Update and Arizona Thoracic Society Position Statement on Stem Cell Therapy for Lung Disease

Summary

Infusions of stem cells are increasingly being offered for a variety of diseases, including chronic lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cystic fibrosis. However, the potential for harm, the lack of any proven benefit, and the high fees that many of these programs charge make recommending stem cell therapy untenable. At the time of this writing (April 2019) it appears that stem cell therapy can be safely performed, although the long-term side effects remain unknown. However, the little data available show no benefit in meaningful outcomes, such as mortality, morbidity or patient well-being, for stem cell treatment of chronic lung disorders. Patients with severe, incurable diseases may be motivated to seek innovative therapies. We encourage such patients to contact their primary care physician or pulmonologist. Clinical trials in the United States and Canada investigating stem cell therapy for lung diseases can be found on the website of the National Institutes of Health at Clinicaltrials.gov. The Arizona Thoracic Society encourages regulatory agencies to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

Introduction

A central component of the mission of medical societies is to translate new scientific information into patient education. There appears to be increasing direct-to-consumer advertising of untested, unapproved, and potentially ineffective “stem-cell” treatments for a variety of diseases, including lung disorders (1). One may come across information regarding stem cell therapy for chronic obstructive pulmonary disorders and fibrotic lung disease, in the United States and worldwide, on the internet, patient support groups, or other sources. Recently, a direct mailing to the home of one of the members of the Arizona Thoracic Society was received (Figure 1).

Figure 1. Direct mailing for stem cell therapy for several diseases including COPD received by one of the members of the Arizona Thoracic Society.

These programs are often characterized by:

• Exorbitant fees
• Misrepresentation of risks and benefits
• Overreliance on, and advertisement of, patient testimony
• Poor patient follow-up
• Absence of regulatory oversight and objective clinical evidence for claimed benefits

Therefore, they differ substantially from therapies approved by legitimate regulatory agencies, from well-designed, controlled, and appropriately regulated clinical trials, and from regulated compassionate use of innovative cell therapies.

Chronic Obstructive Pulmonary Disease (COPD)

Stem cells can differentiate into several different lung cell types, including the alveolar epithelial cells. Since COPD is a disease associated with destruction of alveoli induced by cigarette smoke, the concept of rebuilding the alveoli through stem cell therapy is attractive. Pre-clinical trials in animal models have suggested regeneration of alveolar-like structures, repair of emphysematous lungs, and reduction of inflammatory responses, with the greatest success being in acute lung injury models.

Currently, regenerative therapies are divided into extrinsic therapeutic strategies and intrinsic cell therapy methods. Extrinsic cell therapy refers to the vascular infusion of (or endotracheal installation) of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSs), mesenchymal stem cells (MSCs), and human lung stem cells (hLSCs). Intrinsic therapy refers to the delivery of small molecules (retinoid compounds have been the most studied) that can stimulate the endogenous lung stem/progenitor cells to regenerate and replace damaged structures.

A number of recent review articles have summarized the current state of research in the use of stem cells in COPD (2-4). These review articles all contain summaries of trials conducted to date using both extrinsic and intrinsic therapies. There have been several phase I clinical trials, primarily assessing safety, and a handful of small phase II clinical trials that have been negative for meaningful clinical outcomes. Sun et al. (3) point out that the available trials have all been conducted on patients with advanced COPD. The authors suggest that further research is required on how to enhance the engraftment of exogenous mesenchymal stem cells in damaged lungs. Further, considering the anti-inflammatory and immunomodulatory effects of exogenous mesenchymal stem cells, they may be most effective potentially in treating acute lung disease, as opposed to chronic progressive disease with severe structural damage.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease of unknown etiology characterized by a combination of histological changes, including extracellular matrix (ECM) deposition, phenotypic changes of fibroblasts, and alveolar epithelial cells, the formation of fibroblastic foci, and scattered areas of aberrant wound healing interspersed with normal lung parenchyma (5).

