Thalassemia in Children: IAP Guidelines
Thalassemia is an autosomal recessive disease. It is of two main types, i.e., alpha and beta. Alpha-thalassemia Beta-thalassemia Mutation in the HBA1 and HBA2 genes, four such, two from each parent, severity of signs and symptoms directly proportional to the number of genes mutated. Mutation in the HBB gene, two genes, one from each ...
| Alpha-thalassemia | Beta-thalassemia |
| Mutation in the HBA1 and HBA2 genes, four such, two from each parent, severity of signs and symptoms directly proportional to the number of genes mutated. | Mutation in the HBB gene, two genes, one from each parent, involved in the synthesis of beta- globin. |
| With one mutated gene, one has no signs or symptoms but is a carrier of the disease and can pass it on to the children. | Children with one mutated gene will have mild signs and symptoms. Condition also called thalassemia minor or beta-thalassemia. |
| People with two mutated genes will have mild signs and symptoms, also called alpha- thalassemia trait. | Children with two mutated genes will have moderate-to-severe signs and symptoms. This condition is called thalassemia major. These babies are usually healthy at birth and develop signs and symptoms within the first 2 years of life. |
| People with three mutated genes have moderate-to-severe signs and symptoms from birth. | Some children with two mutated genes will manifest a milder form, called thalassemia intermedia. |
| Four mutated genes usually result in stillbirth or death shortly after birth or lifelong transfusion therapy. |
The Indian Academy of Pediatrics (IAP) has released Standard Treatment Guidelines 2022 for Thalassemia in Children. The lead author for these guidelines on Thalassemia in Children is Dr. Ajith Kumar VT along with co-author Dr. Amita Mahajan and Dr. Joy Bhaduri. The guidelines come Under the Auspices of the IAP Action Plan 2022, and the members of the IAP Standard Treatment Guidelines Committee include Chairperson Remesh Kumar R, IAP Coordinator Vineet Saxena, National Coordinators SS Kamath, Vinod H Ratageri, Member Secretaries Krishna Mohan R, Vishnu Mohan PT and Members Santanu Deb, Surender Singh Bisht, Prashant Kariya, Narmada Ashok, Pawan Kalyan.
Following are the major recommendations of guidelines:
Symptoms and Signs:
- Fatigue/weakness/shortness of breath
- Pale or yellowish skin/anemia
- Facial bone deformity
- Slow growth/failure to thrive
- Abdominal swelling
- Hepatosplenomegaly.
Complications:
- Jaundice and pigment gallstones
- Hypersplenism
- Complications of extramedullary hematopoiesis
- Skeletal changes
- Iron overload
- Growth impairment
- Complications of iron overload
- Endocrine and metabolic abnormalities
- Heart failure and arrhythmias
- Pulmonary abnormalities and PH.
Laboratory Findings:
|
Syndrome |
Typical findings on complete blood count (CBC) | Hemoglobin (Hb) analysis [high- performance liquid chromatography (HPLC) or electrophoresis] |
| Hydrops fetalis with Hb Barts | Severe microcytic anemia with hydrops fetalis; usually fatal in utero | Hb Barts (γ globin tetramers); Hb Portland (embryonic hemoglobin); no Hb F, Hb A, or Hb A2 |
| Hb H disease | Moderate microcytic anemia | Hb H (up to 30%); Hb A2 (up to 4%) |
| Minor | Mild microcytic anemia | Hb Barts (3–8%, only in the newborn period) |
| Silent carrier | Normal or mildly decreased hemoglobin, normal or mildly decreased mean corpuscular volume (MCV) | Normal |
| Transfusion-dependent (TDT, beta-thalassemia major) | Severe microcytic anemia with target cells (typical Hb 3–4 g/dL) | Hb A2 (5% or more); Hb F (up to 95%); no Hb A |
| Non-transfusion-dependent (NTDT, beta-thalassemia intermedia) | Moderate microcytic anemia | Hb A2 (4% or more); Hb F (up to 50%) |
| Minor (also called trait or carrier) | Mild microcytic anemia | Hb A2 (4% or more); Hb F (up to 5%) |
| Target pretransfusion hemoglobin | 9.5–10.5 g/dL |
| Blood product | Packed red cells with Hct > 60% not older than 2 weeks |
| Crossmatch | For ABO and Rh, (C, c, D, E, e, Kell where feasible) |
| Frequency | 2–4 weeks |
| Volume | 15–20 mL/kg |
| Rate | 5 mL/kg/hour |
| Processing | Leukodepletion (prestorage/bedside) |
