Clinico-Hematological Profile and Management of Children With Non-Transfusion Dependent Thalassemia (NTDT) at a Pediatric Center in Northern India

Objective: To study the clinico-hematological profile, complications, and management of children with non-transfusion dependent thalassemia (NTDT) in northern India. Method: We retrieved and analyzed the data of 69 children with NTDT diagnosed between January, 2006 to December, 2018, aged under 18 years from our unit’s records. Result: The participants mean (SD) age was 4.4 (3.1) years, and they presented with anemia (29%), jaundice (13%), hemolytic facies (13%), splenomegaly (87%), thromboembolism (2.9%) and pathological short stature (28.5%). The most common cause of NTDT was ?-thalassemia (45%), followed by either compound-heterozygous or homozygous for E?-thalassemia mutation. The most frequent single genotype observed was compound heterozygous for IVS1-5 (G>C) and codon 26 (G>A). The mean (SD) follow-up duration was 3.5 (2.4) years. On follow-up, 27 children (%) remained transfusion free, and 30 (%) needed occasional transfusions. 63% of patients initially presenting with pathological short stature showed improvement in growth. Amongst children older than 10 years (n=20), subclinical hypothyroidism was detected in 6 children and impaired glucose tolerance test in 1 child. Conclusion: Eß-thalassemia was the commonest cause of NTDT in this population.

Correlation of Transient Elastography With MRI T2* and Serum Ferritin Levels in Children With Transfusion-Dependent Thalassemia

Objectives: We investigated the correlation of transient elastography (TE) with MRI R2* values and serum ferritin in patients with transfusion-dependent thalassemia (TDT) Methods: We reviewed hospital records of 59 patients with TDT aged ?8 years without any evidence of chronic liver disease and who had fibroscan within 3 months of MRI T2*, who seen at our center between January, 2014 and December, 2019. Spearman correlation and linear regression analysis were used to evaluate the correlation between TE liver stiffness measurements and R2* MRI values and with serum ferritin. Results: Mean (SD) age of the subjects was 13.0 (3.1) years and body mass index was 16.6 (2.3) kg/m2. Mean liver stiffness measurement, MRI T2*(3T), corresponding MRI R2*(3T), and ferritin values were 6.55 (3.10) kPa, 3.4 (4.6) milliseconds, 616.20 (383.9) Hz, and 2874.69 (1570.7) ng/ mL, respectively. TE measurements correlated with MRI R2* values (r=0.61; P=0.001) and with serum ferritin level (r=0.59, P=0.001). Conclusion: TE is a reliable tool to estimate hepatic iron overload in patients with TDT.

Diagnosis, Treatment and Prevention of Nutritional Anemia in Children: Recommendations of the Joint Committee of Pediatric HematologyOncology Chapter and Pediatric and Adolescent Nutrition Society of the Indian Academy of Pediatrics

Justification: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. Objective: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. Process: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. Recommendations: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

HIV-free Survival at the Age of 18 Months in Children Born to Women With HIV Infection: A Retrospective Cohort Study

Objective: To assess HIV-free survival and nutritional status of HIV-exposed infants.Methods: This retrospective cohort study was conducted on infants born to woman with HIVinfection born at our Institute between January 2011 to March 2016, and followed usingcurrent National guidelines. HIV transmission rate, HIV-free survival, and nutritional statuswere assessed 18 months age. Results: Of the 155 infants, 10 (6.5%) died before 18 monthsof age. Two of 145 surviving infants were confirmed HIV-positive, the remaining were HIV-negative at 18 months (HIV-free survival 92.3%). Of the 10 infants who died, one wasconfirmed HIV-positive and three negative; the rest died before their HIV status could beascertained. HIV infection rate among the 149 infants for whom the test reports were availablewas 2%. At 18 months age, 14% HIV-uninfected infants were wasted, 28% stunted, and 3%had microcephaly. Conclusions: Infants born to mothers with HIV managed as per thecurrent National guidelines have a good outcome at 18 months of age.

