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How to Diagnose Early 5-Azacytidine-Induced Pneumonitis: A Case Report

  • Srimanta Chandra Misra
  • Laurence Gabriel
  • Eric Nacoulma
  • Gérard Dine
  • Valentina Guarino
Open Access
Case Report
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Abstract

Interstitial pneumonitis is a classical complication of many drugs. Pulmonary toxicity due to 5-azacytidine, a deoxyribonucleic acid methyltransferase inhibitor and cytotoxic drug, has rarely been reported. We report a 67-year-old female myelodysplastic syndrome patient treated with 5-azacytidine at the conventional dosage of 75 mg/m2 for 7 days. One week after starting she developed moderate fever along with dry cough and subsequently her temperature rose to 39.5 °C. She was placed under broad-spectrum antibiotics based on the protocol for febrile neutropenia, including ciprofloxacin 750 mg twice daily, ceftazidime 1 g three times daily (tid), and sulfamethoxazole/trimethoprim 400 mg/80 mg tid. High-resolution computed tomography of the chest disclosed diffuse bilateral opacities with ground-glass shadowing and pleural effusion bilaterally. Mediastinal and hilar lymph nodes were moderately enlarged. polymerase chain reaction for Mycobacterium tuberculosis, Pneumocystis jiroveci, and cytomegalovirus were negative. Cultures including viral and fungal were all negative. A diagnosis of drug-induced pneumonitis was considered and, given the negative bronchoalveolar lavage in terms of an infection, corticosteroid therapy was given at a dose of 1 mg/kg body weight. Within 4 weeks, the patient became afebrile and was discharged from hospital. Development of symptoms with respect to drug administration, unexplained fever, negative workup for an infection, and marked response to corticosteroid therapy were found in our case. An explanation could be a delayed type of hypersensitivity (type IV) with activation of CD8 T cell which could possibly explain most of the symptoms. We have developed a decision algorithm in order to anticipate timely diagnosis of 5-azacitidine-induced pneumonitis, and with the aim to limit antibiotics abuse and to set up emergency treatment.

Key Points

Interstitial pneumonitis is a classical complication of many drugs.

Pulmonary toxicity due to 5-azacytidine is rarely mentioned.

It is important to anticipate diagnosis of 5-azacitidine-associated interstitial lung disease to limit antibiotics abuse and to set up emergency treatment.

Introduction

Pneumonitis, often called interstitial lung disease or ILD, is a possible manifestation of many antineoplastic and other drugs, with several ILD subtypes being described in association with drugs. Pulmonary toxicity from 5-azacytidine, a deoxyribonucleic acid (DNA) methyltransferase inhibitor which also exerts cytotoxic effects, has rarely been reported, although the drug has been used since 1982. 5-Azacytidine acts as a hypomethylating agent of the Y globin suppressor gene to induce fetal hemoglobin in thalassemia and, since 2000, to treat high-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) with low blast counts. Here, we report a case of 5-azacytidine-asociated pneumonitis, review the literature, and develop a diagnostic algorithm for this rare condition to avoid delay in medical care and misuse of antibiotics.

Case Report

A 67-year-old woman presented as an outpatient of our Hematology Department in August 2015 for progressive neutropenia, anemia, and fatigue. Peripheral blood examination showed a normochromic normocytic anemia with 9.4 g/dL hemoglobin, 0.350 × 109/L neutrophils and 138 × 109/L platelets. A bone marrow aspirate (BMA) showed hypercellular marrow with trilineage dysplastic features, micromegakaryocytes and 13% myeloblasts. A diagnosis of refractory cytopenia with multilineage dysplasia was given, based on the WHO MDS classification [1]. A trephine biopsy was in accordance with the results from the bone marrow aspirate with 15% myeloblasts displaying dyserythropoiesis and dysmegakaryopoiesis. Karyotype G banding analysis revealed a complex cytogenetic abnormality: 46,XX,del(5)(q14q34) [2]/49,sl,+1,+9,+11 [2]/52,sd1,+11,+22,+22 [16].

