Detection of ALK rearrangement in an octogenarian patient with pleomorphic carcinoma of the lung.

We herein present a rare case of ALK-positive pulmonary pleomorphic carcinoma in an octogenarian patient. A computed tomography scan of the thorax indicated a pulmonary nodule in the right upper lobe of an asymptomatic 87-year-old female. The surgical resection revealed that the disease was pleomorphic carcinoma with pathological T2aN0M0, stage IB. EML4-ALK was evaluated using immunohistochemistry and fluorescence in situ hybridization, and EGFR mutations were analyzed using the Cycleave method. While there were no EGFR mutations detected, she was positive for the ALK rearrangement. This is the first report of ALK rearrangement in an octogenarian patient with pleomorphic carcinoma of the lung.

Organizing Pneumonia in Rheumatoid Arthritis Patients: A Case-Based Review.

We treated 21 patients with organizing pneumonia (OP) associated with rheumatoid arthritis (RA) or related to biological disease-modifying antirheumatic drugs (DMARDs) at our institution between 2006 and 2014. Among these cases, 3 (14.3%) preceded articular symptoms of RA, 4 (19.0%) developed simultaneously with RA onset, and 14 (66.7%) occurred during follow-up periods for RA. In the case of OP preceding RA, increased levels of anti-cyclic citrullinated peptide antibodies and rheumatoid factor were observed at the OP onset. RA disease activity was related to the development of OP in the simultaneous cases. In the cases of OP developing after RA diagnosis, 10 of 14 patients had maintained low disease activity with biological DMARD therapy at the OP onset, and among them, 6 patients developed OP within the first year of this therapy. In the remaining four patients, RA activity was not controlled at the OP onset. All patients responded well to systemic steroid therapy, but two patients suffered from relapses of articular and pulmonary symptoms upon steroid tapering. In most of the RA patients, DMARD therapy was introduced or restarted during the steroid tapering. We successfully restarted a biological DMARD that had not been previously used for patients whose RA would otherwise have been difficult to control. In this study, we also perform a review of the literature on RA-associated or biological DMARD-related OP and discuss the pathogenesis and management of OP occurring in RA patients.

Pneumocystis jirovecii Pneumonia in Rheumatoid Arthritis Patients: Risks and Prophylaxis Recommendations.

Pneumocystis jirovecii infection causes fulminant interstitial pneumonia (Pneumocystis pneumonia, PCP) in patients with rheumatoid arthritis (RA) who are receiving biological and/or nonbiological antirheumatic drugs. Recently, we encountered a PCP outbreak among RA outpatients at our institution. Hospital-acquired, person-to-person transmission appears to be the most likely mode of this cluster of P. jirovecii infection. Carriage of P. jirovecii seems a time-limited phenomenon in immunocompetent hosts, but in RA patients receiving antirheumatic therapy, clearance of this organism from the lungs is delayed. Carriers among RA patients can serve as sources and reservoirs of P. jirovecii infection for other susceptible patients in outpatient facilities. Development of PCP is a matter of time in such carriers. Considering the poor survival rates of PCP cases, prophylactic antibiotics should be considered for RA patients who are scheduled to receive antirheumatic therapy. Once a new case of PCP occurs, we should take prompt action not only to treat the PCP patient but also to prevent other patients from becoming new carriers of P. jirovecii. Short-term prophylaxis with trimethoprim-sulfamethoxazole is effective in controlling P. jirovecii infection and preventing future outbreaks of PCP among RA patients.

Pulmonary Mycobacterium abscessus disease in a patient receiving low-dose methotrexate for treatment of early rheumatoid arthritis.

A 70-year-old woman with methotrexate (MTX)-refractory rheumatoid arthritis (RA) was referred to our hospital for introduction of biological therapy. On high-resolution computed tomography scans, the patient exhibited abnormal findings such as bronchiectasis and centrilobular small nodules, which were highly suggestive of pulmonary nontuberculous mycobacterial (NTM) disease. Although mycobacterial cultures of sputum specimens yielded negative results, cultures of bronchoalveolar lavage fluids grew Mycobacterium abscessus. Frequent follow-up chest radiographs indicated that the patient's pulmonary disease became rapidly worse in 1 month following dose escalation of MTX and administration of low-dose prednisolone. Oral clarithromycin and levofloxacin, chosen on the basis of in vitro susceptibility testing, led to a dramatic recovery from this potentially life-threatening complication. Through our experience with this case, we have learned that (1) pulmonary M. abscessus disease can progress rapidly, even during nonbiological anti-RA therapy; (2) regular follow-up chest radiographs are useful to ensure timely implementation of anti-NTM treatment; (3) bronchoscopic testing should be considered when patients are suspected of pulmonary NTM disease but do not meet the diagnostic criteria; and (4) early isolation, identification, and susceptibility testing of causative NTM species are critical for favorable outcomes.

Pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis.

Accompanying the increased use of biologic and non-biologic antirheumatic agents, patients with RA have been exposed to an increased risk of Pneumocystis jirovecii infection, which causes acute fulminant P. jirovecii pneumonia (PCP). Mortality in this population is higher than in HIV-infected individuals. Several guidelines and recommendations for HIV-infected individuals are available; however, such guidelines for RA patients remain less clear. Between 2006 and 2008 we encountered a clustering event of P. jirovecii infection among RA outpatients. Through our experience with this outbreak and a review of the recent medical literature regarding asymptomatic colonization and its clinical significance, transmission modes of infection and prophylaxis of PCP, we have learned the following lessons: PCP outbreaks among RA patients can occur through person-to-person transmission in outpatient facilities; asymptomatic carriers serve as reservoirs and sources of infection; and short-term prophylaxis for eradication of P. jirovecii is effective in controlling PCP outbreaks among RA outpatients.

Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis.

OBJECTIVE: To identify clinical and genetic risk factors for interstitial lung disease (ILD) or airway disease (AD) in patients with rheumatoid arthritis (RA) and to evaluate differences between the associations of these factors with ILD and AD. METHODS: We reviewed high-resolution computed tomography (HRCT) images and clinical data of 356 RA patients obtained at their first visit. The diagnosis of ILD and AD was based on abnormal HRCT findings. Multinomial logistic regression analysis and likelihood ratio tests were performed. RESULTS: High titers of rheumatoid factor are similarly associated with increased risks of ILD (relative risk ratio, 3.1; p = 0.02) and AD (relative risk ratio, 3.0; p = 0.02). High levels of anti-cyclic citrullinated peptide antibodies were associated strongly with AD (relative risk ratio, 3.8; p = 0.005) and less strongly with ILD (relative risk ratio, 2.7; p = 0.07). Age was the potent risk factor for ILD (relative risk ratio, 4.6; p = 0.003), while that for AD was advanced stage (relative risk ratio, 11.5; p < 0.0005). The carriage of HLA-DRB1*1502 had opposite influences on the two conditions: relative risk ratio = 4.02 for ILD (p = 0.013) and relative risk ratio = 0.15 for AD (p = 0.08). This difference was statistically significant (p = 0.0005). Associations of sex and smoking history with ILD disappeared in the multinomial logistic regression analysis. CONCLUSIONS: The differential associations of ILD and AD with various clinical and genetic factors suggest that ILD and AD have distinct etiologies in RA.

Is continuation of anti-tumor necrosis factor-α therapy a safe option for patients who have developed pulmonary mycobacterial infection? : Case presentation and literature review.

Continuation of anti-tumor necrosis factor-α (TNFα) therapy generally has not been recommended for patients who have developed nontuberculous mycobacterial (NTM) diseases; in daily practice, however, we often encounter patients with refractory rheumatoid arthritis (RA) who experience uncontrollable flares following withdrawal of anti-TNFα agents. Here, we report a case of pulmonary NTM disease caused by Mycobacterium intracellulare occurring in a patient with refractory RA undergoing etanercept therapy. Since there was the concern of an exacerbation of RA symptoms, etanercept was continued during anti-NTM therapy. The patient's pulmonary symptoms and radiological abnormalities were found to have markedly improved in a relatively short time period after beginning the anti-NTM therapy. Additionally, her RA symptoms were adequately controlled without the occurrence of any unexpected adverse events. The continuation of etanercept therapy may be a safe option during anti-NTM therapy if patients' underlying diseases would otherwise be difficult to control. Strictly supervised anti-NTM therapy and patients' informed consent are mandatory. We review the medical literature on NTM disease associated with anti-TNFα therapy for rheumatic diseases and discuss the safety of simultaneous use of anti-TNFα agents in patients during anti-NTM therapy.

