Secondary Pulmonary Alveolar Proteinosis Research Articles

REFRACTORY SIROLIMUS-INDUCED PULMONARY ALVEOLAR PROTEINOSIS IN A PATIENT WITH LUNG TRANSPLANT

SESSION TITLE: Fellows Transplantation Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease with accumulation of proteins and lipids within the alveolar macrophages with considerable morbidity and mortality [1]. PAP etiologies include a primary autoimmune process due to anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibodies while secondary causes include medications, infection, toxic inhalations, or hematological disorders [1]. Sirolimus, an immunosuppressant used in organ transplantation, is a rare cause of reversible PAP [2-6]. We present a patient who worsened despite discontinuation of sirolimus, regional lung lavage and inhaled GM-CSF. CASE PRESENTATION: A 57 year old female underwent bilateral lung transplant for idiopathic pulmonary fibrosis, complicated by acute rejection, bilateral pulmonary embolism, pulmonary artery stenosis requiring stenting, and bilateral airway anastomotic stenosis requiring a left mainstem stent. She presented with hypoxia five years post-transplant on sirolimus and prednisone. Chest CT demonstrated new unilateral ground glass opacities with bilateral septal thickening. Bronchoalveolar lavage (BAL) had milky fluid return, concerning for PAP. Sirolimus was discontinued and cyclosporine started. A segmental large volume BAL of the right upper lobe failed to improve hypoxia or shortness of breath and whole lung lavage was impractical due to bilateral anastomotic stenosis. She had resultant renal failure secondary to cyclosporine while off sirolimus for 3 months. Oxygen requirement and imaging failed to improve. Her anti-GM-CSF antibody test was negative and other causes of secondary PAP were ruled out. Salvage inhaled GM-CSF (sargramostim) was begun for progressive hypoxemic respiratory failure. VV-ECMO and whole lung lavage were offered but the patient declined. After four cycles of inhaled GM-CSF, her condition deteriorated and she passed away on POD 2492. Autopsy confirmed severe PAP. DISCUSSION: Sirolimus is a rare cause of secondary PAP. Typically sirolimus-induced PAP improves with medication discontinuation and potentially whole lung lavage. In this case, whole lung lavage was deemed impractical due to airway anatomy. She did not improve with sirolimus discontinuation or inhaled GM-CSF. Further research into the mechanism related to sirolimus induced PAP is necessary as this medication is widely used in complex patients with solid organ transplants. CONCLUSIONS: Sirolimus is implicated in drug induced PAP with expected reversibility when the medication is discontinued. This refractory case highlights the need for better understanding and treatment options in complex solid organ transplant patients. Reference #1: 1.Borie, R., et al., Pulmonary alveolar proteinosis. European Respiratory Review, 2011. 20(120): p. 98-107. 2.Mattewal, A.S., et al., Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus in lung transplant patients. Chest, 2009. 136(4): p. 23S. 3.Pedroso, S.L., et al., Pulmonary alveolar proteinosis – a rare pulmonary toxicity of sirolimus. Transplant International, 2007. 20(3): p. 291-296. 4.Kadikoy, H., et al., Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus. Nephrology Dialysis Transplantation, 2010. 25(8): p. 2795-2798. 5.Garrean, S., et al., Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clinical transplantation, 2005. 19(5): p. 698-703. 6.Dhawan, K., A. Pope-Harman, and N. Sood, PULMONARY ALVEOLAR PROTEINOSIS SECONDARY TO SIROLIMUS IN A RENAL TRANSPLANT PATIENT. CHEST, 2009. 136(4): p. 34S. DISCLOSURES: No relevant relationships by Brian Boer, source=Web Response no disclosure on file for Heather Strah; No relevant relationships by Grant Turner, source=Web Response No relevant relationships by Navin Victor, source=Web Response