Based on the above data, high-risk MDS was considered. The patient underwent appropriate tests concerning eligibility for allogenic stem cell transplantation. She received the first cycle of 5-azacytidine at the conventional dosage of 75 mg/m2 for 7 days from September 28, 2015. One week after starting 5-azacytidine, she developed moderate fever along with dry cough and, subsequently, her temperature rose to 39.5 °C. She was hospitalized on October 11, 2015. Vital signs and pulse oximetry were normal. She was placed under broad-spectrum antibiotics based on the protocol for febrile neutropenia, including ciprofloxacin 750 mg twice daily, ceftazidime 1 g three times daily (tid), and sulfamethoxazole/trimethoprim 400 mg/80 mg tid. Fever did not abate. All routine bacteriological investigations were negative. Procalcitonin levels were within the normal range. The chest and sinus radiographs were normal, as were precipitins against Aspergillus and titers against Cytomegalovirus (CMV) and Epstein-Barr virus (EBV). CMV antigenemia was negative. An interferon-γ release assay was negative. Marrow re-aspiration revealed a 22% increment of blast number, suggesting a transformation towards acute myeloid leukemia. During her second week in hospital, the patient complained of dyspnea on October 22, 2015. Blood gas showed a PaO2 of 59 mmHg and PaCO2 of 29 mmHg. Pulse oxygen saturation was 91% (room air). High-resolution computed tomography (HRCT) of the chest disclosed diffuse bilateral opacities with ground-glass shadowing and pleural effusion bilaterally (Fig. 1). Mediastinal and hilar lymph nodes were moderately enlarged. The patient was transferred to the intensive care unit on October 23 for bronchoalveolar lavage (BAL), which showed 170 red blood cells/mm3 and 10 white blood cells/mm3. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis, Pneumocystis jiroveci, and CMV were negative. Immunofluorescence test for Pneumocystis was also negative. Cultures including viral and fungal were all negative. The patient was maintained on antibiotics. A diagnosis of drug-induced pneumonitis was considered and, given the negative BAL in terms of an infection, corticosteroid therapy was given at a dose of 1 mg/kg body weight on October 28. Within 4 days, a significant improvement in clinical status and imaging was noted. A repeat chest computed tomography (CT) scan at 1 week also showed significant improvement. Temperature was normal and C-reactive protein returned to normal within 1 week. Following 2 days of quick steroid tapering, the patient again developed fever. Left upper chest pain corresponding to lobulated pleural effusion was noted and 1200 mL of serosanguinous fluid was removed via chest tube. Pleural fluid was a predominantly neutrophilic exudate containing 4 g/dL proteins. Corticosteroids were maintained and antibiotics were discontinued. The patient remained afebrile and was discharged from hospital on November 9. She eventually received a haploidentical bone marrow transplant on December 23, 2015.
Fig. 1

High-resolution computed tomography of the chest disclosed diffuse bilateral interstitial opacities with ground-glass shadowing, and pleural effusion bilaterally

Discussion

Clinical features of 5-azacytidine-associated ILD include cough, dyspnea, pleuritic chest pain, and hypoxemic respiratory failure [2]. Like many antineoplastic agent-induced lung diseases, prominent imaging findings include diffuse multifocal ground-glass shadowing, interstitial thickening, and pleural effusion.

Here we review 12 earlier cases of 5-azacytidine-associated pneumonitis (Table 1). Delayed diagnosis following failure of broad-spectrum antibiotic therapy was common [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Corticosteroids were used depending on severity.
Table 1

Clinical characteristics, examination, and treatment of myelodysplastic syndrome and acute myeloid leukemia patients with 5-azacitidine-induced interstitial lung disease

Study

Disease

Sex

Age

Clinical symptoms

Time of onset of symptoms

Examination

Treatment

Evolution

Rechallenge

Adams et al. 2005; USA [3]

MDS

M

71

Bilateral crackles and wheezing

<7 days

Chest radiograph: patchy bilateral, perihilar airspace disease, organizing pneumonitis

Bronchoscopy: scattered petechiae, thin watery secretions, with no lesions or evidence of hemorrhage

Cultures negative

Biopsy: acute and chronic interstitial and alveolar fibrosis with chronic inflammation, marked atypia of pneumocytes, no pathogens

1. Cefotaxime, azithromycin, metronidazole

Died

No

Hueser and Patel 2007; USA [4]

MDS

F

55

Hyperthermia, hypoxic respiratory failure, acute respiratory distress syndrome

5 days

Chest tomography: bilateral interstitial opacities

1. Antipyretic

2. Empiric broad-spectrum antibiotics, antifungal drugs and methylprednisolone 100 mg every 12 hours

Recovered

No

Pillai et al. 2012; UK [5]

MDS

F

74

Fever, dry cough, breathlessness

2 weeks

Tomography scan: peribronchiolar shadowing

Cultures negative

1. Antimicrobial therapy

Recovered spontaneously

Yes

Fever, dry cough, dyspnea

5 days after 2nd cycle

Chest X-ray: bilateral patchy shadowing

CT scan: reticulo-nodular and ground-glass shadowing, pleural effusions

1. IV antibiotics

2. Methylprednisolone 1.5 g/day

Recovered

No

Kotsianidis et al. 2012; Greece [6]

