Objective: To determine the clinicohaematological features, treatment and outcome of children diagnosed with aplastic anemia at a single institution.
Study Design: Observational study.
Place and Duration of Study: The Aga Khan University Hospital, Karachi, from January 1999 till December 2008.
Methodology: Medical records of children aged less than 15 years of age diagnosed with aplastic anemia were reviewed. Clinicohaematological features, treatment and its response to therapy and outcome were recorded. Results were described in percentages.
Results: Ninety patients were diagnosed to have aplastic anemia (AA); 65 were male during the study period. Age ranged from 1 to 15 years. Fever in 65 patients (72.2%), pallor in 53 (58.8%), skin bleeding in 49 (54.4%) and epistaxis in 31(34.4%) were the most common and frequent presenting features. Congenital (Fanconi’s) anemia was found in 15 (16.6%) and acquired idiopathic in 75 (83.4%) of patients. Very severe aplastic anemia (VSAA) was seen in 29 (32.2%), 26 (28.9%) had severe AA and 17 (18.9%) had moderate AA. Eight patients (8.9%) underwent haematopoietic stem cell transplantation (HSCT), 12 (13.3%) received immunosuppressive therapy (IST) and 70 patients (77.7%) received other and supportive therapy. Five (62.5%) patients showed complete response to HSCT and 3 (37.5%) failed to engraft. IST showed complete response in 3 (25%), partial response in 5 (41.6%) and no response in 4 (33.3%). Twenty two patients (24.4%) expired either due to infection in 16 (72.7%, fungal in 6, bacterial in 10) and intracranial haemorrhage in 6 (27.3%) cases.
Conclusion: Majority of cases with AA were acquired and idiopathic in etiology. VSAA and SAA were frequent. Response to HSCT and IST was sub-optimal