HIGH-RESOLUTION COMPUTED TOMOGRAPHY IN ALVEOLAR PROTEINOSIS

TYPE: Abstract Publication TOPIC: Imaging PURPOSE: Although the crazy-paving pattern on computed tomography is characteristic for pulmonary alveolar proteinosis (PAP), it is not specific and has not been compared between idiopathic and secondary PAPs in the large studies. The aim of this study was to determine the high resolution computed tomography (HRCT) features of idiopathic PAP. METHODS: HRCT images of 35 patients (mean age: 38±14years; 54.3% male) with idiopathic PAP (proved by bronchoalveolar lavage or biopsy) were reviewed by two experienced pulmonary radiologist and detailed findings were reported. RESULTS: The predominant HRCT presentation of PAP was interlobular septal thickening (ILST;100%) and ground glass opacities (GGOs; 91.7%), resulting in crazy-paving pattern (83%). All patients had diffuse bilateral lung involvement that was symmetric in 97%. ILST and GGO without crazy-paving were seen in 17% and 14.7%, respectively. The overall extent of parenchymal involvement was 50 to 75% in 80% of patients. Thirty three cases (94%) had areas of geographic sparing within the affected lung. Peripheral sparing was seen in 85.7% of patients, including three patterns with some overlap: costophrenic angle (80%), apices (60%), and subpleural (57%) sparing. Other HRCT findings were: consolidation (63%), pulmonary nodules (31.4%), mediastinal and/or hilar lymphadenopathy (23%), mass-like consolidation (17%), pleural effusion (8.6%), and honey combing (5.7%). All female patients (n=16) had crazy-paving, while 13 out of 19 (68%) male patients had crazy-paving on their lung HRCT (p=0.02). CONCLUSIONS: This study demonstrated that the predominant HRCT presentation of idiopathic PAP was interlobular septal thickening and ground glass opacities, resulting in crazy-paving pattern. CLINICAL IMPLICATIONS: resulting in crazy-paving pattern. DISCLOSURE: No significant relationships. KEYWORD: Pulmonary Alveolar Proteinosis (PAP), Idiopathic PAP, Crazy-Paving, Computed Tomography

Pulmonary alveolar proteinosis: from classification to therapy.

Pulmonary alveolar proteinosis (PAP) is a rare respiratory syndrome characterised by the accumulation of surfactant lipoproteins within the alveoli. According to various pathogenetic mechanisms and aetiologies, PAP is classified as primary, secondary or congenital. Primary PAP is led by a granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling disruption; the autoimmune form is driven by the presence of anti GM-CSF autoantibodies and represents 90% of all the PAP cases; and the hereditary form is the result of mutations in genes encoding GM-CSF receptor. Secondary PAP is associated with various diseases causing a reduction in function and/or number of alveolar macrophages. Congenital PAP emerges as a consequence of corrupted surfactant production, due to mutations in surfactant proteins or lipid transporter, or mutations affecting lung development. The clinical manifestations are various, ranging from insidious onset to acute or progressive respiratory failure, including premature death within the first days of life in neonates with congenital surfactant production disorders. The diagnostic workup includes clinical and radiological assessment (respiratory function test, high-resolution chest computed tomography), laboratory tests (anti-GM-CSF autoantibodies dosage, GM-CSF serum level and GM-CSF signalling test), and genetic tests. Whole-lung lavage is the current gold standard of care of PAP; however, the therapeutic approach depends on the pathogenic form and disease severity, including GM-CSF augmentation strategies in autoimmune PAP and other promising new treatments.Educational aimsTo update knowledge about a rare respiratory syndrome, pulmonary alveolar proteinosis, in order to promote early diagnosis and correct management.To highlight recent treatment options based on pathogenesis and disease severity.

Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case.

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.

A Case of Successful Allogeneic Bone Marrow Transplantation for Secondary Pulmonary Alveolar Proteinosis Complicating Myelodysplastic Syndrome

A Case of Successful Allogeneic Bone Marrow Transplantation for Secondary Pulmonary Alveolar Proteinosis Complicating Myelodysplastic Syndrome

A rare case of secondary pulmonary alveolar proteinosis with adenocarcinoma of lung with retroviral disease.

A rare case of secondary pulmonary alveolar proteinosis with adenocarcinoma of lung with retroviral disease.

