Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia.

AIMS: To evaluate the histological characteristics differentiating chronic hypersensitivity pneumonitis (chronic HP) with a usual interstitial pneumonia (UIP)-like pattern from idiopathic pulmonary fibrosis (IPF)/UIP. METHODS AND RESULTS: Surgical lung biopsy specimens from 22 patients with chronic HP diagnosed as having a UIP-like pattern upon histological examination and 13 patients with IPF/UIP were examined and the incidences of bronchiolitis, perilobular fibrosis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, fibroblastic foci, honeycombing, granulomas, giant cells, lymphocytic alveolitis and lymphoid follicles were compared. Bronchiolitis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, granulomas, giant cells and lymphocytic alveolitis were significantly more frequent among patients with chronic HP than among patients with IPF (all P<0.01). CONCLUSIONS: Centrilobular fibrosis, bridging fibrosis and organizing pneumonia, in addition to bronchiolitis, granulomas and giant cells, are characteristic features of chronic HP with a UIP-like pattern. These features are therefore important in differentiating chronic HP from IPF/UIP, as management strategies differ for the two disorders.

Efficacy and safety of short- and long-term treatment of itraconazole on chronic necrotizing pulmonary aspergillosis in multicenter study.

In the respiratory field, chronic pulmonary aspergillosis, such as chronic necrotizing pulmonary aspergillosis (CNPA) or aspergilloma, is important. We examined the efficacy and safety of short- and long-term itraconazole (ITCZ) administration, involving a switch from injection to an oral preparation, in patients with CNPA. In all hospitals participating in this study, the protocol was approved by the ethics review board. This study started after UMIN registration (UMIN000001727). Subjects enrolled in this study were patients who were clinically or definitively diagnosed with CNPA in the respiratory field, according to the diagnostic criteria of the Japanese "Guidelines for management of deep-seated mycosis 2007," in 16 hospitals that participated in this study between May 2008 and March 2011. Treatment was started with ITCZ injection. Subsequently, the agent was switched to an oral preparation. Efficacy was evaluated with major items (clinical symptoms, fever, imaging findings) and minor items (nutritional status, inflammatory markers). Twenty-nine patients were enrolled; safety was evaluated in 24 and efficacy in 23. Of the 23 patients, 10 (43.5 %) responded. With respect to the administration period, the response rates in 8 patients treated for a short period and 15 treated for a long period were 25.0 % and 53.3 %, respectively. Trough blood concentration of ITCZ reached a level at which ITCZ may be effective for aspergillosis at 3 days after the start of ITCZ injection therapy. After changing to high-dose capsules, its level was also maintained. Adverse events such as liver dysfunction and heart failure were observed in 9 of the 24 patients. Furthermore, 6 patients died. However, there was no relationship between these events and ITCZ. Step-down therapy from ITCZ injection to oral administration may be a useful treatment option in CNPA patients requiring long-term treatment.

[Two cases of microscopic polyangitis with preceding interstitial pneumonia diagnosed by surgical lung biopsy].

We encountered 2 cases of microscopic polyangitis (MPA) with preceding interstitial pneumonia. The patients were elderly men, and radiological findings showed a UIP pattern in both cases. Furthermore, ANCA-associated vasculitis had been suspected since the first admission in case 1, because MPO-ANCA tests were positive, and the surgical lung biopsy revealed vasculitis in a honeycomb lesion. A diagnosis of idiopathic pulmonary fibrosis was made in case 2 because no findings of vasculitis were pathologically confirmed, and MPO-ANCA was not examined. Both patients were followed up without any treatment, but steroid therapy with immunosuppressants was initiated after a diagnosis of MPA was made from a renal failure complication. Remission continued in case 1, but patient 2 died due to a pulmonary hemorrhage complication, despite some temporary improvements. An autopsy revealed massive alveolar hemorrhage and neutrophil infiltration in the alveolar walls that suggested pulmonary capillaritis, in spite of the absence of pathological evidence, which was not detected in the honeycomb lesions. These 2 cases indicate that MPO-ANCA should be examined in the follow-up of chronic interstitial pneumonia. Furthermore, it should be assumed that the size of involved blood vessels, their distribution and the timing of occurrence may be different in individual case of ANCA-associated interstitial pneumonia.

[Three cases of allergic bronchopulmonary mycosis due to Schizophyllum commune].