Immunization of Children with Cancer in India Treated with Chemotherapy – Consensus Guideline from the Pediatric Hematology-Oncology Chapter and the Advisory Committee on Vaccination and Immunization Practices of the Indian Academy of Pediatrics

Justification: Children with cancer need to be immunized against the common vaccine-preventable diseases after completion andsometimes during ongoing treatment of cancer. However, the immunization schedule for these children needs to be altered due todisease and treatment related immune-suppression. Consequently, there are many guidelines/practice statements from around theworld to address this issue, however, there is no such comprehensive guideline from India catering to the need of Indian children withcancer. Process: A guideline was drafted after reviewing the available literature. The draft guideline was discussed and modified in ameeting attended by pediatric oncologists from the PHO chapter and vaccine experts from the ACVIP of the IAP. Subsequently, themodified draft was reviewed and recommendations were finalized.Objective: To review the current evidence and generate a nationallyrelevant guideline for immunization of children receiving chemotherapy for cancer. Recommendations: Live vaccines arecontraindicated during and up to 6 months after end of chemotherapy. Non-live vaccines are also best given after 6 months from the endof treatment for durable immunity. Annual inactivated influenza vaccine is the only vaccine recommended for all children duringchemotherapy whereas hepatitis B vaccine is recommended only for previously unimmunised children with risk of transfusion associatedtransmission of infection. Post-treatment re-immunization/catch-up schedule largely depends on the pre-chemotherapy immunizationstatus. Sibling immunization should continue uninterrupted except for oral polio vaccine which needs to be substituted by the injectablevaccine. Inactivated influenza vaccine is recommended and varicella vaccine is encouraged for all contacts including siblings

Clinico-hematological study of abnormalities of platelet count in children with iron deficiency anemia

Background: Iron deficiency anemia is a major cause of morbidity in developing countries like India. The aim of the study was to assess abnormalities of platelet count in iron deficiency anemia and to relate the severity of thrombocytosis with severity of anemia and its association with erythropoietin (EPO) level.Methods: A prospective observational study comprising of 200 children below 18 years confirmed to have IDA. Erythropoietin (EPO) level was done in patients who had thrombocytosis. Degree of thrombocytosis was correlated with EPO and also with ferritin, haematological indices like hemoglobin and MCV (mean corpuscular volume) and blood counts were followed up while on iron therapy for one month.Results: Thrombocytosis was noted in 24.5%. In 75.5% thrombocytosis was mild. Platelet had negative correlation with Hb (hemoglobin). EPO was elevated in 67.35% of thrombocytosis. EPO showed negative correlation with Hb and Ferritin and positive correlation with platelet however, these were non-significant. All patients were treated with standard preparation of ferrous fumarate (33mg elemental iron every 5 ml) in a dose of 3mg/kg/day of elemental iron along with appropriate dietary advice.' On one month follow up 92% of the study population showed normalization of platelet count.Conclusions: Nearly One-fourth of children had thrombocytosis. Platelet count was inversely related to Hb and ferritin level. EPO was increased in two-third cases of thrombocytosis and showed positive correlation with platelet count. As authors excluded patients with severe IDA requiring blood transfusion, authors did not get any thrombocytopenia in present study.

Comparison of Feeding Options for HIV-Exposed Infants: A Retrospective Cohort Study

Objectives: To compare growth, anemia prevalence, and sickness frequency in HIV-exposed uninfected infants on different feeding modes. Methods: In this retrospectivecohort study, 109 HIV-exposed uninfected infants registered atour center were categorizedintothree groups as per their feeding mode during first 6 months viz. exclusively breast fed(n=50), animal milk fed (n=40) and commercial infant formula fed (n=19). Theiranthropometric parameters, hemoglobin and frequency of sickness at the age of 6 monthswere compared. Results: There were no significant inter-group differences in the weightfor age, weight for length, length for age z-scores (P=0.16, 0.37 and 0.12, respectively);proportion of infants with underweight (P=0.63), wasting (P=0.82), or stunting (P=0.82),and mean hemoglobin levels among the 3 groups at 6 month of age. Animal milk fed andformula fed infant had increased risk of sickness compared to exclusively breastfed infants(OR 2.5 and 2.49, respectively; P<0.01). Conclusions: In circumstances wherebreastfeeding is not feasible or preferred, animal milk feeding offers a viable alternative tocommercial infant feeding formula in HIV exposed infants.

Hemoglobin Agenogi ‑ A rare abnormal beta globin chain variant.

Haemoglobin (Hb) Agenogi is clinically asymptomatic, rare β‑globin chain variant characterized by a substitution of glutamic acid by lysine at position 90 of β‑chain. It elutes in the C‑window on high‑performance liquid chromatography (HPLC). We report a 10‑year‑old male with easy fatigability, lethargy, pallor, and mild splenomegaly. Hematological parameters revealed microcytic hypochromic anemia and mildly raised red blood cells count, suggestive of thalassemia trait. On HPLC, a predominant peak was observed in the C‑window (82.6%) along with raised HbA2 level (9.3%). Based on these findings, a possibility of HbC disease/β‑thalassemia trait doubly heterozygous was considered. Family studies were advised. HPLC findings in father were suggestive of β‑thalassemia trait, while both his mother and brother had an abnormal peak in the C‑window of 42.7% and 40.8%, respectively, with elevated HbA2 values of 5% and 4.9%, respectively. Direct DNA sequencing revealed intervening sequences 1–5 (G → C) in father, confirming β‑thalassemia trait. His mother and brother had heterozygous gene mutation at codon 90 of β‑globin chain (G → A) suggestive of Hb Agenogi. The child carried mutations for both β‑thalassemia trait as well as Hb Agenogi.

