Azacitidine-induced cryptogenic organizing pneumonia: a case report and review of the literature

Prior to the introduction of hypomethylating agents, including azacitidine, as standard therapies for MDS, cytotoxic medications were the main stay of treatment. However, outcomes following these cytotoxic agents were disappointing. Furthermore, factors related to advanced age and comorbidities have limited the eligibility of most patients with MDS for bone marrow transplantation. Azacitidine is a cytidine analog which has a nitrogen atom instead of carbon at position five of the heterocyclic ring. Azacitidine undergoes phosphorylation to azacitidine triphosphate, which is incorporated into the ribonucleic acid (RNA), disrupting its metabolism and protein synthesis. Subsequently, azacitidine diphosphate is dephosphorylated into 5-aza-2'-deoxycytidine, which then undergoes phosphorylation into triphosphate and then binds to DNA methyltransferase inhibiting its action. Hypomethylation of CpG island is thought to accompany neoplastic transformation and silencing of the hypermethylated tumor suppressor gene p15 ^INK4B ; this gene is found in MDS and is probably one of the most important genetic backgrounds in MDS which could be reversed by azacitidine [4].

Azacitidine has been associated with various adverse reactions including nausea, pyrexia, diarrhea, fatigue, cough, dyspnea, and bone marrow suppression which might result in febrile neutropenia, bleeding, and anemia. ILD is probably a rare adverse reaction secondary to azacitidine. A review of literature identified five previously reported cases of ILD in association with hypomethylating agents for treatment of MDS: four were reported with azacitidine [5‐8] and one with decitabine [9]. We provide descriptions of clinical presentations and pulmonary outcomes for these reported cases in Table 1.

In our case the Naranjo scale for adverse drug reaction was probable [10]. Gemcitabine which is another cytidine analog has been associated with lung toxicity as well [11].

We have discussed the case of a 67-year-old man diagnosed with MDS. He received two cycles of azacitidine administered intravenously (75 mg/m², which was 150 mg administered intravenously) from days 1 to 7; he presented with dyspnea 2 weeks following the second cycle. His condition deteriorated significantly despite an early initiation of a wide spectrum of antibiotics. Failure to isolate a specific pathogen with bronchoalveolar lavage, as well as lack of fever, made an infectious etiology less likely.

Cryptogenic organizing pneumonia (COP) is one of the ILDs; the disease affects distal bronchioles, alveolar ducts, and alveoli. Although the pathogenesis is not fully understood, injury to alveolar epithelial cells in addition to imbalance between the activity of matrix metalloproteinase and its inhibitors seem to be the primary event that triggers COP. This leads to leakage of intracellular proteins which triggers an inflammatory reaction with recruitment of inflammatory cells, followed by production of fibromyxoid material resulting in plug formation against pores of Kohn. A high level of apoptosis is one of the striking features of this disease which makes it reversible in many cases [12, 13].

Our patient developed bilateral migratory lung opacities which is usually a striking feature of this disease [14]. The bronchoalveolar lavage as well as the biopsy failed to identify any specific infectious etiology. The biopsy from the new opacity at the zone of the lower lobe of his right lung was consistent with COP; 5-azacytidine was the only recent medication that he had received and as such it was the most likely culprit.

To the best of our knowledge this is the first case of azacitidine-induced COP that has occurred after a second cycle of azacitidine; our explanation for this was that our patient either developed a mild COP which was not apparent clinically or he maintained an immune response which sensitized him to the drug. After exposure to the second cycle these reactions became robust resulting in severe lung inflammation and damage. Furthermore this is the first reported case that has been associated with clinically significant pleural effusion that required tapping; although it is uncommon, pleural effusion can be associated with COP. A multicenter retrospective study of organizing pneumonia showed that 16 out of 74 patients who had either cryptogenic or secondary organizing pneumonia had pleural effusion [15]; de Gispert et al. described pleural effusion in two out of six patients who had organizing pneumonia [16]. Another retrospective study showed that four out of 18 patients with COP had pleural effusion [17]. The type of pleural effusion in those reports was not clear. In our case the patient developed bilateral pleural effusion that was greater on his left side. The analysis of the pleural fluid from his left side showed that it was transudative in nature. All of the following probably account for the transudative nature of his pleural effusion: the early lymphatic obstruction secondary to fibrotic changes in his lungs, the large quantity of intravenously administered fluid he received in the ICU as well on the general medical floor, and the tap that was done approximately 1 week after starting steroids which lessened the inflammatory reaction.

To the best of our knowledge, none of our patient’s regular medications have been associated with lung disease, although a case report was recently published on an association between oral hypoglycemic agents and intestinal lung disease, particularly metformin and glibenclamide [18]. However, our patient has been taking these drugs for many years, which made it highly unlikely that they contributed to the ILD.