Pathophysiological mechanism of non-HIV Pneumocystis jirovecii pneumonia.

While Pneumocystis jirovecii pneumonia (PCP) can occur in immunocompromised patients with HIV infection, the prognosis of non-HIV PCP is still poor, showing a high mortality rate of 30%-75%. The pathophysiological mechanism of non-HIV PCP is quite different from that of HIV-PCP. Aging, underlying disease, dysbiotic gut microbiome, and Th1 predominance, leads to macrophagic polarization shifting from M2 to M1. These cause dysregulation in the host immunity against P. jirovecii, resulting in severe lung injury and a high mortality rate among non-HIV PCP patients. This review describes poor prognostic factors, an issue of predictive values used for general pneumonia practice, and new aspects, including the dysbiosis of the gut microbiome and macrophagic polarization in the treatment of non-HIV PCP.

[THE CORRELATION OF ALLERGY SPECIFIC IGE MEASUREMENT REAGENT IMMNOCAP, ALASTAT, AND ORITON IGE].

BACKGROUND: The reagent which is available for single allergenic tests is Oriton IgE, ImmnoCAP, Alastat in Japan. No study has investigated the correlations of Oriton IgE and ImmnoCAP or Alastat, and, used for specific IgE antibody testing. METHOD: Six frequently tested allergens (dust mite, cedar pollen, dog dander, egg white, milk, and candida) were measured by three methods, and Spearman rank correlation coefficient and class-judged agreement were evaluated. Furthermore, we did the evaluation like other 2 methods when we made small short sample volumes of Oriton IgE. RESULT: As for the examination result of Oriton IgE and ImmnoCAP or Alastat, constant correlation was confirmed. However, the tendency was a different result by assay method and an allergenic item. No significant differences were observed in the results of the Oriton IgE test when standard sample volumes and small short sample volumes were used. CONCLUSION: These comparison results help us to understand each characteristic and select an optimal test method. In addition, it can be inferred that it is beneficial to choose tests requiring small sample volumes in pediatric patients.

Automated computed tomography quantification of fibrosis predicts prognosis in combined pulmonary fibrosis and emphysema in a real-world setting: a single-centre, retrospective study.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a heterogeneous clinico-radiological syndrome without a consensus definition. There are limited data on the relation between the amount of parenchymal fibrosis and prognosis. In this study, we assessed the prognostic implications of the extent of fibrosis assessed by an automated quantitative computed tomography (CT) technique and the radiological and functional change over time in patients with a broad spectrum of fibrotic interstitial lung diseases (ILDs) encountered in a real-world setting. METHODS: We conducted a single-centre, retrospective study of 228 consecutive patients with CPFE, encountered from 2007 to 2015 at Kameda Medical Center, Chiba, Japan. We investigated the prognostic value of automated CT fibrosis quantification and the subsequent course of CPFE. RESULTS: Among 228 patients with CPFE, 89 had fibrosis affecting < 5% of their lungs, 54 had 5 to < 10% fibrosis, and 85 had ≥ 10% fibrosis at the time of diagnosis. Lower volume of fibrosis correlated with lower rates of mortality and acute exacerbation (p < 0.001). In particular, among those with < 5% fibrosis, only 4.5% died and none experienced acute exacerbation during follow-up, whereas 57.6% and 29.4% of those with ≥ 10% fibrosis experienced death and acute exacerbation, respectively. Although, the ≥ 10% fibrosis group had the poorest overall survival as well as the highest incidence of acute exacerbation, the incidence of decline in pulmonary function tests, change per year in total lung volume, and progression of fibrosis on chest CT was highest in the 5 to < 10% fibrosis group. The Cox proportional hazard model for CPFE progression (defined by composite criteria of death, acute exacerbation, and decline in forced vital capacity or diffusing capacity) showed fibrosis proportion was a risk factor independent of age, sex, smoking pack-years, the Charlson Comorbidity Index, lung cancer, connective tissue disease, and idiopathic pulmonary fibrosis. CONCLUSIONS: Less severe (< 5%) fibrosis at baseline was associated with disease stability and better prognosis compared to more severe fibrosis in CPFE occurring with fibrotic ILDs. Further studies including a validation cohort will be needed. Trial Registration Retrospectively registered.

Refractory diffuse alveolar hemorrhage caused by eosinophilic granulomatosis with polyangiitis in the absence of elevated biomarkers treated successfully by rituximab and mepolizumab: A case report.