We report 3 cases of allergic bronchopulmonary mycosis (ABPM) due to Schizophyllum commune. The first patient, an 82-year-old woman, presented with atelectasis of the left upper lobe with mucoid impaction due to Schizophyllum commune. The second patient, a 53-year-old woman, presented with atelectasis of the right middle lobe with mucoid impaction due to Schizophyllum commune. The last patient, a 49-year-old woman, underwent a left lingular lobectomy with a diagnosis of lung abscess, but the diagnosis was retrospectively changed to ABPM in a later review of the findings of the surgical specimens. The diagnosis and treatment of ABPM are not well defined, and this considerably delayed our diagnosis in these three cases. We hope to establish a more definitive diagnosis and treatment for ABPM through ongoing encounters with patients.

[Evaluation of KL-6 CLEIA reagent].

KL-6 is a high-molecular-weight sialylated glycoprotein, classified as a cluster 9 pulmonary cell antigens, and is a sensitive marker for the clinical diagnosis of interstitial pneumonia and its activity, especially in the acute phase. Additionally, it is necessary to diagnosis that patient was not pneumothirax, pulmonary thromboembolism and heart failure. In this study, we evaluated a new assay system based on chemiluminescence EIA (CLEIA) on a fully automated analyzer. Both plasma and serum samples were used, and the master calibration method was applied, eliminating the need for a standard curve preparation. The assay time was shortened to less than 1 hour. Good correlations were observed between this assay and conventional assay kits, y = 1.094x-6.849, r = 0.986 using 326 samples, and between serum and plasma y = 0.997x-1.211, r = 0.997 using 225 paired samples. In addition, the alteration of KL-6 concentration in patients undergoing chemotherapy treatment resulted in similar results that with conventional kits, and elevated KL-6 concentrations were observed in samples from patients with interstitial pneumonia. These results underscore the usefulness of this new assay kit as a rapid test, particularly for the medical examination of outpatients and the treatment of emergency cases in the acute phase of interstitial pneumonia.

[Clinical comparison of male and female patients with pulmonary disease caused by Mycobacterium avium complex (P-MAC)].

OBJECTIVES: The objective of this study was to clarify clinical feature of Pulmonary Mycobacterium avium complex disease (P-MAC). METHOD: The present study was performed in 120 patients with P-MAC diagnosed during the period from January 2000 to March 2007. We divided P-MAC patients into four groups by the clinical disease type and gender, and retrospectively examined the clinical characteristics. RESULTS: The subjects were 15 male (NB-M) and 71 female (NB-F) patients with nodular bronchiectatic disease (NB), and 24 male (FC-M) and 10 female (FC-F) patients with fibrocavitary disease (FC). The average age was lowest in the NB-F group (58.0 yrs), and highest in the FC-M group (65.8 yrs). There were 17 patients in the FC-M group and only two patients in the FC-F group with a history of smoking. The average body mass index (BMI) was 16.9, with the lowest value in the FC-F group. In the FC-M group, most of the patients had underlying pulmonary disease, whereas in the FC-F group, only four patients had underlying old pulmonary tuberculosis. The average anterior-posterior dimension was 75.2 mm, being lowest in the FC-F group, and more than 90 mm in the other groups. The proportion of refractory cases was lowest in the NB-M group. CONCLUSION: We thought that we were able to clarify characteristics of patients with disease caused by MAC by analyzing the types of the disease separately in men and women.

Disseminated cryptococcosis complicated with bilateral pleural effusion and ascites during corticosteroid therapy for organizing pneumonia with myelodysplastic syndrome.

An 83-year-old man with myelodysplastic syndrome was admitted to our hospital due to dyspnea and abnormal shadows on chest X-ray films during corticosteroid therapy for organizing pneumonia. He was diagnosed as having disseminated cryptococcosis with pulmonary lesions after detecting Cryptococcus neoformans. Both bilateral pleural effusion with or without ipsilateral pulmonary lesions and ascites ensued, and it was assumed that both direct involvement and serositis were associated with the fluid accumulation. Cryptococcal yeast was only detected in the right pleural effusion, and the titer of cryptococcal antigen was quite different between body cavities, even though it was positive in all sites.

[Case of acute bird fancier's lung caused by a yellow-shouldered Amazon bird associated with lung cancer].

