The Egyptian Journal of Haematology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 45  |  Issue : 1  |  Page : 8--15

Clinical audit on management of aplastic anemia at hematology unit of Assiut University Children Hospital


Catherine S Attia1, Gehan MK El-Din2, Khalid I El-Sayeh2,  
1 Faculty of Medicine, Assiut University, Egypt
2 Professor of Pediatrics Faculty of Medicine, Assiut University, Egypt

Correspondence Address:
Catherine S Attia
Faculty of Medicine, Assiut University, 5 Taksem Elias Balash el Nemes Street Assiut, 71511,
Egypt

Abstract

Background Aplastic anemia (AA) is a rare bone marrow failure disorder with high mortality rate, which is characterized by peripheral blood pancytopenia, with a hypocellular bone marrow. Objective The aim was to evaluate the management of aplastic anemia in Assiut University Children Hospital, trying to find any defects and suggest methods of their correction. Patients and methods A retrospective cross-sectional study was done on 50 children having AA for a period of 1 year. Results Management of AA in Assiut University Children Hospital is compatible with the British Committee for Standards in Hematology guideline 2015 except for some defects such as using high dose of cyclosporine alone, due to no availability of antithymocyte globulin in definitive drug therapy. There is no availability of stem cell transplantation, although it is the only curative treatment. Conclusion Management of AA in Assiut University Children Hospital is compatible with British Committee for Standards in Hematology guideline (2015), but there are some defects owing to limited recourses.



How to cite this article:
Attia CS, El-Din GM, El-Sayeh KI. Clinical audit on management of aplastic anemia at hematology unit of Assiut University Children Hospital.Egypt J Haematol 2020;45:8-15


How to cite this URL:
Attia CS, El-Din GM, El-Sayeh KI. Clinical audit on management of aplastic anemia at hematology unit of Assiut University Children Hospital. Egypt J Haematol [serial online] 2020 [cited 2020 Nov 23 ];45:8-15
Available from: http://www.ehj.eg.net/text.asp?2020/45/1/8/294783


Full Text



 Introduction



Although aplastic anemia (AA) is relatively rare in childhood, its medical effect remains high with life-threatening consequences entailing complex medical therapies and potential long-term complications. The rapidly growing era of tests for genetic factors contributing to AA raises new questions with regard to diagnostic workup and treatment decisions [1].

Acquired AA is thought to be due to immune-mediated destruction of hematopoietic cells in the bone marrow (BM). Great advances have been made in the past decade in understanding its pathogenesis and treatment, which is now associated with excellent overall survival, surpassing 90%. Allogeneic bone marrow transplantation (BMT) offers the opportunity for cure in children if a suitable histocompatible donor is available. Comparable long-term survival in severe aplastic anemia (SAA) is achieved with immunosuppressive therapy (IST). However, a quarter of children with AA will not respond to primary IST and will require second-line therapy and 10–30% of responders will relapse; moreover, there is an increased risk of clonal hematopoiesis, leukemia, autoimmunity, and cancer, which requires a long-term follow-up by a specialized center.

 Aim



The aim was to conduct a retrospective, quantitative, descriptive audit on management of cases of AA in children admitted to Hematology Unit of Assiut University Children Hospital.

 Patients and methods



This study included 50 cases with AA admitted to Hematology Unit, Assiut University Children Hospital (1-year study). Ethics comitte approval statement Study is done by data collection and verbal concent from patients parents.

Inclusion criteria

All patients with an established diagnosis of AA over a 12-month period were included.

Exclusion criteria

Patients with other causes of pancytopenia with BM failure, BM infiltration, or owing to sequestration/destruction were excluded.

The following data were collected and recorded for each patient:Sociodemographic characteristics: name, sex, and age.Clinical presentation: symptoms of anemia, leukopenia, and thrombocytopenia.History of exposure to causes of acquired AA and family history.Full clinical examination: general, systemic examinations, and presence of stigma of congenital AA.All investigations done to confirm the diagnosis of AA and exclude other causes of pancytopenia with BM failure, BM infiltration, or owing to sequestration/destruction.Imaging studies such as chest radiography, echocardiography, and abdominal sonar.Complications.Management of each type of AA, including supportive treatment, other medical treatment, or referral to centers of BMT.Follow-up and referral.