Here we report on a 61-year-old man with refractory eosinophilic granulomatosis with polyangiitis (EGPA) who presented with dyspnea. Despite treatment with glucocorticoids, intravenous cyclophosphamide, and plasma exchange, his symptoms worsened despite his eosinophil count and myeloperoxidase antineutrophil cytoplasmic antibody titer trending downwards. EGPA with diffuse alveolar hemorrhage was diagnosed on analysis of bronchoalveolar lavage fluid. The patient was treated with rituximab and methylprednisolone pulse therapy and a remission was achieved. He has been receiving mepolizumab since then and remains in remission. It should be recognized that refractory diffuse alveolar hemorrhage can occur in patients with EGPA without elevation of biomarkers if they are receiving systemic corticosteroids.

Low-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia in non-human immunodeficiency virus-infected immunocompromised patients: A single-center retrospective observational cohort study.

BACKGROUND/PURPOSE: The efficacy of low-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be acceptable for the treatment of pneumocystis pneumonia (PCP) in non-human immunodeficiency virus (HIV)-infected patients, with a low incidence of adverse reactions. This study is aimed to evaluate the efficacy and safety of such a regimen for the treatment of non-HIV PCP. METHODS: We retrospectively enrolled 24 consecutive patients diagnosed with non-HIV PCP who were treated with low-dose TMP-SMX (TMP, 4-10 mg/kg/day; SMX, 20-50 mg/kg/day). Data of the conventional-dose treatment were used as reference. The primary endpoints were the 30- and 180-day survival rates from the day of treatment, and secondary endpoints were the incidence of each adverse reaction and dropout rate from the initial TMP-SMX regimen. The survival rate was estimated using the Kaplan-Meier method with 95% confidence interval (CI). RESULTS: The median age of patients was 72 years (54.2% men), and connective tissue disease was the most frequent underlying disease (66.7%) in the low-dose group. The 30- and 180-day survival rates were 95.8% (95% CI: 88.2-100.0%) and 91.0% (95% CI: 79.9%-100.0%), respectively, in the low-dose group and 69.0% (95% CI: 54.0%-88.0%) and 51.5% (95% CI: 36.1%-73.4%), respectively, in the conventional-dose group. The total adverse reaction rate was 58.3% in the low-dose group and 72.4% in the conventional-dose group. A total of 75.0% of patients in the low-dose group and 31.0% in the conventional-dose group completed treatment with the initial regimen. CONCLUSION: Low-dose TMP-SMX may be a treatment option for patients with non-HIV PCP.

Clinical Manifestations and Prognostic Factors of Pneumocystis jirovecii Pneumonia without HIV.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PCP) can occur in HIV patients but also in those without HIV (non-HIV PCP) but with other causes of immunodeficiency including malignancy or rheumatic diseases. OBJECTIVE AND METHODS: To evaluate the clinical presentation and prognostic factors of non-HIV PCP, we retrospectively reviewed all patients diagnosed as having PCP without HIV at Kameda Medical Center, Chiba, Japan, from January 2005 until June 2012. For the purpose of examining a prognostic factor for non-HIV PCP with 30-day mortality, we compared the characteristics of patients, clinical symptoms, radiological images, Eastern Cooperative Oncology Group performance status (PS), and the time from the onset of respiratory symptoms to the start of therapy, in both survival and fatality groups. RESULTS: A total of 38 patients were eligible in this study. Twenty-five survived and 13 had died. The non-HIV PCP patients in the survivor group had a better PS and received anti-PCP therapy earlier than those in the nonsurvivor group. Rales upon auscultation and respiratory failure at initial visits were seen more frequently in the nonsurvivor group than in the survivor group. Lactate dehydrogenase and C-reactive protein values tended to be higher in the nonsurvivor group, but this was not statistically significant. Multivariate analyses using 5 variables showed that a poor PS of 2-4 was an independent risk factor for non-HIV PCP patients and resulted in death (odds ratio 15.24; 95% confidence interval 1.72-135.21). CONCLUSION: We suggest that poor PS is an independent risk factor in non-HIV PCP, and a patient's PS and disease activity may correlate with outcome.

[PULMONARY TUBERCULOSIS AND TUBERCULOUS PLEURISY COMPLICATED WITH RIFAMPICIN-INDUCED HYPOTHYROIDISM: A CASE REPORT].