MDS

M

55

Fever, respiratory failure, hypoxemia, hypercapnia

27 days

NA

1. Broad-spectrum antibiotics

2. Prednisolone 0.5 mg/kg/day + oxygen

Recovered and died of sepsis after 5 months

No

Sekhri et al. 2012; USA [7]

MDS

M

56

Dry cough, dyspnea

7 days

Cultures negative

 

Recovered

Yes

Fever, cough, dyspnea, hypoxia

2 days after 2nd cycle

Cultures negative

Tomography scan: extensive bilateral airspace disease with nodular opacities

Biopsy: interstitial lung disease and bronchocentric granulomatous pattern

BAL negative

1. Broad-spectrum antibiotics

2. IV methylprednisolone

Recovered

No

Nair et al. 2012; USA [8]

MDS

M

76

Dyspnea, non-productive cough, fever

3 weeks

Chest X-ray: bilateral interstitial infiltrates

CT scan: diffuse bilateral patchy infiltrates

Biopsy: organizing pneumonia with intra-alveolar plugs and fibroblastic tissue, predominant eosinophilic infiltration

Cultures negative

1. Ceftriaxone + azithromycin IV

2. IV methylprednisolone 1 mg/kg twice daily

Recovered

NA

Hayashi et al. 2012; Japan [9]

MDS

M

74

Fever, dry cough, worsening shortness of breath

2 days

Chest X-ray: infiltration in the right middle lung field

Cultures negative

Chest tomography: organizing pneumonia

1. Cefepime

2. Piperacillin/tazobactam

3. Meropenem + vancomycin

4. Methylprednisolone 1000 mg/day

Recovered

No

Kuroda et al. 2014; Japan [10]

MDS

M

72

Moderate pyrexia, dyspnea, dry cough, bloody sputum and wheezing, hypoxic respiratory failure

3 days

Chest X-ray: patchy airspace disease

Tomography scan: areas of interstitial opacity and ground-glass shadowing

No infections in cultures

1. Oxygen

2. Broad-spectrum antibiotics and antifungal agents

3. IV methylprednisolone (500 mg) + sulfamethoxazole trimethoprim, vancomycin, micafungin

Died

No

Verriere et al. 2015; France [11]

AML

F

86

Grade III skin reaction, nausea, gastric pain, dry cough, hyperthermia, ear pain, asthenia, anorexia, hyperthermia

2nd day of the 3rd cycle

CT scan: diffuse interstitial opacities and ground-glass shadowing (mediastinal and hilar lymph nodes)

1. Piperacillin/tazobactam

2. Imipenem/cilastatin

3. Corticotherapy 0.75 mg/kg per day + oxygen therapy

Recovered

No

Patel et al. 2015; USA [12]

MDS

M

74

Fever, cough, shortness of breath

2 days after 2nd cycle

Chest radiograph and tomography: bilateral interstitial infiltrates and ground-glass opacities

Cultures negative

BAL inflammatory

1. Corticosteroids

Recovered

NA

Ahrari et al. 2015; Canada [13]

MDS

M

73

Fever, chills, night sweats

Start of 3rd cycle

Blood culture: Mycobacterium fortuitum

Chest radiograph: bilateral hilar enlargement and bilateral perihilar ground-glass opacities

Chest tomography: bilateral ground-glass opacities with reticulation in the mid- and upper lung zones and patchy peripheral airspace consolidation

BAL negative

1. Levofloxacin

2. Clarithromycin + ciprofloxacin + sulfamethoxazole trimethoprim

3. High-dose prednisone

Died

No

Alnimer et al. 2016; USA [14]

MDS

M

67

Worsening shortness of breath, mild productive cough

2 weeks after 2nd cycle

CT scan: massive multifocal bilateral pulmonary consolidations, surrounding ground-glass opacities, pleural effusion

Cultures negative

Lung biopsy: chronic nonspecific inflammation with macrophages

4. Levofloxacin + piperacillin/tazoactam

5. Caspofungin + teicoplanin + oseltamivir + meropenem + levofloxacin

6. Methylprednisolone 60 mg twice daily

Recovered

No

AML acute myeloid leukemia, BAL bronchoalveolar lavage, CT computed tomography, DILD drug-induced lung injury, F female, IV intravenous, M male, MDS myelodysplastic syndrome, NA not available