 Results



The study included 50 children having AA who were managed at the Assiut University Children Hospital (1-year study) ([Table 1],[Table 2],[Table 3],[Table 4],[Table 5],[Table 6],[Table 7]).{Table 1}{Table 2}{Table 3}{Table 4}{Table 5}{Table 6}{Table 7}

 Discussion



Regarding on sex and age

In our studied 50 cases, 23 (46.0%) cases were males and 27 (54.0%) were females. The age range of the studied cases was from 3 months to 17 years, with a mean of 8.29±4.51 years. There is little difference between male and female ratio, and also there is incidence peak from 2 to 5 years, which is in agreement with Issaragrisil et al. [2].

Regarding final diagnosis

Congenital (inherited) AA was more frequently found in studied cases [22 (44.0%) cases] to be followed by idiopathic AA in 21 (42.0%) cases and acquired cases in only seven (14.0%) cases.

Most cases of acquired AA are idiopathic, which is in agreement with Marsh et al. [3].

Moreover, there is a history of exposure to recent viral infection (post-Hepatitis A) and ionizing radiation plus chemotherapy, which was recorded in 12.0% (six cases) and 2.0% (one case) of the total cases, respectively. These were the main causes of acquired AA, represented by 14.0% of the total studied cases with AA.

Fanconi anemia was the most common form of congenital AA cases (19 (38.0%) of 22 cases). This is in agreement with Howlett et al. [4].

The degree or severity of studied cases of AA was classified as being nonsevere AA, severe AA, and very severe AA in 50.0, 38.0, and 12.0% of studied cases, respectively.

Most children with aplastic anemia present with signs and symptoms resulting from advanced pancytopenia

Symptoms of anemia in the form of weakness, fatigue and dizziness, shortness of breath, headache, palpitation, in ability to concentrate, anxiety, and hair loss were recorded in 98, 96, 96, 92, 88, 88, 80, 72 and 56% of cases, respectively. Symptoms of leukopenia in the form of recurrent infections, recurrent fever, and mouth sores in 66, 64, and 30% of cases, respectively, were seen. The most common symptoms of thrombocytopenia were spontaneous bleeding in 62% of patients, excessive bruising in 62% of patients, bleeding from gums and nose in 60% of cases, and prolonged bleeding from cuts in 60% of cases. There is no history of body swellings in 66% of cases; only three (6.0%) patients were complaining of generalized enlargement of lymph nodes, 12 (24.0%) cases had history of edema of lowe limb (LL), and two (4.0%) cases had a history of abdominal distention. Symptoms found in patients are in agreement with Samarasinghe and Webb [5].

The most common signs of anemia in studied cases were pallor and tachycardia in 96.0% of patients, and the most common signs of thrombocytopenia were petechial rashes, purpura, and ecchymosis each in 70.0% of patients, epistaxis in 56.0% of patients, and bleeding per gum in 54% of patients. Only four (8%) patients had bleeding per rectum, and no patients in our study had any neurological manifestations suggestive of intracranial haemorrhage. The most common signs of infection due to leukopenia were fever, recurrent chest infection, mouth sores, skin infection and abscesses, and fungal infection in 58.0, 50.0, 28.0, 26.0, and 12.0% of the studied cases, respectively. This is in agreement with Walne and Dokal [6].

