Pneumocystis pneumonia High dose co-trimoxazole or pentamidine then lifelong prophylaxis Tuberculosis Multi-agent therapy (drug resistance common) lifelong isoniazid prophylaxis Fungal pneumonia Amphotericin B then lifelong prophylaxis CMV pneumonitis/retinitis Ganciclovir/foscarnet then lifelong prophylaxis CNS toxoplasmosis Pyrimethamine then lifelong prophylaxis. Cryptococcal meningitis Amphotericin/fluconazole AIDS-related Kaposi \200\231s sarcoma Limited disease: local DXT, cryotherapy, intra-lesional vincristine, interferon- ; advanced disease: combination chemotherapy such as adriamycin, bleomycin and vincristine (ABV), liposomal daunorubicin, paclitaxel 419 Non-Hodgkin \200\231s lymphoma Poor prognosis; combination chemotherapy (often standard regimens at reduced dosage due to toxicity) 50% response, median survival <9 mo; CNS lymphoma particularly poor prognosis; pa lliative dexamethasone DXT 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 420 This page intentionally left blank 420 12-Pediatric.qxd 10.12.2003 04.28 PM Page 421 Pediatric hematology 12 Blood counts in children 422 Red c ell transfusion and blood component therapy \200\224special 424 considerat ions in neonates and children Polycythaemia in newborn and childhood 428 Neonatal anemia 430 Anemia of prematurity 432 Haemolytic anemia in the neonate 434 Co ngenital red cell defects 436 Acquir ed red cell defects 438 Haemolytic disease of the newborn (HDN) 440 Hyperbilirubinaemia 444 Neonatal haemostasis 446 Neonatal alloimmune thrombocyto penia (NAIT) 448 Congenital dyserythropoietic anaemias 450 Congenital red cell aplasia 452 Acquired red cell aplasia 454 Fanconi \200\231s anemia 456 Rare congenital marrow failure syndromes 458 Neutropenia in childhood 462 Disorders of neutrophil function 464 Childhood immune (idiopathic) thrombocytopenic purpura (ITP) 466 Hae molytic uraemic syndrome 468 Childhood c ancer and malignant blood disorders 470 Childhood lymphoblasti c leukemia 474 Childhood lymphomas 478 Childhood acute myeloid leukemia 482 Childhood myelodysplastic syndromes and chronic leukaemias 486 Histiocytic syndromes 490 Hematological effects of systemic disease in children 494 12-Pediatric.qxd 10.12.2003 04.28 PM Page 422 Blood counts in children Blood counts in children are often different from adults, to varying degrees at different a ges. The differences are greatest during the neonatal period. Red cells The relatively hypoxic intrauterine environment means that the newborn is polycyt haemic by adult standards, a phenomenon that self-corrects during the first 3 months of lif e by which time the normal infant is anemic relative to adults. Neonatal red cells are also macrocytic by adult stan- dards, a feature that also disappears during the first 6 months as HbA replaces HbF. 2 Neonatal red cells show much greater variation in shape than those from adults, particularly in premature babies \200\224alarming microscopists more used to a dult blood films. 2 Occasional nucleated red cells are normal in the first 24 \200\22348h of life. 2 Iron lac k is common around 12 months of age due to increased demand from 4 red cell mass and (often) poor oral intake \200\224cows \200\231 milk has vir tually no iron content. The MCV falls to what would be abnor- mally low levels for adults a s a reflection of this. 2 In healthy premature neonates all these red cell differences may be exaggerated, with a nadir Hb at 2 \200\2233 months of 8 \200\2239g/dL in those with birth w eight 1 \200\2231.5kg. 2 Children have slightly lower Hb than adults until puberty. White cells The most striking difference between children and adults is the high lym- phocy te count in infants and young children. This means that the normal differential WBC in thos e <4 years shows more lymphocytes than neu- trophils. Otherwise most of the changes in whit e cell counts seen in chil- dren are similar to those seen in adults and due to the same ca uses, with a few exceptions: 422 2 Healthy term babies show a transiently raised neutrophil count in the first 24h after bir th (7 \200\22314 109/L) which returns to the normal (adult) range by 48h. 2 Immature neutrophils (band cells and myelocytes) may comprise 5 \200\22310% of the total WBC in healthy neonates. 2 Sick neonates with bacterial infections commonly show a paradoxical neutropenia, with or without an increased band cell count. 2 Black children have lower neutrophil counts that other ethnic groups. 2 Lymphocytoses wit h very high counts occur in children with specific infections \200\224notably pertussis. Platelets Platelet counts in children are essentially the same as adults as far as the lowe r limit is concerned, but there is greater volatility at the upper end and infants tend to produce high counts (>500 109/L) as part of an acute phase reaction more frequently. The re is a statistically significant fall in the upper limit (95th centile) from 4 years onwar ds from around 500 to reach 350 \200\223400 by the end of childhood. