551 ACQUIRED IMMUNE DEFICIENCIES Combined B- and T-lymphocyte abnormalities Causes \200 Chronic lymphocytic leukemia. \200 Intensive chemotherapy. \200 Extensive radiotherapy. \200 Severe malnutrition. Clinical features and treatment E See Acquired T-lymphocyte abnormalities, p.550. Neutrophil/macrophage abnormalities Reduced numbers E See Neutropenia, p.600. Abnormal function E See Myelodysplasia, p.624, Myeloproliferative disorders, p.624, Histioc ytic syndromes, p.628. Clinical features Bacterial and fungal sepsis. Treatment Treat specifi c infections and consider prophylaxis. Hyposplenism Hyposplenism is an acquired immunodefi ciency without lymphocyte or neutrophil abnormalities. It arises either following splenectomy, or due to functional defi ciency as part of another disorder, especially sickle cell disease, infl ammatory bowel disease, and following BMT. It gives rise to susceptibility to overwhelming infection with certain orga nisms due to lack of the spleen \200\231s function as a fi lter. These include: \200 Stre ptococcus pneumoniae. \200 Neisseria menigitidis. \200 Haemophilus infl uenzae type B. \200 Falciparum malaria. The risk of hyposplenic infection is greatest in children in the fi rst 6 years of life. It dwindles thereafter but the risk continues into adult life. All facing splenectomy should be vaccinated against HIB, pneumococcus, and meningococcus type B and all splenectomized ch ildren and young adults (and those with sickle cell disease) should take prophylactic pheno xy- methylpenicillin 250mg bd (if allergic to penicillin use erythromycin). 552 CHAPTER 11 Immunode \201 ciency HIV infection and AIDS Infection with HIV-1 or HIV-2 produces a large number of haemato- lo gical eff ects and can simulate a number of hematological conditions during both the latent pre-clinical phase and once clinical syndrome of AIDS has developed. HIV infection divided into 4 stages. Stage 1: 1 infection Entry of HIV-1 or HIV-2 through a mucosal surface after sexual conta ct, direct inoculation into the bloodstream by contaminated blood products, or IV drug abus e can be followed by a transient febrile illness up to 6 weeks later associated with oral u lceration, pharyngitis, and lymphad- enopathy. Photophobia, meningism, myalgia, prostration , encepha- lopathy, and meningitis may also occur. FBC may show lymphopenia or lymphocytosi s often with atypical lymphocytes, neutropenia, throm- bocytopenia, or pancytopenia. Major diff erential diagnoses are acute viral meningitis and infectious mononucleosis. False +ve IM serology may occur. Specifi c IgM then IgG antibody to HIV appears 4 \200\22312 weeks af ter infection and routine tests for HIV may be \210\222ve for up to 3 months. However, the virus is detectable in plasma and CSF from infected indi- viduals during this period and t he patient is highly infectious. Stage 2: pre-clinical HIV infection Although viral titres fall in the circulation at this t ime there is signifi cant and persistent virus replication within lymph nodes and spleen. T he clini- cally latent period may last 8 \200\22310 years and circulating CD4 T-cell count remains normal for most of this period. However, there is a delayed, gradual, but progressi ve fall in CD4 T lymphocytes in most patients, who may remain asymptomatic for a prolonged period despite modest lymphopenia. A number of minor skin problems such as seborrhoeic derm atitis are characteristic of the end of the latent phase. A patient with latent HIV infecti on may have isolated thrombocyto- penia on routine blood testing. This is due to an immune mechanism and may be confused with ITP as there is frequently i platelet associated immunog lobulin. Stage 3: clinical symptoms Marked by onset of symptoms, rising titre of circulating virus, and decline in circulating CD4 T-cell count to <0.5 \227 109/L. Wide varia- tion in indivi dual patient \200\231s rate of progression at this stage. A number of minor opportunistic i nfections are common: oral/genital candida, herpes zoster, oral leucoplakia. Lethargy, PUO, and weight loss occur frequently. Deepening lymphopenia (CD4 <0.2 \227 109/L) invariably present when opportunistic infection occurs. Persistent generalized