Examination of the patients for physical stigmata of inherited AA revealed short stature, abnormal skin patches (café au lait patches), microcephaly and microphthalmia, skeletal abnormalities (10 cases with absent thumb and one case with absent radi), cardiac congenital anomalies [ventricular septal defect (VSD) in two cases, transpotion of great artries (TGA) in one case, and Fallot’s Tetralogy S in one case], renal congenital anomalies (three cases diagnosed later as ectopic pelvic kidney and one case had congenital hydronephrosis), and hypogonadism in 40.0, 30.0, 24.0, 22.0, 8.0, 8.0 and 8.0% of studied cases, respectively. Two cases of cardiac congenital anomalies (VSD and TGA) underwent an open cardiac surgery. No other physical stigmata of inherited AA such as hair (Sparse and lightly pigmented hair) and teeth abnormalities, dysplastic nails, oral leukoplakia, cleft lip/palate or developmental delay were detected in our cases. This is in agreement with description of physical stigmata of fanconi anemia in Nathan et al. [7]. Findings that may suggest an alternative diagnosis such as organomegaly (hepatosplenomegaly) and lymphadenopathy were detected in 8.0 and 6.0% of cases, respectively.

Regarding investigations required for diagnosis

Laboratory investigations for establishing diagnosis and severity of AA were done in all cases (50 cases − 100%), except for BM cytogenetics or FISH (chr 5, 7, and 8).

Laboratory investigations for exclusion of inherited bone marrow failure syndromes (IBMF)S, which would lead to alternative therapies, such as peripheral blood chromosomal breakage analysis (diepoxybutane test), peripheral blood leukocyte telomere length analysis for dyskeratosis congenita, c-MPL (thrombopoietin receptor) testing − amegakaryocytic thrombocytopenia-associated gene, and additional diagnostic and genetic testing for BMFS if suspected, were not done for any case suspected to be one of IBMFS, and measurement of HbF % was done in only seven (14.0%) cases, whereas macrocytosis was tested for in all cases (100%).

There is a defect in the investigations because they are not available in our hospital. This disagrees with who stated they are important to exclude IBMFS. Laboratory investigations to assess for specific causes and association showed that diagnostic tests to exclude viral causes of AA (viral serology) such as hepatitis B and C, Epstein-Barr virus, cytomegalovirus, and HIV were done in 78.0, 30.0, 76.0, and 78.0% of studied cases, respectively. The status of hepatitis A, herpes simplex virus), vesicular stomatitis virus, human herpes virus 6, or parvovirus B19 was not evaluated.

Antinuclear antibody and antidouble-stranded DNA levels to evaluate autoimmune or inflammatory disease were measured in 50% of the studied cases [8].

No measurement for vitamin B12 and folate or ferritin serum levels was done, which agrees with Marsh et al. [8]. Flow cytometry for BM T, B, and CD34+ cells or as paroxismal nucturnial hemoglobin urea (PNH) screen for Glycosylphosphatidylinositol (GPI)-anchored proteins of peripheral blood and human leukocyte antigen typing of siblings were not done.

Radiographic and ultrasound investigations performed for diagnosis of AA such as chest radiography, radiographies of the hands, forearms and feet, abdominal ultrasound, and echocardiography were done in 60.0, 44.0, 80.0, and 44.0% of cases, respectively, whereas no computed tomography scan of the chest was requested. Routine investigations such as urine analysis, stool analysis, and erythrocyte sedimentation rate were done for all studied cases, which agrees with Marsh et al. [8].

Regarding management of each type of aplastic anemia including supportive care measurements or definitive treatment

Supportive care measures for studied cases with AA were as follows: blood product transfusion was received in 98.0% of cases in the form of packed red blood cells only (in 30.0% of cases) and platelet-rich plasma or platelet concentrate only according to availability in 6.0% of cases or both in 62.0% of cases. Dose of packed red blood cells was10–15 ml/kg, platelet-rich plasma was 10 ml/kg, and for platelet concentrate was one unit/10 kg. Blood product preparations received were not leukoreduced or radiated. Red cell administered to have lower acceptable hemoglobin level (6–8 g/dl) and to keep patients asymptomatic, in agreement with Carson et al. [9].

Platelets were administered to maintain platelets above 20 000/µl in severe neutropenic patients with hemorrhagic risk factors. No prophylactically transfused platelets in steady state was given, in accordance with British Committee for Standards in Hematology guidelines. Granulocyte transfusion facilities were not available and never utilized.