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 423 Pediatric hematology Cord blood platelets are less reactive to aggregating agents in vitro and have other featur es of hypofunction compared with mature platelets. Normal blood count values from birth to adulthood (source Pediatric Hematology 2E; eds. Lil leyman, Hann and Blanchette; Churchill Livingstone, London 1999). Age Hb (g/dL) MCV (fL) Neuts Lymph Platelets 14.9 \200\22323.7 100 \200\223125 Birth 13.4 \200\22319.8 88 \200\223110 2 weeks 2 months 9 .4 \200\22313.0 84 \200\22398 6 months 10.0 \200\22313.0 73 \200\22384 1 year 10.1 \200\223 13.0 70 \200\22382 2 \200\2236 years 11.5 \200\22313.8 72 \200\22387 6 \200\22312 years 11. 1 \200\22314.7 76 \200\22390 Adult 9 12.1 \200\22316.6 77 \200\22392 Adult 3 12.1 \200\2231 5.1 77 \200\22394 2.7 \200\22314.4 1.5 \200\2235.4 0.7 \200\2234.8 1 \200\2236 1 \200\2238 1.5 \200\2238.5 1. 5 \200\2238 1.5 \200\2236 1.5 \200\2236 2 \200\2237.3 2.8 \200\2239.1 3.3 \200\22310.3 3.3 \200\22311.5 3.4 \200\22310.5 1.8 \200 \2238.4 1.5 \200\2235 1.5 \200\2234.5 1.5 \200\2234.5 150 \200\223450 170 \200\223500 210 \200\223650 210 \200\223560 200 \200\223550 210 \200 \223490 170 \200\223450 180 \200\223430 180 \200\223430 Neuts, neutrophils; lymph, lymphocytes and platelets, all 109/L 423 Other hematological variables in childhood There are important differences in the concentration of various clotting factors during ear ly infancy as described on p690. Other laboratory inves- tigations where children differ in clude: 2 Reticulocyte counts low in the first 8 weeks of life as neonatal poly- cythaemia corrects itself. 2 HbF comprises 75% of the total Hb at birth, 10% at 5 months, 2% at 1 year and <1% thereafter. 2 Some red cell enzymes (G6PD, PK, hexokinase) have greater activity (150 \200\223200% of adult values) in neonatal RBC. 2 The lower limit of normal for serum ferritin at 1 year (12.5mg/L) is 50% of the LLN at 12 years (25mg/L). 2 B12 and folate levels are around 2 higher in infants and younger chil- dren than adults. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 424 Red cell transfusion and blood component therapy \200\224special considerations in neonates and children Babies in Special Care Baby Units are now amongst the most intensively transfused of our ho spital patients. 2 To replace blood losses of investigative sampling. 2 To alleviate anemia of prematurity. Note: 2 Hb estimation alone is an inadequate assessment. 2 Hb reduction with symptoms, e.g. failure to thrive, is needed to justify transfusion. 2 Generally, neonatal Hb <10.5g/dL + symptoms \200\224transfuse; if neonate requiring O2 support, aim for Hb 13.0g/dL. Source of blood Directed donations from \200\230walking donors \200\231 (including donatio ns from rela- tives) cannot be regarded as safe as microbiologically-screened volunteer don or blood \200\224therefore not recommended. Small volume transfusions QUAD \200\230pedipacks \200\231 (SAGM blood) ensure that 4 trans fusions possible from a single donor and so 5 donor exposure in infant needing multiple tra nsfusions. 424 Pre-transfusion testing Maternal and neonatal samples should be taken and tested as follows : Maternal samples 1. ABO and Rh group. 2. Antibody screen. Infant samples 3. ABO and Rh group. 4. DAT. 5. Antibody screen (if maternal sample unavaila ble). Note: Provided no atypical antibodies are present in maternal or infant serum and the DAT o n the infant \200\231s cells is \200\223ve, a conventional cross- match is unnecessary. Sm all volume replacement transfusions can be given repeatedly during the first 4 months of li fe without further serological testing. Transfusion centers may specifically designate a su pply of low anti- A, B titre group O Rh (D) \200\223ve blood for use in neonatal transfusi ons. After the first 4 months, compatibility testing should conform to requirements for adu lts. Exchange transfusions 2 To prevent kernicterus caused by rapidly rising bilirubin. 2 Most c ommonly needed in haemolytic disease of the newborn. 2 Plasma-reduced red cells (Hct 0.50 \200\2230.60). 12-Pediatric.qxd 10.12.2003 04.28 PM Page 425 Pediatric hematology 2 For small volume transfusions, age of red cells does not matter. For exchange transfusions within 5d of collection. ([K+] levels rise in older blood). 2 Transfusion should not take >5h/unit due to risk of bacterial prolifera- tion. 2 Volumes of 5mL/kg/h usually safe. Special hazards 2 GvHD: in congenitally immunodeficient neonates immunocompetent donor T lymphocytes can cause GvHD \200\224rare. 2 Need to irradiate all blood products in these children. Also irradiate if first degree relatives used as donors. 