There are two approved compounds for the treatment of IPF: pirfenidone and nintedanib. Pirfenidone is an antifibrotic compound with an unclear mechanism of action, targeting several molecules, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and interleukin 6 (6). Nintedanib is a tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet derived growth factor receptor (PDGFR) (7). While the use of pirfenidone and nintedanib has been shown to slow the progression of IPF, neither is curative and morbidity and mortality from IPF remains high (8,9).

Because of the inadequacy of therapy in IPF, the use of mesenchymal stem cells (MSCs) has attracted interest as a potential option. Early clinical studies have shown that the MSCs can be safely administered (5,10-12). A phase Ib study of endobronchially administered autologous adipose-derived MSCs showed not only acceptable safety outcomes, but also improvements in quality of life parameters (12). However, there were no significant differences in any of the studied functional parameters (FVC, FVC%pred. and DLCO% pred.) at baseline and 6 and 12 months following 3 endobronchial infusions of MSCs.

Cystic Fibrosis

Cystic fibrosis (CF) is a genetic syndrome usually resulting in a high mortality rate due to progressive lung disease. Several drugs targeting specific mutated cystic fibrosis transmembrane regulator (CFTR) proteins are already in clinical trials. However, new therapies, based on stem cells, are also emerging. Interest has focused on induced pluripotent stem (iPS) cells. It is possible to make iPS cells using cells from people with CF, and then use gene editing to correct CFTR mutations in those cells (13). This suggests the possibility of re-implanting the corrected iPS cells into the lungs of people with CF to generate healthy lung cells. Currently, three trials examining the safety of stem cells in cystic fibrosis are ongoing according to Clinicaltrials.gov. 

Adult Respiratory Distress Syndrome (ARDS)

Four clinical trials are listed on Clinicaltrials.gov for ARDS and stem cells; one, which involved 3 patients, has been completed (14). No outcome information is available.

Other Lung Diseases

We are unaware of any human trials at this time with outcomes in other lung diseases.

Regulatory and Legal Actions

The Food and Drug Administration (FDA) and the Attorney General of New York have both expressed concern over stem cell therapy. The concerns follow reports of three patients becoming blind after receiving injections of stem cells into the eye and twelve patients who became seriously ill after receiving injections that purportedly contained stem cells from umbilical cord blood (15,16). The FDA has issued warning letters to stem cell clinics, including one letter claiming violation of Federal law, and another 20 warnings to clinics of that their claims and actions were subject to FDA approval. The NY Attorney has filed a lawsuit against a for-profit stem cell clinic, Park Avenue Stem Cell, claiming it performed unproven procedures on patients with a wide range of medical conditions, from erectile dysfunction to heart disease (17).

The Arizona Thoracic Society encourages further investigation into stem cell transplantation in lung disease. However, we do not at this time encourage non-investigational use of stem cells since the therapy has not been shown to have meaningful patient benefits. We also encourage state and local regulatory agencies in the Southwest to protect the public health and take appropriate action against non-investigational, for-profit stem cell clinics when appropriate.

