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A 74-year-old male was referred to our critical care department for refractory severe watery diarrhea with advanced leukocytosis (over 70,000/μl) after multiple administrations of eradication therapy against Helicobacter pylori (HP). He was diagnosed as having fulminant colitis due to Clostridioides difficile after antimicrobial eradication therapy. He was given intravenous metronidazole and oral vancomycin. He also received supportive therapy including continuous hemodiafiltration for severe metabolic acidosis. However, despite emergency open sigmoidectomy, he died. The C. difficile isolate recovered was PCR-ribotype 002, which was positive for toxins A and B but negative for binary toxin. HP eradication therapy for prevention of chronic gastritis and stomach cancer is now in widespread use. Although such secondary severe complications are rare, we consider it to be necessary to pay sufficient attention when administering HP eradication therapy.

Background We investigated the incidence of acute kidney injury (AKI) and risk factors associated with vancomycin (VAN) and piperacillin-tazobactam (TZP) combination therapy in non-intensive care unit (ICU) and ICU settings. Methods In this single-center retrospective cohort study, adults who received VAN for ≥48 h during the period from 1 January 2016 through 31 December 2017 were included. The primary endpoint was incidence of AKI. Results Data from 593 adults were analyzed. The incidence of AKI was 10.6% overall, 8.0% in the non-TZP group, and 19.8% in the TZP group. In univariate analysis, the odds ratio (OR) for AKI was higher in the TZP group than in the non-TZP group (2.84, 95% CI = 1.64-4.90). In both the non-ICU and ICU settings, the OR for AKI was higher in the TZP group than in the non-TZP group (non-ICU: OR = 3.04, 95% CI = 1.52-6.09; ICU: OR = 2.51, 95% CI = 1.03-6.08). Furthermore, in propensity score analysis, the OR for AKI was higher in the TZP group than in the non-TZP group (OR = 2.81, 95% CI = 1.52-5.17). In both the non-ICU and ICU settings, the OR for AKI was higher in the TZP group than in the non-TZP group (non-ICU: OR = 2.57, 95% CI = 1.17-5.64; ICU: OR = 3.51, 95% CI = 1.05-11.6). Conclusions Combined use of TZP in patients receiving VAN increased AKI incidence in non-ICU and ICU settings.

The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.

Background Carbapenem-resistant Enterobacteriaceae (CRE) are classified as carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE; the majority of CPE in Japan produce IMP carbapenemase. Objectives We evaluated the clinico-epidemiological and microbiological information and effects of IMP-type carbapenemase production in CRE. Methods Patients with isolations of CRE (MICs of meropenem ≥2 mg/L, imipenem ≥2 mg/L or cefmetazole ≥64 mg/L) from August 2016 to March 2018 were included. Microbiological analyses and WGS were conducted and clinical parameters were compared between groups. Independent predictors for the isolation of CPE from patients were identified by logistic regression. For comparing clinical outcomes, a stabilized inverse probability weighting method was used to conduct propensity score-adjusted analysis. Results Ninety isolates (27 CPE and 63 non-CPE) were collected from 88 patients (25 CPE and 63 non-CPE). All CPE tested positive for IMP carbapenemase. Antibiotic resistance (and the presence of resistance genes) was more frequent in the CPE group than in the non-CPE group. Independent predictors for CPE isolation were residence in a nursing home or long-term care facility, longer prior length of hospital stay (LOS), use of a urinary catheter and/or nasogastric tube, dependent functional status and exposure to carbapenem. Although in-hospital and 30 day mortality rates were similar between the two groups, LOS after CRE isolation was longer in the CPE group. Conclusions IMP-CPE were associated with prolonged hospital stays and had different clinical and microbiological characteristics compared with non-CPE. Tailored approaches are necessary for the investigational and public health reporting, and clinical and infection prevention perspectives for IMP-CPE and non-CPE.