Adil, Salman

Fidoo, Zehra

Naqvi, Muhammad Ahmed

Wali, Rabia

eCommons@AKU

eCommons@AKUDepartment of Pathology and Laboratory Medicine Medical College, PakistanJanuary 2011Aplastic Anemia: Clinicohaematological Features,Treatment and Outcome AnalysisRabia WaliAga Khan UniversityZehra FidooAga Khan UniversitySalman AdilAga Khan UniversityMuhammad Ahmed NaqviAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiolPart of the Maternal and Child Health Commons, Oncology Commons, Pathology Commons,and the Pediatrics CommonsRecommended CitationWali, R., Fidoo, Z., Adil, S., Naqvi, M. A. (2011). Aplastic Anemia: Clinicohaematological Features, Treatment and Outcome Analysis.Journal of the College of Physicians and Surgeons Pakistan, 21(4), 219-222.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/2Journal of the College of Physicians and Surgeons Pakistan  2011, Vol. 21 (4): 219-222 219INTRODUCTIONAplastic anemia (AA) is a term describing pancytopeniawith hypo-plastic marrow. AA is linked to exposure tobenzene, pesticides and other chemicals. Marrow failureis a severe idiosyncratic complication due to the use ofcertain medical drugs. It can follow specific viralinfections, as in postseronegative hepatitis.1The incidence of this disease has been found to be lowin prospective studies from the United Kingdom, France,Brazil, and in the International Agranulocytosis andAplastic Anemia Study (IAAAS) conducted in severalEuropean countries as well as in Israel.2In addition, the incidence of aplastic anemia showsgeographical variability. It seems to be lower in Europe,North America and Brazil, and higher in Asia. Based onthe two epidemiological studies carried out in Europeand Asia that used the same methodology, the incidenceof the disease is two to three fold higher in Asia than inthe West. This variability in incidence rates may reflectdifferences in exposure to environmental factorsincluding viruses, drugs and chemicals, geneticbackground, diagnostic criteria, and study designs.3Severe aplastic anemia (SAA) can occur at any age. Inchildren it is either acquired, idiopathic or is aconsequence of a range of genetic disorders.4 Outcomeof patients with SAA has considerably improved over thelast couple of decades with the better supportive careand advances in treatment modalities. The preferredtreatment for children with AA is haematopoietic stemcell transplantation (HSCT) from a human leukocyteantigen (HLA) - identical sibling. This results inapproximately 90% cure rates.4 The alternativetreatment for patients without a HLA identical donor isan immunosuppressive therapy (IST). This has shown75% cure rates.5 A lot of  Western data is available onaplastic anemia, but very few studies are found from theIndian sub-continent. The aim of this study was to present the data regardingthe clinicohaematological features, the importanttreatment modalities being given and their outcomes.ABSTRACTObjective: To determine the clinicohaematological features, treatment and outcome of children diagnosed with aplasticanemia at a single institution.Study Design: Observational study.Place and Duration of Study: The Aga Khan University Hospital, Karachi, from January 1999 till December 2008.Methodology: Medical records of children aged less than 15 years of age diagnosed with aplastic anemia were reviewed.Clinicohaematological features, treatment and its response to therapy and outcome were recorded. Results weredescribed in percentages.Results: Ninety patients were diagnosed to have aplastic anemia (AA); 65 were male during the study period. Age rangedfrom 1 to 15 years. Fever in 65 patients (72.2%), pallor in 53 (58.8%), skin bleeding in 49 (54.4%) and epistaxis in31(34.4%) were the most common and frequent presenting features. Congenital (Fanconi’s) anemia was found in 15(16.6%) and acquired idiopathic in 75 (83.4%) of patients. Very severe aplastic anemia (VSAA) was seen in 29 (32.2%),26 (28.9%) had severe AA and 17 (18.9%) had moderate AA. Eight patients (8.9%) underwent haematopoietic stem celltransplantation (HSCT), 12 (13.3%) received immunosuppressive therapy (IST) and 70 patients (77.7%) received otherand supportive therapy. Five (62.5%) patients showed complete response to HSCT and 3 (37.5%) failed to engraft. ISTshowed complete response in 3 (25%), partial response in 5 (41.6%) and no response in 4 (33.3%). Twenty two patients(24.4%) expired either due to infection in 16 (72.7%, fungal in 6, bacterial in 10) and intracranial haemorrhage in 6 (27.3%)cases. Conclusion: Majority of cases with AA were acquired and idiopathic in etiology. VSAA and SAA were frequent. Responseto HSCT and IST was sub-optimal.Key words: Aplastic anemia.   