Management of primary pulmonary alveolar proteinosis: A multicentric experience.

Background:Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar accumulation of surfactant material with reduced lung function and resulting hypoxemia. It is characterized by a variable clinical course, and whole lung lavage (WLL) is the standard treatment. Herein, we report our multicentric experience of management of primary PAP.Materials and Methods:This retrospective study included patients with PAP managed at various armed forces respiratory centers from 2009 to 2019. The diagnosis of primary PAP was based on histopathologic confirmation on transbronchial lung biopsy or open lung biopsy and absence of causes of secondary PAP. We analyzed the response to WLL in these patients as well as the safety of the procedure.Results:During the above-specified period, ten patients with a diagnosis of PAP were admitted to various armed forces respiratory centers. The median age of the patients was 34.5 years (range 23–59); there were nine males (90%). The mean duration (± standard deviation) of symptoms was 10.8 (±2.70) months. For management, WLL was done for eight patients with a median volume of 23.5 L (range 18–45) per patient. All the patients showed significant symptomatic response as well as improvement in physiological parameters with no major complications. The median follow-up of all patients was 18 (range 5–44) months.Conclusions:WLL is a safe, effective therapy in an experienced setting in patients with PAP and provides long-lasting benefits.

Rare occupational respiratory diseases

This paper reviews rare occupational respiratory diseases with uncommon causes. Among others, it refers to the Ardystil syndrome characterized by the occurrence of organizing pneumonia in the textile printing sprayers, as a result of inhalation of substances used in aerographic textile printing. Furthermore, secondary pulmonary alveolar proteinosis due to exposure to chemical and organic dusts was described, and so was the occurrence of the "vineyard sprayer's lung" in farm workers in Portugal. Eosinophilic bronchitis, showing a strong resemblance to bronchial asthma, was found to occur, among others, in a baker, a nurse and workers exposed to acrylates, α-amylase or welding gases. Occupational exposure to diacetyl in popcorn production workers might also create a threat to their respiratory system. A newly recognized factor that may cause bronchitis and lung diseases is the fiberglass used by workers building small boats and ships. An increased risk for respiratory ailments is observed in people employed in the textile industry, exposed to commodities or cotton dust. Even the resources used to protect different surfaces against moisture have been recognized as the causative agents of lung diseases. The rare occurrence of some occupational respiratory diseases enables a detailed analysis of the epidemiology and evaluation of the relationship between the etiologic agents and the development of the disease. This literature review highlights the fact that most respiratory diseases require a special analysis of occupational and environmental exposure. Med Pr. 2020;71(1):89-104.

Pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis. PAP can be classified into different types on the basis of the pathogenetic mechanism: primary PAP is characterized by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits); secondary PAP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production. In most patients, pathogenesis is driven by reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. PAP has a prevalence of at least 7 cases per million individuals in large population studies and affects men, women and children of all ages, ethnicities and geographical locations irrespective of socioeconomic status, although it is more-prevalent in smokers. Autoimmune PAP accounts for >90% of all cases. Management aims at improving symptoms and quality of life; whole-lung lavage effectively removes excessive surfactant. Novel pathogenesis-based therapies are in development, targeting GM-CSF signalling, immune modulation and cholesterol homeostasis.