lymphadenopathy is a co ndition where lymphadenopathy >1cm at 2 or more extra-inguinal sites persists for >3 months . It is a prodrome to severe immunodefi ciency, opportunistic infection, and neoplasia. Stage 4: AIDS AIDS is now defi ned as the presence of a +ve HIV antibody test asso- ciated with a CD4 lymphocyte count <0.2 \227 109/L rather than by the 553 HIV INFECTION AND AIDS development of a specifi c opportunistic infection or neoplastic com- plication. This fi na l stage of HIV infection is associated with a marked reduction in CD4 T cells, severe life- threatening opportunistic infection, neoplasia, and neurological degeneration. Severity of these complica- tions usually refl ects the degree of immunodefi ciency as measured by the CD4 T-cell count. However, there is evidence that prophylactic therapy reduces the incidenc e of complications and newer antiviral therapies slow the progression of this stage. Hematological features of HIV infection \200 Lymphopenia \200\224CD4 lymphopenia may be m asked by CD8 lymphocytosis in stage 2; improved by antiviral therapy. Neutropenia \200\224marrow suppression by virus or therapy; splenic sequestration. Normochromic/normocytic anemia due to suppression of marrow by virus or therapy. Microangio pathic haemolysis associated with TTP. Thrombocytopenia \200\224suppression of marrow by virus or therapy or shortened survival du e to immune destruction (may respond to antiviral therapy), infection, TTP, or splenic sequ estration. BM suppression \200\224direct HIV eff ect or complication of antiretroviral therapy, ganciclovir, trimethoprim, or amphotericin therapy. BM infi ltration \200\224by NHL, HL, granulomas due to M. tuberculosis, and atypical mycobacteria or disseminated fungal disease. Complications of HIV infection Opportunistic infections (see Table 11.1) Table 11.1 Complications of HIV infection Pneumonia Pneumocystis jirovecii Fungal Oro-oesophageal Candida albicans Cryptococcus neoformans Meningitis Histoplasma capsulatum Meningo-encephalitis, pneumonia Disseminated, intestinal Mycobacterial M. avium intracellulare Pulmonary, intestinal M. tuberculosis Hepatobiliary, intestinal Cryptosporidium Parasitic Colon, hepatobiliary Isospora Multiple abscesses: CNS ocular, lymphatic Toxoplasma gondii Cytomegalovirus Retinal, hepatic, intestinal, CNS Viral Herpes zoster Mucocutaneous Herpes simplex Mucocutaneous JC virus CNS Haemophilus infl uenzae Meningitis Bacterial Streptococcus pneumoniae Pneumonia, meningitis, septicaemia 554 CHAPTER 11 Immunode \201 ciency Neoplasia \200 AIDS-related Kaposi sarcoma 20 \200\22330% of patients; multiple skin lesions; later lymph nodes, mucous membranes, and visceral organs. ?role of HHV8 (>95% +ve) . NHL up to 10%; 65% diff use large B-cell, 30% Burkitt-like; extranodal esp. small bowel and CNS; 1 eff usion lymphomas; aggressive. ?role of EBV (100% +ve in 1 CNS NHL). Cervical carcinoma. \200 Anal carcinoma. \200 HL; advanced stage, extranodal sites. Direct eff ects of HIV infection \200 BM suppression \200\224dysplastic appearance; pancy topenia. \200 Small bowel enteropathy \200\224malabsorption syndrome. \200 CNS \200\224 dementia, myelopathy, neuropathy. 555 HIV INFECTION AND AIDS 556 CHAPTER 11 Immunode \201 ciency Therapy of HIV infection See Tables 11.2 and 11.3. Table 11.2 Infection prophylaxis, if severely immunocompromised Activity against Drugs Fluconazole/itraconazole Oro-oesophageal candidiasis cryptococcal meningitis Co-trimoxazole Pneumocystis jirovecii ocular/ CNS toxoplasmosis Dapsone/nebulized pentamidinea Pneumocystis jirovecii Rifabutin/azithromycin/clarithromycin M. avium-intracellulare Aciclovir HSV and HZV aIf cannot take cotrimoxazole Antiviral therapy \200 Combination antiretroviral therapy (also called highly active antiretroviral therapy, HAART) is standard of care. Initiation of HAART based predominantly on clinical staging (with stage 3 or 4) and CD4 count. i trend to start HAART earlier (e.g . CD4 count 7 350 \200\223500). Generally two drugs from nucleoside class of viral reverse transcriptase (RT) inhibitors: zidovudine (AZT), didanosine (ddI), lamivudine (3TC), abacav ir, tenofovir (TDF). Used in combination with a non-nucleoside