2 CMV infection: particular risk in low birth weight babies, or immuno- compromised childre n undergoing transplantation. CMV seronegative donations should be used. Alternatively use (modern) leucodepletion filter to reduce risk. 2 Hypocalcaemia \200\224rare now, due to change of additive. 2 Citrate toxicity, also rare nowadays due to improvements in additive. 2 Rebound hypoglycaemia, induced by high glucose levels of blood trans- fusion anticoagulants. 2 Thrombocytopenia \200\224dilution, DIC. 2 Volume overload. 2 Haemolytic transfusion react ions in necrotising enterocolitis. Thought to be due to the \200\230T \200\231 antigen on baby \200\231s RBCs becoming exposed due to action of bacterial toxin entering the blood fr om diseased gut. Anti \200\230T \200\231 is present in almost all donor plasma. 425 Use of 4.5% albumin Use controversial, but may be helpful after large volume paracentesis, as fluid replacement in therapeutic plasma exchange, or in nephrotic syn- drome resistant t o diuretics. There are better products for resuscitation and volume expansion. Should NOT b e used in nutritional protein defi- ciency or chronic hypoalbuminaemia (e.g. cirrhosis or p rotein-losing enteropathy). Risk of infection transmission minimal but not zero. Use of immunoglobulin Intravenous polyvalent immunoglobulin widely used as replacement ther apy in immunodeficiencies, for Kawasaki disease to prevent the for- mation of coronary micr oaneurysms, and also as non-specific agent for reticuloendothelial blockade in immune cytop enias, chiefly (and usually unnecessarily) in childhood ITP. Can get immunoglobulin with pa rticularly high titre against RSV, HZV and hepatitis B. Usually this is for intramus- cular use only and should not be given IV due to risk of complement acti- vation. IVIg has trans mitted hepatitis C in the past due to poor virus inactivation procedures, so should not be used in trivial conditions. Use of FFP Available in aliquots of 50mL. Must be ABO and Rh compatible. Infused via filter . Main indication \200\224DIC. No need for CMV screening, or irradia- 12-Pediatric.qxd 10.12.2003 04.28 PM Page 426 tion. Dose: 10 \200\22315mL/kg. Check PT and APTT. Repeat as necessary. May need cryoprecip itate also ((cid:9) p524, 654), if evidence of 5 fibrinogen (<1.0g/L). Both contain untreat ed plasma, so potential infection risk, though FFP should be virus-inactivated in future. Use of platelets 2 Thrombocytopenia more hazardous in neonates, so prophylactic trans- fusion if count <30 109/L. 2 Reserve for children with marrow failure and counts <10 109/L oth- erwise: \200\223 Only use in immune thrombocytopenia for life-threatening bleeding. \200 \223 Then use massive \200\230swamping \200\231 dose to overwhelm antibody. \200\223 One dose (one pediatric platelet concentrate) contained in 50mL \200\230fresh \200\231 plasma , available either from apheresis or buffy coat derived. \200\223 Check increment 1h later if no clinical response. \200\223 Care with volume over load. \200\223 Must be administered within 2h of receipt on ward. \200\223 Irradiate for immunosuppressed children. \200\223 Refractoriness can arise due to alloimmune antibodies. Use of granulocytes 2 Severely infected neonates may develop profound neutropenia. 2 Usuall y respond to antibiotic therapy. 2 Granulocyte transfusions very rarely given because of la ck of effect, risk of CMV and toxoplasmosis and respiratory distress syndrome. 2 Blood prod ucts now routinely leucodepleted to reduce risk of CMV transmission. 426 12-Pediatric.qxd 10.12.2003 04.28 PM Page 427 Pediatric hematology 427 12-Pediatric.qxd 10.12.2003 04.28 PM Page 428 Polycythaemia in newborn and childhood As in adults, polycythaemia in children may be relative or absolute ((cid:9) p240, 248). Th e condition is usually secondary and most commonly seen as a clinical problem in neonates o r older children with congenital cyan- otic heart disease or high-affinity abnormal haemogl obins. Primary poly- cythaemia is very unusual in childhood; benign familial erythrocytosis is a very rare autosomal dominant self-limiting condition of unknown aeti- ology. Pathophysiology Polycythaemia is physiological in the neonatal period with 4 Hct (range 42 \200\22360% in cord blood) persisting in the first few days of life. Pathological polycytha emia is defined in the neonate as Hct >65% (Hb >22.0g/dL), is uncommon (<5% of all births) and usually due to hypertransfusion or hypoxia. Causes of polycythaemia in the newborn 2 Relative \200\224dehydration, reduced plasma volum e. 2 Hypertransfusion \200\224delayed cord clamping, maternofetal, twin to twin. 2 Hypoxia \200\224placental insufficiency, intrauterine growth retardation. 