Rifampicin can induce hypothyroidism. We report a case of pulmonary tuberculosis and tuberculous pleurisy that was complicated by rifampicin-induced hypothyroidism. The patient received rifampicin-based tuberculosis treatment and experienced persistent appetite loss, which led us to pro- vide concomitant hypothyroidism treatment. An 85-year-old woman with no underlying thyroid-related disease presented to her local hospital with a 3-month history of appetite and weight loss. A chest radiograph revealed pleural effusions and infiltrative shadows in the lower fields of both lungs, and we also detected high levels of lympho- cytes and adenosine deaminase levels (49.6 IU/1) in the pleu- ral effusion, with positive results from a polymerase chain reaction assay of a sputum sample. Thus, we diagnosed the patient with pulmonary tuberculosis and tuberculous pleurisy, and initiated treatment using isoniazid, rifampicin, etham- butol, and pyrazinamide. Her clinical course was good and her anorexia was improved. However, she subsequently experienced recurrent appetite loss, malaise, and bilateral lower-leg edema. Follow-up laboratory testing revealed that she had developed hypothyroidism. We started treatment using levothyroxine without interrupting the tuberculosis treatment. The loss of appetite and other thyroid-related symptoms were improved. The patient's thyroid function had been normal at her admission, and there were no findings of Hashimoto's thyroiditis or other thyroid conditions. Based on the clinical course, we conclude that the rifampicin induced the hypothyroidism. Therefore, rifampicin-induced hypothyroidism should be considered in cases with persistent appetite loss, even if the patient appears to be experiencing anorexia as an adverse drug reaction.

Associations between peripheral blood eosinophil counts in patients with systemic sclerosis and disease severity.

Increased levels of serum pro-fibrotic cytokines have been reported in patients with systemic sclerosis (SSc). Some of these cytokines also play an important role in the differentiation and migration of eosinophils. The aim of this study was to determine whether eosinophilic inflammation is caused in SSc. We retrospectively reviewed the peripheral blood eosinophil counts in 70 untreated patients with SSc and compared them with those in patients with other major collagen diseases. We additionally evaluated a possible association with disease severity. Eosinophil counts were significantly higher levels in patients with SSc than in those with other collagen diseases, whereas total leukocyte counts were not. Eosinophil counts correlated positively with both severe interstitial lung disease (ILD; r = 0.255, p = 0.033) and modified Rodnan total skin thickness score (m-Rodnan TSS) in SSc (r = 0.347, p = 0.003), but did not correlate with ILD severity in other collagen diseases. In conclusion, peripheral eosinophil counts were higher in patients with SSc than in those with other collagen diseases and were correlated with increased disease severity. Our data suggest that eosinophilic inflammation is involved in the pathogenesis and progression of SSc.

Rapidly Progressive Interstitial Lung Disease Associated with Dermatomyositis Treated with Combination of Immunosuppressive Therapy, Direct Hemoperfusion with a Polymyxin B Immobilized Fiber Column and Intravenous Immunoglobulin.

Rapidly progressive interstitial lung disease (ILD) is associated with dermatomyositis (DM) and has a high mortality rate even with immunosuppressive agents. For such cases, there is no evidence on the combined effect of direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin. We herein report a case of 61-year-old woman who presented with respiratory failure. She showed ILD associated with DM which did not improve with immunosuppressive agents, but was improved with the addition of both direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin.

Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis.

OBJECTIVES: Biological therapy represents important advances in alleviating rheumatoid arthritis (RA), but the effect on interstitial lung disease (ILD) has been controversial. The objective of this study was to assess the risk of such treatment for patients with ILD. DESIGN: Case-control cohorts. SETTING: Single centre in Japan. PARTICIPANTS: This study included 163 patients with RA who underwent biological therapy. OUTCOME MEASURED: We assessed chest CT before initiation of biological therapy and grouped 163 patients according to the presence of ILD (with (n=58) and without pre-existing ILD (n=105)). Next, we evaluated serial changes of chest CT after treatment and visually assessed the emergence of ILD or its progression, which was referred to as an 'ILD event'. Then, we also classified the patients according to the presence of ILD events and analysed their characteristics. RESULTS: Tumour necrosis factor (TNF) inhibitors were administered to more patients with ILD events than those without ILD events (88% vs 60%, p<0.05), but recipients of tocilizumab or abatacept did not differ in this respect. Of 58 patients with pre-existing ILD, 14 had ILD events, and that proportion was greater than for those without pre-existing ILD (24% vs 3%, p<0.001). Of these 14 patients, all were treated with TNF inhibitors. Four patients developed generalised lung disease and two died from ILD progression. Baseline levels of KL-6 were similar in both groups, but increased in patients with ILD events. CONCLUSIONS: TNF inhibitors have the potential risk of ILD events, particularly for patients with pre-existing ILD, and KL-6 is a valuable surrogate marker for detecting ILD events. Our data suggest that non-TNF inhibitors are a better treatment option for these patients.

Effect of glucocorticoid monotherapy on pulmonary function and survival in Japanese patients with scleroderma-related interstitial lung disease.