reverse transcriptase inhibi tor (e.g. nevirapine (NVP) or efavirenz (EFV) or a protease inhibitor (e.g. lopinavir, rito navir, darunavir, atazanavir). Specifi c therapy is followed within hours by rapid clearance of virions from the circulati on and subsequently by reappearance of circulating T cells and a rising count over several weeks. Viral resistance develops with time on combination therapy if adherence is suboptima l. 557 THERAPY OF HIV INFECTION Table 11.3 Treatment of complications Systemic fl uconazole or amphotericin then lifelong prophylaxis Oro-oesophageal candidiasis High-dose co-trimoxazole or pentamidine then lifelong prophylaxis; pyrmethamine, dapsone, a nd leucovorin weekly Pneumocystis pneumonia Multiagent therapy (drug resistance common) lifelong isoniazid prophylaxis Tuberculosis Amphotericin then lifelong prophylaxis Fungal pneumonia CMV pneumonitis/retinitis Ganciclovir/foscarnet then lifelong prophylaxis Pyrimethamine then lifelong prophylaxis; atovaquone (has in vitro activity against cysts of Toxoplasma gondii and has been used as salvage therapy for cerebral toxoplasmosis. CNS toxoplasmosis Amphotericin/fl uconazole Cryptococcal meningitis Limited disease: local DXT, cryotherapy, intra- lesional vincristine, interferon alfa; adva nced disease: combination chemotherapy such as doxorubicin (adriamycin), bleomycin, and vin cristine (ABV), liposomal daunorubicin, paclitaxel AIDS-related Kaposi \200\231s sarcoma Poor prognosis; combination chemotherapy (often standard regimens at reduced dosage due to toxicity) 50% response, median survival <9 months; CNS lymphoma particularly poor prognosis ; palliative dexamethasone DXT Non-Hodgkin lymphoma Sulfadiazine (2 \200\2234g daily in 4 divided doses) + pyrimethamine (25 \200\22350mg/d) is 1st choice for 2 prophylaxis. Folinic acid (10 \200\22325mg/d) is given concurrently 2 prophylaxis This page intentionally left blank 559 Chapter 12 Pediatric hematology Blood counts in children 560 Red cell transfusion and blood component therapy \200\224speci al considerations in neonates and children 562 Polycythaemia in newborn and childhood 566 Neon atal anemia 568 Anemia of prematurity 570 Haemolytic anemia in the neonate 572 Congenital r ed cell defects 574 Acquired red cell defects 576 Haemolytic disease of the newborn 578 Hyp erbilirubinaemia 582 Neonatal haemostasis 584 Neonatal alloimmune thrombocytopenia 586 Cong enital dyserythropoietic anaemias 588 Congenital red cell aplasia 590 Acquired red cell apl asia 592 Fanconi anemia 594 Rare congenital marrow failure syndromes 596 Neutropenia in chi ldhood 600 Disorders of neutrophil function 602 Childhood immune (idiopathic) thrombocytope nic purpura 604 Haemolytic uraemic syndrome 606 Childhood cancer and malignant blood disorders 608 Childhoo d lymphoblastic leukemia 612 Childhood lymphomas 616 Childhood acute myeloid leukemia 620 C hildhood myelodysplastic syndromes and chronic leukaemias 624 Histiocytic syndromes 628 Hematological eff ects of systemic disease in children 632 560 CHAPTER 12 Pediatric hematology Blood counts in children Blood counts in children are often diff erent from adults, to vary ing degrees at diff erent ages. The diff erences are greatest during the neo- natal 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 fi rst 3 months of l ife by which time the normal infant is anemic relative to adults. Neonatal red cells are al so macrocytic by adult standards, a feature that also disappears during the fi rst 6 months as HbA replaces HbF. \200 Neonatal red cells show much greater variation in shape than t hose from adults, particularly in premature babies \200\224alarming microscopists more used to a dult blood fi lms. Occasional nucleated red cells are normal in the fi rst 24 \200\22348h of life. \200 Fe l ack is common around 12 months of age due to i demand from i red cell mass and (often) poor oral intake \200\224cows \200\231 milk has virtually no Fe content. The MCV falls to what would be abnormally low levels for adults as a refl ection of this. In healthy premature neonates all these red cell diff erences 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. Children have slightly lower Hb than adults until