References

1. American Lung Association. Statement on Unproven Stem Cell Interventions for Lung Diseases (July 2016). Available at: https://www.thoracic.org/members/assemblies/assemblies/rcmb/working-groups/stem-cell/resources/statement-on-unproven-stem-cell-interventions-for-lung-diseases.pdf (accessed 4/5/19).
2. Balkissoon R. Stem Cell Therapy for COPD: Where are we? Chronic Obstr Pulm Dis. 2018;5(2):148-53. [CrossRef] [PubMed]
3. Sun Z, Li F, Zhou X, Chung KF, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. J Thorac Dis. 2018 Feb;10(2):1084-98. [CrossRef] [PubMed]
4. Cheng SL, Lin CH, Yao CL. Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science. Stem Cells Int. 2017;2017:8916570. [CrossRef] [PubMed]
5. Tzouvelekis A, Toonkel R, Karampitsakos T, Medapalli K, Ninou I, Aidinis V, Bouros D, Glassberg MK. Mesenchymal stem cells for the treatment of idiopathic pulmonary fibrosis. Front Med (Lausanne). 2018 May 15;5:142. [CrossRef] [PubMed]
6. Kolb M, Bonella F, Wollin L. Therapeutic targets in idiopathic pulmonary fibrosis. Respir Med. 2017;131:49–57. [CrossRef] [PubMed]
7. Fletcher S, Jones MG, Spinks K, et al. The safety of new drug treatments for idiopathic pulmonary fibrosis. Expert Opin Drug Saf. 2016;15:1483–9. [CrossRef] [PubMed]
8. King TE, Bradford WZ, Castro-Bernardini S, et al. Phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. [CrossRef] [PubMed]
9. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. [CrossRef] [PubMed]
10. Tzouvelekis A, Ntolios P, Karampitsakos T, et al. Safety and efficacy of pirfenidone in severe idiopathic pulmonary fibrosis: a real-world observational study. Pulm Pharmacol Ther. 2017;46:48-53. [CrossRef] [PubMed]
11. Tzouvelekis A, Koliakos G, Ntolios P, et al. Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011;9:182. [CrossRef] [PubMed]
12. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171. [CrossRef] [PubMed]
13. The Cystic Fibrosis Foundation. Stem cells for cystic fibrosis therapy. Available at: https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Stem-Cells-for-Cystic-Fibrosis-Therapy/ (accessed 4/5/19).
14. Clinicaltrials.gov. Human Mesenchymal Stem Cells For Acute Respiratory Distress Syndrome (START). Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT01775774?term=Stem+cells&cond=ARDS&rank=4 (accessed 4/5/19).
15. Kuriyan AE, Albini TA, Townsend JH, et al. Vision loss after intravitreal injection of autologous "stem cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-53. [CrossRef] [PubMed]
16. Grady D. 12 People hospitalized with infections from stem cell shots. NY Times. Dec. 20, 2018. Available at: https://www.nytimes.com/2018/12/20/health/stem-cell-shots-bacteria-fda.html?action=click&module=RelatedCoverage&pgtype=Article&region=Footer (accessed 4/9/19).
17. Abelson R. N.Y. attorney general sues Manhattan stem cell clinic, citing rogue therapies. NY Times. April 4, 2019. Available at: https://www.nytimes.com/2019/04/04/health/stem-cells-lawsuit-new-york.html (accessed 4/9/19).

Cite as: Arizona Thoracic Society*. Update and Arizona Thoracic Society position statement on stem cell therapy for lung disease. Southwest J Pulm Crit Care. 2019;18(4):82-6. doi: https://doi.org/10.13175/swjpcc020-19 PDF

*The below contributed to the update and position statement on stem cell therapy

• Bhargavi Gali, MD
• Michael B. Gotway, MD
• Kenneth S. Knox, MD
• Timothy T. Kuberski, MD
• Stuart F. Quan, MD
• George Parides, DO
• Richard A. Robbins, MD
• Gerald F. Schwartzberg, MD
• Allen R. Thomas, MD
• Lewis J. Wesselius, MD

Azathioprine Associated Acute Respiratory Distress Syndrome: Case Report and Literature Review

Dmitriy Scherbak, D.O.

Ruth Wyckoff, M.D.

Clement Singarajah, M.D.

Phoenix VA Healthcare System

Phoenix, AZ

Abstract

A 58-year-old Caucasian man treated with azathioprine to prevent rejection of an orthotopic liver transplant, presented to the Carl Hayden VA Medical Center with rapid respiratory decline and appeared septic. He required urgent intubation, mechanical ventilator support and empiric antibiotics. His clinical picture and imaging studies were consistent with acute respiratory distress syndrome; however, extensive infectious work up failed to reveal an offending organism. Review of his current medications implicated azathioprine and upon discontinuation of this agent, the patient made a rapid recovery. He was subsequently extubated, transferred out of the ICU and soon discharged home in good health.

