-1.27) and with sex (OR: 0.469; CI: 0.239-0.902). An evaluation of private rooms showed that female patients also had a lower rate of fever after intervention (OR: 0.0016; 95% CI: 0.000-0.209). The reduced rate of febrile neutropenia after intervention suggests that mold colonization of AHUs had adverse effects on patients with hematological malignancies.

[Cryptococcosis].

Cryptococcosis is a common fungal infection that caused by Cryptococcus neoformans in immunocompetent individuals as well as in immunosuppressive patients with such as the HIV infection. Measurements of the values of glucuronoxylomannan structuring capsule of C. neoformans in serum or cerebrospinal fluid are quite useful to diagnosis of pulmonary cryptococcosis and cryptococcal meningitis as major two forms of cryptococcosis. Azole anti-fungal agents including fulconazole, itraconazole for pulmonary cryptococcosis, and amphotericin B plus flucytosine for cryptococcal meningitis are recommended as first line therapy in Japanese guideline for the diagnosis and treatment of deep seated mycosis revised in 2007. The clinical appearance, diagnostic methods, treatment and prognosis of pulmonary cryptococcosis and cryptococcal meningitis are described based on the Japanese guideline in this manuscript.

Sibling cases of Mycobacterium avium complex disease associated with hematological disease.

A 22-year-old man who was admitted to our respiratory division complaining of fever and cough of 1 month's duration had been diagnosed with myelodysplastic syndrome 5 years earlier. On admission, radiological findings showed bilateral diffuse small nodular shadows. Although the results of an acid-fast bacilli examination of blood, sputum, and urine samples were all negative, we initiated antituberculous therapy for suspected miliary tuberculosis because the histological diagnosis from a bone marrow biopsy was epitheloid granuloma. The abnormalities on his chest radiographs improved, but his left cervical lymph nodes became swollen. The histological result of a lymph node biopsy revealed epitheloid granuloma with caseating necrosis. The DNA-DNA hybridization result of a resected lymph node culture indicated Mycobacterium avium. The final diagnosis was disseminated Mycobacterium avium complex (MAC) disease. Both leukocytopenia and thrombocytopenia had been noted in the patient's 19-year-old younger brother, who had been living in the same home 5 years earlier, and for whom a diagnosis of myelodysplastic syndrome was made from bone marrow aspiration on admission. An infiltration shadow with nodular shadows was noted in the right upper lung field on a chest radiograph. A bronchoscopic examination revealed pulmonary MAC disease. As for the route of infection, although we investigated restriction fragment length polymorphism (RFLP), a different pattern was found in the two brothers. We suspect that they were infected by different species of Mycobacterium avium in the same environment rather than by droplet infection from the younger brother to the older brother.

Four cases of pulmonary Mycobacterium avium intracellulare complex presenting as a solitary pulmonary nodule and a review of other cases in Japan.

OBJECTIVE: To evaluate clinical findings of patients with a solitary pulmonary nodule in Japan caused by pulmonary Mycobacterium avium complex (MAC) disease. METHODS: The authors investigated the clinical features of 12 patients diagnosed as having pulmonary MAC disease who had presented with a solitary pulmonary nodule. RESULTS: The causative microorganisms were M. avium in seven patients, Mycobacterium intracellulare in two and MAC in three. The diagnostic methods were bronchoscopic biopsy or percutaneous lung biopsy in three patients and surgical operations in the remaining nine. Eleven patients had a complete surgical resection of the nodule and antituberculous drugs were administered to eight. On X-ray, there was an absence of calcification, satellite lesions, cavities, or bronchoectasis that are often thought to be characteristic of pulmonary mycobacterial disease. Differentiation from lung cancer was thought necessary in five patients. There was no microbiological or radiological relapse in those who underwent complete surgical resection. CONCLUSIONS: Because treatment is often poorly effective for patients with pulmonary non-tuberculous mycobacterial disease, it is important to identify the causative microorganisms by performing a culture examination of resected lung tissue especially if there is a solitary pulmonary nodule.