We report a case with infective endocarditis (IE) due to Cardiobacterium valvarum . The patient was a 57-year-old male, who was referred to our hospital based on suspected IE detected by transthoracic echocardiography at a neighbourhood clinic. Three sets of blood cultures obtained on admission yielded positive results, and revealed rather slender and linear Gram-negative bacilli with a rosette formation that dyed minimally, with a pale white appearance. Although no isolates were identified by conventional methods, C. valvarum was ultimately identified by 16 S ribosomal RNA genotyping. HACEK group strains are difficult to identify by conventional methods. Therefore, if Gram-negative bacilli are isolated from IE patients, 16 S ribosomal RNA genotyping will be necessary. Furthermore, IE due to C. valvarum is very rare. We thus discuss our case in comparison with previous reports.

In this multicenter, matched case-control study, patients diagnosed with catheter-related bloodstream infection (CRBSI) caused by Bacillus cereus (n = 108) were matched to controls (n = 269). In the multivariable analysis, administration of an amino acid preparation and an indwelling peripheral catheter were significant variables for B cereus-related CRBSI.

Flu vaccinations are administered worldwide every winter for prevention. We herein describe a case of acute lung injury resulting from a pathologically confirmed alveolar hemorrhage, which may have been closely related to a preceding vaccination for pandemic influenza A of 2009/10. The present patient had been hospitalized with an acute lung injury after flu vaccination one year prior to the present hospitalization, however, he received another flu vaccination. We should consider a vaccine-related adverse reaction as a potential cause of pulmonary disease if patients present with this illness during the winter season.

We describe a case of pulmonary nocardiosis due to Nocardia asiatica in an immunocompent 64-year-old-female. Wadowsky-Yee-Okuda-α-ketoglutarate (WYOα) agar, a selective media for Legionella species, was useful for the detection based on the growth-inhibition of normal oral flora and growth-promotion of Nocardia species.

Introduction. We herein describe a case with a neck abscess due to non-typhoidal Salmonella (NTS). NTS habitually reside in our environment and colonize all animals including mammals. Colonizations of pigs, chickens, cows and sheep are important because food poisoning episodes in human are often associated with meat. Extra-intestinal infection due to NTS has numerous presentations and complications, with aortic aneurysms being common. Case presentation. A 26-year-old Japanese male complaining of left-sided neck swelling was referred to our hospital for a suspected deep neck abscess. An enhanced computed tomography scan of the neck revealed a low density lesion in the left-sided deep neck area, and consequently the patient underwent urgent incision and drainage. After this urgent operation, Salmonella Choleraesuis was isolated from a greyish-white abscess. The patient ultimately recovered with antimicrobial administration, though re-incision for lymphadenectomy was necessary. The neck abscess may have developed because he had eaten raw meat. Furthermore, untreated diabetes mellitus was diagnosed at presentation. Conclusion. Salmonella enterica serovar Choleraesuis infections are rare in Japan. NTS are generally recognized as important pathogens in food poisoning globally, and attention is required to avoid the development of extra-intestinal infections. In Japan, the increasing lifestyle diversity in recent years highlights the importance of recognizing rare infections.

Objectives: The Mycoses Forum in Japan has developed management bundles for candidaemia to incorporate into bedside practice. The aim of this study was to investigate nationwide compliance with the bundles and their impact on clinical outcomes. Methods: Non-neutropenic patients treated with antifungals for candidaemia were surveyed. Bundles consist of nine items to complete. Data were sent to the central office between July 2011 and April 2012. Results: Six hundred and eight patients were analysed. The compliance rate for achieving all elements was 6.9%, and it increased to 21.4% when compliance was analysed by the bundle except for oral switch. There was a significant difference in clinical success between patients with and without compliance [92.9% versus 75.8% (P ¼0.011)]. Compliance with the bundles, however, failed to be an independent factor associated with favourable outcomes. When step-down oral therapy was excluded from the elements of compliance, compliance with the bundles was revealed to be an independent predictor of clinical success (OR 4.42, 95% CI 2.05 –9.52) and mortality (OR 0.27, 95% CI 0.13 – 0.57). Independent individual elements contributing to clinical success were removal of central venous catheters within 24 h, assessment of clinical efficacy on the third to the fifth day and at least 2 weeks of therapy after clearance of candidaemia. Conclusions: Compliance with the bundles for candidaemia had a beneficial effect on clinical outcomes. Promotion of the bundles approach may have the potential to narrow the gap between clinical evidence and bedside practice.

Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P.0005).These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

Background Data of a multicenter study on CRE from Japan are limited. Comparative analyses of carbapenemase-producing Enterobacteriaceae (CPE) and non-carbapenemase-producing CRE (NCP-CRE) have not yet been conducted. Methods Cases with CPE or CRE (defined as (1) meropenem [MPM] MIC, ≥2 mg/L or (2) imipenem [IPM] MIC, ≥2 mg/L and cefmetazole MIC, ≥64 mg/L [CLSI criteria]) were included from August 2016 to May 2017. PCR was used to detect carbapenemase. Results From five tertiary hospitals, 24 isolates (14 CPE and 10 NCP-CRE) were collected from 22 patients. Of the 10 NCP-CRE, seven were Enterobacter aerogenes and three were Enterobacter cloacae; of the 14 CPE, five were Klebsiella pneumoniae; 3, E. cloacae; 3, E. coli; 2, Citrobacter freundii; and 1, E. aerogenes. CPE were frequently isolated from the urine (5 [42%]) and sputum (3 [25%]) and NCP-CRE from sputum (4 [40%]), bile (3 [30%]), and urine (2 [20%]). Cases with CPE were older with more frequent use of urinary catheter and/or NG tube than NCP-CRE (table). The 30-day mortality or length of hospital stay (LOS) did not differ between the two groups. Majority (n = 12) of CPE were identified to carry blaIMP (MPM MIC, ≥2 mg/L), and two CPE were positive for blaOXA-181 and blaOXA-232 (MPM MIC, ≤1 mg/L). All NCP-CRE had IPM MIC of ≥2 mg/L; 7 (70%) had MPM of ≤1 mg/L. Resistance to amikacin (AMK) and levofloxacin (LFX) was noted in one and five CPE, respectively, whereas all NCP-CRE were sensitive, and nine blaIMP and 1 blaoxa-232 were transferable by conjugation. Conclusion CPE and NCP-CRE had different clinical characteristics. Non-β-lactam treatment options were more available for NCP-CRE than CPE. CPE and NCP-CRE might require different control strategies. Disclosures All authors: No reported disclosures.

For the first time in 16 years, a food-borne outbreak of typhoid fever due to Salmonella enterica serotype Typhi was reported in Japan. Seven patients consumed food in an Indian buffet at a restaurant in the center of Tokyo, while one was a Nepali chef in the restaurant, an asymptomatic carrier and the implicated source of this outbreak. The multiple-locus variable-number tandem repeat analysis showed 100% consistency in the genomic sequence for five of the eight cases.

Idiopathic pulmonary fibrosis (IPF) is a disease with a worse prognosis than some types of cancer. In patients with IPF, lung cancer is critical because of the associated high mortality rate from its progression and fatal complications from anticancer treatments. Therefore, preventing lung cancer in patients with IPF is primordial. Pirfenidone is an anti-fibrotic agent that reduces the decline in forced vital capacity. This study aimed to assess the effect of pirfenidone in the development of lung cancer in patients with IPF.Data from 261 patients with IPF with and without pirfenidone were retrospectively reviewed, and the incidence of lung cancer was analyzed.In the pirfenidone group, the incidence of lung cancer was significantly lower than in the non-pirfenidone group (2.4% vs. 22.0%, P0.0001). Multivariate Cox proportional hazards regression analysis demonstrated that pirfenidone decreased the risk of lung cancer (hazard ratio, 0.11; 95% confidence interval, 0.03 to 0.46; P = 0.003), whereas coexisting emphysema increased the incidence of lung cancer (hazard ratio, 3.22; 95% confidence interval, 1.35 to 7.70; P = 0.009).Pirfenidone might correlate with a decreased risk of lung cancer in patients with IPF. However, no definite conclusion can be drawn from this retrospective study, and a multicenter, prospective cohort study is still warranted to confirm the effect of pirfenidone on lung cancer in patients with IPF.