Treatment.   Outcome.   Idiopathic.  Haematopoietic stem cell transplantation.   Immunosuppressive therapy.Department of Paediatrics and Child Health1/Pathology2,The Aga Khan University Hospital, Karachi.Correspondence: Dr. Rabia Wali, 339-X, Phase III, DHA,Lahore.E-mail: rabia_wali@yahoo.comReceived  June 15, 2010;  accepted  February 26, 2011.Aplastic Anemia: Clinicohaematological Features, Treatment and Outcome Analysis Rabia Wali1, Zehra Fadoo1, Salman Adil2 and Muhammad Ahmed Naqvi1CLINICAL PRACTICE ARTICLEMETHODOLOGYThe charts of children less than 15 years of age from theyear 1999 till 2008 were studied at the Aga KhanUniversity Hospital, Karachi. The selection of patientswas based on the diagnosis of aplastic anemiaconfirmed by bone marrow trephine biopsy. The datacollected by chart review included age, gender, date ofdiagnosis, prior treatment, clinical features, familyhistory, complete blood count, bone marrow aspirateand trephine biopsy features, chromosomal breakagestudies, hepatitis B and C serology, treatment options,complications, response and outcome.Patients were classified according to proposed criteriafor the disease severity. Aplastic anaemia wasconsidered severe (SAA) if the marrow cellularity was< 25%, with at least 2 of either neutrophil count < 0.5 x109/L or platelet count < 20 x 109/L or reticulocyte count< 20 x 109/L.AA was considered very severe (VSAA) if the abovecriteria for SAA were fulfilled, and the neutrophil countwas < 0.2 x 109/L.Moderate AA was defined as a hypo-cellular bonemarrow with at least two of the following haematologicalvalues: neutrophil count < 1 x 109/L, platelet count< 50 x 109/L or reticulocyte count of < 60 x 109/L.6Patients not meeting the above criteria were labelled tohave mild AA.6Patients were treated with HSCT and immuno-suppressive therapy (IST) which included ATG, steroids,and cyclosporine; those who received only cyclosporineand steroids were excluded from the IST regimen. Somepatients got supportive therapy due to financialconstraints. Fanconi’s anemia patients who could notundergo HSCT were given androgens.Criteria for response after immunosuppressive therapy(IST) were divided into complete, partial and noresponse. Complete response (CR) was defined asachieving normal levels of haemoglobin according toage, platelet count > 100 x 109/L and neutrophil count> 1.5 x 109/L. Partial response (PR) was defined astransfusion independence, platelet count > 30 x 109/L,and neutrophil count > 0.5 x 109/L above baseline. Noresponse meant neutrophil count < 0.5 x 109/L, plateletscount < 20 x 109/L and transfusions dependence (meetSAA criteria).6For HSCT complete response (CR) was increased in thewhite cell and platelet count and no response(engraftment failure) was defined by the return ofperipheral blood cell count to levels meeting thedefinition of severe or moderate AA and the requirementfor blood transfusion.7The mortality and cause of death was noted. Descriptivestatistical analysis was carried out using the SPSSversion 16.0 software. RESULTSOver a period of 9 years, 90 children with AA werediagnosed. Children up to 15 years of age wereincluded. The clinicohaematological features are givenin Table I. More than one clinical manifestation wasobserved in patients.Viral serology was done in 56 patients; 2 were positivefor hepatitis B surface antigen and 4 had antibodiespositive to hepatitis C virus.Congenital Fanconi’s anemia was seen in 15 (16.6%)patients and rests were acquired, idiopathic aplasticanemia in 75 (83.4%) patients.Severity of disease is  given in Table I. Eight patients(8.9%) underwent HSCT and 12 (13.3%) received IST.Patients with mild AA were not given any specifictreatment and were observed with weekly blood countswhich normalized within 2-4 weeks (Table II).Complete response (CR) was seen in 5 and engraftmentfailure in 3 patients with HSCT. Among those whoreceived IST therapy, complete response was seen in3 (25%), partial response in 5 (41.6%) and no responsein 4 (33.3%). Outcome of patients with HSCT and IST isshown in Table III.220 Journal of the College of Physicians and Surgeons Pakistan  2011, Vol. 21 (4): 219-222Rabia Wali, Zehra Fadoo, Salman Adil and Muhammad