Alveolar proteinosis with hypersensitivity pneumonitis: a new clinical phenotype

Background and objective: The aim of the present study was to report the features of five patients with concurrent histopathological features of pulmonary alveolar proteinosis (PAP) and hypersensitivity pneumonitis (HP) and their high‐resolution CT (HRCT) appearances. Methods: Patients with histopathological features of both HP and PAP on surgical lung biopsy referred for tertiary review were retrospectively identified. The pathology and HRCT images were semi‐quantitatively scored to evaluate the relative contribution to HP and PAP. Results: Five patients had histopathological features of HP and PAP but had varied HRCT appearances. All had imaging features of PAP to a varying degree with two patients also showing characteristics of HP but three patients had ill‐defined thickened interlobular septa, not typical of either disease. Conclusions: We describe the coexistence of PAP and HP in five patients and discuss possible linkages between these two distinct pathologies.     

Non‐invasive ventilation for obese patients with chronic respiratory failure: Are two pressures always better than one?

Obesity‐related respiratory failure is increasingly common but remains under‐diagnosed and under‐treated. There are several clinical phenotypes reported, including severe obstructive sleep apnoea (OSA), isolated nocturnal hypoventilation with or without severe OSA and OSA complicating chronic obstructive pulmonary disease (COPD). The presence of hypercapnic respiratory failure is associated with poor clinical outcomes in each of these groups. While weight loss is a core aim of management, this is often unachievable, and treatment of sleep‐disordered breathing with positive airway pressure (PAP) therapy is the mainstay of clinical practice. Although there are few long‐term clinical efficacy trials, the lack of equipoise would prevent the utilization of an untreated control group. The current data support the use of PAP therapy to improve respiratory failure and is associated with improvements in health‐related quality of life, reduced healthcare utilization and reduced mortality. Both continuous PAP (CPAP) and non‐invasive ventilation (NIV) appear safe and effective in patients with obesity‐related respiratory failure and OSA, with or without COPD, and the current evidence would not support a single therapy choice in all patients. There are no studies of CPAP in patients with isolated nocturnal hypoventilation, and NIV would be the current recommendation in this patient group. Whichever starting therapy is used, titration should be performed to correct sleep‐disordered breathing and reverse chronic respiratory failure, with consideration of step‐down of the treatment based on a clinical re‐evaluation. In contrast, failure to reach physiological and clinical treatment targets should lead to the consideration of treatment escalation.     

Targeted inhibition of gene expression of pancreatitis‐associated proteins exacerbates the severity of acute pancreatitis in rats

Background: Pancreatitis‐associated protein (PAP) is a secretory protein not normally expressed in healthy pancreas but highly induced during acute pancreatitis. While PAP has been shown to be anti‐bacterial and anti‐apoptotic in vitro, its definitive biological function in vivo is not clear. Methods: To elucidate the function of PAP, antisense oligodeoxyribonucleotides (AS‐PAP) targeting all three isoforms of PAP were administered via intrapancreatic injections (5?mg?kg ^?1 day ^?1 , 2 days) to rats prior to induction of pancreatitis. Results: Severity of pancreatitis and cytokine gene expression in peripheral blood mononuclear cells (PBMC) were evaluated. Administration of AS‐PAP, but not the scrambled oligodeoxyribonucleotide (SC‐PAP) control, reduced pancreatitis‐induced PAP expression by 55.2?±?6.4%, 44.0?±?8.9%, and 38.9?±?10.7% for PAP isoforms I, II, and III, respectively, compared to saline‐treated controls (P?P?Conclusion: This is the first in vivo evidence indicating that PAP mediates significant protection against pancreatic injury. Our data suggest that PAP may exert its protective function by suppressing local pancreatic as well as systemic inflammation during acute pancreatitis.     