Disseminated non-tuberculous mycobacterium (dNTM) infection is rare in humans without human immunodeficiency virus (HIV) infection. Previous reports have shown autoantibodies to human interferon-gamma (IFN-γ), which play important roles in mycobacterium infection, in the sera of patients with non-HIV dNTM disease. Herein, we describe a 53-year-old male who was strongly suspected to have multicentric Castleman disease (MCD) based on bone marrow study and chest radiological findings. However, Mycobacterium kansasii was detected in respiratory samples including pleural effusion. We initiated anti-mycobacterial therapy under intensive care; he died on the 48th hospital day. We detected no hematological disorders, ruling out MCD postmortem. However, we detected M. kansasii in pulmonary, liver, spleen and bone marrow tissues. Moreover, anti-IFN-γ autoantibody was detected with strong neutralizing capacity for IFN-γ. We consider our present report to contribute to understanding of the relationship between anti-IFN-γ autoantibody and disease development.

Summary Background Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear. Objectives To figure out changes in surfactant clearance during GM-CSF inhalation therapy. Methods We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5–21 mg, duration 12–24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg ( n = 10) and low responders with that n = 9). Results Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment. Conclusions GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.

Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) was recently proposed as an entity to be included among rare idiopathic interstitial pneumonias (IIPs). However, the cause, clinical features and prognosis of this rare entity have not been elucidated. Objectives: We aimed to examine the clinical features, outcomes and prognostic factors for IPPFE in comparison to those of idiopathic pulmonary fibrosis (IPF). Methods: We retrospectively analyzed 20 patients with IPPFE and 71 with IPF. We compared clinical features, blood examination data, and respiratory functions at the time of diagnosis. Results: The IPPFE group had a significantly lower body mass index (BMI), percent forced vital capacity (%FVC), total lung capacity (%TLC) and expiratory reserve volume (%ERV), as well as a higher residual volume to TLC (RV/TLC) ratio than the IPF group. The annual FVC changes in the IPPFE group (-326ml/year) were significantly larger than those in the IPF group (-142ml/year). Survival was significantly poorer in the IPPFE than in the IPF group (P = 0.021). BMI and the partial pressure of oxygen in arterial blood (PaO2) were significantly related to the outcome of IPPFE. Conclusions: Our present results indicate the prognosis of IPPFE patients to be poorer than that of IPF patients. We advocate that BMI and arterial blood PaO2 be determined at the first visit as these parameters are closely related to patients’ outcomes. Prospective evaluation of IPPFE starting in the subclinical phase is necessary to assure that appropriate measures are taken before progression. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 35-40)

Objective and background This study was designed to clarify chest computerized tomography (CT) findings of Mycoplasma pneumoniae pneumonia facilitating differential diagnosis from CAP (community acquired pneumonia) caused by other organisms. Methods We retrospectively reviewed the CT findings of 36 patients (median age 33 years, 15 males, 21 females) with serologically proven M. pneumoniae pneumonia and 52 patients (median age 61 years, 37 males, 15 females) suffering from CAP with no serological evidence of M. pneumoniae infection. The CT images were analyzed by experienced pulmonologists. Results The most common finding in the M. pneumoniae pneumonia group was bronchial wall thickening, when we compared it with the CAP group (p

A 64-year-old woman with rheumatoid arthritis and treated with bucillamine presented with a productive cough. No obvious infiltration was detected in chest radiography, but CT revealed patchy ground glass opacities in bilateral lung fields. Her serum KL-6 level was elevated and transbronchial lung biopsy showed interstitial pneumonia. Drug lymphocyte stimulation test (DLST) for bucillamine was negative for blood lymphocytes, but positive for bronchoalveolar lavage (BAL) lymphocytes. The pneumonitis improved after the cessation of bucillamine. We therefore made a diagnosis of bucillamine-induced interstitial pneumonia. DLST with BAL lymphocytes is thus suggested to be useful for such diagnoses.