Ahmed NaqviTable I: Showing the clinicohaematological features in aplastic anemia.Patients’ characteristics Number of patients (n=90)Male / Female 65/25 (72.2%/27.8%)Median age at diagnosis (years) 8Presentation Fever 65 (72.2%)Pallor 53 (58.8%)Skin bleed 49 (54.4%)Epistaxis 31 (34.4%)Causes of aplastic anemia Fanconi's anemia 15 (16.6%)Idiopathic 75 (83.4%)Severity of disease Very severe 29 (32.2)Severe 26 (28.8%)Moderate 17 (18.8%)Mild 18 (20%)Table II: Shows the different treatment and outcome in all patientswith AA.Treatment n=90HSCT 8 (8.8%)IST Cyclosporine / ATG/steroids 12 (13.3%)Cyclosporine / steroids 13 (14.4%)Androgens 9 (10%)Supportive 48 (53.3%)Outcome n=90Expired 22 (24.4%)Off treatment 10 (11.1%)On treatment 3 (3.3%)Referred out 10 (11.1%)Lost to follow-up 45 (50%)Twenty two patients (24.4%) expired; out of whom16 (72.7%) had infection (fungal in 6, bacterial in 10) andintracranial bleed in 6 (27.3%). One patient receivingHSCT and 3 patients receiving IST died due to infection.DISCUSSIONIn this study, children upto the age of 15 years wereincluded. The median age of 8 years is consistent withother studies done from different regions.6,8,9 Malepredominance probably reflects gender bias in thedeveloping world.The major presenting feature was fever in 71.4%, pallorin 58.9%, and skin bleed in 54.4% of cases in the currentstudy which is similar to other studies.8,10The frequency of Fanconi’s anemia in these patientswas 16.6%, higher than reported in Western literaturebut similar to the studies from India.11-13 The increasedincidence of Fanconi’s anemia in this population may bebecause of increased consanguinity seen in our country. Hepatitis associated AA was seen in 21% of cases.6Post-hepatitis AA accounts for about 10% of marrowfailure in Western case series.14 In this study as only 56patients were checked for hepatitis serology, therefore, itwas not possible to determine an overall frequency ofpost-hepatitis AA.The current study showed about approximately twothirds of patients having SAA and VSAA in 61% andmoderate AA in 18.9% of cases which is similar toreported elsewhere.6,9 However, Goswami reportedsevere and moderate AA in 33.33% and 57.14% ofcases respectively.10As the expenses of HSCT and IST are high, differenttreatment options were discussed with the family.According to their financial resources, some opted fortransplantation, IST and others remained on supportivetherapy.CR was seen in 25% and PR in 41.6% in patients whoreceived IST in the present study. This response doesnot match with studies done elsewhere. Pongtanakulet al. found 62% complete response and 19% partialresponse to IST with ATG, CS and steroids for childrenwith AA.6 A Japanese pediatric series demonstrated anoverall response rate of 65% and complete responserate of 40% among 60 patients.15 Indeed results haveimproved dramatically in children with VSAA from 37%in the 1980s to 83% in the 1990s.16HSCT has been shown to have 90% cure rate.17Matched sibling donor HSCT routinely provide long-termsurvival in range of 90%, and 75% of patients respondto IST.18 In the current study 62.5% of patients who gotHSCT showed complete (CR). Shamsi reported 78%long-term survival in AA.19 The differences in treatmentgiven to these patients according to financial resourcesmay also be a factor for the differences in obtainedresults.The overall mortality was (24.4%), out of which infectionwas the predominant cause being found in 72.7% ofpatients (45.5% had bacterial and in 27.3% had fungal).Intracranial bleed was observed in 27.3% of patients. AGerman group reported that 11 (13%) patients diedwithin the 4 months and cause of death was cerebralhaemorrhage in 6 (54.5%) patients and bacterialinfection in 5 (45.5%) patients.20 Infections rate was highin this study and the deaths occurred within a year ofdiagnosis.The limitations of study is that data was collected retro-spectively for a period of time, and that the medicalrecord was the source of information. As a result someinformation was missing from the charts.CONCLUSIONThe study shows that the majority of cases with AA areacquired idiopathic AA and in inherited AA, Fanconi’sanemia is seen more commonly. VSAA and SAA aremost frequently seen. The response to IST is poor in thissetup in comparison to international data. The outcomeof HSCT in this study was 62.5% which is also low ascompared to international data. We recommend that further local studies need