December 2019 Pulmonary Case of the Month: A 56-Year-Old Woman with Pneumonia

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 56-year-old woman complained of 6 weeks of increasing cough and shortness of breath. She had been treated for pneumonia with antibiotics, but when she failed to improve, she was begun on prednisone. She was receiving oxygen at 4 L/min by nasal cannula at the time she was seen.

PMH, SH, and FH

Her past medical history, social history and family were unremarkable other than a previous history of silicone breast implants. She was a nonsmoker.

Physical Examination

Her physical examination showed bibasilar crackles but was otherwise unremarkable.

Radiography

Her chest x-ray is shown in Figure 1.

Figure 1. Patient’s chest x-ray taken 6 weeks after the beginning of her illness.

Which of the following should be done at this time? (Click on the correct answer to be directed to the second of seven pages)

1. Coccidioidomycosis serology
2. Sputum gram stain and culture
3. Thoracic CT scan
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. December 2019 Pulmonary case of the month: a 56-year-old woman with pneumonia. Southwest J Pulm Crit Care. 2019;19(6):149-55. doi: https://doi.org/10.13175/swjpcc067-19 PDF

June 2018 Pulmonary Case of the Month

Lewis J. Wesselius, MD

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

The patient is a 53-year-old man who presented in January 2018 for a second opinion on interstitial lung disease first diagnosed in 2011. He lives in Los Angeles and had one year of increasing dyspnea on exertion prior to diagnosis. He had an outside surgical lung biopsy and was treated with prednisone, then started on azathioprine and the prednisone tapered. He was followed regularly and had limited progression over next 7 years.  However, recently he had increasing shortness of breath.

Past Medical History, Social History, Family History

He has no significant past medical history. He is a nonsmoker and denies any significant occupational exposures.

Physical Examination

Physical examination was unremarkable without rales or clubbing.

Which of the following should be obtained at this time? (Click on the correct answer to proceed to the second of five pages)

1. Prior chest x-rays, CT scans, pulmonary function testing and lung biopsy
2. Repeat CT scan, pulmonary function testing
3. Rheumatological serologies
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ. June 2018 pulmonary case of the month. Southwest J Pulm Crit Care. 2018;16(6):296-303. doi: https://doi.org/10.13175/swjpcc063-18 PDF 

Systemic Lupus Erythematosus Presenting As Cryptogenic Organizing Pneumonia: Case Report

Anthony Jedd, MD

Sashank Kolli, MD 

Thomas Liao, MD

Isabel Oliva, MD

Loyola University Of Chicago

Stritch School Of Medicine

Maywood, IL

and

University of Arizona

Tucson, AZ

Introduction

Systemic Lupus Erythematosus (SLE) is a systemic disease with multiorgan involvement. In the respiratory system, SLE can involve the lung parenchyma and pleura with intrathoracic manifestations of pleuritis, alveolar hemorrhage and pulmonary fibrosis. Cryptogenic organizing pneumonia (COP) is a rare complication of SLE. We describe a case of newly diagnosed lupus presenting as COP.

Case Report

An 18-year-old woman with no significant past medical history presented to the Emergency Department complaining of generalized malaise, cough and fever for 4 days. Her cough was productive with white to brownish sputum. She complained of chest heaviness/pressure with inability to take deep breaths. Her only reported sick contact was her mother who had the “flu” one week prior to the onset of her illness. She denied any illicit drug use, alcohol or smoking, as well as any recent travel or exotic pet exposure. On admission, her vital signs were: temperature 38.4°C, pulse rate 129 bpm, blood pressure 159/108 mmHg, respiratory rate 29 rpm and oxygen saturation 94% on room air. On physical exam, the patient was in moderate distress with tenderness to palpation over her muscles. Left anterior cervical adenopathy was present and lung auscultation revealed coarse bilateral crackles. She was alert and oriented times 3 with no neurological deficits. 