Background: Several studies have confirmed that pirfenidone ameliorates disease progression, as reflected by the reduction of pulmonary-function decline and prolonged progression-free survival, in patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). Aims: We conducted the current study to confirm the clinical efficacy of pirfenidone in patients with severe fibrosing interstitial pneumonia. Methods: We evaluated the clinical data of patients who received pirfenidone between 2009 and 2014 for the treatment of severe fibrosing interstitial pneumonia, diagnosed by published guidelines, with either stage III or IV disease according to the Japanese disease severity score. Changes in respective forced vital capacity (ΔFVC) during the 3-, 6-, 9-, and 12-months periods before (pre-ΔFVC) and after (post-ΔFVC) the commencement of pirfenidone treatment were compared using a paired t -test. Results: This study included 48 patients (35 male, 13 female). Of these, 25 had IPF, 19 had nonspecific interstitial pneumonia, and 4 had other forms of the disease. The mean dose of pirfenidone and duration of therapy were 1343 mg/day and 21 months, respectively. Using the Japanese disease severity score, 15 patients had stage III disease and 33 had stage IV. The mean FVC and %FVC before pirfenidone treatment were 1.89 L and 63.1%, respectively. Compared with the pre-ΔFVC, post-ΔFVC taken after treatment at months 3, 6, 9, and 12 showed considerable improvement; notably, there was significant improvement after 3 months of pirfenidone treatment (p = 0.0155). Conclusions: Pirfenidone may be effective in improving pulmonary function even in patients with severe fibrosing interstitial pneumonia.

We describe a case of pulmonary nocardiosis due to Nocardia asiatica in an immunocompent 64-year-old-female. Wadowsky-Yee-Okuda-α-ketoglutarate (WYOα) agar, a selective media for Legionella species, was useful for the detection based on the growth-inhibition of normal oral flora and growth-promotion of Nocardia species.

Pseudomonas oryzihabitans (formerly Flavimonas oryzihabitans) is a glucose non-fermentative, Gram-negative bacillus which is rarely isolated from human specimens. When isolated, it is on very rare occasion as a causative pathogen of catheter-related bloodstream infection in an immunocompromised patient. Herein, we describe two hematological malignancy patients suspected to have P. oryzihabitans bacteremia. We also review cases with bacteremia due to this pathogen and its microbiological characteristics.

Giant left atrium due to mitral stenosis with massive atelectasis: A successful case with perioperative approach☆ Atsushi Tanita , Yusuke Hosokawa ⁎, Takeshi Tomiyama , Maiko Kato , Junya Matsuda , Keisuke Sawai , Yoshie Arita , Toshiyuki Aokage , Hiroomi Suzuki , Hiroshige Murata , Hideki Miyachi , Toshiyuki Shibui , Takahito Nei , Koichi Akutsu , Takeshi Yamamoto , Shinhiro Takeda , Takashi Nitta , Kunio Tanaka , Kyoichi Mizuno , Keiji Tanaka a

Recently, interferon gamma release assays (IGRAs) have become an important clinical tool for detecting latent tuberculosis. However, IGRA results may impede making a diagnosis. We herein present an interesting case of miliary tuberculosis with a nonspecific IGRA reaction due to hemophagocytosis.

Background Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections. Methods For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications. Results DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (>18.9 mg/day, n = 16) than treated with low-dose prednisolone (≤18.9 mg/day, n = 15) divided by median daily dose (p

Interstitial lung disease is the most common complication and cause of death among patients with scleroderma. Scleroderma-related interstitial lung disease has usually been treated with cyclophosphamide; however, its effect was evaluated to be modest and long-term administration of this drug is associated with adverse effects. Herein, we report our clinical experience of administering pirfenidone, which is an antifibrotic agent, in five patients with scleroderma-related interstitial lung disease. All patients demonstrated an increase in vital capacity.

Previous studies demonstrated that antigranulocyte colony-stimulating factor autoantibody (GMAb) was consistently present in patients with autoimmune pulmonary alveolar proteinosis (aPAP), and, thus, represented candidature as a reliable diagnostic marker. However, our large cohort study suggested that the concentration of this antibody was not correlated with disease severity in patients. We found that the κ/λ ratio of GMAb was significantly correlated with the degree of hypoxemia. The proportion of λ-type GMAb per total λ-type IgG was significantly higher in severely affected patients than those in mildly affected patients, but the proportion of κ-type was unchanged. The κ/λ ratio was significantly correlated with both KL-6 and SP-D, which have been previously reported as disease severity markers. Thus, the light chain isotype usage of GMAb may not only be associated with the severity of aPAP, but may also represent a useful disease severity marker.