| Screening | Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), human immunodeficiency virus (HIV), malaria [ideally nucleic acid testing (NAT)-tested) |
| Furosemide/chlorpheniramine/ hydrocortisone | Not indicated routinely |
| When to start | Serum ferritin >1,000 µg/L (usually after 10–20 transfusions) |
| Target ferritin | <1,000 µg/L |
| Monitoring | Serum ferritin 3–6 monthly, T2* MRI annually above 8–10 years of age. Liver function test (LFT) and serum creatinine to be monitored monthly for 3 months than 3 monthly |
| When to stop | Not recommended. Can continue at very low doses if ferritin < 500 µg/L |
| Chelator | Deferasirox | Deferoxamine | Deferiprone |
| Route | Oral (dispersible tablet/ film-coated tablet) | Subcutaneous/IV if intensive chelation warranted | Oral |
| Dose | DT: 20–40 mg/kg/d FCT: 14–28 mg/kg/d | 30–40 mg/kg/d, 5–7 days/ week | 75–100 mg/kg/d |
| Frequency | Once daily | 12-hour infusions | Three divided doses |
| Side effects | Gastrointestinal (GI) disturbances, transaminitis, azotemia, microalbuminuria | Local reactions, ototoxicity, and retinopathy | Agranulocytosis and arthralgias |
| Monitoring | LFT/serum creatinine, urine monthly to begin with then 3 monthly | Annual ophthalmic and auditory review | CBC every 2 weeks |
| Growth and development | To be routinely monitored |
| Folic acid | Supplement in small doses |
| Vitamin C | Only in patients on deferoxamine infusion not exceeding 2 mg/kg/d |
| Other vitamins | Ensure optimal levels of vitamin D3 |
| Dietary restrictions | None in optimally managed patients |
| Dietary supplements | Not routinely recommended |
| Immunization | As per schedule including hepatitis B. Hepatitis A vaccine also recommended in view of increased severity in patients with iron overload in liver. Ensure adequate titers of anti-HBs or give booster doses every 5 years |
| Monitoring | Annual monitoring for endocrinopathy and bone health after 10 years of age |
| Optimal age | 2–10 years |
| Optimal patient status | Optimally chelated, no organomegaly, and no organ dysfunction |
| Ideal donor | Fully human leukocyte antigen (HLA)-matched sibling donor |
| Optional donors | Matched unrelated donor and haploidentical donor from family |
| Source of stem cells | Bone marrow (BM) preferred to peripheral blood stem cells |
Newer Modalities:
| Modality | Mechanism of action | Route of administration | Current status |
| Luspatercept | Anti-apoptotic, prolongs red cell lifespan | Subcutaneous injection 3-weekly | Approved for patients > 12 years Not available in India |
| Thalidomide | HbF induction, immunomodulation | Oral | Currently being evaluated in this setting |
| Ruxolitinib | JAK-2 inhibition | Oral | May help in reduction of splenomegaly |
| Gene therapy | - | Not available in India |
| Parameters | Patients |
| Monitoring of growth, Hb, organomegaly, iron overload, and dysmorphism | Indicated in all patients |
| Folic acid | Recommended for all patients |
| Hydroxyurea | Therapeutic trial in all patients at 10–20 mg/kg/d |
| Intermittent transfusion | Indicated in acute drop in Hb secondary to infection |
| Regular transfusion | To be decided by the hematologist taking into account—Hb, growth, organomegaly, facial disfigurement, and quality of life |
- Cappellini MD, Cohen A, Porter J, Taher A, Viprakshit V. Guidelines for the Management of Transfusion Dependent Thalassemia, 3rd edition. Nicosia, Cyprus: Thalassemia International Federation; 2014.
- Cappellini MD, Farmakis, Porter J, Taher A. Guidelines for the Management of Transfusion Dependent Thalassemia, 4th edition. Nicosia, Cyprus: Thalassemia International Federation; 2021.
- Cappellini MD, Musallam M, Taher A. Guidelines for the Management of Non-transfusion dependent Thalassemia, 2nd edition. Nicosia, Cyprus: Thalassemia International Federation; 2017.
- Ministry of Health and Family Welfare. Guidelines on Hemoglobinopathies in India. Government of India: Ministry of Health and Family Welfare; 2016.
The guidelines can be accessed on the official site of IAP: https://iapindia.org/standard-treatment-guidelines/
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