Laboratory data on admission: white blood cell count 5100/µL with 43% bands, hemoglobin 10.6 g/dL, platelets 125 x 10⁹/L, blood urea nitrogen 37mg/dL, and creatinine 2.0 mg/dL. Urinalysis revealed a large amount of microscopic blood, small amount of leukocyte esterase, moderate bacteria and protein > 300 mg/dl. ABG of pH 7.39/pCO2 28 mm Hg/pO2 of 68 mm Hg on 2L/min by nasal cannula. Initial chest radiograph (CXR) demonstrated bilateral perihilar infiltrates (Figure 1).   

  

Figure 1. CXR on admission.

She was started on ceftriaxone and azithromycin with a working diagnosis of sepsis secondary to community-acquired pneumonia with impending respiratory failure.

She continued to be febrile, hypoxic and tachycardic. A 4-day follow-up CXR demonstrated interval worsening of bilateral airspace disease (Figure 2).

Figure 2. CXR on hospital day 4.

Despite antibiotic therapy for 5 days she was intubated due to continued deterioration. Diagnostic bronchoscopy was performed showing a positive mycoplasma IgM, while samples for bacterial, viral and fungal sources as well blood cultures were negative. GMS stain for Pneumocystis was also negative. At this time infectious disease recommended switching the antibiotics to vancomycin and aztreonam.  

The patient continued to have persistent anemia, thrombocytopenia and urine containing large amounts of protein raising suspicion for an autoimmune hemolytic anemia with bone marrow failure. Rheumatologic panel revealed ANA titer of 2,560 (normal <40), anti-ds DNA antibody >300 IU/ml (normal <10) and normal complement C3,C4. HIV testing was non reactive. Per rheumatology's recommendations, she was started on methylprednisolone 1 g daily for 3 days and later switched to prednisone 100 mg daily and 600 mg cytoxan for the working diagnosis of systemic lupus erythematosus (SLE). After about 1 week of persistent extensive bilateral lung infiltrates and continued ventilator dependence, an open lung biopsy was performed which demonstrated bronchoalveolar tissue showing organizing pneumonia of unknown etiology (Figure 3). No histological findings for vasculitis or alveolar hemorrhage were identified.

 

Figure 3. Panel A: patchy fibroblastic plugs in bronchioles and alveolar ducts (bronchiolitis obliterans) (black arrows). Panel B: Organizing pneumonia within alveoli (black circle).

She was diagnosed with SLE involving multiple organs, which included lung, kidneys and bone marrow. Prednisone 100 mg daily was continued for 2 weeks. Broad spectrum antibiotics were discontinued, but she finished a 2 week coarse of azithromycin for the positive mycoplasma antibodies. Her respiratory status gradually improved and she was extubated on her 14th hospital day. As an outpatient, prednisone was tapered slowly over the next 2 months to 10 mg daily and then she was transitioned to mycophenolate. Follow-up CXR showed resolution of the airspace disease (Figure 4).

Figure 4. CXR 2 months after admission to ICU.

Discussion

Cryptogenic organizing pneumonia is a noninfectious inflammatory pulmonary process that leads to the formation of fibromyxoid connective tissue plugs that adhere to the walls of the alveolar ducts and alveoli (1,2,4). COP can be idiopathic or secondary to several etiologies, including drug toxicity, infection, connective tissue diseases (CTD), malignancy and bone marrow transplantation (6). The diagnosis of SLE-related COP is rare with no cohort studies showing a dominant type of CTD resulting in COP.

Oymak S et al. (8) reviewed etiologic and clinical features in 26 patients with COP and found that 58% were idiopathic. The other 42% were secondary, but the causes were not described. Yoo JW et al. (9) further compared cryptogenic organizing pneumonia and connective tissue disease-related organizing pneumonia (CTD-OP). The study showed rheumatoid arthritis, Sjogren’s syndrome and polymyositis/dermatomyositis were predominant types of CTD and no patients were mentioned with SLE (9). Other studies mention polymyalgia rheumatica and SLE as potential causes of COP, but there are no reported cases of the two entities presenting together in adults (10-12). 

