Naohiko Inase

Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias

Background: Chronic bird fancier’s lung (BFL) has often been misdiagnosed as one of the idiopathic interstitial pneumonias (IIPs). Methods: To define the clinical and pathological characteristics of chronic BFL, 26 patients with chronic BFL from whom a surgical lung biopsy specimen was taken between October 1992 and June 2001 were evaluated. The histopathological characteristics of the surgical lung biopsy specimens were examined and correlations between the histopathology and clinical characteristics were analysed. The quality of chronic inflammatory and fibrotic changes was expressed according to the 2002 ATS/ERS consensus classification of IIPs. Results: Two patients were diagnosed as having bronchiolitis obliterans organising pneumonia (BOOP)-like lesions, five as having cellular non-specific interstitial pneumonia (NSIP)-like lesions, and eight as having fibrotic NSIP-like lesions. The other 11 patients were considered to have usual interstitial pneumonia (UIP)-like lesions because of the temporal heterogeneous appearances of the fibrotic changes. However, fibrosis in these patients had developed in centrilobular as well as perilobular areas, suggestive of hypersensitivity pneumonitis. Nineteen patients (73.1%) had multinucleated giant cells, often with cholesterol clefts, while only five patients (19.2%) had granulomas. Patients with BOOP-like or cellular NSIP-like lesions tended to have recurrent acute episodes, whereas patients with UIP-like lesions had an insidious onset. Patients with BOOP-like or cellular NSIP-like lesions had a more favourable outcome than those with fibrotic NSIP-like and UIP-like lesions. Conclusions: The qualities of chronic inflammatory and fibrotic lesions vary significantly among patients with chronic BFL but correlate with clinical features and prognosis.

Clinical features of recurrent and insidious chronic bird fancier's lung

BACKGROUND Chronic bird fanciers lung (BFL) can be subgrouped into two types. One subgroup of patients develops interstitial pulmonary fibrosis after recurrent acute episodes (recurrent BFL), and the other subgroup of patients has no history of acute episodes but has slowly progressive chronic respiratory disease (insidious BFL). OBJECTIVE To define the clinical characteristics of both types of BFL and to provide clues for diagnosis. METHODS We performed a retrospective review of the medical records of patients with chronic BFL who were evaluated between October 1992 and March 2001 at the Tokyo Medical and Dental University Hospital in Japan. Patients were evaluated for their clinical characteristics, including history, laboratory, and immunologic findings; imaging; bronchoalveolar lavage; and histologic findings. RESULTS Thirty-two patients with chronic BFL were included in this study; 15 patients had recurrent BFL and 17 had insidious BFL. The patients with recurrent BFL tended to breed dozens of pigeons in a loft, whereas the patients with insidious BFL were likely to be exposed to smaller birds kept indoors. Specific antibodies against pigeon dropping extracts or budgerigar dropping extracts were positive in 87% of the recurrent BFL cases and 35% of the insidious BFL cases. Antigen-induced lymphocyte proliferation was positive in more than 90% of both groups. The upper lung field was frequently involved in both groups as demonstrated by chest radiographic findings. In all of the patients with insidious BFL, the diagnosis was confirmed by positive laboratory-controlled inhalation test results. CONCLUSIONS Insidious BFL may be misdiagnosed as idiopathic pulmonary fibrosis if a careful history is not taken and antigen-induced lymphocyte proliferation, careful imaging evaluation, and laboratory-controlled inhalation challenge testing are not conducted. In contrast, the clinical findings of recurrent BFL are consistent with hypersensitivity pneumonitis induced by other antigens.

Clinical Predictors and Histologic Appearance of Acute Exacerbations in Chronic Hypersensitivity Pneumonitis