to bedone in order to obtain better information with regard totreatment selection and outcome.REFERENCES1. Issaragrisil S, Kaufman DW, Anderson T, Chansung K,Leaverton PE, Shapiro S, et al. The epidemiology of aplasticanemia in Thailand. Blood 2006; 107:1299-307. Epub 2005Oct 27.2. Kaufman DW, Kelly JP, Levy M, Shapiro S. The drug etiology ofagranulocytosis and aplastic anemia. New York: Oxford UniversityPress; 1991.3. Issaragrisil S, Sriratanasatavorn C, Piankijagum A, VannasaengS, Porapakkham Y, Leaverton PE, et al. Incidence of aplasticanemia in Bangkok. Blood 1991; 77:2166-8.4. Kurre P, Johnson FL, Deeg HJ. Diagnosis and treatment ofchildren with aplastic anemia. Pediatr Blood Cancer 2005; 45:770-80.5. Frickhofen N, Rosenfeld SJ. Immunosuppressive treatment ofaplastic anemia with antithymocyte globulin and cyclosporine.Semin Hematol 2000; 37:56-68.6. Pongtanakul B, Das PK, Charpentier K, Dror Y. Outcome ofchildren with aplastic anemia treated with immunosuppressivetherapy. Pediatr Blood Cancer 2008; 50:52-7.Journal of the College of Physicians and Surgeons Pakistan  2011, Vol. 21 (4): 219-222 221Aplastic anemiaTable III: Showing outcome of patients treated with HSCT and IST.Treatment         HSCT IST Total (n=20)OutcomeExpired 1 (25%) 3 (25%) 4Alive 6 (75%) 3 (25%) 9Referred out - 1 (8.3%) 1Lost to follow-up 1 (25%) 5 (41.6%) 6Total 8 12 20222 Journal of the College of Physicians and Surgeons Pakistan  2011, Vol. 21 (4): 219-2227. Chandra J, Naithani R, Ravi R, Singh V, Narayan S, Sharma S,et al. Antithymocyte globulin and cyclosporin in children withacquired aplastic anemia.  Indian J Pediatr 2008; 75:229-33.8. Kazi MY, Shahnaz I, Khan HI. Aplastic anemia in children.Pak Paed J 1998; 22:71-4.9. Montané E, Ibáñez L, Vidal X, Ballarín E, Puig R, García N, et al.Epidemiology of aplastic anemia: a prospective multicenterstudy. Haematologica 2008; 93:518-23.10. Goswami BK, Chakrabarti S, Paul PC, Pramanik R, Raha K, DasS. Clinicohaematological analysis of aplastic anemia amongchildren of northern districts of West Bengal. J Indian Med Assoc2009; 107:17-8.11. Pinto FO, Leblanc T, Chamousset D, Le Roux G, Brethon B,Cassinat B, et al. Diagnosis of  Fanconi’s anemia in patients withbone marrow failure. Haematologica 2009; 94:487-95.12. Gupta V, Tripathi S, Singh TB, Tilak V, Bhatia BD. A study of bonemarrow failure syndrome in children. Indian J Med Sci 2008; 62:13-8.13. Varma N, Varma S, Marwaha RK, Malhotra P, Bansal D, Malik K,et al. Multiple constitutional etiological factors in bone marrowfailure syndrome (BMFS) patient from North India. Indian J Med Res2006; 124:51-6. Comment in: p. 11-2.14. Safadi R, Or R, Ilan Y, Naparstek E, Nagler A, Klein A, et al. Lackof known hepatitis virus in hepatitis- associated aplastic anemiaand outcome after bone marrow transplantation. Bone MarrowTransplant 2001; 27:183-90.15. Kojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H,et al. Immunosuppressive therapy using antithymocyte globulin,cyclosporine, and danazol with or without human granulocytecolony-stimulating factor in children with acquired aplasticanemia. Blood 2000; 96:2049-54.16. Locasciulli A, Oneto R, Bacigalupo A, Socié G, Korthof E,Bekassy A, et al. Outcome of patients with acquired aplasticanemia given first bone marrow transplant or immuno-suppressive treatment in the last decade: a report from theEuropean Group for Blood and Marrow Transplantation (EBMT).Haematologica 2007; 92:11-8.17. Peter K, Leonard J, Joachim HD. Review: diagnosis andtreatment of children with aplastic anemia. Pediatr Blood Cancer2005; 45:770-8.18. Guinan EC. Acquired aplastic anemia in childhood. Hematol OncolClin North Am 2009; 23:171-9119. Shamsi Ts, Hashmi K, Adil S, Ahmad P, Irfan M, Raza S, et al.The stem cell transplant program in Pakistan--the first decade.Bone Marrow Transplant 2008; 42:S114-S117.20. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. TheGerman aplastic anemia study group. Antithymocyte globulinwiht or wihtout cyclosporin A: 11-year follow-up of a randomizedtrial companing treatment of aplastic anemia. Blood 2003;101:1236-42.l l l l lOl l l l lRabia Wali, Zehra Fadoo, Salman Adil and Muhammad Ahmed Naqvi 

Aplastic Anemia: Clinicohaematological Features, Treatment and Outcome Analysis

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Aplastic Anemia: Clinicohaematological Features, Treatment and Outcome Analysis

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