PULMONARY ALVEOLAR PROTEINOSIS PRESENTING AS INTRACEREBRAL NOCARDIOSIS

SESSION TITLE: Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 07:30 am - 08:30 am INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disorder with an incidence of 0.5 / million people [1]. PAP is caused by the accumulation of surfactant in the alveoli, leading to hypoxemic respiratory failure and increased risk of opportunistic infections [2]. First-line therapy after infection eradication is whole-lung lavage. Treatment with exogenous granulocyte macrophage colony stimulating factor (GM-CSF) is under investigation. PAP can be a diagnostic challenge due to its low prevalence and nonspecific presentation. Here we describe a unique presentation that was diagnosed as PAP. CASE PRESENTATION: A 56 year old male farmer, never smoker, with no past medical history presented with right-sided weakness, two months of dyspnea, and dry cough. Brain MRI demonstrated multiple cerebral rim-enhancing abscesses (Fig 1A). He underwent a craniotomy and evacuation of cerebral abscesses with acid fast cultures positive for Nocardia farcinica. Chest CT showed a "crazy paving" pattern consistent with PAP (Fig 1B, C). Serum anti GM-CSF antibody was positive. Bronchoscopy showed opaque fluid on bronchoalveolar lavage, with negative cultures, and clumps of amorphous proteinaceous material consistent with PAP. Disseminated Nocardia was treated with ciprofloxacin for 1 year and sulfamethoxazole/ trimethoprim for 6 months. He underwent a whole lung lavage with resolution of symptoms. DISCUSSION: PAP is caused by surfactant accumulation due to incomplete removal by alveolar macrophages. Autoimmune PAP (primary PAP) accounts for the majority of cases [1]. Autoimmune PAP is caused by anti GM-CSF antibodies that disrupt macrophage activation, antigen presentation, and phagocytosis [2]. Secondary PAP is thought due to a relative deficiency of GM-CSF usually in the setting of hematologic diseases or dust exposures. The ensuing macrophage dysfunction leads to increased infection risk. Opportunistic infections including Nocardia, Mycobacterium, and fungi in otherwise immunocompetent patients with PAP have been previously reported [2]. In a report of 7 patients with disseminated Nocardiosis without PAP, 5 patients were found to have anti GM-CSF antibodies; two of these patients were also found to have radiographic characteristics of PAP [3]. CONCLUSIONS: Primary PAP is a rare autoimmune disorder that confers an immunocompromised state due to impaired alveolar macrophage activation. Opportunistic infections such as Nocardiosis are frequently seen with PAP. Eradication of the opportunistic infections, and targeted whole lung lavage are effective at relieving hypoxia in PAP. A high diagnostic suspicion is essential in the work-up of PAP. Reference #1: Clinics in Chest Medicine. 2016;37(3):431-440. https://doi.org/10.1016/j.ccm.2016.04.006 Reference #2: Journal of Infectio. 2012;65(2):173-179. https://doi.org/10.1016/j.jinf.2012.03.020 Reference #3: Clinical Infectious Disease. 2014;60(7):1017-1025. https://doi.org/10.1093/cid/ciu968 DISCLOSURES: No relevant relationships by David Dennis, source=Web Response No relevant relationships by Ulysses Magalang, source=Web Response No relevant relationships by Virgil Secasanu, source=Web Response

New interplay between interstitial and alveolar macrophages explains pulmonary alveolar proteinosis (PAP) induced by indium tin oxide particles

Occupational exposure to indium tin oxide (ITO) particles has been associated with the development of severe lung diseases, including pulmonary alveolar proteinosis (PAP). The mechanisms of this lung toxicity remain unknown. Here, we reveal the respective roles of resident alveolar (Siglec-Fhigh AM) and recruited interstitial (Siglec-Flow IM) macrophages contributing in concert to the development of PAP. In mice treated with ITO particles, PAP is specifically associated with IL-1α (not GM-CSF) deficiency and Siglec-Fhigh AM (not Siglec-Flow IM) depletion. Mechanistically, ITO particles are preferentially phagocytosed and dissolved to soluble In3+ by Siglec-Flow IM. In contrast, Siglec-Fhigh AM weakly phagocytose or dissolve ITO particles, but are sensitive to released In3+ through the expression of the transferrin receptor-1 (TfR1). Blocking pulmonary Siglec-Flow IM recruitment in CCR2-deficient mice reduces ITO particle dissolution, In3+ release, Siglec-Fhigh AM depletion, and PAP formation. Restoration of IL-1-related Siglec-Fhigh AM also prevented ITO-induced PAP. We identified a new mechanism of secondary PAP development according to which metal ions released from inhaled particles by phagocytic IM disturb IL-1α-dependent AM self-maintenance and, in turn, alveolar clearance.