The mechanism by which SLE can lead to the development of COP is unknown. Otsuka et al. (13) suggested that elevated antiphospholipid antibodies contribute to the development of Masson bodies, macrophages and fibrin found within pulmonary alveoli, due to an inhibited inflammatory repair mechanism within the airways, which may contribute to the development of COP. The hypothesis of epithelial damage by the immune system is supported by the response to steroid therapy, which prevents and/or resolves deposition of IgM, IgG and infiltration of plasma cells into the bronchiolar walls (14,15).

The development of SLE-related COP remains a rare entity. Our patient’s presentation was unique in that COP was the initial manifestation of her SLE. Additionally, the pattern of airspace disease on chest radiograph was atypical for organizing pneumonia, which usually presents as either peripheral or peribronchiolar areas of consolidation. As more cases arise, our understanding of the mechanism and timing of the disease will hopefully become more apparent.

References

1. Epler GR, Colby TV, McLoud TC, Carrigton CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985;312:152-8. [CrossRef] [PubMed]
2. Colby TV. Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 1992;102:38S-43S. [CrossRef] [PubMed]
3. Epler GR. Bronchiolitis obliterans organizing pneumonia. Arch Intern Med. 2001;161:158-64. [CrossRef] [PubMed]
4. Moore SL. Bronchiolitis obliterans organzining pneumonia: a late complication of stem cell transplantation. Clin J Oncol Nurs. 2003;7(6):659-62. [CrossRef] [PubMed]
5. Cordier JF. Organizing pneumonia. Thorax 2000;55:318-28. [CrossRef] [PubMed]
6. Roberton B, Hansell D. Organizing pneumonia: a Kaleidoscope of concepts and morphologies. Eur Radiol 2011;21:2244-54. [CrossRef] [PubMed]
7. Takada H, Saito Y, Nomura A, Ohga S, Kuwano K, Nakashima N, Aishima S, Tsuru N, Hara T. Bronchiolitis obliterans organizing pneumonia as an initial manifestation in systemic lupus erythematosus. Pediatr Pulmonol. 2005;40:257-260. [CrossRef] [PubMed]
8. Oymak S, Demirbas HM. Mavili E, Akgun H, Gulmex I, Demir R, Ozesmi M. Bronchiolitis obliterans organizing pneumonia. Respiration. 2005;72:254-62. [CrossRef]  [PubMed]
9. Yoo JW, Song JW, Jang SJ, Lee CK, Kim MY, Lee HK, Jegal Y, Kim DS. Comparison between cryptogenic organizing pneumonia and connective tissue disease-related organizing pneumonia. Rheumatology 2011;50:932-8. [CrossRef] [PubMed]
10. Douglas WW, Tazelaar HD, Hartman TE, Hartman RP, Decker PA, Schroeder DR, Ryu JH. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164(7):1182-5. [CrossRef] [PubMed]
11. Katzenstein ALA, Myers J, Prophet WD, Corley LS 3rd, Shin MS. Bronchiolitis obliterans and usual interstitial pneumonia. Am J Surg Pathol. 1986;10:373-81. [CrossRef] [PubMed]
12. Lynch D. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24(4):299-309. [CrossRef] [PubMed]
13. Otsuka F, Amano T, Hashimoto N, Takahashi M, Hayakawa N, Makino H, OtaZ, Ogura T. Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus with antiphopholipid antibody. Intern Med. 1996;35:341-4. [CrossRef] [PubMed]
14. Myers JL, Katzenstein AL. Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia. Am J Pathol. 1988;132(1):102-9. [PubMed]
15. Ippolito JA, Palmer L, Spector S, Kane PB, Goveric PD. Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Semin Arthritis Rheum. 1993;23(1):70-8. [CrossRef] [PubMed]

Reference as: Jedd A, Kolli S, Liao T, Oliva I. Systemic lupus erythematosus presenting as cryptogenic organizing pneumonia: case report. Southwest J Pulm Crit Care. 2015;10(2):87-92. doi: http://dx.doi.org/10.13175/swjpcc164-14 PDF 

A 39 Year Old Female with Progressive Dyspnea, Dry Cough and Hypoxia: A Case Report

Sabeen Yaqub, MD 

Michelle S. Harkins, MD

Division of Pulmonary, Critical Care and Sleep Medicine

Department of Internal Medicine.

