Pulmonary Alveolar Proteinosis in Hereditary and Autoimmune Forms With 2 Cases Seda Sirin Kose, MD,* Suna Asilsoy, MD,* Nevin Uzuner, MD,* Ozkan Karaman, MD,* Erdener Ozer, MD,† and Ozden Anal, MD* Abstract: Pulmonary alveolar proteinosis (PAP) is a respiratory pathol- ogy characterized by the accumulation and increase of surfactant-derived material in the lungs. In clinical practice, PAP may present as the primary form, which includes autoimmune and hereditary PAP, or as the secondary form. Diffuse alveolar radiopacities on chest x-ray and the crazy-paving pattern on high-resolution computed tomography are important, although not specific findings for PAP. Bronchoalveolar lavage biopsy is a diagnos- tic method, and whole-lung lavage remains the criterion standard for the treatment of PAP. Evidence is required regarding treatment with exogenous anti–granulocyte/macrophage colony-stimulating factor. Here, we present a 13-year-old male patient with hereditary PAP and a 15-year-old female patient with autoimmune PAP who presented with complaints of easy fatigability and weakness to emphasize the importance of keeping in mind PAP as a differential diagnosis in patients with respiratory failure findings. Key Words: autoimmune, hereditary, pulmonary alveolar proteinosis, whole-lung lavage (Pediatr Emer Care 2018;00: 00–00) P ulmonary alveolar proteinosis (PAP) is a respiratory pathology characterized by the accumulation and increase of surfactant- derived material in the lungs which appears to be rare in clinical prac- tice. In clinical practice, PAP may present as the primary form, which includes autoimmune and hereditary/congenital PAP, or as the second- ary form. 1 Autoimmune PAP is associated with granulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies that inhibit the activ- ity of endogenous GM-CSF, leading to a state of macrophage dys- function. Hereditary PAP is caused by genetic mutations in the α/ β chain of the GM-CSF receptor (only 3 cases reported). 2–5 Secondary PAP is commonly associated with dust inhalation, immunodeficiency disorders, malignancies, and hematopoietic disorders. Secondary PAP is likely to be related to a relative deficiency of GM-CSF or a defect in GM-CSF signaling and related macrophage dysfunc- tion which may be associated with overimmunosuppression. 6 Bronchoalveolar lavage (BAL) and biopsy are diagnostic for PAP. Here, we present a 13-year-old male patient and a 15-year-old female patient who presented with complaints of easy fatigability and weakness and were diagnosed as having hereditary and auto- immune PAP, respectively. CASE 1 A 13-year-old male patient had initially referred to another outpatient clinic at 7 years of age with complaints of easy fatigabil- ity and weakness. His history during the postnatal and early infancy period was unremarkable, and his parents were not consanguineous. His physical examination was normal, and height and weight were appropriate for the relevant age percentiles. In laboratory assess- ment, anti–GM-CSF antibody was detected in serum autoim- mune antibody panel. Complement component 3 and 4 levels were normal. Sildenafil citrate therapy was initiated because pul- monary hypertension was diagnosed by echocardiogram (tricuspid regurgitation peak velocity, 3.2 m/s; systolic pulmonary artery pressure, 62 mm Hg; parent did not allow to perform angiography to confirm pulmonary hypertension). With the sildenafil citrate treatment, pulmonary hypertension was reversed but weakness and anemia persisted. The patient presented at our department with exercise-induced dyspnea and digital clubbing at the age of 10 years. In our laboratory assessment, the immunological param- eters were unremarkable. Thorax computed tomography (CT) revealed diffuse pulmonary alveolar radiopacity particularly in the upper lobes (Fig. 1A). The bronchoscopic biopsy was unremarkable with mucous glands under the thickened basement membrane of respiratory epithelium. Bronchoalveolar lavage fluid showed hemosiderin- laden macrophages. Based on these clinical and biopsy findings, a diagnosis of pulmonary hemosiderosis was established. Treatment with prednisolone 2 mg·kg·d was started. During the first 3-year- long follow-up of steroid treatment, the patient was hospitalized 3 times for pneumonia and once for dental abscess. The steroid dose was reduced gradually over 3 years. Meanwhile, pulmonary bleeding, arthralgia, and microscopic hematuria occurred at 13 years of age. Because of respiratory failure, the patient was intubated and thorax CT was performed. Thorax CT revealed diffuse alveolar radiopacity, consolidation in the left lower lobe posterior segment with air bronchograms, scattered cavitary lesions in lung parenchyma with the largest 2 of 2 and 4 cm in diameter, with thick walls in both left and right lower lobes (Fig. 1B). Aspergillus galactomannan antigen was found positive in BAL. Amphotericin B and voriconazole were added to the treatment. Because of clinical deterioration and resistance to treatment, a new lung biopsy with video-assisted thoracoscopic surgery was performed, revealing alveolar proteinosis by demonstration of PAS-positive material. The results from the serum GM-CSF autoantibody test and GM-CSF receptor-α protein detection test were normal but signal transducer and activator of transcription 5 (STAT5) and GM-CSF receptor β were not detected. CSF2RB gene (22q12.3; OMIM No. 138981) sequence analysis revealed a homozygous mutation (p.Gly254Arg), and the patient was diagnosed as having hereditary PAP. At the diagnosis of disease, severity and prognosis score of PAP, 7 which includes smoking status, symptoms of disease, arterial partial pressure of oxygen, high-resolution computed tomography (HRCT) score, and single-breath diffusing capacity of carbonmonoxide, was determined as 8 of 10. All immunosuppressive treatments were discontinued, but antifungal antibiotherapy was continued because mycotic brain abscess occurred during the follow-up. Although whole-lung lavage (WLL) was performed twice, the patient became dependent on home ventilator. CASE 2 A 15-year-old girl was referred to our department due to ex- ertional dyspnea while she was climbing stairs and giggling. Her From the *Department of Pediatric Allergy and Immunology, Dokuz Eylul University Faculty of Medicine; and †Department of Pathology, Dokuz Eylul University, Izmir, Turkey. Disclosure: The authors declare no conflict of interest. Reprints: Seda Sırın Kose, MD, Department of Pediatric Allergy and Immunology, Dokuz Eylul University Faculty of Medicine, Mithatpasa cad. no 1606 inciralti yerleskesi, 35340 Balcova, Izmir, Turkey (e‐mail: sedasirin85@yahoo.com). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0749-5161 ILLUSTRATIVE CASE Pediatric Emergency Care • Volume 00, Number 00, Month 2018 www.pec-online.com 1 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.