Secondary pulmonary alveolar proteinosis: a single-center retrospective study (a case series and literature review)

BackgroundSecondary pulmonary alveolar proteinosis (sPAP) is an extremely rare disease. The clinical features of sPAP patients remain to be summarizeds. MethodsPatients pathologically diagnosed with PAP and with negative results for anti-granulocyte macrophage colony stimulating factor (GM-CSF) autoantibodies from Peking Union Medical College Hospital between January 2000 and July 2016 were retrospectively studied. The PubMed database was also searched for literature to collect published cases.ResultsIn our center, nine patients were diagnosed as sPAP with a median age of 37 years. Hematological disorders, including myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and pulmonary tuberculosis (TB) infection were the underlying diseases. Cases secondary to MDS had very poor prognosis as all of them survived less than 2 years after their diagnosis, while those secondary to TB had favorable prognosis. Only 33.3% of cases showed interlobular septal thickening in our sPAP group. Through literature review, 164 sPAP cases were collected. The age at diagnosis was 45.0 ± 14.8 years old and the gender radio was 1.20:1 (M:F). 61.9% of cases were diagnosed by bronchoscopy. MDS and CML were common underlying diseases in 34.1% and 15.2% of patients, respectively. Patients with sPAP secondary to hematological diseases had a short survival time and half of them died within 14.95 months after diagnosis.ConclusionsMDS and TB infection were the most frequent underlying causes of sPAP in this single-center research in China, with cases secondary to MDS having a poor survival rate. sPAP was more likely to be secondary to hematological disorders, especially MDS and CML and had a fairly poor prognosis in published cases. sPAP should be suspected in PAP patients whose CT scan presents only ground-glass opacities without interlobular septal thickening.

WHOLE LUNG LAVAGE WITH VENO‐VENOUS EXTRA‐CORPOREAL MEMBRANE OXYGENATION (ECMO) FOR SECONDARY PULMONARY ALVEOLAR PROTEINOSIS

RespirologyVolume 22, Issue S3 p. 228-228 APSR Poster Abstracts WHOLE LUNG LAVAGE WITH VENO-VENOUS EXTRA-CORPOREAL MEMBRANE OXYGENATION (ECMO) FOR SECONDARY PULMONARY ALVEOLAR PROTEINOSIS First published: 23 November 2017 https://doi.org/10.1111/resp.13207_368Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume22, IssueS3Supplement: 22nd Congress of the Asian Pacific Society of Respirology, International Convention Centre, Sydney, Australia, 23–26 November 2017November 2017Pages 228-228 RelatedInformation

Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-γ released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.

Pulmonary Alveolar Proteinosis After Exposure to Cleaning Fluids

SESSION TITLE: Critical Care 1 SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Sunday, October 29, 2017 at 10:45 AM - 12:00 PM INTRODUCTION: Pulmonary Alveolar Proteinosis (PAP) is a rare disorder characterized by the accumulation of amorphous, periodic acid-Schiff positive material composed of surfactant phospholipids and apoproteins. This can be congenital, primary or secondary. We present a case of secondary PAP in a housecleaner after exposure to cleaning fluids. CASE PRESENTATION: 64 year old woman, with 30 pack smoking years, presented with worsening shortness of breath and dry cough over 6 months. She was initially diagnosed with pneumonia and had partial response to treatment with antibiotics and steroids. Subsequent high resolution computed tomography scan (CT) of the chest revealed bilateral diffuse ground glass infiltrates with intralobular septal thickening with crazy pavement pattern. Further history brought to light her house cleaning occupation using commercial cleaning products. Bronchoscopy revealed the presence of opaque lavage and transbronchial biopsies confirmed alveolated parenchyma with eosinophilic granular material, periodic acid Schiff stain positive foamy exudates. Blood testing for antibodies against Granulocyte Macrophage-Colony Stimulating Factor was negative. The patient was interested in whole lung lavage, however, given her clinical picture and high suspicion for secondary PAP, we recommended a conservative approach with a focus on pulmonary rehabilitation, quitting smoking and avoidance of exposure to cleaning chemicals. At 3 months follow up, her symptoms dramatically improved and a repeat CT chest showed marked resolution of previous findings. DISCUSSION: Secondary PAP develops in association with conditions involving functional impairment or reduced numbers of alveolar macrophages. Such conditions include some hematologic cancers, pharmacologic immunosuppression, inhalation of inorganic dust or toxic fumes1 including silica, paint, wood powder, titanium and welding smoke. Cleaning fluids are commonplace in certain occupations and in domestic life, hence unanswered questions regarding variation in susceptibility after exposure, patient phenotype, level of exposure and constituent chemicals persist and warrant further investigation. Temporal improvement after avoidance of the exposure lends credence to the etiological role played by these agents. CONCLUSIONS: 1Exposure history is paramount when investigating secondary PAP, even outside of the realm of traditional occupational exposures. Reference #1: Trapenll B. et.al, Pulmonary Alveolar Proteinosis N Engl J Med 2003; 349:2527-2539 DISCLOSURE: The following authors have nothing to disclose: Karthika Linga, Minkyung Kwon, Brendon Colaco, Vichaya Arunthari, Neal Patel No Product/Research Disclosure Information

