Azacitidine-induced pneumonitis and literature review

Abstract

We present a case of azacitidine-induced pneumonitis which is a rare adverse drug reaction and reported in less than 0.1% of cases. Common side effects of azacitidine are weakness, nausea, vomiting, constipation, injection site reactions, insomnia, among others. Our patient received azacitidine to treat her acute myeloid leukaemia and began to develop shortness of breath which progressed to dyspnoea at rest after completing a 7-day course of azacitidine and venetoclax. Initial chest X-ray revealed severe airspace disease for which the patient began receiving broad spectrum antibiotics, antifungals and antivirals therapy. Although infectious workup revealed invasive aspergillosis she did not clinically and radiologically improve despite being on isavuconazole until high-dose glucocorticoids were initiated. This case illustrates the importance of recognising and understanding the potential side effects of azacitidine and other chemotherapy agents as some adverse drug reactions can be life-threatening.

Background

Adverse drug reactions (ADR) are a well-known entity in medicine. However, the total incidence of ADRs is unknown. Edwards and Aronson defined ADR as ‘an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.’¹ Being familiar with ADRs is important because 7 out of every 100 persons in a hospital will experience an ADR and 3 out of every 1000 persons admitted may die due to a serious ADR.² The Naranjo scale is the most commonly used metric to determine an ADR. The scale is based on a questionnaire that can be scored <0 and to a max score of 13. Scores of <0 are deemed doubtful, 1–4 possible, 5–8 probable and >9 definite. Our patient had a Naranjo score of 6 which falls in the range of probable ADR.

Case presentation

A 75-year-old Caucasian woman with medical history significant for essential thrombocytopenia (on hydroxyurea), newly diagnosed acute myeloid leukaemia (AML), group 2 pulmonary hypertension, paroxysmal atrial fibrillation (a-fib) on apixaban, diastolic heart failure, who presents to the emergency department (ED) after being sent from the oncology clinic for hypoxemia, worsening haemoptysis and hypotension (92/38 mm Hg). The patient had completed her first cycle of chemotherapy with azacitidine and venetoclax just 11 days prior. However, she did return to the oncology clinic 3 days after starting chemotherapy for worsening shortness of breath and it was deemed her symptoms were attributed to her diastolic heart failure. After completing a 7-day cycle of azacitidine and venetoclax, her shortness of breath had progressed to the point where she was short of breath at rest.

Investigations

Vital signs in the ED revealed hypotension at 82/38 mm Hg, tachycardia at 104 beats per minute, saturating 90% on room air. Further workup revealed pancytopenia with haemoglobin 46 g/L, mean corpuscular volume 91.4 FL, white cell count 0.4×10⁹/L, and platelet count of 15×10⁹/L, elevated lactic acid of 2.7 mMol/L. Chest X-ray showed severe airspace disease (figure 1). The patient was subsequently admitted to the medical intensive care unit and placed on vancomycin, cefepime azithromycin, acyclovir and fluconazole for presumed sepsis secondary to community acquired pneumonia versus cytomegalovirus (CMV) pneumonitis as there was an elevated CMV IgM and IgG of 36.7 and 7.0 AU/mL on labs prior to admission. The patient received two units of blood via simple transfusion for her symptomatic normocytic anaemia but continued to have haemoptysis. Due to her being anticoagulated with apixaban for her paroxysmal a-fib, it was thought that her haemoptysis was secondary to pulmonary haemorrhage. Patient’s oxygen requirement increased as she needed 10 L of high-flow nasal cannula to maintain a saturation above 90%. Additional imaging with CT of the chest revealed ground glass/consolidative changes throughout the lungs involving all lobes with primary central distribution and small bilateral pleural effusions (figures 2 and 3). A bronchoscopy with bronchoalveolar lavage (BAL) was performed to further evaluate the cause of haemoptysis. Bronchoscopy revealed right and left lower lobe mucosa thickening and friability, however, subsequent aspirate was not haemorrhagic thus not consistent with diffuse alveolar haemorrhage. BAL fluid was sent to the lab for further workup. Meanwhile, infectious workup with blood, sputum and fungal cultures, legionella urine antigen, streptococcus pneumoniae antigen were negative with CMV PCR pending. Vancomycin was discontinued as cultures were negative for methicillin-resistant Staphylococcus aureus but the patient continued to receive cefepime, completed 5-day course of azithromycin, prophylactic acyclovir and fluconazole. BAL fluid analysis resulted in a lymphocyte predominance with 87% lymphocytes, fungal, pneumocystis culture and stain, viral PCR were all negative. However, Aspergillus antigen was elevated at 0.730 (reference range <0.5), therefore, isavuconazole was initiated for invasive aspergillosis. Furthermore, CMV PCR resulted in <137 copies which was not consistent with causative infection thus was not treated with ganciclovir. Although this patient was treated with antibiotics, antiviral and antifungal agents, her respiratory status did not improve which prompted the initiation of high-dose glucocorticoid therapy for presumed pneumonitis secondary to azacitidine. Within 2–3 days of starting prednisone 30 mg two times a day, her oxygen requirements improved as she was able to be weaned off high flow nasal cannula to regular nasal cannula.