Bordetella holmesii is a fastidious Gram-negative rod first identified in 1995. Though rare, it is isolated mainly in immunocompromised and asplenic hosts and is associated with bacteremia, pertussis-like respiratory tract infection, and endocarditis. Herein, we describe a unique B. holmesii infectious pericarditis patient with malignant lymphoma.

To the Editors: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterised by excessive accumulation of surfactant materials within alveolar spaces [1]. Patients with autoimmune PAP (aPAP) present a high level of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (GM-Ab) in the serum as well as in bronchoalveolar lavage fluid (BALF) [2]. GM-Ab neutralise the biological activity of GM-CSF in the lung [3], impairing terminal differentiation of alveolar macrophages and macrophage-mediated pulmonary surfactant clearance [4]. Based on the aetiology, clinical trials of exogenous GM-CSF supplementation have been carried out by a number of physicians with variable response rates ranging from 40 to 62% [5–9]. Previously, we reported that in three patients who received a pilot GM-CSF inhalation therapy, oxygenation was improved and the concentration of GM-Ab in BALF was reduced [7]. Bonfield et al . [8] also reported that the serum titre of GM-Ab was reduced during successful treatment of aPAP with subcutaneously injected GM-CSF. However, our recent phase II trial of GM-CSF inhalation involving 35 patients revealed that serum levels of GM-Ab remained unchanged throughout the therapy, suggesting that GM-CSF inhalation therapy did not affect the production of GM-Ab [9]. Thus, the effect of exogenous GM-CSF administration on GM-Ab levels in the serum remains controversial. This discrepancy may be due to differences in the route of administration and/or the dose of GM-CSF. Aerosolised GM-CSF reaches the lower respiratory tract and may stimulate immature alveolar macrophages directly to promote terminal differentiation and improve the local clearance of the accumulated surfactant and GM-Ab, although it does not affect the production of systemic GM-Ab. To test this hypothesis, …

The granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) is the causative agent underlying autoimmune pulmonary alveolar proteinosis (aPAP). It consists primarily of the IgG isotype. At present, information on other isotypes of the autoantibody is limited. We detected serum the IgM isotype of GMAb (IgM-GMAb) in more than 80% of patients with aPAP and 22% of healthy subjects, suggesting that a continuous antigen pressure may be present in most patients. Levels of the IgM isotype were weakly correlated with IgG-GMAb levels but not IgA-GMAb, suggesting that its production may be associated with that of IgG-GMAb. The mean binding avidity to GM-CSF of the IgM isotype was 100-fold lower than the IgG-GMAb isotype, whereas the IC50value for neutralizing capacity was 20,000-fold higher than that of IgG-GMAb, indicating that IgM-GMAb is only a very weak neutralizer of GM-CSF. In bronchoalveolar lavage fluid from nine patients, IgG-GMAb was consistently detected, but IgM-GMAb was under the detection limit in most patients, confirming that IgM-GMAb is functionally a bystander in the pathogenesis of aPAP. It rather may be involved in the mechanism for development of IgG-GMAb in vivo.

A 79-year-old man with a 3-month history of lymphedema of the lower limbs, and diabetes mellitus, was admitted to our hospital for suspected deep venous thrombosis. Several hours after admission, leg pain and purpura-like skin color appeared. On the 2nd hospital day, he was referred to our department for possible acute occlusive peripheral artery disease (PAD) and skin necrosis with blisters; however, computed tomography with contrast showed no occlusive lesions. He had already developed shock and necrotizing deep soft-tissue infections of the left lower leg. Laboratory findings revealed renal dysfunction and coagulation system collapse. Soon after PAD was ruled out, clinical findings suggested necrotizing deep soft-tissue infections, shock state, disseminated intravascular coagulation, and multiple organ failure. These symptoms led to a high suspicion of the well-recognized streptococcal toxic shock syndrome (STSS). With a high suspicion of STSS, we detected Group G β-hemolytic streptococci (GGS) from samples aspirated from the leg bullae, and the species was identified as Streptococcus dysgalactiae subsp. equisimilis (SDSE) by 16S-ribosomal RNA sequencing. However, unfortunately, surgical debridement was impossible due to the broad area of skin change. Despite adequate antimicrobial therapy and intensive care, the patient died on the 3rd hospital day. The M-protein gene (emm) typing of the isolated SDSE was revealed to be stG6792. This type of SDSE is the most frequent cause of STSS due to GGS in Japan. We consider it to be crucial to rapidly distinguish STSS from acute occlusive PAD to achieve life-saving interventions in patients with severe soft-tissue infections.