Prescribed for organ transplant rejection and a wide array of autoimmune diseases, azathioprine has been rarely correlated with pneumonitis and rapid respiratory failure. No reported cases were found in which azathioprine was used to treat liver transplant rejection and associated with development of the adult respiratory distress syndrome (ARDS). However, there have been ARDS cases in which azathioprine was used for other purposes. We review all the available cases of azathioprine associated ARDS. The patients in these reports had similar clinical symptoms on presentation as our patient: hypoxia, febrile episodes and rapid development of ARDS with no infectious etiology. Most notable is the rapid resolution of ARDS after discontinuation of azathioprine.

Although azathioprine toxicity related respiratory failure is rare, this correlation should still be considered in the differential for immunosuppressed patients presenting with rapid pulmonary decline. Further studies are needed and warranted to better correlate this connection, but it is imperative to recognize that the relationship exists.

Introduction

Since its first use in 1961, azathioprine (a derivative of 6-mercaptopurine) has been used as a steroid sparing immunosuppressive agent in numerous disorders including prevention of graft rejection for solid organ transplantation (1-2). Azathioprine side effects are commonly gastrointestinal complaints such as nausea and vomiting, occurring in ~19% of patients. Laboratory abnormalities such as leukopenia are also common (17%) with thrombocytopenia and anemia being less common (3-4%) (3). Hepatotoxicity has been reported as well. Pulmonary toxicity is not usually noted as a side effect (1). Sixteen cases have been reported in the literature implicating azathioprine with pulmonary toxicity (1-2, 4-12). In 10 of these cases, the patient developed acute respiratory distress syndrome (ARDS) (1,2,6,8,9,11).

Pulmonary infections have been the leading cause of complications in immunosuppressed recipients of solid organs (13). Therefore, when a patient presents with respiratory distress, an abnormal chest x-ray and fevers, such infections are high on the differential, but the possibility of lung injury resulting from the immunosuppressive agent is often overlooked (1). We present a case of azathioprine induced ARDS in a liver transplant recipient and review the available ARDS cases associated with azathioprine use.

Case Report

We present a 58-year-old white man with a past medical history of end-stage liver disease due to hepatitis C cirrhosis and hepatocellular carcinoma who received an orthotopic liver transplant (OLT) 9 months prior to presentation. He was being treated with azathioprine 150mg daily and tacrolimus 1.5 mg daily to prevent rejection. He presented to the emergency department 9 months after his transplant with shortness of breath and increasing hypoxia. He was admitted to the intensive care unit where he developed respiratory failure that night requiring intubation and ventilator support. He had fevers as high as 105.1⁰F. He had pancytopenia with white blood cell count (WBC) 2.3 thousand cells at presentation, hemoglobin (HGB) 9.8 g/dL and platelets (PLT) 119 thousand cells.

Chest x-ray showed bilateral patchy pulmonary infiltrates. CT of the chest was done as well showing bilateral ground glass opacities and diffuse scattered pulmonary consolidations (Figure 1).

Figure 1. Representative images from chest CT with contrast done on admission showing diffuse ground glass opacities and scattered pulmonary consolidations.

Since he was immunosuppressed he was started on empiric antibiotic coverage with vancomycin, levofloxacin, pipercillin/tazobactam, gancyclovir and fluconazole. Trimethoprim-sulfamethoxazole was added on day 2 of hospitalization. A bronchoscopy with bronchial alveolar lavage (BAL) was done prior to antibiotics. Cell count and differential showed 160 white blood cells, 11% segmented neutrophils and 3% eosinophils, the other 86% of cells were pulmonary macrophages/monocytes and reactive respiratory epithelial cells. No organisms or evidence of malignancy were seen. BAL cultures showed no growth on bacterial, viral, acid fast or mycology cultures. Influenza A and B and a pneumocystis smear were also negative. Blood cultures were taken twice during the patient’s hospitalization during febrile episodes and showed no growth both times in two sets of cultures. On day 6 of hospitalization anti-microbial therapy was discontinued.

The patient’s clinical status continued to deteriorate. Chest x-rays continued to show increasing bilateral pulmonary infiltrates (Figure 2).

Figure 2. Chest x-ray at worst (hospital day 8) showing worsening bilateral pulmonary infiltrates.