A 69-year-old man was admitted to our hospital complaining of generalized weakness and cough for one month. Chest computed tomography (CT) demonstrated bilateral ground-glass opacities and a nodule in right S6 about 11mm in diameter with multiple mediastinal lymph node swellings. After admission the patient's symptoms improved without therapy and examination of the bronchoalveolar lavage fluid (BALF) and transbronchial lung biopsy (TBLB) revealed findings compatible with acute hypersensitivity pneumonitis. We did not consider that the acute hypersensitivity was caused by the patient's Amazon bird, because he had been breeding them for 40 years. However after obtaining a careful history, it became clear that close and frequent contact with the bird had occurred for the first time in the previous year. On the basis of the anti-bird excreta antibody found in the patient's serum and BALF, we diagnosed this case as a case of acute bird fancier's lung caused by the yellow-shouldered Amazon bird. We diagnosed the nodule in right S6 as lung adenocarcinoma by a thoracoscopic lung biopsy, and performed lower lobe lobectomy. We considered that the mediastinal lymph node swellings were caused by hypersensitivity pneumonitis.

[A study on clinical features of Mycobacterium kansasii pulmonary disease in women].

OBJECTIVES: To clarify clinical features of M. kansasii pulmonary disease in women. METHODS: We performed a retrospective analysis of M. kansasii pulmonary disease in women compairing with that in men. We focused on 8 female cases of M. kansasii pulmonary disease during the past 7 years from June 1998 to August 2005. RESULTS: The cases of M. kansasii pulmonary disease in women have increased in the latter few years. The mean age of female cases was higher than that of male cases, 65.6 and 53.1 years old, respectively. The number of female cases with smoking history was lower than that of male cases, 37.5% and 90.0%, respectively. Two female cases had underlying pulmonary diseases, as compared with 10 male cases, 25.0% and 33.3%, respectively. The radiological findings in female cases included 2 cavitary opacities, 1 infiltrative opacity and 5 nodular, bronchiectatic opacities, as compared with 27 cavitary opacities, 1 infiltrative opacity, 1 solitary nodular opacity and 1 nodular, bronchiectatic opacity in male cases. MAC was also detected in 2 female cases, who presented with nodular, bronchiectatic opacities. On the other hand, there were 6 female cases, in which no other NTM was detected. 3 cases showed cavitary or infiltrative opacities, which improved with the following 3 tuberculous drugs INH, RFP, and EB (HRE), while others showed nodular, bronchiectatic opacities, in which 2 cases showed radiological exacerbations without any treatment and another one revealed an improvement with HRE. CONCLUSIONS: M. kansasii pulmonary disease in women tends to be identified in elderly who smoke less and have no underlying pulmonary diseases, and most of radiological findings in female cases revealed nodular, bronchiectatic opacities. Summing up all these findings, clinical features of M. kansasii pulmonary disease in women was considered to resemble that of MAC infection, and it was speculated that the increase of M. kansasii pulmonary disease in women has some relationship with that of MAC infection in middle or lingular lobe. However, it was confirmed that some cases of M. kansasii pulmonary disease in women might primarily present with nodular, bronchiectatic lesions, regardless of MAC infection.

Inhalation of inorganic particles as a risk factor for idiopathic pulmonary fibrosis--elemental microanalysis of pulmonary lymph nodes obtained at autopsy cases.

Exposure to inorganic particles may induce fibrosis in the lung. However, the association between exposure to inorganic particles and the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is obscure. We examined inorganic particles in the pulmonary hilar lymph nodes affected by IPF/UIP to investigate whether inhaled elements are involved in the etiology, and whether there is an increasing risk of developing IPF/UIP. Twenty-three IPF/UIP cases and 23 controls without IPF/UIP were investigated. Pulmonary hilar lymph nodes constituted the study material. The elemental analysis was performed using scanning electron microscopy with an energy dispersive X-ray spectroscope, and we analyzed particles quantitatively and qualitatively. The results showed that the cases contained silicon and aluminum as compared with the control in lymph nodes, and these deposits were statistically significantly associated with an increased risk of IPF/UIP (adjusted odds were 2.99, 95% CI: 1.29-6.85 and 57.84, 95% CI: 1.45-2306.19, respectively). In addition, higher nickel levels in lymph nodes were associated with lung cancer. This study shows that inorganic particles, such as Si and Al, have higher concentrations in the hilar lymph nodes in IPF/UIP, and may play a role in one of the risk factors in the pathogenesis of IPF/UIP.

Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. NOD2 mutations have been shown to predispose to granulomatous diseases, including Crohn's disease, Blau syndrome, and early-onset sarcoidosis, but not to adult sarcoidosis. We found that intracellular Propionibacterium acnes, a possible causative agent of sarcoidosis, activated NF-kappaB in both NOD1- and NOD2-dependent manners. Systematic search for NOD1 gene polymorphisms in Japanese sarcoidosis patients identified two alleles, 796G-haplotype (156C, 483C, 796G, 1722G) and 796A-haplotype (156G, 483T, 796A, 1722A). Allelic discrimination of 73 sarcoidosis patients and 215 healthy individuals showed that the frequency of 796A-type allele was significantly higher in sarcoidosis patients and the ORs were significantly elevated in NOD1-796G/A and 796A/A genotypes (OR [95% CI]=2.250 [1.084, 4.670] and 3.243 [1.402, 7.502], respectively) as compared to G/G genotype, showing an increasing trend across the 3 genotypes (P=0.006 for trend). A similar association was found when 52 interstitial pneumonia patients were used as disease controls. Functional studies showed that the NOD1 796A-allele was associated with reduced expression leading to diminished NF-kappaB activation in response to intracellular P. acnes. The results indicate that impaired recognition of intracellular P. acnes through NOD1 affects the susceptibility to sarcoidosis in the Japanese population.

[Diagnostic criteria of neurosarcoidosis].

We have collaborated with Japanese Sarcoidosis Society and Japanese Society of Respiratory Disease to provide a new diagnostic criteria of neurosarcoidosis. At least two of six examinations are important. These include bilateral hilar lymphadenopathy, abnormal uptake of 67Ga scintigraphy, broncho alveolar lavage fluid examination, elevated serum ACE, negative tuberculin reaction, and elevated serum or urinary calcium level. (definite) Having positive clinical findings which suggest a neurosarcoidosis. Pathology proven case. (probable) Having positive clinical findings which suggest a neurosarcoidosis. Pathology proven in other organ. At least two of six examinations are positive. (possible) Having positive clinical findings which suggest a neurosarcoidosis. At least two of six examinations are positive. CNS sarcoidosis, sarcoid neuroopathy and sarcoid myopathy are separately diagnosed. Kveim reaction which is time consuming, not so specific, and difficult to obtain its antigen is no more necessary.

[A case of volcanic ash lung: report of a case].

A 57-year-old woman inhaled much volcanic ash without using a mask every day during the eruption of the Miyake Volcano in August 2000. An abnormal shadow was pointed out on her chest radiography by chance, after she sought refuge in Higashimurayama city in September. She had no respiratory symptoms and her chest radiography in an annual health check in July 2000 had showed no abnormality. She was admitted to our hospital and thoracoscopic lung biopsy was performed. We diagnosed it as lung inflammation caused by volcanic ash. The reasons for diagnosis were because the abnormal shadow appeared after the inhalation of volcanic ash, chest computed tomography showed diffuse irregular shadows with air bronchogram, thoracoscopic lung biopsy showed cellular-bronchiolitis around crystals, and the results of mineralogical analysis of the particles in alveolar macrophages detected in the biopsy specimen by scanning electron microscopy (SEM) were very similar to those of volcanic ash. The shadow on her chest radiography disappeared gradually without any treatment, but she avoided further exposure to volcanic ash. It is necessary to consider volcanic ash capable of causing lung inflammation.

Sarcoidosis with acute recurrent polyarthritis and hypercalcemia.

A 45-year-old woman had bleary eyes and recurrent episodes of fever and arthritis in the knees and ankles. The patient had anterior uveitis, negative findings of the tuberculin test, and an increased serum lysozyme level, but bilateral hilar lymphadenopathy (BHL) was absent. During the course of her disease, the serum calcium and angiotensin-converting enzyme levels gradually increased to above the normal level, and the patient was clinically diagnosed as having sarcoidosis. The clinical features of arthritis were typical of those of Löfgrens syndrome although BHL and erythema nodosum were absent. The patient was successfully treated with 15 mg/day of prednisolone.