BACKGROUNDS: Previously, we demonstrated that neutralizing capacity but not the concentration of GM-CSF autoantibody was correlated with the disease severity in patients with autoimmune pulmonary alveolar proteinosis (PAP)1-3. As abrogation of GM-CSF bioactivity in the lung is the likely cause for autoimmune PAP4,5, it is promising to measure the neutralizing capacity of GM-CSF autoantibodies for evaluating the disease severity in each patient with PAP. Until now, neutralizing capacity of GM-CSF autoantibodies has been assessed by evaluating the growth inhibition of human bone marrow cells or TF-1 cells stimulated with GM-CSF6-8. In the bioassay system, however, it is often problematic to obtain reliable data as well as to compare the data from different laboratories, due to the technical difficulties in maintaining the cells in a constant condition. OBJECTIVE: To mimic GM-CSF binding to GM-CSF receptor on the cell surface using cell-free receptor-binding-assay. METHODS: Transgenic silkworm technology was applied for obtaining a large amount for recombinant soluble GM-CSF receptor alpha (sGMRα) with high purity9-13. The recombinant sGMRα was contained in the hydrophilic sericin layers of silk threads without being fused to the silk proteins, and thus, we can easily extract from the cocoons in good purity with neutral aqueous solutions14,15. Fortunately, the oligosaccharide structures, which are critical for binding with GM-CSF, are more similar to the structures of human sGMRα than those produced by other insects or yeasts. RESULTS: The cell-free assay system using sGMRα yielded the data with high plasticity and reliability. GM-CSF binding to sGMRα was dose-dependently inhibited by polyclonal GM-CSF autoantibody in a similar manner to the bioassay using TF-1 cells, indicating that our new cell-free assay system using sGMRα is more useful for the measurement of neutralizing activity of GM-CSF autoantibodies than the bioassay system using TF-1 cell or human bone marrow cells. CONCLUSIONS: We established a cell-free assay quantifying the neutralizing capacity of GM-CSF autoantibody.

Background Disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signalling causes pulmonary alveolar proteinosis (PAP). Rarely, genetic defects in neonatal or infant-onset PAP have been identified in CSF2RA. However, no report has clearly identified any function-associated genetic defect in CSF2RB. Methods and results The patient was diagnosed with PAP at the age of 36 and developed respiratory failure. She was negative for GM-CSF autoantibody and had no underlying disease. Signalling and genetic defects in GM-CSF receptor were screened. GM-CSF-stimulated STAT5 phosphorylation was not observed and GM-CSF-Rβc expression was defective in the patient's blood cells. Genetic screening revealed a homozygous, single-base deletion at nt 631 in exon 6 of CSF2RB on chromosome 22, which caused reductions in GM-CSF dependent signalling and function. Both parents, who were second cousins, showed no pulmonary symptoms, and had normal GM-CSF-signalling, but had a CSF2RB allele with the identical deletion, indicating that the mutant allele may give rise to PAP in an autosomal recessive manner. Conclusions This is the first report identifying a genetic defect in CSF2RB that causes deficiency of GM-CSF-Rβc expression and impaired signalling downstream. These results suggested that GM-CSF signalling was compensated by other signalling pathways, leading to adult-onset PAP., Journal of medical genetics, 48(3), pp.205-209; 2011

An 82-year old man was admitted to our hospital for evaluation of progressive general malaise. He had previously been in good health. His chest roentgenogram showed reticular shadows and we suspected interstitial lung disease. On admission, his roentgenographic images showed deterioration compared with previous images. Acute lung injury was diagnosed by transbronchial lung biopsy, and steroid administration was started. He initially responded to treatment, but bilateral spontaneous pneumothorax occurred. Despite treatment, he died of respiratory failure. Amitani disease (idiopathic pulmonary upper lobe fibrosis) was suspected based on postmortem pathology, but his lung parenchyma was poor due to the presence of changes producing diffuse alveolar damage. We report and discuss this case because there are apparently no previous similar cases.