Pulmonary alveolar proteinosis

PAP is an ultra‐rare disease in which surfactant components, that impair gas exchange, accumulate in the alveolae. There are three types of PAP. The most frequent form, primary PAP, includes autoimmune PAP which accounts for over 90% of all PAP, defined by the presence of circulating anti‐GM‐CSF antibodies. Secondary PAP is mainly due to haematological disease, infections or inhaling toxic substances, while genetic PAP affects almost exclusively children. PAP is suspected if investigation for ILD reveals a crazy‐paving pattern on chest CT scan, and is confirmed by a milky looking BAL that gives a positive PAS reaction indicating extracellular proteinaceous material. PAP is now rarely confirmed by surgical lung biopsy. WLL is still the first‐line treatment, with an inhaled GM‐CSF as second‐line treatment. Inhalation has been found to be better than subcutaneous injections. Other treatments, such as rituximab or plasmapheresis, seem to be less efficient or ineffective. The main complications of PAP are due to infections by standard pathogens (Streptococcus, Haemophilus and Enterobacteria) or opportunistic pathogens such as mycobacteria, Nocardia, Actinomyces, Aspergillus or Cryptococcus. The clinical course of PAP is unpredictable and spontaneous improvement can occur. The 5‐year actuarial survival rate is 95%.     

Systolic Papillary Muscle Dyssynchrony Predicts Recurrence of Mitral Regurgitation in Patients with Ischemic Cardiomyopathy (ICM) Undergoing Mitral Valve Repair

Objective: We investigated the impact of papillary muscle dyssynchrony (DYS‐PAP) in predicting recurrent mitral regurgitation (MR) in patients with ischemic cardiomyopathy (ICM) undergoing undersized mitral ring annuloplasty (UMRA). Methods: One hundred forty‐four ICM patients (left ventricular ejection fraction <35%) in sinus rhythm undergoing UMRA between January 2001 and December 2010 at three Institutions (University Hospital, Maastricht, The Netherlands; Careggi Hospital, Florence, Italy; Civic Hospital, Brescia, Italy) were recruited. The primary endpoint was the recurrence of MR at the latest echocardiographic study defined as insufficiency ≥2+ in patients with no/trivial MR at discharge. The assessment of DYS‐PAP was performed by applying two‐dimensional (2D) speckle‐tracking imaging. Results: In patients with MR recurrence, DYS‐PAP significantly worsened (84.1 ± 8.8 msec vs.65.4 ± 8.8 msec at baseline, P < 0.001) whereas in patients with no MR recurrence, DYS‐PAP did not vary (22.3 ± 5.3 msec vs. 25.9 ± 7.2 msec at baseline, P = 0.8). Recurrent MR was positively correlated with preoperative DYS‐PAP (P < 0.001), baseline anterior mitral leaflet tethering angle α (P < 0.001) and tethering symmetry index α/β before surgery (P < 0.001). There was no significant correlation between MR recurrence and other echocardiographic parameters. Logistic regression analysis revealed that baseline values of DYS‐PAP (OR: 5.4 [95% CI: 3.1–7.7], P < 0.001), α (OR: 5.0 [2.6–6.7], P < 0.001), and α/β (OR: 3.9 [2.5–5.7], p < 0.001) were predictors of recurrent MR. A DYS‐PAP value ≥ 58 msec predicted recurrence of MR with 100% sensitivity and 83% specificity (area under the curve [AUC]: 0.92 [0.7–1], P < 0.001). Conclusions: A DYS‐PAP cutoff value of 58 msec is useful to identify patients in whom UMRA is likely to fail. That way decision making in ischemic functional MR might be facilitated.     

Total lung lavage by awake flexible fiberoptic bronchoscope in a 13-year-old girl with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare, heterogeneous diffuse lung disease in childhood. We report a case of an asymptomatic 13-year old girl with PAP. She had radiolographic findings suggesting the diagnosis, which was confirmed by the "milky" bronchoalveolar lavage fluid and the histology of transbronchial biopsy. Total lung lavage was performed by flexible fiberoptic bronchoscope under local anesthesia with success. This is the first reported case of a PAP in a child that was treated by being awake during bronchoscopy. After one-year of follow-up, the patient remains free of symptoms.     

The association between difficulty using positive airway pressure equipment and adherence to therapy: a pilot study

Purpose

Little is known about the ease of use of positive airway pressure (PAP) equipment and whether PAP equipment usability is associated with adherence. This pilot project aims to determine whether perceived difficulty with the mechanics of using PAP equipment is associated with nonadherence.