Trimethoprim-sulfamethoxazole-induced hypersensitivity syndrome associated with reactivation of human herpesvirus-6.

A 27-year-old man who had a history of bronchial asthma, eosinophilic enteritis, and eosinophilic pneumonia presented with fever, skin eruptions, cervical lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and eosinophilia two weeks after receiving trimethoprim (TMP)-sulfamethoxazole (SMX) treatment. After the withdrawal of TMP-SMX and the administration of high-dose steroid, these systemic symptoms gradually resolved. During the disease course, the patient showed a transient increase in anti-human herpesvirus (HHV)-6 antibody titers and HHV-6 DNA in the peripheral blood, indicating the reactivation of a latent HHV-6 infection. This is the first case of TMP-SMX-induced hypersensitivity syndrome associated with the reactivation of a latent viral infection.

[A case of eosinophilic bronchiolitis complicated with eosinophilic sinusitis].

A 42-year-old man was admitted to our hospital, complaining of dyspnea and cough for six months. Chest CT demonstrated thickening of the bronchial walls and some centrilobular nodules. From the laboratory data and the clinical course, he was first suspected to have bronchial asthma. However, it was necessary to rule out bronchiolitis due to other causes, because he had no previous asthma history and also because of the CT findings. We performed surgical lung biopsy to make a definite diagnosis. The pathological findings revealed eosinophilic bronchiolitis. While dyspnea and the eosinophilic nasal polyp improved by treatment with oral steroid therapy, the eosionophilic sinusitis and bronchiolitis relapsed after steroid tapering. Improvement and relapse of nasal and lower airway symptoms were synchronously observed. Eosinophilic bronchiolitis and eosionophilic sinusitis in this case may be considered to be a category of airway eosinophilic inflammation.

Evaluation of microsatellite markers in association studies: a search for an immune-related susceptibility gene in sarcoidosis.

Association studies using linkage disequilibrium (LD) between candidate loci and nearby markers have been proposed to identify susceptibility genes for complex diseases. We analyzed polymorphisms of microsatellites (MSs) and LD patterns of the regions in which candidate genes related to the Th1 immune response have been annotated and attempted to identify a susceptibility gene for sarcoidosis in a marker-based association study. Nineteen MSs were identified in six Th1-related genes (IFNGR1, IFNGR2, IL12RB1, IL12RB2, STAT1 and STAT4) and then eight were further characterized as useful polymorphic markers. Most of these MSs showed LD with single nucleotide polymorphisms (SNPs) on both 5' and 3' ends of these candidate genes, in which r(2) values between at least one of the MS marker alleles and the SNPs were higher than 0.1. A significant association with one MS allele near STAT4 was shown and a cluster of SNPs in LD with the MS marker was associated with sarcoidosis. These results suggest that association studies using not only SNPs but also multi-allelic MS within or near candidate loci would be useful markers to search for a disease susceptibility gene, especially in populations with unknown LD structure.

[Diagnostic criteria of neurosarcoidosis].

We have collaborated with Japanese Sarcoidosis Society and Japanese Society of Respiratory diseases to make a new diagnostic criteria of neurosarcoidosis. (definite) Having positive clinical findings which suggest a neurosarcoidosis. Pathology proven case. (probable) Having positive clinical findings which suggest a neurosarcoidosis. Pathology proven in other organ. Elevated serum ACE or BHL demonstrated by chest XP or CT scan. (possible) Having positive clinical findings which suggest a neurosarcoidosis. Elevated serum ACE or BHL demonstrated by chest XP or CT scan. CNS sarcoidosis, sarcoid neuropathy and sarcoid myopathy are separately diagnosed. To evaluate our criteria, about 100 papers on neurosarcoidosis published worldwide in these 6 years were retrospectively examined. Our criteria showed a better results than 1988 criteria (former Japanese criteria) and Zajicek's criteria which was published in 1999 (QJ Med 92: 103). Point is there is no more need to depend upon Kveim reaction which is time consuming, not so specific and difficult to obtain its antigen. Our new criteria is calculated to be sensitivity of 78-98% (BHL or ACE), and specificity of 83-99% (ACE). Because of their low specificity, Gallium scintigraphy and broncho alveolar lavage fluid examination are excluded from our diagnostic criteria, however, their high sensitivity are still useful to begin with.