Multiple Segmental Lung Lavages in the Treatment of Secondary Alveolar Proteinosis

SESSION TITLE: Pulmonary Manifestations of Systemic Disease 4 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of periodic acid-Schiff (PAS)-positive material in the lungs. We present a case of multiple segmental lung lavages (MSLL) in the treatment of secondary PAP where whole-lung lavage (WLL) was precluded due to severe refractory hypoxemia. CASE PRESENTATION: A 34-year-old man with history of myelodysplastic syndrome (MDS) status post allogeneic bone marrow transplant was admitted to the intensive care unit (ICU) due to acute on chronic hypoxemic respiratory failure. He was afebrile, hemodynamically stable, his oxyhemoglobin saturation was 92% on 10L of oxygen via non-rebreather mask, and coarse breath sounds were present bilaterally. He had a history of Mycobacterium avium complex (MAC) pulmonary disease and a recent bone marrow biopsy showed MDS recurrence with positive familial GATA2 mutation. Computer tomography (CT) of the chest showed diffuse bilateral groundglass and interstitial opacities. Except for sputum culture positive for MAC, his infectious workup was negative. He was intubated and mechanically ventilated. A bronchoalveolar lavage demonstrated a milky fluid sample with proteinaceous sediment positive for PAS, suggesting PAP. MonoMac syndrome1 was suspected given his MAC pulmonary infections, MDS/GATA2 mutation, and PAP. With severe refractory hypoxemia, WLL was precluded and MSLL were considered as an alternative. Initially, the right lower lobe was lavaged with sequential instillations of saline 35mL-aliquots until the fluid became clear. Within 24 hours, FiO2 requirements decreased from ~0.8-1.0 to 0.65. Segmental lavages of the left lower lobe, and the right upper and middle lobes were completed within the next 48 hours. Unfortunately, the patient developed multiple organ system failure (MOSF) and his family opted for comfort cares. DISCUSSION: Secondary PAP can be found in association with MonoMac syndrome. This case was a diagnostic and therapeutic challenge due to the patient’s comorbidities, decreased functional status at baseline, and atypical findings for PAP on CT of the chest. MSLL resulted in decreased oxygen requirements; however, the impact of these interventions on the final outcome was lessened by the development of MOSF in this case. CONCLUSIONS: When severe hypoxemia among patient with PAP precludes WLL as a therapeutic intervention, multiple segmental lung lavages could be an alternative treatment option, or a temporizing method allowing clinical improvement prior to WLL. Reference #1: 1.Blood.2011;118:2656-2658 DISCLOSURE: The following authors have nothing to disclose: Gustavo Cortes Puentes, Darlene Nelson, James Utz No Product/Research Disclosure Information

Pulmonary Fibrosis on High-Resolution CT of Patients With Pulmonary Alveolar Proteinosis.