Synchronus presentation of early-stage small cell carcinoma and adenocarcinoma in the same lung lobe.

A 73-year-old man with no symptoms was admitted to our hospital with a nodular shadow (>2 cm) in the left upper lung field on chest X-ray. A histological diagnosis (small cell carcinoma) was obtained by bronchoscopic examination including a transbronchial lung biopsy (TBLB). The preoperative clinical staging was T1N0M0 (StageIA). After preoperative chemotherapy (CDDP + CPT11) was carried out, a nodule in the left S(1+2) diminished remarkably, but a smaller nodule in the left S3 (>8 mm) remained unchanged. While the nodule in the left S(1+2) (small cell carcinoma) had become completely necrotic by the time the final diagnosis was made after resection of the left upper lobe, histological diagnosis of the nodule in the left S3 revealed a well differentiated adenocarcinoma. Synchronous presentation of early-stage lung cancer consisting of small cell carcinoma and adenocarcinoma was identified in the same left upper division of the lung. Because there have been the few previous reports regarding cases of synchronous presentation of early-stage lung cancer in the same lung lobe, we also report on the clinical characteristics, thus adding this case to the five previously reported cases.

Infectious bulla of the lung caused by Mycobacterium intracellulare.

A healthy 24-year-old man who was admitted to our hospital was suspected of having an infectious bulla of the lung because an intrabullous effusion was seen on a chest radiograph. A bulla of the right lung had been found 2 years earlier during a periodic health examination. On a chest radiograph, a bullous lesion with a niveau-like shadow (14 x 7 cm) was noted in the right lower lobe of the lung. On puncture aspiration, the bulla fluid was found to be exudative and contained mostly lymphocytes. A smear examination for acid-fast bacilli was positive, as was polymerase chain reaction (PCR) examination for Mycobacterium intracellulare. Therefore, a diagnosis of infectious lung bulla caused by M. intracellulare was made. A right lower lobectomy was performed. On macroscopic examination of the resected lesion, the area surrounding the bulla was whitish in color, and microscopic examination of this area showed a caseating epitheloid granuloma with acid-fast bacilli. We report this case because there have been no previous reports in the literature of infectious lung bulla caused by M. intracellulare although there have been several reports dealing with lung bulla caused by Mycobacterium tuberculosis.

Hermansky-Pudlak syndrome with interstitial pneumonia without mutation of HSP1 gene.

A 57-year-old man with occulocutaneous albinism was admitted to our hospital because of exertional dyspnea and an abnormal shadow on chest roentgenogram. Chest CT revealed diffuse interstitial shadows with reticulonodular opacities in the bilateral whole lung fields and his pulmonary function test was consistent with a restrictive finding. Histologically, intraluminal diffuse fibrosis and interstitial fibrosis existed and ceroid-like materials within alveolar macrophages were demonstrated in a transbronchial lung biopsy specimen. In addition, because platelet dysfunction and ceroid-like materials within the reticuloendothelial cells of urine and bone marrow aspiration were recognized, we made a diagnosis of Hermansky-Pudlak syndrome (HPS). Gene analysis of the patient's peripheral blood cells did not reveal that he was a compound homogeneity for HPS1 gene mutations. Concerning treatment, although corticosteroid therapy was administered, his clinical symptoms and abnormal chest shadow have not changed.

[Clinical analysis of pulmonary actinomycosis].

