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Childhood Anaemias.

Prof. Y. Mava MBBS, FWACP, FIMC, LMIH

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Anaemia in childhood�

Defn= as a decrease in the concentration of haemoglobin (Hb) in the peripheral blood below the normal for the age and sex.

Fall of the Hb below normal value is usually, but not invariably accompanied by a fall of the red cell count below normal value.

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Anaemia in childhood…�

Anaemia is not disease, but a symptom \ sign of an underlying disorder.

Many children in the tropics are anaemic.

Treatment must therefore be preceded by an accurate diagnosis of the cause of anaemia.

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Anaemia in childhood…�

Anaemia is a norm in rural communities of the developing world including Nigeria
WHO reported more than half of the children of Asia were anaemic
Genes and the environment play major role
Nutrition is a major environmental factor in the causation of childhood anaemia.
poverty, ignorance, and traditional practices are main background in developing world

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Anaemia in childhood…

The WHO recommended that anaemia should be considered :

- Hb levels are lower than 11 g / dl (6monts – 6 yrs),

- Hb less than 12 g / dl in older children 6- 14 yrs.

However, these levels are seldom attainable in the tropical developing countries.
Children may become symptomatic when Hb concentration is below 9.5 g / dl

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Clinical features of anaemia are:

Due to anaemia it self.
Disorder causing the anaemia.
Rate of development of the anaemia
Age of the patient.

Symptoms of Anaemia

Weakness
Easy fatigability
Dyspnoea
Irritability
Oedema
Palpitations.

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Clinical Features of Anaemia Cont.

Clinical presentation of anaemia is widely variable.
May present with non – specific eg fatigue, shortness of breath, pallor, and tachycardia.
Incidental finding
Manifestation of another known disease process.

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Clinical Features….

Medical history – etiology of the anaemia
History of exposure to drugs and toxins or heavy metals such as lead
Thorough family history – hereditary
Complete review of systems – eg liver, kidney diseases, endocrine disease, and malignancy
Digital rectal examination for occult fecal blood loss

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Clinical features cont. Examinations�

Examination of the mucous membrane of the mouth, conjunctivae, nail beds, skin 🡺 Looks Pale
Sclera of the eyes 🡺 jaundice
Interference of growth (Chronic case).
Heart murmurs – haemic murmur.
Hepatosplenomegaly
Heart failure
Oedema
Other findings depend on the cause

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Classification of Anaemia�

Resulting primarily from inadequate production of red cells or Hb

a. Decrease of red cell precursor in the marrow eg pure red cell anaemia

b. Inadequate production – Anaemia of infection, inflammation and cancer.

c. Deficiency of specific factors—vitamin B 12 deficiency, folic acid deficiency, Lead poisoning etc.

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Classification of Anaemia…�

2. Hemolytic anaemia

a. Intrinsic abnormality of RBC – Hereditary spherocytosis

b. Enzyme deficiency – G6PD def., Pyruvate kinase def.

c. Defects in the synthesis of Hb eg Thalassemias, SCA

d. Extrinsic anaemias

Immunologic disorders –passively acquired antibodies (Hemolytic disease of the newborn).
Non-Immunologic disorders – Toxins, infection.

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3. Morphologic Classification

Hypochromic microcytic anaemia

Iron deficiency
Anaemia of chronic disease
Thalassemia
Lead poisoning

Macrocytic Anaemia

Megaloblastic anaemia (B12 or folate deficiency)
Liver disease
Alcohol
Hypothyroidism

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Morphologic classif. Cont.�

Normochromic normocytic anaemia

Acute blood loss
Renal failure
Anaemia of chronic disease

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4. Aetiologic Classification

A. Increased Red Cell Loss

Blood loss
Haemolysis

Intracorpuscular

Membrane disorder
Enzymopathy
Haemoglobinopathy

Extracorpuscular

Immune
Mechanical
Infections

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Aetiologic Classification…..�

B. Decreased Red Cell Production

Abnormalities of the stem cells

Aplastic Anaemia

Defective DNA Synthesis

Megaloblastic anaemia

Defective Haemoglobin Synthesis eg Iron deficiency, Thalassemia, lead poisoning

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Aetiologic Classification…..

Displacement of normal haemopoietic progenitors

Haematologic malignancies
Metastatic tumours
Fibrosis

Decreased erythropoietin

Chronic Renal failure

Multi-factorial eg Anaemia of chronic disease like HIV infection.