Methods

Within a larger study of insomnia treatments, we screened (via telephone interview) 148 adults for sleep apnea/prior PAP use and asked them to describe the degree of difficulty putting on their PAP mask, adjusting their mask straps, turning dials/pushing PAP machine buttons, disconnecting tubing, and removing the machine's water chamber (five items; five-point Likert-like scale) and to report their PAP use (0 versus ≥1 days in the past week).

Results

Mean age of participants was 66.7 years (SD 7.0). Thirty respondents (20.3 %) reported at least “some difficulty” with at least one aspect of PAP equipment usability, and 15 respondents (10.1 %) reported at least “quite a lot of difficulty” with one or more aspects of PAP equipment usability. Of the participants, 43.9 % reported not using PAP equipment at all during the past week. Participants (73.3 %) with substantial PAP equipment difficulty (at least quite a lot of difficulty) versus 40.6 % without substantial difficulty reported zero nights of PAP use in the past week (chi-square 5.86, p?=?.015).

Conclusions

Difficulty using PAP equipment is associated with PAP nonadherence. Studies are needed to confirm these findings and to identify determinants of poor usability. If findings are confirmed, strategies could be developed to improve PAP usability, which may improve adherence.     

Pulmonary Arterial Hypertension Induced by Immune Checkpoint Inhibitor Combined Therapy in a Patient with Intrahepatic Cholangiocarcinoma: A Case Report

Immune Checkpoint Inhibitors (ICIs) have dramatically revolutionized the therapeutic approaches by which we treat a series of cancers accompanied by immune-related adverse events (irAEs). Herein, we reported an intrahepatic cholangiocarcinoma male patient with a history of ankylosing spondylitis developing pulmonary arterial hypertension (PAH) under ICI combined therapy with pembrolizumab and lenvatinib. The indirect measurement of cardiac ultrasound showed a pulmonary artery pressure (PAP) of 72mmHg after 21 three-week cycles of ICI combined therapy. The patient partially responded to the treatment of glucocorticoid and mycophenolate mofetil. The PAP decreased to 55mmHg 3 months after the ICI combined therapy was discontinued, but increased to 90mmHg after the ICI combined therapy was rechallenged. We treated him with adalimumab -an antitumor necrosis factor-alpha (ani-TNF-α) antibody- combined with glucocorticoid and immunosuppressants under lenvatinib monotherapy. The patient responded again with PAP decreasing to 67mmHg after 2 two-week cycles of adalimumab. Accordingly, we diagnosed him to have irAE-related PAH. Our findings supported the use of glucocorticoid disease-modifying antirheumatic drugs (DMARDs) as a treatment option in refractory PAH.     

Successful whole lung lavage in a child with pulmonary alveolar proteinosis secondary to hematologic malignancy

Pulmonary alveolar proteinosis (PAP) describes the accumulation of surfactant in the alveolar space. Secondary PAP has been reported in a variety of diseases, and in rare cases has been associated with hematologic malignancy. Treatment for PAP is based on the underlying disease process, and may include whole lung lavage, inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor, or statins. PAP secondary to hematologic malignancy has been reported to demonstrate poor response to whole lung lavage. We report a case of successful treatment of a pediatric patient with acute myeloid leukemia and secondary PAP using whole lung lavage.     

Massive haemoptysis from a central pulmonary arterial pseudoaneurysm secondary to advanced lung cancer: successful treatment by Guglielmi detachable coil embolization

Massive haemoptysis is a life‐threatening condition in patients with lung cancer. Endovascular embolization has been well‐established as an effective means of treating this condition. Haemoptysis of pulmonary arterial origin is rare, and a pulmonary artery pseudoaneurysm (PAP) is generally the main cause. PAP due to lung cancer is also very rare, and the site of bleeding always involves the peripheral lung. We report an unusual case of central PAP secondary to advanced central squamous‐cell carcinoma of the lung in a patient with acute massive haemoptysis. The sac of the pseudoaneurysm underwent successful embolization using various Guglielmi detachable coils (GDCs). The patient died of lung cancer without recurrence of haemoptysis 42 days post‐embolization. To the best of our knowledge, this case report is the first to describe massive haemoptysis caused by central PAP due to lung cancer and its successful treatment by GDC embolization.     

