
 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 . 

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 .
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    10/l neutrophils and 138    10/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 .
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 ) /49,sl,+1,+9,+11 /52,sd1,+11,+22,+22 .
she received the first cycle of 5-azacytidine at the conventional dosage of 75  mg / m 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 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 .
the chest and sinus radiographs were normal , as were precipitins against aspergillus and titers against cytomegalovirus ( cmv ) and epstein - barr virus ( ebv ) .
marrow re - aspiration revealed a 22% increment of blast number , suggesting a transformation towards acute myeloid leukemia . during her second week in hospital ,
blood gas showed a pao2 of 59  mmhg and paco2 of 29  mmhg .
high - resolution computed tomography ( hrct ) of the chest disclosed diffuse bilateral opacities with ground - glass shadowing and pleural effusion bilaterally ( fig .  1 ) .
the patient was transferred to the intensive care unit on october 23 for bronchoalveolar lavage ( bal ) , which showed 170 red blood cells / mm and 10 white blood cells / mm .
polymerase chain reaction ( pcr ) for mycobacterium tuberculosis , pneumocystis jiroveci , and cmv were negative .
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 .
left upper chest pain corresponding to lobulated pleural effusion was noted and 1200  ml of serosanguinous fluid was removed via chest tube .
1high - resolution computed tomography of the chest disclosed diffuse bilateral interstitial opacities with ground - glass shadowing , and pleural effusion bilaterally 
  high - resolution computed tomography of the chest disclosed diffuse bilateral interstitial opacities with ground - glass shadowing , and pleural effusion bilaterally
clinical features of 5-azacytidine - associated ild include cough , dyspnea , pleuritic chest pain , and hypoxemic respiratory failure . 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 [ 314 ] .
corticosteroids were used depending on severity.table  1clinical characteristics , examination , and treatment of myelodysplastic syndrome and acute myeloid leukemia patients with 5-azacitidine - induced interstitial lung diseasestudydiseasesexageclinical symptomstime of onset of symptomsexaminationtreatmentevolutionrechallengeadams et al .
2005 ; usa mdsm71bilateral crackles and wheezing<7 dayschest radiograph : patchy bilateral , perihilar airspace disease , organizing pneumonitisbronchoscopy : scattered petechiae , thin watery secretions , with no lesions or evidence of hemorrhagecultures negativebiopsy : acute and chronic interstitial and alveolar fibrosis with chronic inflammation , marked atypia of pneumocytes , no pathogens1 .
cefotaxime , azithromycin , metronidazolediednohueser and patel 2007 ; usa mdsf55hyperthermia , hypoxic respiratory failure , acute respiratory distress syndrome5 dayschest tomography : bilateral interstitial opacities1 .
empiric broad - spectrum antibiotics , antifungal drugs and methylprednisolone 100  mg every 12 hoursrecoverednopillai et al .
2012 ; uk mdsf74fever , dry cough , breathlessness2 weekstomography scan : peribronchiolar shadowingcultures negative1 .
antimicrobial therapyrecovered spontaneouslyyesfever , dry cough , dyspnea5 days after 2nd cyclechest x - ray : bilateral patchy shadowingct scan : reticulo - nodular and ground - glass shadowing , pleural effusions1 .
mg / kg / day + oxygenrecovered and died of sepsis after 5 monthsnosekhri et al .
negativerecoveredyesfever , cough , dyspnea , hypoxia2 days after 2nd cyclecultures negativetomography scan : extensive bilateral airspace disease with nodular opacitiesbiopsy : interstitial lung disease and bronchocentric granulomatous patternbal negative1 .
2012 ; usa mdsm76dyspnea , non - productive cough , fever3 weekschest x - ray : bilateral interstitial infiltratesct scan : diffuse bilateral patchy infiltratesbiopsy : organizing pneumonia with intra - alveolar plugs and fibroblastic tissue , predominant eosinophilic infiltrationcultures negative1 .
2012 ; japan mdsm74fever , dry cough , worsening shortness of breath2 dayschest x - ray : infiltration in the right middle lung fieldcultures negativechest tomography : organizing pneumonia1 .
2014 ; japan mdsm72moderate pyrexia , dyspnea , dry cough , bloody sputum and wheezing , hypoxic respiratory failure3 dayschest x - ray : patchy airspace diseasetomography scan : areas of interstitial opacity and ground - glass shadowingno infections in cultures1 . oxygen2 .
micafungindiednoverriere et al . 2015 ; france amlf86grade iii skin reaction , nausea , gastric pain , dry cough , hyperthermia , ear pain , asthenia , anorexia , hyperthermia2nd day of the 3rd cyclect scan : diffuse interstitial opacities and ground - glass shadowing ( mediastinal and hilar lymph nodes)1 .
corticotherapy 0.75  mg / kg per day  +  oxygen therapyrecoverednopatel et al .
2015 ; usa mdsm74fever , cough , shortness of breath2 days after 2nd cyclechest radiograph and tomography : bilateral interstitial infiltrates and ground - glass opacitiescultures negativebal inflammatory1 .
2015 ; canada mdsm73fever , chills , night sweatsstart of 3rd cycleblood culture : mycobacterium fortuitum 
 chest radiograph : bilateral hilar enlargement and bilateral perihilar ground - glass opacitieschest tomography : bilateral ground - glass opacities with reticulation in the mid- and upper lung zones and patchy peripheral airspace consolidationbal negative1 .
2016 ; usa mdsm67worsening shortness of breath , mild productive cough2 weeks after 2nd cyclect scan : massive multifocal bilateral pulmonary consolidations , surrounding ground - glass opacities , pleural effusioncultures negativelung biopsy : chronic nonspecific inflammation with macrophages4 . levofloxacin + piperacillin / tazoactam5 .
methylprednisolone 60  mg twice dailyrecoveredno 
 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 
  clinical characteristics , examination , and treatment of myelodysplastic syndrome and acute myeloid leukemia patients with 5-azacitidine - induced interstitial lung disease 
 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 .
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 .
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 ] .
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 .
although the histopathological evidence is rarely possible in immunocompromised patients with hematological malignancy , sekhri et al .
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 .
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
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 . 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 ) .
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 .
misra , l. gabriel , e. nacoulma , g. dine , and v. guarino declare that they have no conflict of interest .
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 .
 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 . 