Figure 1.

Initial chest X-ray showing severe airspace disease.

Figure 2.

Coronal chest CT image on patient presentation showing diffuse ground glass and dense infiltrates.

Figure 3.

Axial chest CT image on presentation showing diffuse ground glass and dense infiltrates.

Differential diagnosis

The differential diagnosis in this patient based on clinical, laboratory and radiological findings included a variety of infections such as community acquired multifocal pneumonia, CMV pneumonitis and pneumocystis jiroveci pneumonia. The patient was immunocompromised and had pancytopenia secondary to chemotherapy thus the aforementioned differentials. However, given that our patient was afebrile, with non purulent sputum production and CT thorax showing pulmonary oedema and small bilateral pleural effusions with brain natriuretic peptide of 859, other differentials included acute exacerbation of right-sided heart failure due to severe pulmonary hypertension (transthoracic echo: right ventricular systolic pressure of 71 mm Hg and grade I diastolic dysfunction), acute pulmonary haemorrhage secondary to anticoagulation therapy (on eliquis) and dyspnoea secondary to acute post pulmonary haemorrhagic anaemia (haemoglobin 46 g/L). Additionally, the possibility of other drug-induced pneumonitis was also considered. Her home medications were bisoprolol, apixaban, albuterol, brimonidine, acyclovir, fluconazole and allopurinol. Of the medications being taken, apixaban is the only other drug that has been reported to cause interstitial lung disease (ILD) but has only been seen in Japanese men with decreased creatinine clearance.³ Bronchoscopy with BAL was performed galactomannan came back positive thus indicating probable invasive pulmonary aspergillosis. Ultimately, the patient did not improve despite receiving blood transfusions, diuretics, antibiotics, antivirals and antifungal therapy until high-dose glucocorticoid therapy with prednisone was initiated. Given that the patient rapidly improved after initiating prednisone, led to our diagnosis of exclusion azacitidine-induced pneumonitis.

Outcome and follow-up

Our patient responded well and her clinical condition markedly improved after initiating high-dose glucocorticoids with prednisone 30 mg two times a day. She was discharged to a subacute rehab facility to recondition herself and to complete a total of 5 weeks of glucocorticoids with taper. Although, apixaban has been reported to cause ILD it is unlikely in this case as our patient was taking apixaban for quite some time prior to developing respiratory symptoms and continued to take apixaban after being discharge without symptoms. On her 2-month follow-up oncology clinic visit, she is doing much better and has an Eastern Cooperative Oncology Group performance scale is a 2, which indicates the patient is ambulatory and capable of self care but unable to perform any work activities. Moreover, she is no longer requiring supplemental oxygen. Her repeat chest CT showed marked interval improvement in previously demonstrated extensive consolidative changes with residual ground glass changes (figures 4 and 5).

Figure 4.

Coronal chest CT image following treatment with systemic corticosteroids showing almost complete resolution of the pulmonary infiltrates.

Figure 5.

Axial chest CT image following treatment with systemic corticosteroids showing almost complete resolution of the pulmonary infiltrates.

Discussion

AML is a heterogeneous group of aggressive blood cell cancers and the diagnosis increases with age. Median age of diagnosis in the USA is 68.⁴ This haematopoietic disorder causes clonal expansion of myeloid and lymphoid progenitor cells which interferes with hematopoiesis. This in turn causes cytopenias that can lead to bleeding or infections. Treatment options vary, but one option is low intensity treatment with azacitidine, which has been shown to respond appropriately and may prolong survival compared with supportive care alone. Azacitidine is a pyrimidine analogue of citidine. The mechanism of action of azacitidine is that it incorporates into DNA and reversibly inhibits DNA methyltransferase. Doing so blocks DNA methylation and may activate tumour suppressor genes that may be inhibited by hypermethylation thus leading to antitumor effects.⁵ Common adverse effects of azacitidine are weakness, nausea, vomiting, constipation, injection site reactions, insomnia, among others. However, one rare adverse effect is pneumonitis, which is seen in less than <0.1% of cases and has only been reported in limited medical literature. Drug-induced pneumonitis is typically a diagnosis of exclusion and commonly presents with fever, cough and dyspnoea. Therefore, infectious aetiology along with cardiac and other processes need to be excluded prior to diagnosis. Table 1 depicts all of the previous reported cases of azacitidine-induced pneumonitis along with how and when they presented with symptoms. Based on our literature review of the cases reported, the age range of pneumonitis seen was between 55 and 86. Of the 16 total cases, symptoms started acutely typically within 7 days of initiating treatment regardless of cycle. Common reported symptoms were fever, cough and dyspnoea, which progressed and did not improve after initiation of antibiotics, antifungal or antiviral medications. Clinical improvements in all cases were not noticed until high-dose corticosteroids were initiated. Therefore, physicians should be aware of this adverse effect in patients receiving azacitidine and to halt treatment once symptoms develop. Furthermore, prompt exclusion of other medical processes causing these manifestations warrant initiation of high-dose corticosteroids as the mortality rate in these cases was approximately 19%.

Table 1.