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Anaemia of chronic Disease (ACD): Pathophysiology

ACD is defined as “the anaemia that accompanies chronic inflammatory, infectious, or neoplastic disorders.”
The red cell life span is decreased by increased destruction by a hyperactive reticuloendothelial system.
Further, there are abnormal Iron metabolisms including defective Iron release from the tissues into the plasma.
In renal failure, toxins accumulate which directly inhibits erythropoiesis

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Laboratory findings in ACD

Hb concentration – 6 – 9 g / dl
Anaemia- normochromic and normocytic, occasionally, modest hypochromia and microcytic.
Retic count normal or decreased
Leucocytosis common
Free erythrocyte protoporphyrin (FEP) level moderately elevated (>35ug / dl whole blood)

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Laboratory findings….

Serum Iron is low
No increases in total iron – binding capacity.
Serum Ferritin is often elevated
Bone marrow has normal cellularity
Increased hemosiderin

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Secondary anaemia. a and b Erythrocyte morphology in secondary hypochromic anaemia: the erythrocytes vary greatly in size (anisocytosis) and shape (1) (poikilocytosis), and show basophilic stippling (2). Burr cell (3), which has no specific diagnostic significance. Occasionally, the erythrocytes stain a soft gray–blue (4) (polychromasia). c Bone marrow cell overview in secondary anaemia. Cell counts in the white cell series are elevated (promyelocytes = 1), eosinophils (2),and plasma cells (3); erythropoiesis is reduced (4).

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Treatment and Prognosis

Identify and Treat underlying disorder.
Transfusion therapy is the traditional standard for severe cases.
Alternatively is to transfuse with rhEPO.
rhEPO effective in correcting the anaemia associated with chronic conditions
It is given subcutaneously at a dose of 25 – 250 U/kg three times weekly for 8 – 12 weeks

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PHYSIOLOGICAL ANAEMIA OF INFANCY�

Newborn has higher Hb and PCV, within the 1st week of life; there is a progressive decline- for 6 – 8 weeks. referred to as physiologic anaemia of infancy.
It rarely fall below 9 g / dl

pathophysiology

1^st there is abrupt cessation of erythropoiesis with onset of respiration, when arterial oxygen saturation rises from 45 to 95%,
concomitantly, the high fetal level of erythropoietin drop to undetectable levels.

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Physiological Anaemia of infancy…

The fetal Hb cells have a shorter life span (60 – 90 days)
Sizable expansion of blood volume that accompanies rapid weight gain during the first 3 months of life. => Creates a situation, which has aptly been described as “bleeding into circulation”.
Deficiency of folic acid or vitamin E
Switch from primary to definitive site of erythropoiesis

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Megaloblastic Anaemia of Infancy:�

1. Folic acid deficiency

Megaloblastic anaemia of infancy
Caused by a deficiency in intake or absorption of folic acid.
Dietary deficiency compounded by rapid growth or infection, which may increase folic acid requirements.
Normal daily requirement 20 – 50 ug/24 hrs
Goat milk is clearly deficient of folic acid
Powdered milk is a poor source

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Cont.

Folate deficiency:

Alcoholism
Deficient intake
Increased needs: pregnancy, infant, rapid cellular proliferation, and cirrhosis
Malabsorption
Intestinal and jujenal resection
(indirect) Deficient thiamine and factors (e.g., enzymes) responsible for folate metabolism.

Combined Deficiency (Tropical sprue):Vit B12 & folate

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Other causes

Inherited Pyrimidine Synthesis Disorder
Inherited DNA Synthesis Disorder
Toxins and Drugs:

Folic acid antagonist (methotrexate)
Purine synthesis antagonists (6 – mercaptopurine)
Pyrimidine antagonists (Cytosine arabinoside)
Phenytoin

Erythroleukemia

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Manifestations of FA Deficiency:�

VLBW infants
Peak incidence at 4 –7 month of age.
Affected infants are irritable, fail to gain weight adequately
Chronic diarrhoea
Thrombocytopenic haemorrhage
Concomitant signs of vitamin C deficiency
Folic acid deficiency may accompany kwashiorkor or marasmus.

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Laboratory findings in FA def:

RBC count is disproportionally lower than the PCV
Macrocytic (MCV >100 FL)
Variable red cell sizes and shape are common
Reticulocyte count is low
Neutropenia and thrombocytopenia,
Level of red cell folate are a better indicator of chronic deficiency state
Serum activity of lactic acid dehydrogenase is markedly elevated.

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Laboratory findings FA def..

Bone marrow is hypercellular, because of erythroid hyperplasia.

Megaloblastic changes – prominent, large, abnormal neutrophils form (giant metamyelocytes) with cytoplasmic vacuolization

Hypersegmentation of the nuclei of megakaryocytes.