Control of bleeding in the form of epistaxis by nasal packing, vitamin K amp (amri K 10 mg/1 ml with dose: 5 mg/12 h), dicynone amp (diethylammonium 1,4 dihroxybenzenesulfonate 250 mg), antiox 0.8 mg/2 ml, kapron amp (tranexamic acid 500 mg/5 ml), and platelet-rich plasma transfusion was recorded in 26 (52.0%) cases.

Control of infection, especially recurrent chest infection, in 34 studied AA cases was done by using antibiotics. Amikacin (Amikin Dose: 15 mg/kg/day)+ceftazidime third generation cephalosporins (fortum vial intravenously), 50–100 mg/kg/day, antibiotics are used until infection subsides. Micafungin (Mycamine 50 vial) 2 mg/kg/day intravenous infusion over 1 h was used as antifungal therapy for indicated cases. However, our unit did not use any prophylactic antibacterial or antifungal agents regardless of blood counts. It should follow local hospital and National Institute for Health and Care Excellence guidance [10].

Regarding neutropenic precautions and vaccination policy, no specific instructions regarding cooking foods, hand washing, bathing daily, wearing of masks, and other instructions were given as a part of local hospital policy. Patients are uniformly instructed to seek medical attention for any temperature elevation. Instructions regarding returning to school were also quite varied from ‘any time they are not in the hospital’ to more detailed recommendations. Similarly, no set recommendations policy regarding immunizations was followed.

In our unit, granulocyte colony-stimulating factor (G-CSF) was only used in neutropenic patients when ANC is less than 500 (in the setting of an active infection) or if there was fever that did not respond to antibiotics and no ANC recovery. It was used in 20.0% of cases only, because it is very expensive drug and there is shortage in its availability in the hospital, which is in agreement with Quillen et al. [11]. We did not use GM-CSF, although it is occasionally used in combination with G-CSF if there is an active infection and the patient’s ANC has not responded to G-CSF in some institutions.

Regarding definitive therapy for AA cases, an IST regimen consisting of antithymocyte globulin (ATG) and cyclosporine A was used in the treatment of only one patient before hematopoietic stem cell transplantation, which was successfully done out of our unit in Om El Massreen Hospital, and 48.0% of patients were treated with cyclosporine only (dose of 10 mg/kg/day). All but one of the institutions used an IST regimen consisting of ATG and cyclosporine A. The remaining institutions utilized high-dose cyclophosphamide alone for immunosuppression. The majority of institutions consider initiating IST within 21 days of diagnosis to be very important for successful outcome.Methylprednisolone was added to 48.0% of our cases to minimize the risk of serum sickness as well as to reduce infusion reactions.

IST regimen was not used in the treatment of IBMFS.

In addition to supportive care measures, 38.0% of the patients diagnosed as Fanconi anemia were treated with androgen (Danazole) − dose of 200 mg/day oral for life.

Although the only therapy that can cure pancytopenia is stem cell transplantation, androgens, to which ∼50–75% of patients respond, are used for those in whom transplantation is not an option. This is in agreement with Bizzetto et al. [12]. Regarding complications, on follow-up and referral of the studied 50 (100%) cases, 28.0% of cases developed anemic heart failure, 26.0% of cases had severe uncontrolled infection, and 24.0% of patient had severe uncontrolled bleeding not responding to treatment or transfusion.

Overall, 30.0% of cases experienced complications from the therapy in the form of nausea, vomiting, and hair loss as adverse effects to cyclosporine.

Nine cases were referred; five cases of them were referred to receive matched sibling donor-hematopoietic stem cell transplantation (four cases to Nasser Institute and 1one patient to Om El Massryeen Hospital) and four cases were complicated by development of malignancy (three cases of them referred to South Egypt Cancer Institute and one case to 57 357 Hospital).

Otherwise, all patients were followed up, and their data were preserved in our Hematology Unit in written sheets and electronic database.

 Conclusion



AA in childhood is a life-threatening disorder, and if left untreated, the disease may progress to major complications.

