Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Does maternal autoantibody that transfer to newborn cause disease?

Autoimmune pulmonary alveolar proteinosis (aPAP) is associated with excess amount of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) in the lung and blood. We experienced a female case with severe aPAP who could continue her pregnancy under home oxygen therapy and delivered a newborn by caesarean section. Maternal serum GMAb remained high level for up to one year after the delivery, although aPAP entered remission by whole lung lavage. While the newborn oxygen saturation as well as serum Krebs von den Lungen-6 and surfactant protein-D levels had been normal until one year. As GMAb likely transfer to the newborn and might cause the same disease, we carefully monitored both maternal and the newborn serum GMAb levels after the birth for up to one year. We confirmed that GMAb passively transferred to the newborn circulation but rapidly decreased exponentially to the cut-off level. It is suggested that this rapid decrease might prevent the newborn from developing aPAP.

A Semiquantitative Computed Tomographic Grading System for Evaluating Therapeutic Response in Pulmonary Alveolar Proteinosis.

RATIONALE: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. OBJECTIVES: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. METHODS: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. RESULTS: CT grade score and CT extent score had significant correlation with diffusing capacity of the lung for carbon monoxide percent predicted (%DlCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than ΔCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DlCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. In multivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2. CONCLUSIONS: Although a number of CT variables were collected, the currently proposed grading system that correlates well with PaO2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis. A Report of Five Intractable Cases.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures.

BACKGROUND: Whole lung lavage (WLL) is the current standard of care treatment for patients affected by pulmonary alveolar proteinosis (PAP). However, WLL is not standardized and international consensus documents are lacking. Our aim was to obtain a factual portrayal of WLL as currently practiced with respect to the procedure, indications for its use, evaluation of therapeutic benefit and complication rate. METHODS: A clinical practice survey was conducted globally by means of a questionnaire and included 27 centers performing WLL in pediatric and/or adult PAP patients. RESULTS: We collected completed questionnaires from 20 centres in 14 countries, practicing WLL in adults and 10 centers in 6 countries, practicing WLL in pediatric patients. WLL is almost universally performed under general anesthesia, with a double-lumen endobronchial tube in two consecutive sessions, with an interval of 1-2 weeks between sessions in approximately 50 % of centres. The use of saline warmed to 37 °C, drainage of lung lavage fluid by gravity and indications for WLL therapy in PAP were homogenous across centres. There was great variation in the choice of the first lung to be lavaged: 50 % of centres based the choice on imaging, whereas 50 % always started with the left lung. The choice of position was also widely discordant; the supine position was chosen by 50 % of centres. Other aspects varied significantly among centres including contraindications, methods and timing of follow up, use of chest percussion, timing of extubation following WLL and lung isolation and lavage methods for small children. The amount of fluid used to perform the WLL is a critical aspect. Whilst a general consensus exists on the single aliquot of fluid for lavage (around 800 ml of warm saline, in adults) great variability exists in the total volume instilled per lung, ranging from 5 to 40 liters, with an average of 15.4 liters/lung. CONCLUSIONS: This international survey found that WLL is safe and effective as therapy for PAP. However these results also indicate that standardization of the procedure is required; the present survey represents the a first step toward building such a document.

Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study.

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 < 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p < 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study. CONCLUSION: The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.

A mathematical model to predict protein wash out kinetics during whole-lung lavage in autoimmune pulmonary alveolar proteinosis.

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10-30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and ß2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of ß2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

Urinary 8-hydroxydeoxyguanosine is a potential indicator for estimating pulmonary rehabilitation-induced oxidative stress in COPD patients.

Chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease and is an important cause of morbidity worldwide. The aim of this study was to evaluate whether pulmonary rehabilitation (PR) improves the oxidant/antioxidant imbalance, exercise capacity and health-related quality of life (HRQL) in patients with different stages of COPD. Eighteen stable COPD patients participated in 8-week PR; the exercise intensity was set at 70% of the VO2 peak. Subjects were divided into 2 groups: moderate to severe (stages II/III: n = 12) and very severe COPD with FEV1 < 30% predicted (stage IV: n = 6). In patients at stages II/III, PR improved exercise capacity (6-minute walking test: 431.2 ± 26.6 vs. 489.1 ± 26.5 m, P < 0.01 and shuttle walking test: 329.2 ± 41.4 vs. 378.2 ± 41.5 m, P < 0.01) and HRQL, whereas no significant change was observed in erythrocyte lipid peroxidation and urinary 8-hydroxydeoxyguanosine, a marker for DNA damage. In contrast, PR for stage IV patients did not improve exercise capacity and HRQL, but significantly increased urinary 8-hydroxydeoxyguanosine (14.5 ± 1.7 vs. 24.3 ± 2.6 ng/mg Cr, P < 0.05). In both groups, erythrocyte antioxidants (superoxide dismutase, glutathione peroxidase, and catalase) did not change significantly after PR. Thus, urinary 8-hydroxydeoxyguanosine is a useful indicator for the PR-induced oxidative stress in COPD patients. In conclusion, appropriate exercise program in COPD patients can improve exercise capacity and HRQL without further increase of oxidative stress. However, PR for very severe COPD patients enhanced exercise-induced oxidative stress.

Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan.

BACKGROUND: Secondary pulmonary alveolar proteinosis (sPAP) is a very rare lung disorder comprising approximately 10% of cases of acquired PAP. Hematological disorders are the most common underlying conditions of sPAP, of which 74% of cases demonstrate myelodysplastic syndrome (MDS). However, the impact of sPAP on the prognosis of underlying MDS remains unknown. The purpose of this study was to evaluate whether development of sPAP worsens the prognosis of MDS. METHODS: Thirty-one cases of sPAP and underlying MDS were retrospectively classified into mild and severe cases consisting of very low-/low-risk groups and intermediate-/high-/very high-risk groups at the time of diagnosis of MDS, according to the prognostic scoring system based on the World Health Organization classification. Next, we compared the characteristics, disease duration, cumulative survival, and prognostic factors of the groups. RESULTS: In contrast to previous reports on the prognosis of MDS, we found that the cumulative survival probability for mild MDS patients was similar to that in severe MDS patients. This is likely due to the poor prognosis of patients with mild MDS, whose 2-year survival rate was 46.2%. Notably, 75% and 62.5% of patients who died developed fatal infectious diseases and exacerbation of PAP, respectively, suggesting that the progression of PAP per se and/or PAP-associated infection contributed to poor prognosis. The use of corticosteroid therapy and a diffusing capacity of the lung for carbon monoxide of less than 44% were predictive of poor prognosis. CONCLUSION: Development of sPAP during the course of MDS may be an important adverse risk factor in prognosis of patients with mild MDS.

Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. TRIAL REGISTRY: ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

Clinical efficacy and safety of arbekacin sulfate in patients with MRSA sepsis or pneumonia: a multi-institutional study.

Arbekacin (ABK) is an aminoglycoside and widely used in Japan for treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). Although, ABK has concentration-dependent antibacterial activity, the peak serum concentration (C (peak)) of ABK has not yet been fully investigated as an indicator of the efficacy of ABK. The present study was conducted in patients admitted to hospitals affiliated with the ABK Dose Finding Study Group, between October 2008 and June 2011, who had pneumonia or sepsis, the cause of which was identified or suspected to be MRSA. The initial target C (peak) was set at 15-20 µg/mL and therapeutic drug monitoring was conducted. Then the relationship between serum concentration and efficacy/safety of ABK was prospectively examined to obtain sufficient clinical efficacy. In total, 89 patients from 11 clinical sites in Japan were enrolled and 29 of these patients were subjected to efficacy analysis. The mean initial dose and C (peak) were 306.9 mg/day and 16.2 µg/mL, respectively. The efficacy rate was 95 % (19/20 patients) at 5-6 mg/kg or higher, 87.5 % (7/8) for sepsis and 90.5 % (19/21) for pneumonia, and the overall efficacy rate was 89.7 % (26/29). There was no increase in the incidence of adverse events. In conclusion, we recommend the initial dose of ABK at 5-6 mg/kg or higher and the dosage regimen should be adjusted to achieve C (peak) at 10-15 µg/mL or higher in the treatment of patients with pneumonia or sepsis caused by MRSA. This strategy would surely achieve low incidence of adverse events while obtaining high clinical efficacy.

IgM-type GM-CSF autoantibody is etiologically a bystander but associated with IgG-type autoantibody production in autoimmune pulmonary alveolar proteinosis.

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 IC(50) value 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 case of HAPE on K2 and literature review.

HAPE (High Altitude Pulmonary Edema) is a serious and fatal disease in mountains. Early diagnosis and immediate descent are important for successful treatment. One of the authors (GS), who was healthy and a well trained climber, participated in the expedition to K2 (8611 m) in 2006 and developed HAPE. Under the severe environmental condition, it was difficult to evaluate his condition in its early stage. The earliest symptoms were nonspecific for HAPE as reported in many papers. Neither had he suffered from HAPE on the previous expeditions. These facts probably delayed the diagnosis in spite of its typical onset. This is a rare case report by a medical doctor who suffered from HAPE. The present case may remind the climbers of the difficulties in diagnosing HAPE on a mountain.

Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in healthy subjects and patients with COPD.