A clinical analysis of four patients diagnosed as pulmonary actinomycosis in our respiratory division during the last seven years was performed. All of the patients were males with an average age of 61 years. Three patients had a past history. The clinical diagnosis on admission was lung cancer or pulmonary suppuration in three patients showing a mass-like shadow and pneumonia in one patient with an infiltration shadow. Suspected pulmonary infectious disease was detected from clinical symptoms in two patients, while suspected lung cancer was detected in the other two patients during health examinations. The lesions dominantly existed in the right upper lobe. Such findings as central low attenuation (LAA), bronchiectasis and pleural thickening were characteristic on chest computed tomography (CT). The diagnostic methods were all negative procedures; video-assisted thoracoscopic surgery (VATS) in two patients, a specimen obtained by bronchoscopy in one and a specimen taken by percutaneous aspiration in one. Because penicillin antibiotics were administered for a long time for all patients after obtaining a definite diagnosis, the prognosis was good and there were no relapse.

[Current status of patients discharging Mycobacterium tuberculosis after admission to Kawasaki Medical School Hospital].

OBJECTIVES: To investigate the current status of patients with tuberculosis in Kawasaki Medical School Hospital which has closed tuberculosis isolation ward and review the nosocomial tuberculosis infection control. MATERIALS AND METHODS: Clinical analysis was performed and nosocomial tuberculosis infection control were examined in 39 patients from whom Mycobacterium tuberculosis was isolated in Kawasaki Medical School Hospital between January 2001 and August 2004. RESULTS: Mycobacterium tuberculosis was isolated in 16 patients in the Respiratory Division of the Department of Internal Medicine and in 23 patients in non-respiratory divisions. Thirty-four patients had underlying diseases and of these 14 patients had malignant diseases. The final diagnosis was pulmonary tuberculosis in 23 patients, and pulmonary tuberculosis was suspected in 13 patients on admission. The remaining 10 patients were treated for pneumonia on admission. M. tuberculosis was isolated most frequently from the sputum in 21 patients and 13 of them were smear positive who needs nosocomial infection control measures. Health examinations of the families and hospital staff in contact with these 13 patients with smear positive sputum after the diagnosis of tuberculosis revealed no active case of tuberculosis. CONCLUSIONS: This study has shown that there are many cases with an atypical pattern for pulmonary tuberculosis among patients with underlying diseases, especially malignant diseases. There are still many tuberculosis patients who were diagnosed pneumonia after the admission and were administered antibiotics. We believe that more educational guidance regarding tuberculosis is needed for the hospital staff.

Multifocal micronodular pneumocyte hyperplasia in a man with tuberous sclerosis.

We report a peculiar case of multifocal micronodular pneumocyte hyperplasia (MMPH) occurring in a 43-year-old man with tuberous sclerosis. Computed tomography of the chest demonstrated multiple micronodules, measuring up to 5 mm in size, present bilaterally in the lung fields, with no cystic change. Histologically, a proliferation of type II pneumocytes without the typical nulclear atypia lined the thickened alveolar septa in an adenomatoid pattern. Proliferation of immature smooth muscle cells suggestive of LAM was not observed. The characteristic findings of the positive immunohistochemical stains for cytokeratin and surfactant apoprotein A and B, and negative stains for HMB-45, alpha-1 smooth muscle actin, desmin, p53 and carcinoembryonic antigen confirmed the presence of alveolar lining cells in each MMPH lesion. Since the MMPH was observed in a male and did not appear to possess malignant potential, the MMPH appears to be a hamartomatous proliferation occurring in a male with tuberous sclerosis that is separate from lymphangiomyomatosis (LAM) which is related to estrogen and progesterone receptors.

[A case of pulmonary adenosquamous cell carcinoma with thin-wall cavities].