Determinants of Nutritional Anemia in Adolescents.

Objectives: To associate the severity of nutritional anaemia with serum levels of ferritin, vitamin B12 and folate; and to determine demographic, socio-economic and nutritional correlates for nutritional anemia in adolescents. Methods: Cross-sectional hospital-based study among 200 adolescents (10-18 y) with anemia. Dietary intake (24-h recall), and serum levels of folate, vitamin B12 and ferritin were estimated. Results: Iron, folate and vitamin B12 deficiency was present in 30.5% 79.5% and 50% of adolescents, respectively. Statistically significant association was observed between severity of anemia and serum vitamin B12 levels, iron intake, folate intake, Vitamin B12 intake, vegetarian diet, attainment of menarche and history of worm infestation. Conclusions: Folate and vitamin B12 deficiencies are more common than iron deficiency in anemic adolescents. Low dietary intake of these nutrients seems to be a significant determinant of their deficiencies.

What regulates hepcidin in poly-transfused β-Thalassemia Major: Erythroid drive or store drive.

Background: Hepcidin, a key regulator of iron homeostasis, is increased by iron overload and infl ammation while suppressed by hypoxia. In spite of iron overload in β-Thalassemia Major (β-TM), a paradoxical decrease in hepcidin is observed. Aim: To assess the opposing effects of enhanced erythropoiesis due to anemia and iron overloading on hepcidin in β-TM patients. Setting and Design: This prospective observational study was done at our tertiary care hospital. Materials and Methods: Eighty-three pediatric polytransfused (> 20 transfusions) patients of β-TM were compared with 70 children who served as controls. Serum assays for ferritin, transferrin receptors (sTfR) and hepcidin were performed. Statistical analysis: Independent Student t test was used to compare variables between both the groups. A Pearson correlation coeffi cient was used to fi nd any correlation between ferritin, sTfR and hepcidin. Results: The mean value of hepcidin in β-TM children was 13.88±10.68 ng/ml (range, 0.9-60 ng/ml) and showed signifi cant negative correlation with sTfR (r = –0.296, P < 0.0066). However, there was no correlation of hepcidin with ferritin. Ferritin and sTfR were signifi cantly elevated in β-TM children compared to controls (P < 0.001). The mean serum hepcidin/ferritin index in the study group (0.00552) was signifi cantly lower (P value < 0.001) than the controls (0.378) thus indicating inappropriate levels of hepcidin to iron overload. Conclusion: In polytransfused β-TM children increased iron demand dominates over iron overload in regulating hepcidin. In spite of excessive iron load, the inappropriate hepcidin levels may further contribute to iron overload enhancing iron toxicity.

Profile of HIV Infected Children from Delhi and Their Response to Antiretroviral Treatment.

Objectives: (i) To study the clinical and immunological profile of HIV infected children attending the ART centre; (ii) To correlate CD4 count with clinical staging at diagnosis; and, iii) To study the clinical and immunological response to antiretroviral treatment. Setting: Antiretroviral therapy (ART) centres of two tertiary care hospitals of Delhi. Patients: 100 children attending the centres between December 2008 to June 2009. Methods: The clinical features, immunological profile (CD4 count) and response to ART were recorded in a structured proforma. Design: Prospective follow-up. Results: Average age of enrolled children was 6.24 y (range 1-14 years) and mode of transmission was parent to child in 92%. Most common clinical presentation was fever (83%), cough (50.8%) and diarrhea (38.9%). Tuberculosis was the most common opportunistic infection seen in 11% of children. 59% of enrolled children were malnourished. Antiretroviral treatment (ART) was initiated in 33 children. Children who were initiated on ART had a significant improvement in both clinical and immunological staging at the 6 months follow up. Immunological response (rise in CD4 count) to ART was better in children with lesser degree of immunosuppression. The measure of agreement between the clinical and immunological stage at presentation was poor. Conclusions: Baseline CD4 counts rather than clinical staging can be a primary determinant for initiation of antiretroviral treatment in HIV infected children.

Critical evaluation of peripheral smear in cases of anemia with high mean corpuscular hemoglobin concentration in children: A series of four cases.