Percutaneous device embolization of an aneurysmal pulmonary artery in an infant weighing <3 kilograms

Pulmonary artery aneurysm (PAA) and pulmonary artery pseudoaneurysm (PAP) are rare diagnoses in the pediatric population and carry a high risk of mortality if rupture occurs. There is currently no standard therapeutic approach to PAAs and PAPs. Reports of surgical intervention describe high mortality. We present a case of an infant with a PAP that was successfully treated with a percutaneous device closure. Our approach included deployment of a 6‐mm Amplatzer Vascular Plug 2 (Abbott, St. Paul, MN) in the right lower pulmonary artery segmental branch just proximal to the origin of the pseudoaneurysm. Subsequent imaging 1‐month post‐procedure demonstrated a >50% reduction in the size of the PAP when compared to original imaging studies and near‐complete resolution 14 months following the intervention. Percutaneous device placement to occlude the vessel supplying peripheral PAAs and PAPs may be a reasonable alternative to open surgical resection when treating patients with this rare, but potentially life‐threatening vascular anomaly. To our knowledge, this is the first case describing a successful device closure of a PAP in an infant weighing <3 kg.     

Experimental acute pancreatitis in PAP/HIP knock-out mice

BACKGROUND AND AIMS: PAP/HIP was first reported as an additional pancreatic secretory protein expressed during the acute phase of pancreatitis. It was shown in vitro to be anti-apoptotic and anti-inflammatory. This study aims to look at whether PAP/HIP plays the same role in vivo. METHODS: A model of caerulein-induced pancreatitis was used to compare the outcome of pancreatitis in PAP/HIP(-/-) and wild-type mice. RESULTS: PAP/HIP(-/-) mice showed the normal phenotype at birth and normal postnatal development. Caerulein-induced pancreatic necrosis was, however, less severe in PAP/HIP(-/-) mice than in wild-type mice, as judged by lower amylasemia and lipasemia levels and smaller areas of necrosis. On the contrary, pancreas from PAP/HIP(-/-) mice was more sensitive to apoptosis, in agreement with the anti-apoptotic effect of PAP/HIP in vitro. Surprisingly, pancreatic inflammation was more extensive in PAP/HIP(-/-) mice, as judged from histological parameters, increased myeloperoxidase activity and increased pro-inflammatory cytokine expression. This result, in apparent contradiction with the limited necrosis observed in these mice, is, however, in agreement with the anti-inflammatory function previously reported in vitro for PAP/HIP. This is supported by the observation that activation of the STAT3/SOCS3 pathway was strongly decreased in the pancreas of PAP/HIP(-/-) mice and by the reversion of the apoptotic and inflammatory phenotypes upon administration of recombinant PAP/HIP to PAP/HIP(-/-) mice. CONCLUSION: The anti-apoptotic and anti-inflammatory functions described in vitro for PAP/HIP have physiological relevance in the pancreas in vivo during caerulein-induced pancreatitis.     

Associations of factor VIIIc,D‐dimer,and plasmin–antiplasmin with incident cardiovascular disease and all‐cause mortality

To examine the associations of three understudied hemostatic factors—D‐dimer, factor VIII_c, and plasmin‐antiplasmin (PAP) complex—with incident cardiovascular disease (CVD) and all cause mortality in the Multiethnic Study of Atherosclerosis cohort. Hemostatic factors were measured at baseline in 45–84‐year‐old patients (n = 6,391) who were free of clinically recognized CVD. Over 4.6 years of follow‐up, we identified 307 CVD events, 207 hard coronary heart disease events, and 210 deaths. D‐dimer, factor VIII_c, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D‐dimer and factor VIII_c were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI 15–54) for each quartile increment of D‐dimer, 26% (11–44) for factor VIIIc, and 20% (4–38) for PAP. This prospective cohort study did not find D‐dimer, factor VIII_c, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D‐dimer and factor VIII_c were associated with increased cancer death. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

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.     