[An elderly case of anomalous systemic arterial supply to the normal basal segment of the left lower lobe and summary of reports of the disease in Japan].

A 69-year-old asymptomatic woman was admitted because of an abnormal chest shadow. Chest X-ray films showed a tumorous shadow behind the heart. Chest CT scans showed an aberrant artery branching from the thoracic aorta and supplying the left basal segment, but the bronchial tree was normal. The left lung vein was normal but wide, and the left lower pulmonary artery could not be observed. Based on these findings, we diagnosed anomalous systemic arterial supply to the normal basal segment of the left lower lobe. Because this patient had a high risk of heart failure and pulmonary hypertension, we decided to perform a left lower lobectomy, but she refused the operation. As this disease is generally found in younger patients, diagnosis in older age, as in the present case, is rare. In this report we also summarize 39 other reports of this disease in Japan.

Small airway obstruction in patients with rheumatoid arthritis.

This work was intended to evaluate the prevalence of obstructive small-airway disease in patients with rheumatoid arthritis (RA) and its association with clinical characteristics. Pulmonary function testing (PFT) and high-resolution computed tomography (HRCT) were performed on 189 consecutive RA patients. Each case was diagnosed based on abnormal HRCT findings. We defined obstructive dysfunction of small airways as a forced expiratory flow from 25% to 75% of vital capacity (FEF(25-75)) value >1.96 residual standard deviation (RSD) below predicted values. We found 19 patients (10.1%) with an interstitial pneumonia (IP) pattern and 15 (7.9%) with a bronchiolitis pattern; the other 155 (82.0%) had no abnormal HRCT patterns. In patients with neither abnormal pattern, median values of percentage predicted for carbon monoxide diffusing capacity (DL(CO)) and ratio of DL(CO) to alveolar ventilation (DLco/VA) were within the normal range, but median FEF(25-75), forced expiratory flow at 25% of vital capacity (V(25)), and V(25)/height were <70% of predicted values. Forty-seven patients (30.3%) in this group had obstructive small-airway dysfunction. Multivariate logistic regression analysis indicated that this type of abnormality is strongly associated with respiratory symptoms [odds ratio (OR) 5.18; 95% confidence interval (CI) 1.70-15.75; p = 0.012), smoking history (OR 2.78; 95% CI 1.10-6.99; p = 0.03), and disease duration >10 years (OR 2.86; 95% CI 1.27-6.48; p = 0.012). Parenchymal micronodules, bronchial-wall thickening, and bronchial dilatation on HRCT scans were also predictive factors for abnormal FEF(25-75), although these morphological changes were too limited for us to diagnose these patients with the bronchiolitis pattern. Obstructive dysfunction of small airways is apparently common among RA patients, even among those with neither the IP nor the bronchiolitis pattern on HRCT scans. Factors significantly associated with abnormal FEF(25-75) are respiratory symptoms, smoking history, and RA duration.

[A case of pulmonary nontuberculous mycobacteriosis aggravated during treatment with etanercept for rheumatoid arthritis].

A 81-year-old woman with rheumatoid arthritis (RA) was admitted to our hospital because of a productive cough and bloody sputum. She had been treated with etanercept, a tumor necrosis factor (TNF) antagonist, for 9 months before admission. A chest CT scan on admission showed small nodules, bronchiectasis and consolidations in bilateral lung fields. A diagnosis of pulmonary nontuberculous mycobacteriosis (NTM) was established by positive cultures for Micobacterium intracellulare both in her sputum and bronchial secretions obtained by bronchoscopy. It has been reported that bacterial pneumonia, tuberculosis (TB) and pneumocystis pneumonia (PCP) occur during treatment with etanercept or infliximab. However, there were few reports of NTM in post-marketing surveys of etanercept or infliximab in Japan. As pulmonary is NTM related to treatment with etanercept or infliximab and may progress rapidly with few drugs effective against NTM, we should be aware of pulmonary NTM as well as TB and PCP in the treatment of RA with etanercept or infliximab.

Acute respiratory distress syndrome associated with rapid aggravation of rheumatoid arthritis.