University on New Mexico

Albuquerque, NM 87131

Emails: sabeenyaqub@gmail.com

             MHarkins@salud.unm.edu

None of the authors of the above manuscript has declared any conflict of interest, which may arise from being named as an author on the manuscript.

Reference as: Yaqub S, Harkins MS. A 39 year old female with progressive dyspnea, dry cough and hypoxia: a case report. Southwest J Pulm Crit Care 2011;3:134-40. (Click here for a PDF version of the manuscript)

 Case Presentation

A previously healthy 39 year old female presented with progressive shortness of breath on exertion, dry cough, fatigue, fevers and hypoxia for the last four months. Her symptoms worsened despite being on several courses of antibiotics. Her past medical history is significant for hypertension and diabetes and medications include metoprolol and fosinopril. There is no previous history of cigarette smoking, drugs or alcohol abuse. She denied any weight loss. She was evaluated by a pulmonologist at an outside facility before being transported to our facility. Workup included chest x-ray and CT scan which showed patchy areas of consolidation. A bronchoscopy with bronchial alveolar lavage (BAL) was also performed but she became profoundly hypoxic and was transferred to the ICU intubated.

Physical Exam

An obese female who was intubated and sedated on pressure targeted ventilation with delta P 28, rate 15, FiO2 60% peep 8. Her vitals revealed a T_max of 38.6 C and blood pressure of 146/85. There were coarse breath sounds bilaterally and mild diffuse crackles in all lung fields. No clubbing or cyanosis was noted. The rest of the exam was unremarkable with a normal abdominal, cardiac and skin exam.  There was no adenopathy.

Labs

Complete blood count, electrolytes and liver function tests were normal.  HIV testing was negative.

Radiological findings

Chest x-ray demonstrated perihilar and bibasilar opacities.

CT scan is shown below in Figure 1.

Figure 1: CT Scan - Diffuse and geographic ground glass opacities accompanied by interlobular septal thickening consistent with the classic “crazy paving” with geographic distribution.

Bronchoscopy

Bronchoscopy with bronchoalveolar lavage (BAL) was performed which revealed an opaque appearing fluid with particulate matter. An open lung biopsy was performed to confirm the suspected diagnosis.

Pathology

Open Lung Biopsy revealed normal alveolar architecture with eosinophilic staining debris within the alveolar spaces that was Periodic Acid Schiff (PAS) + (Figure 2).

Figure 2: Open Lung Biopsy: Numerous alveolar spaces filled with abundant eosinophilic material (A) which is PAS positive (B) and occasional dense globular clumps with intra-alveolar macrophages. The alveolar septae are delicate without evidence of fibrosis.

Diagnosis:  Pulmonary Alveolar Proteinosis (PAP)

Hospital Course 

She underwent a partial whole lung lavage of the right lung first and remained intubated post procedure.  She underwent a repeat lavage of the right lung four days later and then a whole lung lavage on the left one week later due to bilateral infiltrates and difficulty weaning from the ventilator. Each lavage consisted of 12 liters of warmed saline and there was progressive clearing of the cloudy material obtained by the end of the lavage.  BAL cultures were obtained which were positive for Staphlococcus aureus and Klebsiella but were negative for Nocardia, Pneumocystis, and acid fast bacilli. She was treated with antibiotics for 7 days for the bacterial infection.  She was then successfully extubated.

Discussion

PAP also known as pulmonary alveolar phospholipoproteinosis is a diffuse lung disease characterized by accumulation of amorphous PAS+ lipoproteinaceous material in the distal airspaces with little or no inflammation and preservation of the underlying lung architecture.^1-3

Three forms of PAP are recognized; congenital, secondary and acquired. Congenital form is present in neonates and results from mutations in genes for surfactants or GM-CSF receptors. The acquired form is the most common and GM-CSF antibodies contribute to macrophage dysfunction and impaired processing of surfactant. The secondary form is associated with high level dust exposure (silica, aluminium, titanium), hematologic malignancy and after allogenic bone marrow transplant for myeloid malignancy and infection (Nocardia, viral, Pneumocystis). Macrophages are overwhelmed by accumulation of surfactant rich material and they lose the ability to phagocytize.