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Hyperchromic anaemia. a Marked anisocytosis. In addition to normalsized

erythrocytes (1), macrocytes (2) and large ovoid megalocytes are seen (3). Hypersegmented granulocyte (4). b In hyperchromic anaemia, red cell precursors may be released into the peripheral blood:here,a polychromatic erythroblast. c and d Bone marrow in megaloblastic anaemia: slight (1) or marked (2) loosening up of the nuclear structure, in some cases with binuclearity (3). Giant forms of band granulocytes and metamyelocytes (4) are often present.

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Treatment of FA def�

Initially folic acid parenterally or orally 1 –5 mg / 24 hrs, haematological response is expected within 72 hrs

Transfusion indicated only when anaemia is severe or child is very ill.

Folic acid therapy continues for 3- 4 weeks.

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2.Vitamin B ₁₂ Deficiency (Cobalamin)

Vitamin B ₁₂ derived from cobalamin in food
Mainly animal source
Human can not synthesize vitamin B ₁₂
Cobalamin released in the acidity of the stomach, it combine with the R-Protein and intrinsic factor (IF).
It transverse the duodenum, where proteases break down the R- Protein and are absorbed in the distal ileum, via specific receptors.
In plasma, vitamin B ₁₂ is bound to transcobalamin TC2

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Vitamin B₁₂ deficiency� May result from:

Inadequate intake
Surgery involving the stomach or terminal ileum
Lack of secretion of intrinsic factor
Consumption or inhibition of the B ₁₂ – intrinsic factor complex
Abnormalities in the receptors
Abnormalities of the TC2

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Juvenile Pernicious Anaemia.

Rare autosomal recessive.

Due to inability to secrete gastric intrinsic factor.

Different from that of the adult because the stomach secretes acids normally and is histologically normal.

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Clinical features B12�

Symptoms become prominent between 9 month and 11 years of life.
Interval is consistent with exhaustion of the stores of vitamin B ₁₂ acquired in utero
Anaemia becomes severe leading to weakness, irritability, anorexia and listlessness occur
Tongue is smooth, red and painful
Neurological manifestations include ataxia, paresthesias, hyporeflexia, Babinski response, clonus and coma

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Examination of the PB Smear

Polychromasia indicates a reticulocytosis.
Oval macrocytes, red cell fragments and hypersegmented neutrophils are features of megaloblastic anaemia. Leucopenia and thrombocytopenia may also be present.
Round macrocytes are found in the non-megaloblastic macrocytic anaemias.
Dysplasia of red cells, white cell or platelets may suggest myelodysplastic syndromes.

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Macrocytosis in Liver Disease

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Laboratory Findings:�

Anaemia is macrocytic, with prominent macro-ovalocytosis
Neutrophils are large and hypersegmented
Advanced cases – Neutropenia and thrombocytopenia, simulating aplastic anaemia or leukemia
Vitamin B ₁₂ levels < 100 pg / ml.
Serum iron and serum folic acid are normal or elevated

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Peripheral blood smears showing hypersegmented neutrophils, characteristic of megaloblastic anaemia

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Oval Macrocytes and Hypersegmented Neutrophils in Vitamin B12 Deficiency

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Laboratory Findings …�

Serum LDH activity is markedly increased
Moderate elevation of serum bilirubin may be seen
Excessive excretion of methylmalonic acid in the urine (normal 0 – 3.5 mg / 24hrs) is a reliable and sensitive index of vitamin B₁₂ deficiency

Absorption of vitamin B₁₂ is usually assessed by the Schilling test.

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Treatment:�

Parenteral administration of vitamin B₁₂ – 1mg => prompt response with reticulocytosis in 2-4 days.
If neurological manifestation, give 1 mg of vitamin B₁₂ IM daily for 2 wks.

Maintenance therapy of 1 mg IM monthly for life.

Oral administration may succeed with high doses, but generally not advisable due to uncertainty of absorption.

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Microcytic Anaemia:�

. Iron deficiency anaemia

Sideroblastic anaemia
Lead poisoning
Rare types of Hypochromic microcytic anaemia

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1.Iron Deficiency Anaemia:�

It is the most common hematological disorder of infancy and childhood.
NB Infant has about 0.5g of iron, whereas adult content of iron is 5.0 g.
0.8 – 1.5 mg of iron must be absorbed each day, less than 10% of dietary iron is absorbed, a diet containing 8 – 15mg of iron is necessary for optimal nutrition.