A 76-year-old woman with seropositive rheumatoid arthritis (RA) developed acute respiratory distress syndrome (ARDS) following an appearance of severe inflammatory symptoms in multiple synovial joints. High-dose pulse therapy with methylprednisolone induced a marked improvement in pulmonary conditions. To the best of our knowledge, this is the first case in the literature to show a causal relationship between ARDS and RA. We should be alert to the possibility that ARDS can occur as an acute-type pulmonary complication of RA, particularly when patients show rapid aggravation of rheumatic activity.

A followup study of asymptomatic carriers of Pneumocystis jiroveci during immunosuppressive therapy for rheumatoid arthritis.

OBJECTIVE: To examine the preventive effects of prophylaxis against Pneumocystis jiroveci-induced pneumonia (PCP) in patients receiving immunosuppressive therapy for rheumatoid arthritis (RA) who are colonized by this organism. METHODS: We performed molecular testing by polymerase chain reaction (PCR) for P. jiroveci on induced sputum or bronchoalveolar lavage fluids of 82 patients with RA. During primary prophylaxis, asymptomatic carriers of this organism were examined by high-resolution computed tomography and PCR every 2 weeks. RA patients who had developed PCP received PCR tests every week. Once negative results were obtained, PCR testing was scheduled at Months 1, 3, and 6, followed by reexaminations every 6 months. RESULTS: We found 9 cases of asymptomatic carriage of P. jiroveci. All the carriers had received low doses of methotrexate. Upon introduction of PCP prophylaxis, 5 cases tested negative for PCR within 1 month. Three carriers developed PCP before starting prophylaxis, but these tested negative for PCR after short periods (1-2 weeks) of PCP treatment. Once P. jiroveci was eradicated, all cases maintained negative PCR results during followup without prophylactic intervention, even after resuming immunosuppressive therapy. One patient refused PCP prophylaxis, but no PCP developed. CONCLUSION: RA patients with asymptomatic carriage of P. jiroveci benefited from short-term prophylaxis against PCP. Positive PCR results appeared to be predictive of future development of PCP in RA patients. Identification of P. jiroveci carriers will encourage prompt introduction of PCP prophylaxis when rheumatologists consider immunosuppressive therapy for RA.

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with active lung tuberculosis.

This study was intended to evaluate the utility of anti-cyclic citrullinated peptide antibodies (second generation, anti-CCP2) as a diagnostic marker for rheumatoid arthritis (RA) in patients with active tuberculosis. Among 89 patients with active tuberculosis, anti-CCP2 was detected in six (6.7%), and three of these (3.4%) were strongly positive for anti-CCP2. The positive rate of anti-CCP2 in patients with newly diagnosed RA was 82.1% (87 of 106 cases), while the rate in healthy control subjects was 0.4% (one of 237 individuals). The mean level of anti-CCP2 among the RA group was 159.3 U/ml, which was significantly higher than both that among the tuberculosis group (15.4 U/ml) and that among the healthy controls (0.7 U/ml). IgM rheumatoid factor (RF) was detected in 16 patients from the tuberculosis group (18.0%) with a mean serum level of 18.6 IU/ml and in 77 patients of the RA group (72.6%) with a mean level of 164.0 IU/ml. Only two cases in the tuberculosis group were positive for both anti-CCP2 and IgM RF. These observations show that measurement of anti-CCP2 seems to be a reliable serological tool for identifying early RA in patients with active tuberculosis.

[Evaluation of the incidence of pneumothorax and background of patients with pneumothorax during noninvasive positive pressure ventilation].

Pneumothorax (PTX) can be a serious complication of noninvasive positive pressure ventilation (NPPV). However, the exact incidence or background of PTX during a following NPPV therapy remains unclear. In our hospital, we examined patients with PTX related to NPPV therapy and compared them with non-PTX patients over a period of 7 years. Until 2004, 5 (5 patients) of 72 episodes (63 patients) of NPPV in acute chronic respiratory failure (RF) were accompanied by PTX (incidence, 6.9 percent). The 5 patients consisted of 4 men and 1 woman (mean age, 78.4 years and range, 74-84 years). The underlying diseases were interstitial lung diseases (ILDs) in 3 patients, chronic obstructive pulmonary disease in 1, and pneumonia in 1. The stage of RF in the 5 patients was acute in 4 and chronic in 1, and the duration between the initiation of NPPV and occurrence of PTX was within 10 days in 3 patients, 11-20 days in 1, and more than 20 days in 1 (mean duration, 15.6 days). The mean inspiratory positive airway pressure/expiratory positive airway pressure (IPAP/EPAP) of the 5 patients (10.6/4.1 cm H2O) was similar to that of 58 non-PTX patients (9.9/4.0 cm H2O). With regard to underlying diseases, the ratio of ILDs was higher in PTX patients (60%) than in non-PTX patients (8.6%) (p < 0.02). Patients at a high risk of PTX should be treated carefully with NPPV. Further, the therapy should be appropriately managed, especially in the early stage of NPPV initiation.