2 Endocrine \200\224conge nital adrenal hyperplasia, thyrotoxicosis. 2 Maternal disease \200\224toxemia of pregnancy, DM, heart disease, drugs e.g. propranolol. 2 Other miscellaneous conditions such as Down syndrome. 428 Clinical features Hyperviscosity may give rise to vomiting, poor feeding, hypotonia, hypo- glycaemia, lethargy, irritability and tremulousness. On examination \200\224 plethora, cyan osis, include intracranial hemorrhage, respiratory distress, cardiac failure, necrotising e nterocolitis and neonatal thrombosis. jaundice, hepatomegaly. Complications Diagnosis 2 Clinical presentation may suggest the diagnosis e.g. anemic twin. 2 FBC (free-f lowing venous sample) 4 neonatal Hct >65%. 2 Hypoglycaemia, hypocalcaemia, unconjugated hyp erbilirubinaemia. 2 Hb studies for excess HbA \200\224? maternal hemorrhage. 2 Radiology: C XR shows 4 vascularity, infiltrates, cardiomegaly. Management 2 Supportive \200\224IV fluids, close observation for complications. 2 Exchange transfusion \200\224partial with FFP/albumin to 5 Hct<60%. Vol of exchange (mL) = Blood vol (observed \200\223 desired Hct) observed Hct Treatment As required for associated abnormalities. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 429 Pediatric hematology Outcome Provided the condition is identified early and appropriate measures taken to reduce the hyperviscosity, the outcome should be good. 429 12-Pediatric.qxd 10.12.2003 04.28 PM Page 430 Neonatal anemia Intrauterine conditions require a state of polycythaemia. Congenital anemia is present with cord blood Hb <14.0g/dL in term babies. In the healthy infant, Hb drops rapidly after birt h ((cid:9) Blood Counts in Children p690) and by end of the neonatal period (4 weeks in a t erm baby), the mean Hb may be as low as 10.0g/dL. With 4 RBC destruction, there is a concom itant 4 in serum bilirubin. Thus complex changes occur in this period making distinction be tween physiology and pathology difficult. Pathophysiology In normal full term babies, red cell production 5 in the first 2 \200\2233 months of life. RBC survival shortens; reticulocytes and erythropoietin production 5; iron, folate and vitamin B12 stores are normal. Anemia in the neonate may be due either to impai red production of RBCs or to increased destruc- tion or loss. Impaired production Increased destruction Anemia of prematurity Overt or concealed hemorrhage; repeated Infection a thalassaemia DBA Fanconi anemia CDA venepuncture Haemolytic anemia Non-immune TORCH infection Congenital RBC abn. Maternal autoimmune haemolytic anemia Drugs, MAHA Immune Rh/ABO HDN TORCH, toxoplasmosis, rubella, CMV, herpes simplex; DBA, Diamond \200\223Blackfan anemia; C DA, congenital dyserythropoietic anemia; Rh/ABO HDN, rhesus/ABO haemolytic disease of the n ewborn; MAHA, microangiopathic haemolytic anemia. 430 Blood loss during delivery is common, in 1% severe enough to produce anemia. Infection is also a significant cause of anemia; primary haemato- logical disorders are rare. Anemia in premature infant is almost invariably present, induced and multifactorial. Jaundice arises in 90% healthy infants making interpretation of a raised bilirubin ((cid:9) hyperbilirubina emia, p444) a critical piece of the jigsaw when investigating an anemic neonate. Clinical features History may make the diagnosis. Check events at time of delivery, past ob stetrical history, maternal and family history. Non-specific symptoms \200\224 lethargy, re luctance to feed, failure to thrive \200\224all may indicate anemia. Laboratory tests 2 FBC and reticulocytes. 2 MCV and RBC morphology, bilirubin and Kleihauer (on mother) Interpret as follows: \200\223 Reticulocyte count normally very low in first 6 weeks of life. \200\223 4 haemol ysis, blood loss. \200\223 +ve Kleihauer suggests fetomaternal bleed (quantitate amount). \200\223 Bilirubin 4 (unconjugated). \200\223 Check DAT: +ve in immune haemolytic anemia (except ABO HDN). 12-Pediatric.qxd 10.12.2003 04.28 PM Page 431 Pediatric hematology \200\223 Negative in other haemolytic anaemias, including ABO HDN). \200\223 Bilirubin 4 (conjugated/mixed look for hepatobiliary obstruction/dysfunction). 2 Blood movie \200\223 Note: 4 polychromasia, occasional NRBC, poikilocytes and sphero- cytes day 1 \200\2234 in healthy babies. \200\223 RBC morphology may suggest congenital spherocytosis, other RBC membrane disorders or HDN. 2 5 MCV \200\224a thalassaemia syndromes. 2 4 WBC \200\224?reactive, ?congenital leukemia. 2 Neutropenia \200\224?sepsis, ?marrow failure. 