Reported cases of azacitidine-induced pneumonitis

Study (reference)	Age/sex	Cycle of azacitidine	Day of onset after administration	Symptoms	Chest CT findings	Bronchoscopy finding	Infectious workup	Naranjo score	Outcome
Adams et al; USA6	71/M	First	Unknown	Wheezing	Diffuse, bilateral, interstitial, and alveolar process	Scattered petechiae, thin watery secretions, with no lesions or evidence of haemorrhage	Negative	Probable	Died
Hueser; USA7	55/F	First	3	Fever then dyspnoea	Bilateral interstitial opacities	Performed, reported as negative.	Negative	Probable	Survived
Sekhri et al; USA8	56/M	First	Within 1 week	Dry cough, dyspnoea	N/A	N/A	Negative	N/A	Survived
	56/M	Second	2	Fever, cough, dyspnoea, hypoxia	Extensive bilateral airspace disease with many areas demonstrating nodular opacities	Performed, no reported findings.	Negative	N/A	Survived
Hayashi et al; Japan9	74/M	First	2	Fever, dry cough, SOB	Non-segmental consolidations with air bronchogram, and surrounding GGO	N/A	Negative	Probable	Survived
Pillai et al; UK10	74/F	First	2 weeks	Fever, dry cough, breathlessness	Peribronchiol-ar shadowing in both lower lobes and bilateral small effusions	Indeterminate	Negative	N/A	Survived
		Second	5	Fever, dry cough, dyspnoea	Reticulo-nodular and ground-glass shadowing, pleural effusion	N/A	N/A	N/A	Survived
Kotsianidis et al; Greece11	55/M	First	27	Fever, respiratory failure, hypoxemia, hypercapnia	N/A	N/A	Negative	Definite	Survived
Nair et al; USA12	76/M	Second	3 weeks	Dyspnoea, non-productive cough, fever	Diffuse bilateral patchy pulmonary infiltrates more pronounced in the peripheries, with surrounding ground-glass opacities, and enlargement of mediastinal and bilateral hilar lymph nodes	N/A	Negative	N/A	Survived
Kuroda et al; Japan13	72/M	First	3	Fever, DOE, cough, bloody sputum, wheezing	Interstitial opacities, ground glass shadowing in RUL and b/l Lower lobes. b/l small pleural effusions and mediastinal LN swelling	N/A	Negative	Definite	Died
Patel et al; USA14	74/M	Second	2	Fever, cough, SOB	Bilateral interstitial infiltrates with GGO	Inflammatory changes with diffuse alveolar hyperplasia.	Negative	N/A	Survived
Ahrari et al; Canada15	73/M	Third	Unknown	Fever, chills, night sweats	Bilateral ground-glass opacities with reticulation in the mid and upper lung zones and patchy peripheral airspace consolidation	Performed, no reported findings	Blood cultures showed Mycobacterium fortuitum	N/A	Died
Verriere et al; France16	86/F	Third	2	Grade three skin reaction, nausea, gastric pain, dry cough, hyperthermia, ear pain	Diffuse interstitial opacities and ground glass shadow- ing as well as mediastinal and hilar lymph nodes	N/A	Negative	Probable	Survived
Alnimer et al; USA17	67/M	Second	14	SOB, productive cough	Massive multifocal bilateral pulmonary consolidations, with surrounding ground-glass opacities, pleural effusion	Performed, not reported	Negative	Probable	Survived
Misra et al; France18	67/F	First	7	Fever and dry cough	Diffuse bilateral opacities with ground-glass shadowing and pleural effusion bilaterally	Performed, not reported	Negative	Probable	Survived
Makita et al; Japan19	77/M	Second	4	Fever and hypoxia	Diffuse GGO in both lungs	N/A	Negative	N/A	Survived
Oka et al; Japan20	75/F	Third	4	Dry cough	Enlarged right hilar lymph node and nonsegmental consolidations with ground glass shadowings	Intestinal lung disease with nonresolving organising pneumonia and sarcoid-like granulomatous patterns	Negative	Probable	Survived
Present Case	75/F	First	3	SOB	Ground glass/consolidative changes throughout the lungs involving all lobes with primary central distribution	Mucosa thickening and friability.	Aspergillus Ag (+)	Probable	Survived

F, female; GGO, ground glass opacities; M, male; SOB, shortness of breath.

Learning points.

• Azacitidine-induced pneumonitis is an extremely rare drug reaction and the diagnosis should be addressed once all investigations have ruled out alternative explanations, including infectious or pulmonary causes.

• In general chemotherapy-induced pneumonitis can present with many radiographic findings, such as ground glass opacities, consolidations, alveolar or interstitial opacities, pleural effusions or interlobular septal thickening.

• The treatment of choice for azacitidine-induced pneumonitis is discontinuation of the drug. Supportive care consist of supplemental oxygen. Systemic glucocorticoid therapy includes oral prednisone 40–60 mg daily in patients having shortness of breath at rest, oxygen saturation less than 90% or more than 4% decrease in patient’s baseline oxygen saturation and worsening clinical picture. Intravenous glucocorticoids may be used in patients having signs and symptoms of impending respiratory failure.