Secondary pulmonary alveolar proteinosis in hematologic malignancies

Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra-alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19-year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as “intra-alveolar coagulum”. This is probably the first reported case of PAP in relation to hematologic malignancy. Much progress has been made on PAP first described by Rosen which is currently classified as idiopathic or primary or autoimmune PAP. Idiopathic PAP occurs as a result of auto-antibodies directed against granulocyte–macrophage colony stimulating factor (GM-CSF) impeding the surfactant clearing function of alveolar macrophages leading to progressive respiratory failure. Whole lung lavage and GM-CSF therapy has improved outcomes in patients with idiopathic PAP. Despite major advancement in the management of hematologic malignancy and its complications, little is known about the type of PAP first described by Levinson and now known as secondary PAP; a term also used when PAP occurs due to other causes such as occupational dusts. In this article we review and analyze the limited literature available in secondary PAP due to hematologic malignancies and present a case of PAP associated with chronic lymphocytic leukemia successfully treated with bendamustine and rituximab.     

Acute and subacute idiopathic interstitial pneumonias

Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE‐IPF) and AE‐NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug‐induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody‐targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value‐laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia.     

Pancreatitis-associated protein： From a lectin to an anti-inflammatory cytokine

Pancreatitis-associated protein (PAP) was discovered in the pancreatic juice of rats with acute pancreatitis. PAP is a 16 kDa secretory protein structurally related to the C-type lectins although classical lectin-related function has not been reported yet. Then, it was demonstrated that PAP expression may be activated in some tissues in a constitutive or injury- and inflammation-induced manner. More recently, it has been found that PAP acts as an anti-inflammatory factor in vitro and in vivo.PAP expression can be induced by several pro- and anti-inflammatory cytokines and by itself through a JAK/STAT3-dependent pathway. PAP is able to activate the expression of the anti-inflammatory factor SOCS3 through the JAK/STAT3-dependent pathway. The JAK/STAT3/SOCS3 pathway seems to be a common point between PAP and several cytokines. Therefore,it is reasonable to propose that PAP is a new antiinflammatory cytokine.     

Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease

BACKGROUND AND AIMS: Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation. PATIENTS AND METHODS: Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor kappaB (NFkappaB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo. RESULTS: Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn's disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-alpha induced NFkappaB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression. CONCLUSIONS: PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFkappaB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.     

An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare idiopathic autoimmune lung disease in adults characterized by the accumulation of lipoproteinaceous material within the alveoli of the lung. The natural history of this disease is poorly defined. Current therapy of bilateral whole-lung lavage (WLL) under general anesthesia is invasive and has its limitations. Data suggest that relative granulocyte macrophage colony stimulating factor (GM-CSF) deficiency may be involved in the pathogenesis of this disease. There have been several case series that have described clinical improvement with exogenous GM-CSF therapy in a subset of patients with PAP. We describe the results of a prospective, open-label clinical trial of daily subcutaneous GM-CSF therapy in a group of adult patients with idiopathic PAP. In this series of 25 patients, the largest reported to date, administration of GM-CSF improved oxygenation as assessed by a 10 mm Hg decrease in alveolar-arterial oxygen gradient, as well as improvement in other clinical and quality of life parameters in 12 of 25 patients (48%) with moderate symptomatic disease who completed the trial. In addition, the serum anti-GM-CSF antibody titer correlated with lung disease activity and was a predictor for responsiveness to therapy. These data indicate that subcutaneous GM-CSF therapy is a promising alternative to WLL for symptomatic patients with PAP.     

Autoimmune pulmonary alveolar proteinosis: Treatment options in year 2013

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of a periodic acid Schiff (PAS)‐positive eosinophilic material in the distal airways. For decades, the standard treatment of PAP has been whole lung lavage (WLL), where large quantities of saline are instilled into the lungs to remove the proteinaceous material. However, not all patients respond to this treatment. Thus, new treatment modalities, such as subcutaneous or inhaled granulocyte macrophage colony‐stimulating factor (GM‐CSF), and the CD20 antibody rituximab and plasmapheresis, have been investigated. Based on the current literature, a stepwise treatment plan is suggested starting with WLL, continuing to inhaled GM‐CSF, and then to rituximab if the former treatment regimes are unsuccessful.