BACKGROUND: Scleroderma-related interstitial lung disease (SSc-ILD) is a chronic, progressive condition that is characterized by a restrictive ventilator defect. Cyclophosphamide (CYC), with or without glucocorticoid, effectively alters the course of SSc-ILD. However, the effect of glucocorticoid monotherapy remains unclear. METHODS: Seventy-one patients with SSc-ILD were classified into 2 groups: 21 in the treatment group (glucocorticoid monotherapy [n=14] or immunosuppressive agents [n=7]) and 50 in the non-treatment group. Their backgrounds and prognoses were analyzed retrospectively. We also classified these patients into survival (n=55) and non-survival (n=16) groups to assess prognostic factors. RESULTS: The median follow-up period was 9.8 years. The treatment group had a greater proportion of patients with diffuse systemic sclerosis or respiratory symptoms than the non-treatment group. The treatment group's annual change in forced vital capacity (FVC) compared to baseline, which was 170.4mL (157.8mL for the glucocorticoid monotherapy subgroup and 191.3mL for the immunosuppressive agent subgroup), was better than that of the non-treatment group, -60.8mL (p<0.01). Still, in terms of 5- and 10-year survival, there was no statistically significant difference between these groups. No incidence of SSc renal crisis was reported in the treatment group. The non-survival group included more patients with pulmonary hypertension than the survival group, but multivariate analysis showed no other statistically significantly difference between these groups. CONCLUSIONS: Similar to CYC, glucocorticoid alone improved pulmonary function of Japanese SSc-ILD patients, suggesting that this monotherapy is a good alternative when CYC is contraindicated.

Non-HIV Pneumocystis pneumonia: do conventional community-acquired pneumonia guidelines under estimate its severity?

BACKGROUND: Non-HIV Pneumocystis pneumonia (PCP) can occur in immunosuppressed patients having malignancy or on immunosuppressive agents. To classify severity, the A-DROP scale proposed by the Japanese Respiratory Society (JRS), the CURB-65 score of the British Respiratory Society (BTS) and the Pneumonia Severity Index (PSI) of the Infectious Diseases Society of America (IDSA) are widely used in patients with community-acquired pneumonia (CAP) in Japan. To evaluate how correctly these conventional prognostic guidelines for CAP reflect the severity of non-HIV PCP, we retrospectively analyzed 21 patients with non-HIV PCP. METHODS: A total of 21 patients were diagnosed by conventional staining and polymerase chain reaction (PCR) for respiratory samples with chest x-ray and computed tomography (CT) findings. We compared the severity of 21 patients with PCP classified by A-DROP, CURB-65, and PSI. Also, patients' characteristics, clinical pictures, laboratory results at first visit or admission and intervals from diagnosis to start of specific-PCP therapy were evaluated in both survivor and non-survivor groups. RESULTS: Based on A-DROP, 18 patients were classified as mild or moderate; respiratory failure developed in 15 of these 18 (83.3%), and 7/15 (46.7%) died. Based on CURB-65, 19 patients were classified as mild or moderate; respiratory failure developed in 16/19 (84.2%), and 8 of the 16 (50%) died. In contrast, PSI classified 14 as severe or extremely severe; all of the 14 (100%) developed respiratory failure and 8/14 (57.1%) died. There were no significant differences in laboratory results in these groups. The time between the initial visit and diagnosis, and the time between the initial visit and starting of specific-PCP therapy were statistically shorter in the survivor group than in the non-survivor group. CONCLUSIONS: Conventional prognostic guidelines for CAP could underestimate the severity of non-HIV PCP, resulting in a therapeutic delay resulting in high mortality. The most important factor to improve the mortality of non-HIV PCP is early diagnosis and starting of specific-PCP therapy as soon as possible.

Early diagnosis and treatment are crucial for the survival of Pneumocystis pneumonia patients without human immunodeficiency virus infection.

The mortality of Pneumocystis pneumonia (PCP) patients without human immunodeficiency virus (HIV) infection ranges from 0 to 70 %, whereas that of HIV-infected PCP patients ranges from 10 to 20 %. The reasons for these differences are not known. We retrospectively analyzed factors contributing to the survival of 23 patients with PCP and without HIV infection, in whom PCP developed as community-acquired pneumonia (CAP). The interval from admission to the start of PCP-specific treatment was significantly shorter for survivors (2.71 ± 3.64 days; n = 14) than for non-survivors (8.67 ± 5.5 days; n = 9; p = 0.003). Moreover, although the severity scores/classes assessed by A-DROP, CURB-65, and PSI were no different on admission, scores/classes at the start of PCP-specific treatment were significantly higher for non-survivors. Overall mortality was 39 %, but mortality was approximately 70-100 % for patients classified as severe grade by A-DROP, CURB-65, or PSI scores/classes at the time when PCP-specific treatment was started, which was far higher than expected for these guidelines. In conclusion, early diagnosis and treatment within 3 days are crucial for the survival of PCP patients without HIV infection. We emphasize the limitations of application of guidelines for CAP to patients with PCP.