The diagnosis of acute respiratory distress syndrome (ARDS) was established. His ventilator settings followed the NHLBI ARDS Network protocol, and on day 6 he was even placed in a prone position. On day 7 of hospitalization his white blood cell count dropped to a nadir of 0.5 thousand cells, hemoglobin dropped to 6.5 g/dL and platelets down to 69 thousand cells). Azathioprine was discontinued due to the pancytopenia and due to finding a few case reports in which it was implicated in ARDS. Within 3 days of azathioprine discontinuation (day 10 of hospitalization), the patient’s chest x-rays and pulmonary function had dramatically improved and he was successfully extubated by the fifth day of azathioprine being withdrawn (day 12 of hospitalization). Daily chest x-rays showed continued resolution of infiltrates (Figure 3).

Figure 3. Chest x-ray from hospital day 15 showing dramatic improvement of infiltrates after azathioprine discontinuation.

He improved rapidly and was discharged from the ICU on day 17 and discharged home from the hospital on day 18 with complete resolution of his pulmonary symptoms. His azathioprine was not restarted but he resumed tacrolimus for immunosuppression. Six months after admission, the patient was in good health with no clinical symptoms.

Discussion

Azathioprine is a nitroimidazole derivative of 6-mercaptopurine (4). It was first used in 1961 and has since become a common medication for treatment of numerous auto-immune disorders and as an immunosuppressant in transplant recipients (1). It has been described to have several reversible dose dependent side effects including bone marrow suppression, hepatotoxicity, anorexia, nausea and vomiting (4). Hypersensitivity reactions have also been described and include fevers, rigors, arthralgia, myalgia, cutaneous reactions, headaches, interstitial nephritis, pancreatitis, dyspnea, cough and pneumonitis (1-4, 6).

In our case the patient developed pneumonitis and ARDS which resolved rapidly after the discontinuation of azathioprine. A review of the literature using broad search terms in OVID, Pub-Med and Google Scholar revealed only 10 articles constituting 16 cases of pulmonary toxicity linked to azathioprine. Detailed analysis showed only 5 reported cases of ARDS linked to azathioprine toxicity (2,6,8,9,11), and a single case series of 7 cases of which 2 also have an infectious etiology (1). Data from these cases are summarized on table 1.

Table 1. Cases of Azathioprine induced ARDS in the literature.

The four remaining articles not appearing in table 1 were excluded because they either represented an immediate hypersensitivity reaction to azathioprine or had infectious pneumonitis which could have contributed to the development of ARDS (4,5,10,12).

Neither our case nor those in the literature contain irrefutable proof that azathioprine was directly responsible for lung injury. However, the similarities between the cases in which the patient survived lead us to conclude that azathioprine is involved in this adverse reaction. First, all 8 cases in which the patient survived show a rapid improvement within one to two weeks after discontinuation of azathioprine. Second, all of these patients present in the same way with hypoxia, pulmonary infiltrates, and fevers. Third, none of the cases show any other possible causes and the ones that go to biopsy have non-specific findings (UIP or diffuse alveolar damage) (1,2,6,7,11). These observations are circumstantial, but the diagnosis of drug-induced pulmonary toxicity is usually based on clinical history of drug exposure and the absence of other known causative agents. Additionally, diffuse interstitial pulmonary disease is the most common form of lung pathology caused by drugs (1,14).

Leukopenia or pancytopenia were present in our case as well as 4 of the 10 reported cases (6,8,9,11). No other side effects from azathioprine were reported in any of the cases. Therefore ARDS is likely a unique effect and unrelated to other potential side effects of azathioprine. The dose of azathioprine was widely variable in the known cases (25-150mg daily) leading us to believe that the development of ARDS is not dose-dependent. All of the cases had patients who had been on azathioprine for months (years in one case) prior to developing pneumonitis or ARDS, leading us to speculate that ARDS is not an acute hypersensitivity. It may be that ARDS development is a function of dose effect over time.