Clinical signs and symptoms include dyspnea on exertion, cough, fatigue, weight loss and low grade fevers.  Clubbing, cyanosis and crackles on physical exam may be present. Patients with PAP have an increased risk of opportunistic infection with Nocardia, Mycobacteria, fungi and Pneumocystis due to impaired macrophage and neutrophil function. Laboratory abnormalities include polycythemia, hypergammaglobulinemia, and increased LDL. On Chest x-ray bilateral symmetrical alveolar opacities are located centrally in the mid and lower lung zones in a ‘bat wing’ distribution. CT scan reveals heterogenous distribution of ground glass opacification and septal thickening.

The diagnostic work-up should include a history and physical consistent with PAP, a CT scan, fiberoptic bronchoscopy to obtain lavage fluid and transbronchial biopsies and serum assay for Anti-GM-CSF antibodies.  To exclude the presence of concurrent infections special stains and cultures for opportunistic infection should be obtained. In one of the largest cohort studies of 248 PAP patients, diagnosis was made by High Resolution CT (HRCT) scan and BAL in 59%; HRCT, BAL and transbronchial biopsy in 34% and VATS biopsy in 7%.⁴ Characteristic findings on BAL are an opaque or milky appearance due to abundant lipoproteinaceous material, alveolar macrophages that are engorged with PAS positive material, increased SP-A levels and large acellular eosinophilic bodies. On histological specimens, the normal alveolar architecture is preserved although the alveolar septa may be thickened due to type-2 cell hyperplasia. There is little or no inflammatory cell infiltrate. The terminal bronchioles and alveoli are filled with PAS positive lipoproteinaceous material.

The treatment options vary with the severity of disease. In the cohort study, asymptomatic patients were the most likely to have a stable course and only 8% worsened during follow up. ⁴ Among symptomatic patients the proportion of stable, improved and worsening disease was 45%, 30%, and 25% respectively. Patients with longer duration are likely to have progressive disease.

Asymptomatic patients can be observed with periodic reassessment of symptoms, pulmonary function testing (PFTs) and chest x-rays (CXRs). In patients with mild symptoms (mild hypoxia on exertion, normoxia on rest) supplemental oxygen is appropriate. Patients with moderate to severe disease may elect for whole lung lavage or a trial of experimental treatment with GM-CSF or plasmapheresis. Whole lung lavage under general anesthesia via a double lumen endotracheal tube is recommended for patients who have moderate to severe disease.^5-7 Indications for lung lavage include resting PaO2 <65, A-a gradient >40, shunt fraction>10-12% and severe hypoxia or dyspnea on rest and exertion. Clinical course is variable. Thirty-forty percent of patients require one lavage while others require lung lavage at intervals of 6-12 months.

Experimental therapy with GM-CSF has been used. ^8-13 In an open trial of 25 patients, GM-CSF was given subcutaneously and 48% experienced symptomatic and radiological improvement. However the proportion of responders to whole lung lavage appears to be the largest.^11-12 Given the experimental nature of GM-CSF therapy, lung lavage as primary therapy is recommended. Lung transplant is reserved for patients who deteriorate despite whole lung lavage but recurrence in allograft has been reported.¹⁴ Treatment with rituximab and plasmapheresis have had mixed results.^15-16 Though the most recent open label trial of rituximab given in 10 PAP patients demonstrated that it is well tolerated and improved oxygenation parameters up to six months after therapy and may have decreased the need for whole lung lavage.   The exact mechanism of benefit is unclear but is likely related to clearing of the autoantibodies present in the lung.¹⁷ There is no role for glucocorticoids as therapy for PAP.  