A case of novel swine influenza A (H1N1) pneumonia complicated with virus-associated hemophagocytic syndrome.

Influenza related to complications such as pneumonia and encephalitis have sporadically been reported. However, influenza A (H1N1)-virus-associated hemophagocytic syndrome (VAHS) has rarely been reported. A 39-year old woman complained of high fever and was referred to us. Chest infiltrations in both lungs and a positive polymerase chain reaction (PCR) for novel swine origin influenza A (H1N1) in bronchial alveolar lavage fluid (BALF) specimen was confirmed and she was diagnosed with influenza A (H1N1) pneumonia. Pancytopenia was found, and hemophagocytic syndrome (HPS) was diagnosed by bone marrow aspiration. Following intravenous administration of antiflu drug and combination therapy of steroid pulse and erythromycin IV, the patient's respiratory dysfunction and lab data gradually improved and she was discharged on day 21. Whereas secondary HPS related to viral infections such as Epstein­Barr virus, cytomegalovirus, and human herpesvirus type 6 are commonly seen, H1N1 pneumonia complicated with secondary VAHS is rare.

[Relationship between the prognosis of interstitial pneumonia and its comorbidities].

BACKGROUND: To investigate the relationship between the prognosis of chronic interstitial pneumonia (IP) and its comorbidities, we conducted a retrospective study for clinically and radiologically diagnosed IP. We assessed comorbidities by using the Charlson Comorbidity Index (CCI). METHODS: We classified 224 patients given clinical diagnoses of chronic IP (excluding the patients who had clear causes such as collagen disease, infection, drugs or radiation) in our institution between April 2000 and June 2010, into 2 groups; those with clinical diagnoses of idiopathic pulmonary fibrosis (IPF:108 cases) and those with other chronic IP but without honeycomb lung (116 cases); and analyzed their backgrounds and comorbidities. We also classified them into survival and non-survival groups to assess their prognostic factors. RESULTS: Although the smoking status of patients with clinically diagnosed IPF was higher, and SpO2 was lower than those with other chronic IP without honeycomb lung, the mean age, comorbidities and CCI did not differ between them. The 5-year overall survival of the clinically-diagnosed IPF group was lower than that of the other chronic IP without honeycomb lung group (50.8% vs. 76.3%, p<0.01). In cases of other chronic IP without honeycomb lung, the CCI of non-survival cases was higher than that of survival cases (4.05 vs. 2.47, p<0.01), although patient backgrounds did not differ between survival and non-survival cases in those with clinically diagnosed IPF (CCI : 2.32 vs. 2.98, p = 0.70). CONCLUSIONS: Our analysis revealed the possibility that comorbidities and CCI were prognostic factors in other chronic IP cases without honeycomb lung, although the prognosis of IPF was not affected by their comorbidity.

[The efficacy of influenza vaccine for acute exacerbation of chronic obstructive lung disease in elderly patients].

OBJECTIVE: Acute exacerbations adversely affect the quality of life and prognosis of patients with chronic obstructive lung disease (COPD). Prevention of future exacerbations is extremely important, especially for elderly patients. In this study, we evaluated the efficacy of influenza vaccine for acute exacerbation of COPD in elderly patients. METHODS: A prospective cohort study was conducted among 289 patients over 65 years of age with COPD (FEV1/FCV<0.70) during the 2001-2002 influenza season. Background data, outpatient visits for wheezing and hospitalizations were compared between the vaccinated group (n = 189) and the unvaccinated group (n = 100). RESULTS: The number of patients who visited hospital for wheezing was 11 of 189 (5.8%) in the vaccinated group and 23 of 100 (23%) in the unvaccinated group (RRR: relative risk reduction 74.7%, 95% CI: confidence interval 0.51-0.87). The number of hospitalizations for pneumonia was 8 of 189 (4.2%) in the vaccinated group and 14 of 100 (14%) in the unvaccinated group (RRR 69.8%, 95% CI: 0.32-0.87). The costs of hospitalization were lower in the vaccinated group with direct savings of 91,525 yen per patient. CONCLUSIONS: For elderly COPD patients, influenza vaccine decreases acute exacerbation due to pneumonia and bronchoconstriction, and also may minimize the costs of hospitalization.