Although there are very few reported cases, It is possible that azathioprine induced lung injury is more common than it appears. When an immunosuppressed patient presents with respiratory distress, some form of infectious etiology is usually involved and the immunosuppressants are often discontinued (1). It is possible that in some of these cases azathioprine itself is the cause or may at least contribute to the development of ARDS. We believe it is important that azathioprine lung toxicity be included in the differential for ARDS causes because prompt discontinuation of azathioprine has led to rapid recovery and good outcome in 8 of the 10 known cases (1,2,6,8,9,11).

Acknowledgments

Sarah Waybright, Pharm.D. and Lindsay Kittler, Pharm.D. The clinical pharmacists who noted case reports of azathioprine causing pulmonary toxicity and recommended it’s discontinuation in our patient.

References

1. Bedrossian CW, Sussman J, Conklin RH, Kahan B. Azathioprine-associated interstitial pneumonitis. Am J of Clin Pathol. 1984;82(2):148-54. [PubMed]
2. Weisenburger DD. Interstitial pneumonitis associated with azathioprine therapy. Am J of Clin Pathol. 1978;69(2):181-5. [PubMed]
3. Whisnant JK, Pelkey J. Rheumatoid arthritis: treatment with azathioprine (IMURAN (R)). Clinical side-effects and laboratory abnormalities. Ann Rheum Dis. 1982;41:44-47. [CrossRef] [PubMed]
4. Stetter M, Schmidl M, Krapf R. Azathioprine hypersensitivity mimicking Goodpasture's syndrome. Am J of Kidney Dis. 1994;23(6):874-7. [CrossRef] [PubMed]
5. Krowka MJ, Breuer RI, Kehoe TJ. Azathioprine-associated pulmonary dysfunction. Chest. 1983;83(4):696-8. [CrossRef] [PubMed]
6. Rubin G, Baume P, Vandenberg R. Azathioprine and acute restrictive lung disease. Aust N Z J Med. 1972 Aug;2(3):272-4. [CrossRef] [PubMed]
7. Bidinger JJ, Sky K, Battafarano DF. Henning JS. The cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome. [Review] J Am Acad Dermatol. 2011;65(1):184-91. [CrossRef] [PubMed]
8. Carmichael DJS, Hamilton DV, Evans DB, Stovin PGI, Calne RY. Interstitial pneumonitis secondary to azathioprine in a renal transplant patient. Thorax. 1983;38:951-952. [CrossRef] [PubMed]
9. Perreaux F, Delphine Z, Capron F, Trioche P, Odievre M, Labrune P. Azathioprine-induced lung toxicity and efficacy of cyclosporine a in a young girl with type 2 autoimmune hepatitis. J Ped Gastroenterol Nutr. 2000;31:190-192. [CrossRef]
10. Ananthakrishnan AN, Attila T, Otterson MF, Lipchik RJ, Massey BT, Komorowski RA, Binion DG. Severe pulmonary toxicity after azathioprine/6-mercatopurine initiation for treatment of inflammatory bowel disease. J Clin Gastroenterol. 2007;41(7):682-688. [CrossRef] [PubMed]
11. Brown AL, Corris PA, Ashcroft T, Wilkinson R. Azathioprine-related interstitial pneumonitis in a renal transplant recipient. Nephrol Dial Transplant. 1992;7:362-364. [PubMed]
12. Frost J, Carion G, Mazer J. A case of azathioprine hypersensitivity syndrome, acute respiratory distress syndrome, and shock. Crit Care Med Suppl. 2011;32(12):926.
13. De Gasperi A, Feltracco P, Ceravola E, Mazza E. Pulmonary complications in patients receiving a solid-organ transplant. Curr Opin Crit Care. 2014;20(4):411-419. [CrossRef] [PubMed]
14. Camus P, Fanton A, Bonniaud P, Camus C, Foucher P. Interstitial lung disease induced by drugs and radiation. Respir. 2004;71:01-326. [CrossRef] [PubMed]

Reference as: Scherbak D, Wyckoff R, Singarajah C. Azathioprine associated acute respiratory distress syndrome: case report and literature review. Southwest J Pulm Crit Care. 2014;9(2):94-100. doi: http://dx.doi.org/10.13175/swjpcc087-14 PDF