BACKGROUND Acute exacerbations (AEs) in idiopathic pulmonary fibrosis (IPF) are critical factors for its clinical course and prognosis. We have seen AEs and poor prognosis consequent to AE in patients with chronic hypersensitivity pneumonitis (HP), as has been seen in patients with IPF. The aim of this study was to evaluate the clinical features of the patients with AE in those with chronic HP. METHODS We reviewed 100 consecutive patients with chronic bird fancier lung (BFL) from 1993 to 2006, and analyzed the clinical characteristics, including history, and laboratory and immunologic, imaging, BAL, and histologic findings. RESULTS AE developed in 14 patients during this observation period (AE group), whereas 86 patients remained stable (non-AE [NAE] group). The 2-year frequency of AE among patients with chronic BFL having usual interstitial pneumonia (UIP)-like lesions seen on surgical lung specimens was 11.5%. Patients with AE were more likely to be smokers (p = 0.003). In pulmonary function test results, the mean total lung capacity (TLC) and diffusing capacity of the lung for carbon monoxide (Dlco) were lower in patients with AEs (TLC: AE patients, 63.0 +/- 16.8%; NAE patients, 81.6 +/- 20.0%; Dlco: AE patients, 41.9 +/- 19.0%; NAE patients, 60.0 +/- 19.4%). The mean number of lymphocytes in BAL fluid were lower (AE patients, 13.7 +/- 7.5 lymphocytes; NAE patients, 37.2 +/- 29.7 lymphocytes), while the number of neutrophils were greater in AE patients (AE patients, 10.7 +/- 17.6 neutrophils; NAE patients, 3.6 +/- 4.4 neutrophils). Histologic and/or radiologic findings revealed that all AE patients had UIP-like lesions. Diffuse alveolar damage was observed in six cases, whereas organizing pneumonia superimposed on preexistent fibrotic lesions was observed in two cases. CONCLUSIONS The present study showed several predictive factors for AE at the time of diagnosis. Low TLC and Dlco, low lymphocyte levels in BAL fluid, and a UIP-like pattern in histology at the time of diagnosis may be the risk factors for AE.

Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small‐cell lung cancer

Small‐cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. To identify accurate predictive biomarkers and effective therapeutic modalities, we focus on a long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR), and investigated its expression, cellular functions, and clinical relevance in SCLC. In this study, HOTAIR expression was assessed in 35 surgical SCLC samples and 10 SCLC cell lines. The efficacy of knockdown of HOTAIR by siRNA transfection was evaluated in SBC‐3 cells in vitro, and the gene expression was analyzed using microarray. HOTAIR was expressed highly in pure, rather than combined, SCLC (P = 0.012), that the subgroup with high expression had significantly more pure SCLC (P = 0.04), more lymphatic invasion (P = 0.03) and more relapse (P = 0.04) than the low‐expression subgroup. The knockdown of HOTAIR in SBC‐3 cells led to decreased proliferation activity and decreased invasiveness in vitro. Gene expression analysis indicated that depletion of HOTAIR resulted in upregulation of cell adhesion‐related genes such as ASTN1, PCDHA1, and mucin production‐related genes such as MUC5AC, and downregulation of genes involved in neuronal growth and signal transduction including NTM and PTK2B. Our results suggest that HOTAIR has an oncogenic role in SCLC and could be a prognostic biomarker and therapeutic target.

Pathology of hypersensitivity pneumonitis.

Purpose of review Hypersensitity pneumonitis, caused by inhalation of various antigens, is characterized by interstitial mononuclear cell infiltration, nonnecrotizing granulomas, cellular bronchiolitis, and fibrosis. The pathological picture of chronic hypersensitivity pneumonitis is, however, complicated; it is sometimes difficult to differentiate chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, and connective-tissue-related lung disease. The clinical, radiological, and pathological features of chronic hypersensitivity pneumonitis have recently been described. This study reviews the previously reported information and provides new insights into the pathological features of chronic hypersensitivity pneumonitis. Recent findings The pathological features of chronic hypersensitivity pneumonitis comprise overlapping usual interstitial pneumonia-like pattern with subpleural patchy fibrosis, alternating normal alveoli and fibroblastic foci, a nonspecific interstitial pneumonia-like pattern, and centrilobular fibrosis. In contrast to pathological features of acute and subacute hypersensitivity pneumonitis, epithelioid cell granulomas are sparse or absent, but giant cells are seen in the interstitium. Bridging fibrosis between peribronchiolar area and perilobular areas is an outstanding feature of chronic hypersensitivity pneumonitis. Autopsy cases of chronic hypersensitivity pneumonitis have demonstrated not only upper lobe contraction but also lower lobe contraction, mimicking usual interstitial pneumonia pattern and diffuse alveolar damage. Summary The present review focuses on the pathological features of chronic hypersensitivity pneumonitis and presents that centrilobular fibrosis and bridging fibrosis are the important hallmarks of chronic hypersensitivity pneumonitis, even with a usual interstitial pneumonia-like pattern.

Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer

Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.