[Background] In patients with chronic obstructive pulmonary disease (COPD), early lactic acidosis during exercise should be considered as playing a role in the limitation of exercise tolerance. It was hypothesized that the relationship between blood lactate concentrations (LA) and tissue oxygenation index (TOI) is available for the prediction of aerobic capacity of skeletal muscle. [Methods] Changes of LA and TOI in the vastus lateralis muscle were measured during incremental cycling exercise in 12 healthy subjects and 4 patients with COPD. The relationship between TOI and LA was examined in 12 healthy subjects and 4 COPD patients, and changes in the relationship were examined at an interval of several years (3.3 +/- 1.0). [Results] (1) From the pattern LA as related to TOI, the healthy subjects were classified into the three groups. Group A (n = 3); LA increased slowly with a decrease in TOI. Group B (n = 3); LA increased steeply after the half point of maximal exercise. Group C (n = 6); LA increased steeply before the half point of maximal exercise. (2) In 3 patients with COPD, the relationship between TOI and LA shifted rightward at the second examination. [Conclusion] The steep increase in LA from the approximate resting value of TOI during exercise suggests that the aerobic capacity of working skeletal muscle decreased.

Bilateral phrenic nerve paralysis manifested by orthopnea for 6 months in a patient with neuralgic amyotrophy.

Bilateral phrenic nerve paralysis (BPP) is a relatively rare disease manifested by slight dyspnea at rest and on exertion in the sitting and standing positions and by dyspnea in the supine position. A 67-year-old man, who was a painter, presented with severe pain in both shoulder regions that had evolved into orthopnea and forced him to sleep in a sitting position at night. Dyspnea and paradoxical respiratory movement in the supine position raised suspicions of BPP. The most striking feature in this case was that the rapid onset of pain in both shoulder regions was followed by BPP. The BPP was considered to be secondary to neuralgic amyotrophy (NA).

Comparative study of high-resolution CT findings between autoimmune and secondary pulmonary alveolar proteinosis.

BACKGROUND: Acquired pulmonary alveolar proteinosis (PAP) has been reclassified into autoimmune or secondary PAP according to the occurrence of serum granulocyte macrophage colony-stimulating factor autoantibody. Most patients undergo high-resolution CT (HRCT) scanning in order for physicians to make a differential diagnosis of diffuse lung diseases, but no information is available to distinguish the HRCT scan features of secondary PAP from those of autoimmune PAP. The objective of this study was to characterize the HRCT scan features of autoimmune and secondary PAP. METHODS: HRCT scans of 42 patients (21 patients each in the autoimmune PAP and secondary PAP groups) were centrally collected and evaluated in a blinded manner. RESULTS: Ground-glass opacities (GGO) were a major finding in both the autoimmune PAP and secondary PAP groups. In the secondary PAP group, GGOs typically showed a diffuse pattern (62%), whereas GGOs showed a patchy geographic pattern in the autoimmune PAP group (71%; p < 0.005). The so-called "crazy-paving" appearance and subpleural sparing were frequently seen in the autoimmune PAP group (both 71%), whereas they were less frequently seen in the secondary PAP group (14% and 33%, respectively). The involved area of GGO was even in craniocaudal distribution for the secondary PAP group, whereas it was predominant in the lower lung field compared with the upper lung field in the autoimmune PAP group (p < 0.05). CONCLUSIONS: Typical HRCT scan findings for autoimmune PAP patients were GGO with a patchy geographic pattern, subpleural sparing, crazy-paving appearance, and predominance in the lower lung field. These findings were rather infrequent for secondary PAP patients.

Acute idiopathic thrombocytopenic purpura complicated with diffuse alveolar hemorrhage in an elderly patient.

Idiopathic thrombocytopenic purpura (ITP) is a hemorrhagic disease that often occurs in the elderly. It generally presents as a chronic disease with insidious onset, and is frequently resistant to various therapies. Compared to patients less than 40 years old, those older than 60 years tend to show a higher rate of ITP-related mortality. The present report describes a 73-year-old patient with acute ITP who experienced diffuse alveolar hemorrhage that responded well to high-dose intravenous immunoglobulin therapy combined with corticosteroid pulse therapy.

[Unilateral total pulmonary lavage for pulmonary alveolar proteinosis and an algorithm to select lavage procedures].

In 8 patients with pulmonary alveolar proteinosis (7 with autoimmune pulmonary alveolar proteinosis and 1 with secondary pulmonary alveolar proteinosis related to Behcet disease), we performed unilateral total pulmonary lavage 41 times (including 2 sessions in which lavage was discontinued) between March 1991 and January 2008. Reasons for discontinuation consisted of severe hypoxemia and leakage of lavage fluid into the non-washed lung. In this study, we describe changes in arterial blood gas and limitations in 41 sessions of unilateral total pulmonary lavage, and report an algorithm for lavage procedures prepared based on our experience and previous studies regarding unilateral total pulmonary lavage.

Pulmonary alveolar proteinosis in a patient with Behcet's disease.

Secondary pulmonary alveolar proteinosis (PAP) has been described in several clinical settings that can be grouped into three main categories: infections of the lung; haematological malignancies and other conditions that alter the patient's immune status; and exposure to inhaled chemicals and minerals. Recent studies reported that anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody was present in the serum of patients with idiopathic PAP but not in patients with secondary PAP or in normal subjects. The present report describes the interesting case of a patient with Behcet's disease and PAP. The absence of anti-GM-CSF antibodies in this patient suggested a diagnosis of secondary PAP.