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Etiology Iron def�

LBW and significant perinatal haemorrhage is associated with a decrease in neonatal Hb mass and stores of iron
The reclaimed iron from the high Hb as the Hb level falls within the 1st 2 – 3 months is usually sufficient for blood formation for the 1st 6 – 9 month of life.
Transplacental iron stores are exhausted by the time birth weight is approximately 3 xs. Anaemia due solely to inadequate dietary iron is unusual during the 1st 4 – 6 months, but becomes common from 9 – 24 months of life.

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Etiology…..�

Consumption of large amount of milk and CHO unsupplemented with iron.
Blood loss
Chronic iron deficiency – occult bleeding, due to GIT lesions such as peptic ulcer, Meckel diverticulum's, polyps or hemangioma, Hookworm infestation.
Cow milk intolerance which will lead to chronic intestinal blood loss

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Clinical Manifestations fe2+ def�

Pallor => mild to moderate, Hb 6- 10 g/dl. The compensatory mechanism is an increase in 2, 3-DPG and a shift of the oxygen dissociation curve, few symptoms are noticed.
Hb falls below 5.0 g/dl; you now experience irritability, anorexia, tachycardia, systolic murmur and cardiac dilatation. Spleen is enlarged in 10 –15% of cases.
Long standing cases may show widening of dipole of the skull.

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Clinical Manifestations…..�

Child may be obese, or underweight with evidence of malnutrition.
Pica sometimes becomes prominent.
The irritability and anorexia are characteristics of advanced cases, which may reflect deficiency in tissues iron stores.
Iron deficiency produces a decrease in the activities of enzymes, such as catalyses and cytochromes.
Has effects on neurologic and intellectual function, affects attention span, alertness and learning of both infants and adolescents

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Examination of the PB smear may provide some clues:

Pencil cells and occasional target cells suggest iron deficiency.
A raised Red Cell Count is suggestive of Thalassemia Trait.
Marked increase in target cells, occasional fragments and basophilic stippling are features of Thalassemia intermedia and Thalassemia major
Basophilic stippling is a feature of Lead poisoning.

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Laboratory data�

In progression of iron deficiency anaemia, a sequence of biochemical and hematological events occur:

Decrease in iron stores; decrease in hemosiderin content of liver and bone marrow
Decrease in levels of serum ferritin to < 10ng / ml (childhood mean level of serum ferritin is 35 ng / ml).
Decrease in level of serum iron <30 ug / dl, the iron binding capacity of the serum increases to > 350 ug / dl, and the % of saturation falls below 15%.

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Iron deficiency anaemia. a and b Erythrocyte morphology in iron deficiency

anaemia: ring-shaped erythrocytes (1), microcytes (2) faintly visible target cells

(3), and a lymphocyte (4) for size comparison. Normal-sized erythrocytes (5) after transfusion. c Bone marrow cytology in iron deficiency anaemia shows only increased

hematopoiesis and left shift to basophilic erythroblasts (1). d Absence of iron deposits after iron staining (Prussian blue reaction). Megakaryocyte (1).

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Differential Diagnosis Fe2+ def��

Lead poisoning
B – thalassemia trait

Treatment of def

Oral administration is the best
Ferrous sulfate – elemental iron is 20%
Ferrous gluconate – elemental iron is 10 –12%
Daily total dose of 6 mg / kg of elemental iron in 3 divided doses. Doses exceeding 6 mg / kg do not result in a more rapid hematologic response.
Dose given in between meals
Decrease ingestion of large amount of milk.
Parental iron given in cases of compliance, but not superior to oral form

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Treatment…..�

Clinical and hematologic responses to iron therapy

12 –24 hrs, replacement of intracellular iron enzyme, there is subjective improvement, decrease in the irritability.
36 –48 hrs, you have initial bone marrow response, erythroid hyperplasia.
48 –72 hrs, Reticulocytosis, peaks at 5 – 7 days.
By 1 –3 months – repletion of stores.

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Depiction of red blood cell morphologies that may appear on a peripheral smear, showing: (A) basophilic stippling, (B) Howell-Jolly bodies, (C) Cabot's ring bodies and (D) Heinz's bodies.

)

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Laboratory findings

Basophilic stippling (Figure a) representing aggregated ribosomes can be seen in thalassemia syndromes, iron deficiency and lead poisoning.
Howell-Jolly bodies (Figure b) are nuclear remnants seen in asplenia, pernicious anemia and severe iron deficiency.
Cabot's ring bodies (Figure c) are also nuclear remnants and are seen in lead toxicity, pernicious anemia and hemolytic anaemias.
Heinz's bodies (Figure d) are from denatured aggregated hemoglobin and can be seen in thalassemia, asplenia and chronic liver disease

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Hereditary Spherocytosis�

Transmitted as an autosomal dominant trait.
Approximately 25% of cases are sporadic and presumably represent new mutations.
Basic defect is the abnormality of the spectrin of the red cell membrane.
Affected cells are unduly permeable to sodium and acquire the characteristic spherocytic shape because of loss of membrane function and increase in volume
The Splenic circulation imposes a metabolic and mechanical stress sequestration and destruction.