431 12-Pediatric.qxd 10.12.2003 04.28 PM Page 432 Anemia of prematurity Anemia is an almost invariable finding in the premature infant. By week 3 \200\2234 of life the Hb may be as low as 7.0g/dL in untreated infants. In a study of very low birth weight infants (750 \200\2231499g) 75% required blood transfu- sion. A number of factors are causa l. Pathogenesis 2 RBC production and survival are 5. 2 Erythropoietin production very low in t he first few weeks. 2 Iatrogenic from repeated blood sampling (depletes the RBC mass and Fe stores \200\224by 4 weeks the premature baby may have had its total blood volume removed). Clinical features The increased oxygen needs and metabolic demand of the premature baby mak es them less able to tolerate 5 Hb. Over 50% infants <30 weeks gestation develop tachycardi a, tachypnoea, feeding difficulties and 5 activity when anemic. High HbF level and 4 O2 aff inity exaggerates the hypoxia. Treatment 2 Delayed cord clamping increases Fe stores. 2 Close control of blood sampling is important. 2 Transfusion indications will vary in neonatal units \200\224decide on clinica l grounds, particularly if ventilated. The following are guidelines only: \200\223 Prems < 2 wk with Hb <14.0g/dL, Hct <40%. \200\223 Prems >2 wk, Hb <11.0g/dL, Hct <32%. 432 2 A rising reticulocyte count in some centers is used as a sign to with- hold transfusion. 2 Some studies have shown better weight gain in transfused infants (not confirmed by others). 2 Fe supplementation (2mg/kg/d PO) after first 2 weeks and until iron sufficient. 2 Erythropoietin \200\224controversial. It can be effective but its indiscriminate use is n ot encouraged. Large randomized trials have shown it to have an effect, but its expense mak es cost effectiveness a concern and modern neonatal practice has already reduced the need f or transfusion making it less necessary. Its best use is probably reserved for transfu- sio n avoidance in infants weighing <1000g. A suitable regimen would be 200 \200\223250u/kg SC 3/week between day 3 and week 6. Natural history Despite the growing safety of blood and its ready availability and conve- n ient packaging to reduce donor exposure, blood transfusion carries defi- nite risks and is to be avoided. It is likely that in affluent societies the use of erythropoietin will incre ase, despite its limited effect. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 433 Pediatric hematology 433 12-Pediatric.qxd 10.12.2003 04.28 PM Page 434 Haemolytic anemia in the neonate Normal red cell life span in term infants is <80 days, in pre-term infants <50 days. Red ce ll \200\230cull \200\231 in first month with jaundice is physiologic. Pathological haemoly sis, when present, is most commonly due to isoim- mune HDN secondary to fetomaternal blood group incompatibility in Caucasian populations. In other ethnic groups G6PD deficiency and con- genital infection are major causes. Pathophysiology Physiological haemolysis occurs soon after birth and there is a marked drop in the Hb and RBC count in the first weeks of life. Neonatal RBCs are more susceptible to oxidative stress and there is altered RBC enzyme activity compared to adult RBC and reticul ocytes. So pathological haemol- ysis occurs in the neonatal period more than at any other t ime. Causes of haemolytic anemia Haemolysis may be due to intrinsic defects of the RBC, usually congenital, or to acquired extracorpuscular factors which may be immune or non- immune as d escribed below. Clinical features 2 Pathological jaundice may be clinically obvious at birth or within 24h (distinguishing it from the common physiological anemia which occurs >48h after birth, (cid :9) Hyperbilirubinaemia, p444). 2 Anemia may be severe depending on cause. 2 Infections are common cause of hyperbilirubina emia ((cid:9) p444) with specific clinical findings. In utero infections (TORCH) do not usu ally cause severe jaundice cf. post-natal bacterial sepsis where jaundice may be striking a nd associated with MAHA. 434 2 Splenomegaly at birth indicates a prenatal event; when noted later it may be secondary to splenic clearance of damaged RBC and is non-specific. 2 Kernicterus is the major complicat ion of neonatal hyperbilirubinaemia. 2 Family history and drug history may be informative. Laboratory diagnosis of haemolysis 2 4 unconjugated bilirubin with anemia is hallmark of ha emolytic anemia. 2 4 reticulocytes (haptoglobins are unreliable in the newborn). 2 Blood movie \200\224may s how RBC abnormalities e.g. spherocytes, ellipto- cytes, fragmented cells. 2 DAT, if +ve indicates immune haemolysis; \200\223ve does not rule this out \200\224 especially consider ABO HDN. 2 Heinz body test \200\224positive in drug-induced haemolysis, G6PD defi- ciency and occasionally other enzyme disorders. 2 Intravascular haemolysis \200\224look for haemoglobinuria/haemoglobinaemia. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 435 Pediatric hematology 435 12-Pediatric.qxd 10.12.2003 04.28 PM Page 436 Congenital red cell defects Pathophysiology The neonate is uniquely disadvantaged when it comes to handling patho- logi cal haemolysis because of hepatic immaturity and altered enzyme activity. Thus congenital d efects of the RBC commonly present in the newborn except for defects involving the b globin chain (e.g. SCD, b tha- lassaemia) which become clinically manifest several weeks after bi rth but can be diagnosed in utero, or in the neonatal period if suspected. HS is the common est congenital haemolytic anemia in Caucasian populations; half present in the neonatal per iod. Worldwide, G6PD deficiency occurs in 3% population; neonatal presentation is common in Mediterranean and Canton peoples. a thalassaemia is incompatible with life causing hydrops fetalis (all 4 a globin genes deleted), or may present as HbH disease (3 of the 4 a globin genes deleted) with mild to moderate haemolysis in neonate. Hereditary RBC defects in neonatal haemolytic anemia 2 Membrane defects \200\223 Hereditary spherocytosis, hereditary elliptocytosis and variants e.g. stomatocyto sis and pyropoikilocytosis (Afro-Americans). 2 Hemoglobin defects \200\223 adb thalassaemia. \200\223 Unstable haemoglobins (e.g. HbK ln, HbZurich). 2 Enzyme defects \200\223 Glycolytic pathway; pyruvate kinase and other enzyme deficiencies. \200\223 Hexo se monophosphate shunt; G6PD deficiency, other enzymes. 436 Clinical features Congenital haemolytic anemia with mild or moderate unconjugated hyperbili rubinaemia. No gross excess of bile pigments in urine (old collec- tive name jaundice \200 \231), hepatosplenomegaly. A +ve family history is common but not invariable. for these diseases was \200\230acholuric Laboratory investigation May be difficult to diagnose in neonate, especially if post-transf usion. Often have to wait until clinically stable some weeks/months later. 2 Exclude acquir ed disorders, and immune lysis (DAT). 2 RBC morphology is one key to diagnosis and further investigation, but spherocytes not specific for HS. 2 Further tests for suspected \200\223 Membrane defect (osmotic fragility, autohaemolysis, membrane chemistry). \200\223 Hb defect; Hb electrophoresis, HbF, A2 measurement. \200\223 Enzyme defect; Hein z body prep, screening tests for specific enzymes, G6PD, PK. 2 Heinz body test +ve \200\223 Drug or chemical induced in neonate without hereditary defect. \200\223 Enzyme d eficiency: G6PD commonest but consider others. \200\223 Unstable Hb. \200\223 a thalassae mia. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 437 Pediatric hematology Outcome Given supportive management including transfusion if necessary, most problems due t o congenital red cell defects other than haemoglo- binopathies will improve during the firs t weeks and months of life as the infant matures. 437 12-Pediatric.qxd 10.12.2003 04.28 PM Page 438 Acquired red cell defects These may be either immune or non-immune. Main cause of the latter will be underlying infec tion either acquired in utero or in the days following delivery. Drug-induced haemolysis in the newborn is rare. Pathophysiology Neonatal RBCs have 4 sensitivity to oxidative stress due to altered enzyme activity, and are more liable to be destroyed by altered physical conditions, mechanical fa ctors, toxins and drugs than adult RBC. Infection acquired in utero post-natally is a commo n cause of mild to moderate haemolytic anemia. The mechanism is multifactorial, and include s 4 retic- uloendothelial activity and microangiopathic damage. Drug-induced haemolysis and Heinz body formation is occasionally noted as a transient phenomenon in normal neonatal RB Cs as a result of chemical or drug tox- icity but is much more often seen when there is an underlying RBC defect such as G6PD deficiency. Acquired RBC defects causing congenital haemolytic anemia 2 Infection \200\223 Congenital TORCH infections (TOxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex), also rare but serious are malaria (can cause stillbirth) and syphilis. \200\223 Post-natal, either viral or (more commonly) bacterial. 2 Microangiopathy \200\2242 to severe infections DIC, also Kasabach \200\223Merritt syndrome (giant haemangioma with haemolysis and thrombocytopenia). 2 Drug or chemically induced. 2 Infantile pyknocytosis ((cid:9) Vitamin E deficiency, below ). 2 (Rare) metabolic disease such as Wilson \200\231s disease, galactosaemia. 