Mean corpuscular hemoglobin concentration (MCHC), a parameter that is reported as a part of a standard complete blood count by automated analyzer, is a measure of the concentration of hemoglobin in a given volume of packed red blood cell. Values of MCHC significantly above reference range are not physiologically possible due to limitations on solubility of hemoglobin. The high MCHC can give us a clue to certain type of hemolytic anemia and necessitate critical evaluation of peripheral smear to reach a definitive diagnosis. Here we are presenting a series of four cases with raised MCHC, emphasizing the importance of systematic and meticulous examination of the peripheral smear to render a definitive diagnosis.

Megaloblastic anemia: Back in focus.

Megaloblastic anemia (MA), in most instances in developing countries, results from deficiency of vitamin B12 or folic acid. Over the last two to three decades, incidence of MA seems to be increasing. Of the two micronutrients, folic acid deficiency contributed to MA in a large majority of cases. Now deficiency of B12 is far more common. In addition to anemia, occurrence of neutropenia and/or thrombocytopenia is increasingly being reported. Among cases presenting with pancytopenia, MA stands out as an important (commonest cause in some series) cause. This article focuses on these and certain other aspects of MA. Possible causes of increasing incidence of MA are discussed. Observations on other clinical features like neurocognitive dysfunction, associated hyperhomocysteinemeia and occurrence of tremors and thrombocytosis during treatment are highlighted.

Clinicohematological study of thrombocytosis.

Objective. To find out etiology and clinical course of thrombocytosis in Indian pediatric population. Methods. A total of 250 patients having thrombocytosis (defined as platelet count >500 x 109/L) on haematological investigations were studied over one yr period. All patients were evaluated clinically and were subjected to investigations, including complete blood counts (CBC) with peripheral smear examination. To elucidate the possible role of inflammatory cytokines in pathogenesis of RT, levels of Interleukin-6 (IL-6) and C - reactive protein (CRP) were estimated. Results. Infants and young children (<2 yr age) were most common group, contributing 60% of total cases. Out of total 250 cases, only 3 (1.2%) cases were found to have primary thrombocytosis and remaining 98.8% cases were having RT. Among RT patients, infections (alone or in association with iron deficiency anemia) were most common cause, accounting for 65% cases, while iron deficiency anemia (IDA) was second most common cause accounting for 41.3% cases (12.6% IDA alone and 28.7 % in association with infections). Other causes included nutritional dimorphic anemia and patients on treatment for megaloblastic anemia, acute lymphoblastic leukemia (during treatment) and lymphoma. Among various groups of RT, IL-6 and CRP levels were higher in patients with infection with or without IDA than IDA alone. One child with essential thrombocytosis and one child with RT had thrombotic complications. On follow up, platelet counts normalized in most of the patients with treatment of underlying conditions. Conclusions. Results of this study suggest that essential thrombocytosis is extremely rare in children. Infections and IDA (alone or in association with infections) are common causes of RT. IL-6 and CRP levels are increased in patients with RT, to a higher level in patients with infections than in patients with IDA. Most patients with RT have uneventful recovery of platelet counts to normal range with treatment for underlying condition.

Evaluation of serum transferrin receptor and sTfR ferritin indices in diagnosing and differentiating iron deficiency anemia from anemia of chronic disease.

Objective. The present study was conducted to assess the utility of serum transferrin receptor (sTfR) and sTfR ferritin indices to differentiate ACD from IDA and also to diagnose coexisting IDA and ACD. Methods. The study group comprised of 30 IDA patients, 30 cases of ACD and 30 age and sex matched controls. Complete hemogram with peripheral smear examination, markers of ACD, iron profile including serum ferritin and serum transferrin receptor levels were done in all patients and controls. Serum TfR and ferritin indices were calculated. Results. sTfR levels were significantly higher in the IDA group compared to ACD group (p<0.001). ACD group was further subdivided into two groups on the basis of sTfR levels (B1<3 μg/ml and B2 ≥ μg/ml), suggesting coexisting IDA in group B2. sTfR/log ferritin index was > 1.5 in all cases of IDA and ACD with coexisting IDA while all pure ACD cases and control subjects had sTfR/log ferritin index < 1.5. All case in IDA group had log sTfR/serum ferritin index > 2.55 and all patients with ACD with or without associated iron deficiency had log sTfR/serum ferritin ratio < 2.55. Conclusion. The sTfR levels along with the above mentioned indices can be very useful in differentiating pure IDA, ACD and ACD with coexisting iron deficiency, thus providing a noninvasive alternative to bone marrow iron.