Follow up in our patient

The patient was followed in clinic after discharge. She continued to complain of an increased cough productive of clear mucus. She denied any changes in activity level or shortness of breath. PFTs were slightly worse than before. CT chest was concerning for increased bilateral densities.  She had a GM-CSF antibody titer of 1:6400 which confirms acquired PAP (a 1:400 titer is considered abnormal).

She was given a 3 month trial of inhaled GM-CSF and seen in clinic after 3 months with repeat PFTs and CT chest. She denied any changes in symptoms. PFTs also were unchanged from those done 3 months prior.  However, CT chest did look slightly worse with increased markings in the upper lobes.

She continued inhaled GM-CSF for another 3 months and sputum cultures for AFB, Nocardia and other pathogens were negative. After consulting with National Jewish Physicians, she was started on Mycophenolate mofetil orally advanced to the maximum dose of 3 gm/day. She has done well with improvement in her cough, lung function, six minute walk tests and CT scans and has not needed further whole lung lavage.  There are currently no reports of using this drug in this condition and thus it warrants further study for proof of benefit. Our patient has done well thus far, but there is also a case report of Mycophenolate actually causing PAP when used as an immunosuppressant in a patient with Wegener’s Granulomatosis so caution when using this is advised.¹⁸

References

1. Shah, PL, Hansell, D, Lawson, PR, et al. Pulmonary alveolar proteinosis: Clinical aspects and current concepts on pathogenesis. Thorax 2000; 55:67.

2. Kariman, K, Kylstra, JA, Spock, A. Pulmonary alveolar proteinosis: Prospective clinical experience in 23 patients for 15 years. Lung 1984; 162:223.

3. Milleron, BJ, Costabel, U, Teschler, H, et al. Bronchoalveolar lavage cell data in alveolar proteinosis. Am Rev Respir Dis 1991; 144:1330.

4. Inoue, Y, Trapnell, BC, Tazawa, R, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med 2008; 177:752.

5. Claypool, WD, Rogers, RM, Matuschak, GM. Update on the clinical diagnosis, management, and pathogenesis of pulmonary alveolar proteinosis (phospholipidosis). Chest 1984; 85:550.

6. Larson, RK, Gordinier, R. Pulmonary alveolar proteinosis. report of six cases, review of the literature, and formulation of a new theory. Ann Intern Med 1965; 62:292.

7. Beccaria, M, Luisetti, M, Rodi, G, et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23:526.

8. Seymour, JF, Dunn, AR, Vincent, JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis [letter]. N Engl J Med 1996; 335:1924.

9. Barraclough, RM, Gillies, AJ. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax 2001; 56:664.

10. De Vega, MG, Sanchez-Palencia, A, Ramirez, A, et al. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax 2002; 57:837.

11. Kavuru, MS, Sullivan, EJ, Piccin, R, et al. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000; 161:1143.

12. Venkateshiah, SB, Yan, TD, Bonfield, TL, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 2006; 130:227.

13. Seymour, JF, Doyle, IR, Nakata, K, et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003; 58:252.

14. Parker, LA, Novotny, DB. Recurrent alveolar proteinosis following double lung transplantation. Chest 1997; 111:1457.

15. Kavuru, MS, Bonfield, TL, Thomassen, MJ. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am J Respir Crit Care Med 2003; 167:1036.

16. Borie, R, Debray, MP, Laine, C, et al. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur Respir J 2009; 33:1503.

17.  Kavuru MS, Malur A, Marshall I, Barna BP, Meziane M, Huizar I, Dalrymple H, Karnekar R, Thomassen MJ. An Open-Label Trial of Rituximab Therapy in Pulmonary Alveolar Proteinosis. Eur Respir J. Published on April 8, 2011 as doi: 10.1183/09031936.00197710.

18. Shah S, Phan N, Goyal G, Sharma G. Pulmonary Alveolar Proteinosis in a 67-Year-Old Woman with Wegener’s Granulomatosis. J Gen Intern Med. 2010; 25:1105.