438 Clinical features Congenital infections: all rare with adequate antenatal care. Most infant s with herpes simplex will be symptomatic with DIC and hepatic dysfunction \200\224haemolys is is not a major finding. Haemolytic anemia is also mild in CMV and rubella infections but 50% infants with toxoplasmosis will be anemic (may be severe). Post-natal infections: viral, bacterial and protozoal (congenital malaria can be delayed fo r some days or weeks or it can be acquired early in life). Anemia can be severe and associa ted with DIC. MAHA 2 to toxic damage to the endothelium is rare in the neonate outside the context of D IC and sepsis, and is seen in burns and (classically) in the Kasabach \200\223Merritt syndr ome \200\224a visible or covert giant haemangioma with and profound thrombocytopenia. haemolysis, RBC damage Drugs/chemical exposure are more likely to cause Heinz body haemolysis in premature babies or those with G6PD deficiency. Incriminating agents include sulphonamides, chloramphenicol, mothballs, aniline dyes, maternal intake of diuretics and, in the past, water-soluble vita min K analogs. Vitamin E (a potent antioxidant) has a number of RBC stabilizing activities. Now rare due to dietary supplements, deficiency used to be seen 12-Pediatric.qxd 10.12.2003 04.28 PM Page 439 Pediatric hematology occasionally in premature infants, following oxygen therapy and diets rich in polyunsaturat ed fatty acids. Clinical findings included haemolysis, pre- tibial oedema and CNS signs. Ac anthocytosis/pyknocytosis of the RBC is characteristic, and this may have been the main cau se of infantile pyknocytosis. Infantile pyknocytosis: indicates the diagnostic feature of this uncommon acquired disorder . Haemolysis with increased numbers (>6 \200\22350%) of pyknocytes (irregularly contracted RBCs with multiple projections) in the peripheral blood. Cause unknown, though may be assoc iated with vitamin E deficiency. Anemia may be severe and present at birth, and is most str iking at 3 weeks (Hb <5g/dL reported). Exchange transfusion occasionally required but the condition spontaneously remits by 3 months. Its self-limiting nature and ill-understood pa thology means that it may not be a distinct clinical entity. Metabolic disorders \200\224rare. Laboratory investigation Criteria set out above will establish the diagnosis of haemolytic anemia. A +ve DAT points to an immune process \200\224probably Rh/ABO disease. If non-immun e, further tests to look for a congenital abnormality. The diagnosis may be made by 2 Peripheral blood findings. 2 Heinz body positive \200\224?ch emical/drug-induced haemolysis. 2 RBC enzyme screen to exclude G6PD or PK deficiency. 2 Hb electrophoresis to exclude Hb defects. 439 Often no definitive cause is found and the HA will be presumed 2 to underlying systemic i llness. Management 1. General supportive measures for hyperbilirubinaemia ((cid:9) p444). 2. Treatm ent of specific conditions \200\223 Haemolytic disease of the newborn \200\224(cid:9) p440. \200\223 Neonatal infect ion as appropriate. \200\223 Exchange transfusion almost never needed. Outlook Prognosis is that of the underlying condition. Anemia will usually respond as the c ondition is brought under control. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 440 Haemolytic disease of the newborn (HDN) Arises when there is blood group incompatibility between mother and fetus. Maternal Abs pro duced against fetal RBC antigens cross the pla- centa and destroy fetal RBCs. Most commonly caused by the rhesus D antigen, but maternal passive immunization with rhesus (Rh) D immun oglobulin (anti-D) introduced in the late 1960s transformed the outlook. Despite this, HDN due to anti-D and other red cell antibodies (e.g. anti-c, anti-Kell) still remains an impor tant cause of fetal morbidity. Pathogenesis Placental transfer of fetal cells7maternal circulation is maximal at delivery; the condition does not usually present in the firstborn (Note: ABO incompatibility is an e xception). Previous maternal transfusion, abor- tion, amniocentesis, chorionic villus sampl ing (CVS) or obstetric manipula- tions can cause antibody formation. Maternal IgG crosses p lacenta, reacts with Ag +ve fetal RBCs. Rh HDN classically presents as jaundice in first 24h of life. Mild HDN may go unnoticed and presents as persistent hyper- bilirubinaemia or late anemia w eeks after birth. Severe HDN may result in a macerated fetus, fresh stillbirth or severely anemic, grossly oe dematous infant (hydrops fetalis) with hepato- splenomegaly 2 to compensatory extramedull ary haemopoiesis in utero. Kernicterus: Neurological damage secondary to bilirubin deposition in the brain, depends on a number of factors including the unconjugated bilirubin level, maturity of the baby, the use of interacting drugs. 440 Diagnosis Rh HDN is the commonest cause of neonatal immune haemolysis; routine antenatal sc reening should identify most cases prior to delivery allowing appropriate action. In suspected case at delivery cord blood is tested for 2 ABO and Rh (D) group. 