A 68-year-old man was admitted to our hospital because of continuous cough of three months duration and for investigation of a thin-wall cavitary lesion (> 3 cm) in the right upper lung field. Thin-wall cavity (40 x 35 mm) with notch and spiculation was observed in the right S2 on chest CT. A histological diagnosis of pulmonary adenocarcinoma was obtained by bronchoscopic examination, and he was transferred to the Department of Thoracic Surgery where a right upper lobectomy was performed. Subsequently, cavity formation (45 x 40 x 35 mm) was disclosed in the right S2. Most of the surrounding cavity consisted of the components of a well differentiated squamous cell carcinoma with keratinization and slightly different components of a poorly differentiated adenocarcinoma with mucous production. The final diagnosis was pulmonary adenosquamous cell carcinoma and the postoperative histological classification was T2N2M0 (Stage 3A) because of metastasis to the lymph nodes (#4 and #11). A communicating bronchus was histologically identified and we presumed that the thin-wall cavity developed by a check valve mechanism. Although squamous cell carcinoma has been reported to be the histological type, tending to form thin-wall cavities among patients with lung cancer reported to be squamous cell carcinoma, recently an increasing number of such cavities have been reported among patients with pulmonary adenocarcinoma. Herein, we have reported a rare case of histological diagnosis of pulmonary adenosquamous cell carcinoma with cavity formation.

Pulmonary Mycobacterium avium disease with a solitary pulmonary nodule requiring differentiation from recurrence of pulmonary adenocarcinoma.

A 56-year-old man with a past history of surgical resection of a primary pulmonary adenocarcinoma in the right upper lobe was admitted to our hospital because of a rapidly increasing solitary nodule (50x30 mm) in the right S5 followed on the chest computed tomography (CT) for three months. Although we suspected recurrence of the pulmonary adenocarcinoma and performed a CT-guided lung biopsy, we could not make a definite diagnosis. Therefore, to rule out recurrence of the primary pulmonary adenocarcinoma completely, a partial surgical resection of the right middle lobe was performed and a caseating epitheloid granuloma with acid-fast bacilli was found. As the causative pathogen, Mycobacterium avium complex (MAC) disease should be considered in the differential diagnosis of a rapidly increasing solitary nodule through this peculiar case of pulmonary MAC disease.

[A case of pulmonary Mycobacterium intracellulare infectious disease with a solitary pulmonary nodule in the peripheral lung field].

A 63-year-old woman was admitted to our hospital because of a solitary nodule (20 x 20 mm) in the right S3 which was first detected during a health examination. Because radiological findings for the nodule, such as pleural indentation and spicula on chest CT led us to suspect a pulmonary adenocarcinoma, we could not completely rule out lung cancer and performed a bronchoscopic examination on the third day after admission. However, no definite diagnosis could be made. Therefore, video-assisted thoracic surgery (VATS) was performed, and a caseating epitheloid granuloma with acid-fast bacilli was found. Initially, we administered antituberculous drugs for pulmonary tuberculoma, but then changed to combined chemotherapy using RFP, EB, CAM and SM after identification of Mycobacterium intracellulare by a culture test of resected tissue. We report a rare case with a solitary nodule caused by pulmonary Mycobacterium intracellulare infectious disease which is indicative of lung cancer.

Thoracic actinomycosis with mainly pleural involvement.

A 61-year-old man, who had been diagnosed with pleuritis 5 months earlier, was admitted to our hospital to determine if a tumor shadow that appeared in his right lower lung field on March 2002 was a localized pleural mesothelioma. Although a CT-guided lung biopsy was performed, no definite diagnosis was made. However, because the tumor shadow continued to increase in size, we could not rule out the possibility of a malignant thoracic tumor, and performed video-assisted thoracoscopic surgery (VATS). Histological examination of the surgically resected tissue led to a diagnosis of thoracic actinomycosis in the main component of the pleura. Because the recurrence of pulmonary actinomycosis was also suspected after surgical treatment, penicillin G was administered intravenously and afterward amoxicillin was administered intraorally. Subsequently, the patient's clinical status improved. We considered a case of thoracic actinomycosis that was suspected to have spread directly from the lung to the chest wall with complicating pleural effusion and remained with organization because there was a pulmonary infiltration shadow in the right upper lobe on chest CT at the first admission.

[A case of pulmonary adenocarcinoma coexistent with Igusa pneumoconiosis in one segment of the lung].