A comprehensive laboratory panel is requested to establish the diagnosis of AA, classify its severity, screen for potential causative factors and exclude other causes of pancytopenia, with a hypocellular BM.

Although pediatric AA is sometimes idiopathic, there are a number of etiological factors known to cause AA. It may be congenital or acquired. The most common congenital type is Fanconi anemia.

Patients with AA most commonly present with symptoms of anemia to be followed by infection and bleeding. The presence of lymphadenopathy with/without hepatosplenomegaly should raise the possibility of development of secondary malignancy or an alternative diagnosis. The findings of short stature, caféau lait spots, and skeletal anomalies should alert the clinician to the possibility of a congenital form of AA.

Supportive therapy focuses on the alleviation of suffering and improving the quality of life experienced by patients. However, this approach does not treat the cause of AA and is not a cure.

Hematology units must follow British Committee for Standards in Hematology guidelines, 2015, and if possible, develop individual guidelines for antibiotic prophylaxis and treatment based on the infection rate and the predominant antibacterial resistance.

Improvements in current treatment strategies can only be achieved by joint efforts between treatment centers. Therefore, patients should be referred to experienced centers in clinical trials of stem cell transplantation, and where immunosuppressive treatment is ongoing, early in the course of the disease to offer the patient the best therapeutic options presently available.

Recommendations

Although most AA cases are categorized as idiopathic because their primary etiology is unknown, careful history, clinical examination, and complete diagnostic evaluations are important to help exclude inherited or acquired forms.All patients presenting with AA should be carefully assessed to exclude other possible causes of pancytopenia with hypocellular BM and exclude a possible late-onset inherited BM failure disorder.Prevention and treatment of complications like hemorrhage, bacterial and fungal infections, and of secondary events like alloimmunization to blood products and iron overload have a significant effect on the prognosis of patients with AA.Based on concerns with alloimmunization and iron overload, an approach to utilize as few transfusions as possible to keep the patient relatively asymptomatic while avoiding unnecessary transfusions should be encouraged. Specifically request leukoreduced/‘cytomegalovirus-safe products’ and irradiated blood products and consider iron chelation therapy when the serum ferritin is greater than 1000 μg/l.Our Hematology Unit must use the standard immunosuppressive regimen, which is a combination of ATG and cyclosporine. ATG must only be given as an in-patient treatment. Cyclosporine should be continued for at least 12 months after achieving maximal hematological response, followed by a very slow tapering, to reduce the risk of relapse.Every effort should be made to complete diagnostic evaluations and to initiate therapy within 3–4 weeks of initial diagnosis. Early therapeutic interventions (IST<4 weeks and BMT<12 weeks from presentation) are associated with significantly improved outcomes in acquired AA.Immediate human leukocyte antigen typing of the patient and family should be undertaken to determine the availability of a potential sibling transplant donor.In management of AA, we must ask ourselves, where we stand and where we are going?AA is an unusual disease, and the practicing hematologist/oncologist should feel no hesitation in rapidly referring a patient to a specialized center or in seeking the advice of experts familiar with the diagnosis and management of these patients where there is uncertainty, or when an IBMFS is being considered. Patients should be referred to experienced centers early in the course of the disease to offer the patient the best therapeutic options presently available.As AA is such a rare disease, improvements in current treatment strategies can only be achieved by joint efforts between treatment centers.Because of the paucity of data to guide medical management of AA in children, pediatric hematology centers with an interest in AA must initiate an Egyptian Pediatric Aplastic Anemia Consortium. The EPAAC collaborative working group can conduct a survey of its members to determine current practices for the diagnostic workup, treatment, and medical management of pediatric AA in Egypt.Centers should develop individual guidelines for antibiotic prophylaxis and treatment based on the infection rate and the predominant antibacterial resistance.Patient should be discharged on written treatment plan including name dose, duration of used drugs, and scheduling time of tapering of the drugs.There should be adherence to guidelines as a reference standard if possible to improve the prognosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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