The diagnosis of drug-induced pneumonitis rests on history of drug exposure, clinical imaging, bronchoalveolar lavage, exclusion of other lung conditions, improvement following drug discontinuation, and recurrence of symptoms upon rechallenge with the drug. In the present case, we were reluctant to readminister the drug as the risk of doing so is poorly known. The Naranjo probability score in this case was 6, consistent with probable adverse reaction [15, 16]. In our case, despite steroid use, symptoms relapsed and were characterized as serosanguinous pleural effusion. Serosanguinous pleural exudates with polymorphonuclear leukocyte predominance without bacteriological evidence of infection may be a manifestation of pleurisy such as in lupus erythematosus, which might be induced by the drug in question [17].

Mechanisms for drug-induced ILD are direct cytotoxicity, hypersensitivity, oxidative stress, release of cytokines and thus pyrogens, and lastly impaired repair by type II pneumocytes. Chronology of events, unexplained fever, and steroid response to clinical and radiological signs constitute a hypersensitivity pneumonitis.

5-Azacytidine is a cytosine analog, a potent inhibitor of DNA methyltransferase, with a hypomethylating effect in vivo and in vitro. Unlike gemcitabine, although cytotoxic at high dose, at low dose it is capable of inducing differentiation and hypomethylation. Hence, profound myelosuppression or direct lung injury like capillary leak syndrome is not encountered during 5-azacytidine toxicity. The role of oxidative stress is still unclear although there are a few reports concerning induction of necrosis in vitro by 5-azacytidine [18]. Oxidative stress could contribute to T-cell response by inhibiting the ERK pathway signaling in T cells. Recently we observed drug-associated ILD in two patients treated with an experimental inhibitor of DNA methyltransferase, suggesting a common class effect [19, 20].

Unlike oxaliplatin, anaphylactic reaction is extremely rare in 5-azacytidine. Few patients develop symptoms during the administration of chemotherapy. Although an elevated IgE level was reported in one case by Nair et al., the evidence is not sufficient to conclude a type I reaction [8]. Most patients develop symptoms within a week to a month after administration of 5-azacytidine. Although the histopathological evidence is rarely possible in immunocompromised patients with hematological malignancy, Sekhri et al. presented a bronchocentric granuloma in their report [7]. Hence, another plausible explanation could be a delayed type of hypersensitivity (type IV) with activation of CD8 T cell, which could explain most of the symptoms. This could possibly occur during a relative immune reconstitution phase of an immunocompromised patient.

The pulmonary fibrosis may be due to DNA hypomethylation causing direct upregulation of type I collagen synthesis. Sanders et al. suggested that the DNA methylation is important in idiopathic pulmonary fibrosis (IPF), as an altered DNA methylation profile has been demonstrated in their experiment [21]. Moreover, there are reports suggesting the epigenetic priming by 5-azacytidine confers transdifferentiating properties to various cells. However, it is difficult to establish a relationship at present [22].

Our diagnostic algorithm is based on that of drug-induced interstitial lung disease (DILD), and is not specific for 5-azacytidine (Fig. 2). Any febrile condition in those patients with worsening pulmonary symptoms despite broad-spectrum antibiotics should arouse suspicion of DILD. HRCT and BAL are crucial as 5-azacytidine-induced pneumonitis remains a diagnosis of exclusion, like many other DILDs. Some nonspecific immunological tests could be helpful, like levels of p-ANCA (antineutrophil cytoplasmic antibody) and ANA (antinuclear antibody). Prompt consultation with a pulmonary care unit is of utmost utility.
Fig. 2

Decision algorithm for 5-azacitidine-induced ILD

Conclusions

A high degree of vigilance is advised to entertain the diagnosis in a timely manner, since the condition can be fatal. We now utilize a decision algorithm in order for timely diagnosis of 5-azacitidine-induced ILD to limit antibiotics abuse and to set up emergency treatment.

Notes

Compliance with Ethical Standards

Conflict of interest

S.C. Misra, L. Gabriel, E. Nacoulma, G. Dine, and V. Guarino declare that they have no conflict of interest.

Funding

No financial support was received for the preparation of this manuscript.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent may be requested for review from the corresponding author.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Srimanta Chandra Misra
    • 1
  • Laurence Gabriel
    • 2
  • Eric Nacoulma
    • 1
  • Gérard Dine
    • 1
  • Valentina Guarino
    • 2
  1. 1.Department of Hematology Biology ClinicHôpital des Hauts ClosTroyesFrance
  2. 2.Central PharmacyHôpital des Hauts ClosTroyesFrance

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