An eleven-year-old boy presented with one month\u27s history of fever and weight loss. He was diagnosed with Acute Mycloid Leukemia (AML-M2). During treatment he developed recurrent infections with neutropenia requiring prolonged antibiotics and subsequently developed invasive aspergillosis. He was treated with amphotericin B and Voriconazole. This case shows the efficacy and safety of combined antifungal therapy, including voriconazole, for invasive aspergillosis complicating AML

Azim, Sidra

Fadoo, Zehra

Manzoor, Nauman Fazal

eCommons@AKU

eCommons@AKUDepartment of Paediatrics and Child Health Division of Woman and Child HealthNovember 2010Successful management of invasive aspergillosiswith voriconazole and amphoteracin B therapy in apatient with acute mycloid leukemia (AML-M2)Nauman Fazal ManzoorAga Khan UniversitySidra AzimAga Khan UniversityZehra FadooAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatrPart of the Pediatrics CommonsRecommended CitationManzoor, N., Azim, S., Fadoo, Z. (2010). Successful management of invasive aspergillosis with voriconazole and amphoteracin Btherapy in a patient with acute mycloid leukemia (AML-M2). Journal of the Pakistan Medical Association, 60(11), 977-9.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatr/25977 J Pak Med AssocStudents’ CornerCase ReportSuccessful management of invasive aspergillosis with voriconazole andamphoteracin B therapy in a patient with Acute Mycloid Leukemia (AML-M2)Nauman Fazal Manzoor,1 Sidra Azim,2 Zehra Fadoo3Medical Student,1,2 Department of Paediatrics,3 Aga Khan University Hospital, Karachi.AbstractAn eleven year old boy presented with one month’shistory of fever and weight loss. He was diagnosed withAcute Mycloid Leukemia (AML-M2). During treatment hedeveloped recurrent infections with neutropenia requiringprolonged antibiotics and subsequently developed invasiveaspergillosis. He was treated with amphotericin B andVoriconazole. This case shows the efficacy and safety ofcombined antifungal therapy, including voriconazole, forinvasive aspergillosis complicating AML.IntroductionHaematological malignancies are associated withmany opportunistic infections of which invasiveaspergillosis (IA) represents an important devastatingfungal infection.1 IA complicates 5-29% of the cases ofAcute Mycloid Leukemia (AML) and the risk is correlatedwith the degree of Immuno-suppression which depends onthe disease itself and the subsequent chemotherapy.1-3 IAremains a diagnostic and therapeutic challenge for anyphysician. Despite advanced diagnostic modalities whichallow earlier diagnosis and aggressive intervention, themortality rate remains unacceptably high that is 50-70%.2,3Previously various Anti-Fungal therapeutic agents havebeen used to treat IA in patients with haematologicalmalignancies including Intravenous amphotericin Bdeoxycholate (D AmB), Liposomal Amphotericin B (LAmB), Itraconazole, but the outlook for the patientsremained dismal.3 Voriconazole is a triazole derivativewhich has been used frequently due to its potency, broadspectrum activity, clinical efficacy, safety and tolerance.4,5In the past decades D AmB was the standard therapy, but itwas associated with a poor outcome. Numerous case seriesand randomized control trials have shown that Voriconazoleis superior to amphotericin B in the treatment of IA and isnow considered the First line therapy in many treatmentcenters.6 Here we present a case of AML-M2 complicatedwith invasive aspergillosis being treated with Voriconazole.Case ReportAn eleven year old boy, known case of Atrial SeptalDefect (ASD) with Tricuspid regurgitation, diagnosed atbirth presented to us with one month history of fever andprogressive weight loss. Physical examination revealedhepatomegaly, supraclavicular lymph nodes and pansystolicmurmur. Complete blood count (CBC) showed low countswith peripheral blasts. Subsequent bone marrowexamination and immunophenotyping confirmed thediagnosis of Acute Myeloid Leukaemia (AML-M2).Cerebrospinal Fluid (CSF) was clear. He was started on chemotherapy based on theMedical Research Council (MRC-10) protocol (Details inTable). On fifth day of induction he developed febrileneutropenia for which cultures were sent and he was startedon broad spectrum antibiotics. He was also evaluated byTable: Details of Chemotherapy.