2 Presence o f antibody on fetal RBCs by DAT. 2 Hb and blood movie (spherocytes, increased polychromasia , NRBCs). 2 Serum bilirubin (4). Maternal blood is tested for 2 ABO and Rh (D) group. 2 Serum antibodies against fetal cells (by indirect antiglobulin test, IAGT). 2 Antibody titre. 2 Kleihauer test \200\224detects and quantitates fetal RBCs in maternal c ircula- tion. Diagnostic findings include 2 DAT +ve haemolytic anemia spherocytosis in the infant. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 441 Pediatric hematology 2 Maternal anti-D, or other anti Rh antibody \200\224the next most common to produce severe disease is anti-c. ABO HDN Theoretically should occur more frequently since 1 in 4/5 babies and mothers are A BO incompatible. Usually occurs in group O mothers who may have high titres of naturally oc curring IgG anti-A or B, and with a boost to this during pregnancy haemolysis can occur. Clinical features First pregnancies are not exempt, but condition is usually mild. Presenta tion is later than with Rh HDN (2 \200\2234d, but may be weeks after birth). Diagnosis May be difficult \200\224DAT commonly and puzzlingly \200\223ve, but offending a nti- body can be eluted from infant RBC. Antibody studies Maternal high titre anti-A/B almost always in a group O mother cord- blood /infant \200\231s serum-an inappropriate antibody (e.g. anti-A in a group A baby). Other blood group antibodies Can occasionally produce severe HDN; anti-Kell in particular. Serological testing will establish diagnosis. Maternal autoimmune haemolytic anemia may pro duce a similar picture to alloimmune HDN where the auto-anti- body cross-reacts with the in fant RBC. Usually the diagnosis will have been made antenatally. Severity in infant varies depending on maternal condition. 441 Management \200\224prevention Routine antenatal maternal ABO and Rh D grouping and antibody testing carried out at booking visit ( 12 \200\22316 weeks). If antibody positive repeat at intervals to check the antibody titre. If antibody negative and Rh D negative repeat at 28 weeks \200\231 gestation. Establish if paternal red cells heterozygous, homozygous or negative for the specific Ag. Anti-D prophylaxis 2 250iu IM during pregnancy to Rh D negative women without anti- bodies to cover any intrauterine maneuver or miscarriage. 2 After delivery, a standard dose of 500iu anti-D within 72h unless baby is known to be Rh (D) \200\223ve. 2 If Kleihauer test result shows a bleed of >4mL give further anti-D. Treatment of affected fetus \200\224before delivery Treatment depends on past obstetric his tory, the nature and titre of the antibody and paternal expression of the antigen. The feta l genotype can be established by CVS, fetal blood sampling and PCR. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 442 Examination of the degree of hyperbilirubinaemia is indicated with a poor past history (exc hange transfusion or stillbirth in previous baby) and high titre (1:8 \200\2231:64) of an a ntibody likely to cause severe HDN (e.g. anti-D, anti-c or anti-Kell). The amniotic fluid b ilirubin at optical density 450nm dictates treatment according to the Liley chart (opposite ), which estimates the blood concentration. the amniotic fluid to assess Options include intrauterine transfusion (IUT) if fetus is not deemed mature enough for del ivery (check lung maturity on phospholipid levels) or induction of labor if it is. Intensiv e maternal plasmapheresis may be useful to reduce antibody titre. Advances in management of very premature babies are such that nowadays IUT rarely performed. After delivery 2 Full pediatric support \200\224metabolic, nutritional and respiratory. 2 I f unconjugated hyperbilirubinaemia not a problem, treat anemia (note: cord blood Hb <14.0g/dL) by simple transfusion. 2 Exchange transfusion with Rh (D) neg and (if possible) group specific blood for: \200\223 A severely affected hydropic anemic baby. \200\223 Hyperbilirubinaemi a (bilirubin level at or near 340mmol/L (20mg/dL) or rapidly rising level e.g. >20mmol/h) in first few days of life. \200\223 Signs suggesting kernicterus \200\224exchange transfusion may have to be repeated. 2 Phototherapy to reduce the bilirubin level. 2 Follow-up required \200\224late anemia can be severe particularly if exchange transfusion has not been carried out. 442 Outcome With modern techniques, the outlook is good even for severely affected infants. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 443 Pediatric hematology Liley chart 443 The amount of bilirubin can be quantitated by spectrophotometrically measuring absorbance a t 450nm wavelength in a specimen of amniotic fluid that has been shielded from light. The r esults (delta 450) are plotted on a \200\230Liley \200\231 curve, which is divided into th ree zones.