A clinical study of hypersensitivity pneumonitis presumably caused by feather duvets

BACKGROUND Bird fanciers lung (BFL) is a type of hypersensitivity pneumonitis induced by the inhalation of bird-related antigens. The BFL induced by feathers is difficult to diagnose because feathers are generally unrecognized as a causative antigen. OBJECTIVE To determine the clinical features of BFL presumably induced by feather duvets (feather duvet lung) to provide clues for diagnosis. METHODS We performed a retrospective review of the medical records of patients with feather duvet lung evaluated between April 1, 2000, and June 30, 2003, at the Tokyo Medical and Dental University Hospital in Japan. RESULTS Seven patients with feather duvet lung were included in this study; 4 patients had acute disease and 3 had chronic BFL. Duration of contact with feather duvets was 1 month to 10 years. Serum KL-6 and surfactant protein D levels were elevated in all the patients. Specific antibodies against avian antigens were positive in acute BFL but negative in chronic BFL. Antigen-induced lymphocyte proliferation in peripheral blood or bronchoalveolar lavage cells was positive in all the patients. The diagnosis was confirmed by an environmental or inhalation provocation test. CONCLUSIONS Feather duvets can induce acute and chronic BFL. Physicians should be aware of feather duvets as a cause of BFL because feather duvets are becoming more prevalent.

Serial high-resolution computed tomography findings of acute and chronic hypersensitivity pneumonitis induced by avian antigen.

Purpose: The purpose of this study was to evaluate serial changes and the prognostic value of high-resolution computed tomographic (HRCT) findings in hypersensitivity pneumonitis (HP). Method: The medical records of 112 patients with bird-related HP (17 acute, 33 recurrent, and 62 insidious) were retrospectively reviewed. High-resolution computed tomographic findings at the time of diagnosis and at follow-up were retrospectively interpreted. Results: Ground-glass opacities and centrilobular nodules were predominant findings in acute and recurrent HP, whereas honeycombing was the outstanding feature in insidious HP. Areas of ground-glass opacities and centrilobular nodules decreased in all groups over a long-term follow-up. Areas of honeycombing, on the other hand, increased in chronic HP, especially in the insidious cases. Cox regression models revealed a higher mortality risk in cases with airspace consolidation and honeycombing on HRCT. Conclusion: Acute, recurrent, and insidious HP all have characteristic features on CT. Characteristic HRCT findings can predict the prognosis of chronic HP.

Changes of Circulating Atrial Natriuretic Peptide and Antidiuretic Hormone in Obstructive Sleep Apnea Syndrome

Patients with obstructive sleep apnea (OSA) syndrome are known to exhibit nocturnal natriuresis/diuresis. We studied plasma and urinary levels of atrial natriuretic peptide (ANP), a potent natriuretic hormone released from the heart, and plasma antidiuretic hormone (ADH) levels in patients with OSA during awake and sleeping periods, to compare with those of normal subjects. Seven patients with OSA and 6 normal subjects were studied. Arterial blood samples were drawn during the awake and the sleeping period, while in patients with OSA, blood samples were obtained during the apneic period. Urine samples were collected over two 12-hour periods (9 a.m.-9 p.m. and 9 p.m.-9 a.m.) In patients with OSA, plasma ANP as well as urinary ANP excretion increased during the apneic period compared with the awake period. There was a significant negative correlation between plasma levels of ANP and ADH in patients with OSA. On the other hand, normal subjects had no apparent differences in plasma and urinary ANP levels between the two periods. It is suggested that nocturnal increase in ANP and decrease in ADH are responsible for the nocturnal diuresis and natriuresis associated with OSA.

Th1 and Th17 immune responses to viable Propionibacterium acnes in patients with sarcoidosis

BACKGROUND Propionibacterium acnes and Mycobacterium tuberculosis have emerged as probable candidates responsible for sarcoidosis. This study was conducted to investigate the Th1/Th17 responses elicited by these pathogens in sarcoidosis and to clarify the causative role of these pathogens. METHODS Peripheral blood mononuclear cells (PBMCs) obtained from patients with sarcoidosis and from healthy volunteers were, respectively, co-cultured with viable P. acnes, with Bacille de Calmette et Guérin (BCG) as a viable M. tuberculosis complex, and with the early secretory antigenic target (ESAT)-6. Th1 cytokine production was measured using RT-PCR and enzyme-linked immunospot (ELISPOT) assays, and interleukin (IL)-17 mRNA expression was measured by RT-PCR. RESULTS IL-2 secretion from PBMCs after stimulation with P. acnes was significantly higher in patients with sarcoidosis than in the controls. Similarly, IL-2 and IL-12 mRNA expression after stimulation with P. acnes was significantly higher in PBMCs from patients with sarcoidosis than in PBMCs from controls. In contrast, IL-17 mRNA expression was significantly lower in PBMCs from patients with sarcoidosis than in PBMCs from controls. No significant differences between the groups were observed in the responses to stimulation with BCG or ESAT-6. CONCLUSION Sarcoidosis may arise from an imbalance of Th1/Th17 immune responses against viable P. acnes, but not M. tuberculosis complex.