( Medical Research Council).Induction Ara-C(Cytarabine) 100mg/m2 IV  Day 1-8 Q12Hrly(Course 1& 2) IV Day1, 3 & 5ADE Daunorubicicn 50 mg/m2 IV   Day1-5VP 16(Etoposide) 100mg/m2 Day 1 onlyTriple IT (HC,Ara-C,MTXCourse 3 Idarubicin 10mg/m2 IV Day 1-2Cytarabine 200mg/m2 IV Day 1-5VP 16(Etoposide) 100mg/m2 IV Day1-5Triple IT* (HC,Ara-C,MTX) Day 1 onlyConsolidation Ara-C(Cytarabine) 3gm/m2 IV Day1,2,8 and 9Course 4 Asparginase 6000mg/m2 IM IV  Day 2& 9Clasp* Triple IT (HC,Ara-C,MTX): (Triple Intrathecal): Methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C)Vol. 60, No. 11, November 2010 978cardiologist and was prescribed furosemide and enalapril.After achieving bone marrow remission he received2nd Induction. During this admission he developed fever on3rd day and blood cultures grew salmonella paratyphi forwhich he received IV meropenem, amikacin withamphotericin as empiric for fever/neutropenia.Echocardiogram done at this time revealed vegetations onright coronary sinus. A repeat blood culture grewEnterobacter species sensitive to meropenem. Once hiscounts recovered he was discharged on IV meropenem for atotal of 3 weeks.Course three was tolerated well with no need ofprolonged admission. After 4th cycle he developed febrileneutropenia with redness and pain at portacath site andblood culture grew staphylococus aureus, thus portacathwas removed. He was treated with meropenem,vancomycin, amikacin and amphotericin but fever did notsubside. Serial Chest X-rays (CXR) revealed bilateralpneumonia with pneumatocele formation. Follow up CTscan (Figure-1) demonstrated multiple bilateral cavities inlungs filled with soft-tissue material. Ill-defined lowattenuating areas were also noted in segment 4 and 6 of liverand both kidneys. Appearance was suggestive ofAspergillosis.  After consultation with infectious diseaseteam he was continued on amphotericin with addition ofvoriconozole. He was discharged on oral Voriconazole aftercounts stabilized and fever settled.He was admitted again in January with abdominalpain and was diagnosed as a case of acute appendicitis, andunderwent appendicectomy. Repeat CT scan (Figure-2)revealed complete resolution of fungal balls in the lungcavities but not in the renal lesions. He was then advised IVamphotericin 1mg/kg every other day together with oralVoriconazole and discharged.He completed his full course of ampotericin B (3months) and Voriconazole for 6 months in June 2007.Repeat CT showed resolution of chest and abdominallesions on scan. He has been off therapy and doing well formore than a year after completion of therapy for AML-M2with multiple life threatening events like infectiveendocarditis, Staph aureus sepsis and invasive aspergillosis.DiscussionInvasive aspergillosis (IA) is a frequentlyencountered infection in AML patients undergoinginduction chemotherapy. IA in children is associated withmortality ranging from 68% to 77% as compared to otherInvasive Fungal Infections.7 Studies directed at Paediatriconcology patients show a protean 15-34% survival rate.1,8Exclusion of Haematopoietic Stem Cell Transplantation(HSCT) recipients improves the survivorship to 82% due toprolonged immunosuppression associated with HSCT. Bothacute infection and relapse are particularly associated withsevere neutropenia, use of broad-spectrum antibiotics orhigh-dose corticosteroids. Due to the fact that causativefactor may remain viable in the initial lesions, IA patientshave a higher risk of reactivation of the infection withfurther chemotherapy. Patients with acute leukaemia and ahistory of previously treated IA on additional chemotherapyare at a risk of approximately 50% for recurrent invasiveaspergillosis. Due to the higher benefit risk ratio it isuniversally accepted that IA is not an absolutecontraindication for further chemotherapy.9Invasive aspergillosis remains a diagnostic challengeespecially in paediatric population due to non-specificclinical signs. The physician should have a high degree ofclinical suspicion when dealing with febrile patients onFigure 1 and 2: Pre and Post Treatment Ct scan show cavity of Right side filledwith soft-tissue like material, suggestive of Aspergillosis. Resolution of the diseasewith combination Anti-fungal therapy.12979 J Pak Med Assocchemotherapy.10 However, diagnosis often remains difficultas most of the diagnostic tools in clinical use at presenteither lack specificity or acceptable sensitivity in the earlyphase of the infection. Radiological imaging remains thecorner stone with the "halo" sign and "crescent sign" on CTscan being regarded as diagnostic for invasive pulmonaryaspergillosis (IPA). In febrile neutropenic patientssystematic CT scans allow earlier diagnosis of IPA.11Definitive diagnosis however depends on tissue