The CT findings of pulmonary fibrosis in patients with pulmonary alveolar proteinosis (PAP) are not yet well defined. The objective of this study was to evaluate the CT findings of PAP with a focus on pulmonary fibrosis secondary to PAP. High-resolution CT (HRCT) scans of 44 patients with PAP were evaluated retrospectively with a focus on pulmonary fibrosis: 33 patients had autoimmune PAP, and 11 patients had secondary PAP. The intervals between the initial and last CT examinations ranged from 1 to 284 months (median, 60 months). The HRCT images were assessed by two chest radiologists independently; when the two radiologists disagreed, a final decision was made by consensus. A crazy-paving pattern was a more common HRCT finding in patients with autoimmune PAP than in those with secondary PAP. Traction bronchiectasis was found in four patients (9%) on the initial scans and in 10 patients (23%) on the last scans. There was no honeycombing on the initial scans. Honeycombing developed in two patients (5%): It was detected on 2-year follow-up in one patient and on 6-year follow-up in the other patient. Among the patients with autoimmune PAP, those with fibrosis detected on HRCT during follow-up had a worse prognosis than those without fibrosis detected on HRCT (p = 0.041). Fibrosis develops in approximately 20% of patients with PAP. The CT findings of parenchymal fibrosis suggest a poor outcome.

Pulmonary alveolar proteinosis: Experience from a tertiary care center and systematic review of Indian literature.

Background:Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by deposition of lipoproteinaceous material within alveoli, with a variable clinical course. Here, we report an experience of management of PAP at our center. A systematic review of previously reported cases from India is also included in the article.Materials and Methods:This study included patients with primary PAP managed at our center from 2009 to 2015. Diagnosis of primary PAP was based on histopathologic diagnosis on bronchoalveolar lavage or transbronchial lung biopsy and absence of causes of secondary PAP. For systematic review of Indian publications, the literature search was performed using PubMed and EMBASE databases using the terms “pulmonary alveolar proteinosis'” or “alveolar proteinosis” and “India” or “Indian.”Results:During the above-specified period, five patients with diagnosis of PAP were admitted at our center. Median age of patients was 32 years (interquartile range [IQR] 30.5–59); 80% were female. Mean duration (± standard deviation) of symptoms was 6.2 (±1.79) months. Anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies were elevated in 4 out of 5 patients (80%). For management, whole lung lavage (WLL) was done for four patients with median volume of 32.5 (IQR 18–74) L per patient. All the patients showed significant symptomatic as well as improvement in physiological parameters. Subcutaneous GM-CSF and ambroxol were given to 3 patients and 1 patient, respectively. The median follow-up of all patients was 18 (IQR 5–44) months. A systematic review of all Indian studies of PAP revealed thirty publications.Conclusions:WLL is the most common, effective, and safe therapy in patients with PAP. GM-CSF administration is an efficacious treatment for patients with incomplete response after WLL.

T-cell–restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung

AbstractAlthough overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bettg/wt and T-bettg/tg) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bettg/wt and T-bettg/tg mice, respectively. T-bettg/tg alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bettg/tg mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders.

A novel immunodeficiency syndrome as a rare cause of secondary pulmonary alveolar proteinosis: A diagnosis after 5 decades

Case report of a male patient with a five-decade follow-up history in a tertiary care hospital distinguished for malabsorption syndrome, failure-to-thrive, meningitis and recurrent bacterial, fungal and mycobacterial pulmonary infections. Additionally, he developed epidermodysplasia verruciformis, several in situ spinocellular carcinomas and an uncharacteristic parenchymal lung disease. Surgical lung biopsy suggested pulmonary alveolar proteinosis with fibrotic change. Retrospectively, severe monocytopenia had been overlooked in the past, as well as low B and NK cell blood counts. Flow cytometry confirmed the absence of the previous cell subsets along with an undetectable population of dendritic blood cells.Dendritic cell, monocyte, B and NK lymphoid Human Deficiency Syndrome (DCMLS) is a novel rare immunodeficiency described in 2010, linked to GATA-2 mutation. This syndrome should be highlighted as a rare cause of acquired PAP, with a radiological pattern encompassing potential fibrotic change. Failure to recognize monocytopenia may impede the chance to diagnose.