A 79-year-old man, who had an occupational history of handling rushes (which were treated with pigmented earth containing 25% silica) for 30 years and a past history, eight years earlier, of primary pulmonary adenocarcinoma in the left lower lung (T2N2M0), was admitted to our hospital for the investigation of two nodular shadows in the right upper S3 which showed a double lesion detected on chest CT. A histological diagnosis of pulmonary adenocarcinoma was obtained by bronchoscopic examination, and so he was transferred to the Department of Thoracic Surgery and video-assisted thoracoscopic surgery (VATS) was performed. Subsequently, the large part of the tumor, in the central region, was diagnosed as a pulmonary adenocarcinoma, and the smaller part of the tumor, in the peripheral region, was found to consist of an adhesion of small nodules composed of pneumoconiosis due to the rushes. Multiple small nodules consisting of rush pneumoconiosis were histologically recognized surrounding this smaller part of the tumor. Although, at admission, we first suspected the presence of multicentric, metastatic lung cancer and an inflammatory tumor, the patient's occupational history also proved to be important, and we could not decide on the appropriate diagnosis before VATS because multiple small nodules consisting of rush pneumoconiosis overlapped the tumor.

[Clinical analysis of pulmonary tuberculosis detected during follow-up of other underlying diseases].

OBJECTIVE: The objects of this study were to analyze clinically the outpatients and inpatients who were diagnosed as pulmonary tuberculosis during the follow-up of other underlying diseases at our affiliated hospitals and to review the past problems and to discuss how to improve the situation. METHODS: Sixty five outpatients or inpatients diagnosed as pulmonary tuberculosis during the follow-up of other underlying diseases were collected from 508 patients with pulmonary tuberculosis at our affiliated hospitals over the past 10 years. RESULTS: The proportion of elderly patients over 65 years old among 65 index cases was significantly higher as compared to the control group. Forty three of these index patients were outpatients and 22 were inpatients. The most frequent underlying diseases excluding respiratory diseases were malignant diseases followed by diabetes mellitus, gastrointestinal diseases and psychosomatic diseases in order. Pulmonary tuberculosis without clinical symptoms was detected by periodic chest X-ray in 21 cases (32%). There were some severe TB cases caused by the doctor's delay who were followed for malignant or psychosomatic diseases. CONCLUSION: Although many doctors except for respiratory specialists tended to pay attention to pulmonary tuberculosis as a possible complication during periodic health examination, further intensive education regarding pulmonary tuberculosis is required for doctors who treat malignant or psychosomatic diseases at special hospitals because TB patients who were smear positive when they were detected may cause outbreak of tuberculosis in the hospital.

[Clinical analysis of pulmonary tuberculosis found by mass screening medical examination].

Five hundred twenty-one patients with pulmonary tuberculosis were diagnosed in our three affiliated hospitals during past 10 years. Among them, 43 cases (22 men and 21 women; mean age 54.8 years) who were detected by active case-finding were clinically evaluated. Most of them were detected in an annual mass screening examination, but seven cases were found by contacts examination which was performed on subjects who were contacted with newly diagnosed patients with pulmonary tuberculosis. Fifteen of them were socially jobless on admission. Eighteen cases (41.9%) had underlying diseases, and gastrointestinal diseases and diabetes mellitus were most frequently observed. The final diagnosis was confirmed through bronchoscopic specimens in 18 cases in which Mycobacterium tuberculosis could not be detected from the sputum. Regarding radiological findings according to the criteria of the Japanese Society of Tuberculosis, most cases had unilateral distribution, and were classified as type III (active, non-cavitary) for characteristics and 1 (minimal) for the extent of lesions. Treatment using combination therapy with four drugs including pyrazinamide was performed for over half of these cases and subsequently the clinical efficacy was good except in one case who died due to worsening of the underlying disease. Anti-tuberculous drugs were generally administered to cases suspected of having pulmonary tuberculosis on chest X-ray. However, early diagnosis using bronchoscopy and early treatment seems to be useful, when Mycobacterium tuberculosis is not detected in the sputum.