biopsy,which is precluded by the degree of cytopenia andcoagulation abnormalities in such patients. Antifungal therapy remains the mainstay oftreatment for invasive aspergillosis.12 But the combinationof antifungal treatment and surgical resection has shown todramatically improve the prognosis of IA. Aggressivesurgical resection has been associated with improvedoutcome by eliminating macroscopic foci of IA that couldcomplicate subsequent immunosuppressive chemotherapybut because IA is a multifocal disease at microscopic level,there is no guarantee of complete cure with surgery. The riskof leukaemia relapse or presence of multiple and bilaterallesions makes the surgery impossible. Thus secondaryantifungal prophylaxis is the main option in these patients.13Treatment of IA in the last decade resolved arounddifferent formulations of Amphotericin B. But prolongeduse of amphoB therapy is limited by nephrotoxicity.LipoAMB permits extended therapy due to reduced renaltoxicity.14 Itraconazole may be effective in the treatment ofmicroscopic IA and may prevent recurrence of clinicalinfection. Despite the introduction of lipid formulations ofAmB, about 50% of patients with aspergillosis will failprimary therapy.3In our case, Voriconazole was used together withAmphotericin as combination therapy in a patient withAML and Invasive Aspergillosis not responsive to ampho Btherapy alone. Voriconazole was well tolerated in the patientwith no visual hallucinations or hepatotoxicity. This casehighlights that patients with AML complicated withInvasive Aspergillosis (IA) may complete theirchemotherapy treatment and remain in remission withinitial aggressive intravenous therapy following ambulatorytreatment with oral voriconazole.Reference1. Abbasi S, Shenep JL, Hughes WT, Flynn PM. Aspergillosis in children withcancer: A 34-year experience. Clin Infect Dis 1999; 29: 1210-9.2. Denning DW. Therapeutic outcome in invasive aspergillosis. Clin Infect Dis1996; 23: 608-15.3. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26: 781-803.4. Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, et al.Efficacy and safety of voriconazole in the treatment of acute invasiveaspergillosis. Clin Infect Dis 2002; 34: 563-71.5. Walsh TJ, Lutsar I, Driscoll T, Dupont B, Roden M, Ghahramani P, et al.Voriconazole in the treatment of aspergillosis, scedosporiosis and otherinvasive fungal infections in children. Pediatr Infect Dis J 2002; 21: 240-8.6. Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, OestmannJW, et al. Voriconazole versus amphotericin B for primary therapy of invasiveaspergillosis. N Engl J Med 2002; 347: 408-15.7. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematicreview of the literature. Clin Infect Dis 2001; 32: 358-66.8. Wright JA, Bradfield SM, Park JR, Hawkins DS. Prolonged survival afterinvasive aspergillosis: a single-institution review of 11 cases. J PediatrHematol Oncol 2003; 25: 286-91.9. Martino R, Lopez R, Sureda A, Brunet S, Domingo-Albós A. Risk ofreactivation of a recent invasive fungal infection in patients withhematological malignancies undergoing further intensive chemo-radiotherapy. A single-center experience and review of the literature.Haematologica 1997; 82: 297-304..10. Reichenberger F, Habicht JM, Gratwohl A, Tamm M. Diagnosis and treatmentof invasive pulmonary aspergillosis in neutropenic patients. Eur Respir J2002; 19: 743-55.11. Caillot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, etal. Improved management of invasive pulmonary aspergillosis in neutropenicpatients using early thoracic computed tomographic scan and surgery. J ClinOncol 1997; 15: 139-47.12. Blyth CC, Palasanthiran P, O'Brien TA. Antifungal therapy in children withinvasive fungal infections: a systematic review. Pediatrics 2007; 119: 772-84.13. Nosari A, Oreste P, Cairoli R, Montillo M, Carrafiello G, Astolfi A, et al.Invasive aspergillosis in haematological malignancies: clinical findings andmanagement for intensive chemotherapy completion. Am J Hematol 2001; 68:231-6.14. Lanternier F, Lortholary O. Liposomal amphotericin B: what is its role in2008? Clin Microbiol Infect 2008; 14 (Suppl 4): 71-83.

Successful management of invasive aspergillosis with voriconazole and amphoteracin B therapy in a patient with acute mycloid leukemia (AML-M2)

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Successful management of invasive aspergillosis with voriconazole and amphoteracin B therapy in a patient with acute mycloid leukemia (AML-M2)

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