Congenital bronchobiliary fistula in a 65-year-old woman.

Congenital bronchobiliary fistula (CBBF) is quite a rare malformation and the diagnosis is usually made within a few hours or years from birth because of lower respiratory diseases beginning from early infancy. Surgical repair is necessary. Of the 29 cases reported, 4 occurred in adults aged 22-32 years. We detected CBBF incidentally in a 65-year-old woman. During bronchoscopy and thoracic computed tomographic study of the pulmonary nodules, we found an accessory bronchus descending from the carina and composed of a dark green secretion that contained 10% bilirubin. Drip infusion cholangiography revealed air in the left bile duct. Cholescintigraphy showed dilatation of the left bile duct and radiotracer pooling at the top edge of the left hepatic lobe. These findings indicated a narrow fistula between the airway and biliary duct. We attributed the patient's long survival without major complications to the narrowness of the communication. To our best knowledge, this is the fifth and oldest reported adult diagnosed with CBBF.

Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis.

OBJECTIVE: To identify the predominant radiological abnormalities in the lungs of patients with early rheumatoid arthritis (RA) and in those with longstanding RA. METHODS: We performed high-resolution computed tomography (HRCT) on a total of 126 patients with early RA (n = 65) and longstanding RA (n = 61). The most likely diagnosis for each case was made on the basis of the predominant HRCT findings and their extent in the lungs. Pulmonary function tests were done for RA patients with parenchymal abnormalities. RESULTS: The most frequent finding was bronchial dilatation (41.3%), followed by ground-glass attenuation (27.0%), parenchymal micronodules (15.1%), subpleural micronodules (15.1%), reticulation (11.9%), bronchial wall thickening (11.9%), nodules (10.3%), honeycombing (8.7%), and airspace consolidation (4%). Parenchymal micronodules and bronchial wall thickening, indicative of small airway diseases, were more prominent in the patients with longstanding RA. There were no significant differences in the frequency of interstitial abnormalities such as ground-glass attenuation, reticulation, honeycombing, or consolidation between the 2 groups. We identified 10 patients with bronchiolitis pattern, 11 with nonspecific interstitial pneumonia (NSIP) pattern, 2 with usual interstitial pneumonia (UIP) pattern, and 2 with organizing pneumonia (OP) pattern. Mean values of FEV1/FVC ratio and FEV25-75 were lower in the patients with the bronchiolitis pattern, and DLCO was decreased in the patients with the NSIP or UIP pattern. CONCLUSION: Interstitial abnormalities were frequently observed even in patients with early RA, although most of them had no respiratory symptoms. Bronchiolar abnormalities were associated with the duration of RA.

[Two cases of severe necrotizing pneumonia caused by community-acquired methicillin-resistant Staphylococcus aureus].

We present 2 cases with severe necrotizing pneumonia due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection. The patients were a 89-year-old man and a male student of 15 years of age. Chest X-rays and CT scans demonstrated multiple consolidations with cavitary lesions showing necrotizing pneumonia. MRSA strains were isolated from the sputum cultures on admission in these patients who did not have any established risk factors for MRSA infections such as history of hospitalization, surgery, hemodialysis, the presence of a permanent indwelling catheter or percutaneous medical device, and residence in a long-term care facility. These patients thus satisfied the international criteria for CA-MRSA presented by the Centers for Disease Control and Prevention (CDC). Unfortunately, the first case died of CA-MRSA pneumonia in spite of intensive treatments including anti-MRSA antibiotics. Unlike the severe CA-MRSA cases in western countries, Panton-Valentine leukocidin (PVL) genes were not detected in the present cases, suggesting that factors other than PVL had a significant effect on the severity of necrotizing pneumonia. To the best of our knowledge, this is the first report of severe necrotizing pneumonia caused by CA-MRSA in Japan.