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Clinical Manifestation�

Onset in infancy and may present in the neonatal period with anaemia
increase total serum bilirubin, severe enough to require phototherapy or EBT.
Anaemia variable
Moderate expansion of the marrow cavity of the skull
After infancy, splenomegaly
Gallstones – reported as early as 4 – 5 yrs of age, but they usually do not develop until late childhood or adolescence.

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Laboratory findings�

Evidence of Haemolysis – increase reticulocytes, anaemia, and hyperbilirubinemia.
Spherocytic red cells without central pallor.
Erythroid hyperplasia
Abnormally increased osmotic fragility
Autohemolysis test.

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Treatment of Cong. Spherocytosis�

Splenectomy deferred whenever possible until the patient is 5 – 6 yrs of age or older.

Polyvalent Pneumococcal vaccine should be given prior to Splenectomy

Prophylactic penicillin therapy is given thereafter.

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APLASTIC ANAEMIA

Aplastic anaemia is characterised by a failure of blood cell production resulting in varying degrees of pancytopenia with a markedly hypocellular or aplastic bone marrow.

AETIOLOGY

Acquired

Chemicals eg Benzene
Drugs eg Chloramphenicol
Radiation
Viruses eg EBV, Hepatitis virus
Miscellaneous eg Connective tissue disorders, Pregnancy

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AETIOLOGY…

Hereditary eg Fanconi anaemia
Idiopathic cases about 65%

The onset of aplastic anaemia may be insidious or acute.

Symptoms relate to the cytopenias:

CLINICAL FEATURES

Anaemia = Pallor, weakness, fatigue
Neutropenia = Infections
Thrombocytopenia = Petechial haemorrhages, purpura.

NB: lymphadenopathy and splenomegaly are not ordinarily found in aplastic anaemia and if present, suggest recent infection or an alternative diagnosis such as leukaemia or lymphoma

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LABORATORY FINDINGS

Peripheral Blood.

Varying degrees of pancytopenia. (Lymphocyte counts are relatively well maintained).
Morphology is unremarkable with the exception of macrocytosis in some cases.

Reticulocyte Count

Bone Marrow.

The bone marrow is markedly hypocellular/aplastic with virtual absence of normal haemopoietic precursors.
Again, lymphocytes in the marrow may be relatively well maintained.

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Severe Aplastic Anaemia has been defined as:

Bone marrow cellularity of <25%

Neutrophil count <0.5x109/l

Platelet count <20x109/l

Anaemia with a reticulocyte count <1%

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Treatment, Clinical Course And Prognosis

The median survival of untreated patients with severe aplastic anaemia is 3-6 months.
Prompt and aggressive therapy is therefore indicated for patients with severe disease.
Those patients with less severe disease (Neutrophils >1.0x109/l, do not require red cell or platelet transfusions)
Once the diagnosis is confirmed the patient should be treated in consultation with specialist haematologists since the management of these patients is complex

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Treatment options

Bone Marrow Transplantation.

This is curative in 60-80% of cases.
However only 30% of patients have compatible donors

Immunosuppressive therapy

Certain cases of aplastic anaemia may be mediated by a cellular immune reaction against haemopoietic stem cells. These may respond to immunosuppressive therapy and steroids

Anti-lymphocyte globulin (ALG)
Cyclosporine
High dose steroids

Androgen therapy

These may be effective in cases of moderate/mild hypoplasia.

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Supportive Care

Neutropenic precautions should be applied:

Barrier nursing.
The patient should be in an isolation unit.
Prompt treatment of fever with broad-spectrum antibiotics.

Transfusion support may lead to iron overload
Iron chelation should be considered in these patients

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General Blood Transfusion Order

Simulation Question

This is a sickle cell anaemia patient; his PCV is 10% and requires blood transfusion, assuming that the patient has already been cannulated. Describe the various steps involved in setting up the transfusion I am listening.

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Approach

Introduction and explanation or orientation
Indicate need to group and cross match patients blood
Indicate need to prescribe blood at 15mls/kg for pack cell or 20mls/kg for whole blood
Indicate need to consider prescribing frusemide at 1-2mg/kg
Indicate need for baseline investigations to be recorded
Ensure patient identity data matches that on identity bracelet, case notes, prescription chart, blood compatibility report form and expiring date of the blood

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