puberty. White cells The most striking diff erence between children and adults is the high lymphocyt e count in infants and young children. This means that the normal diff erential WBC in thos e <4 years shows more lymphocytes than neutrophils. Otherwise most of the changes in WCC se en in children are similar to those seen in adults and due to the same causes, with a few e xceptions: \200 Healthy term babies show a transiently raised neutrophil count in the fi rst 24h after birth (7 \200\22314 \227 109/L) which returns to the normal (adult) r ange by 48h. Immature neutrophils (band cells and myelocytes) may comprise 5 \200\22310% of the total WBC in healthy neonates. Sick neonates with bacterial infections commonly show a paradoxical neutropenia, with or without an i band cell count. Black children have lower neutrophil counts than other ethnic groups. \200 Lymphocytoses with very high counts occur in children with specifi c 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 \227 109/L) as part of an acute phase reaction more frequently. There is a statistically signifi cant fall in the upper limit (95th centile) from 4 years o nwards from around 500 to reach 350 \200\223400 by the end of childhood. 561 BLOOD COUNTS IN CHILDREN 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 See Table 12.1. Table 12.1 Normal blood count values from birth to adulthood1 Age Hb (g/dL) MCV (fL) Neuts Lymph Platelets Birth 14.9 \200\22323.7 100 \200\223125 2.7 \200\22314.4 2 \200\2237.3 150 \200\223450 2 weeks 13.4 \200\22319.8 88 \200\223110 1.5 \200\2235.4 2.8 \200\2239.1 170 \200\223500 2 months 9.4 \200\22313.0 84 \200\22398 0.7 \200\2234.8 3.3 \200\22310.3 210 \200\223650 6 months 10.0 \200\22313.0 73 \200\22384 1 \200\2236 3.3 \200\22311.5 210 \200\223560 1 year 10.1 \200\22313.0 70 \200\22382 1 \200\2238 3.4 \200\22310.5 200 \200\223550 2 \200\2236 years 11.5 \200\22313.8 72 \200\22387 1.5 \200\2238.5 1.8 \200\2238.4 210 \200\223490 6 \200\22312 years Adult \231\202 Adult \231\200 11.1 \200\22314.7 76 \200\22390 1.5 \200\2238 1.5 \200\2235 170 \200\223450 12.1 \200\22316.6 77 \200\22392 1.5 \200\2236 1.5 \200\2234.5 180 \200\223430 12.1 \200\22315.1 77 \200\22394 1.5 \200\2236 1.5 \200\2234.5 180 \200\223430 Neuts, neutrophils; lymph, lymphocytes and platelets, all \227 109/L. Reproduced with permission, Elsevier, copyright 1999 Other hematological variables in childhood There are important diff erences in the concentr ation of various clotting factors during early infancy as described in Tables A3.3 and A3.4 (E p.812). Other laboratory investigations where children diff er include: \200 Reticulo cyte counts low in the fi rst 8 weeks of life as neonatal poly- cythaemia corrects itself. HbF comprises 75% of the total Hb at birth, 10% at 5 months, 2% at 1 year, and <1% thereafter. Some red cell enzymes (G6PD, PK, hexokinase) have greater activity (150 \200\223200% of adult values) in neonatal RBC. The LLN for serum ferritin at 1 year (12.5mg/L) is 50% of the LLN at 12 years (25mg/L). B12 and folate levels are around 2 \227 higher in infants and younger children than adults. Reference 1 Lilleyman, J.S. et al. (eds.) (1999). Pediatric Hematology, 2e. London: Churchi ll Livingstone. 562 CHAPTER 12 Pediatric hematology 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 transf used of our hospital patients: \200 To replace blood losses of investigative sampling. \200 To alleviate anemia of prematurity. Note: \200 Hb estimation alone is an inadequate assessment. \200 Hb reduction with symp toms, e.g. failure to thrive, is needed to justify transfusion. 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 relatives) cannot be regarded as safe as microbiologically screened vol- unteer 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 d donor exposure in infant needing multiple tra nsfusions. Pre-transfusion testing Maternal and neonatal samples should be taken and tested as follows : Maternal samples \200 ABO and Rh group. \200 Antibody screen. Infant samples \200 ABO and Rh group. \200 DAT. \200 Antibody screen (if maternal sam ple unavailable). Note: provided no atypical antibodies are present in maternal or infant serum and the DAT o n the infant \200\231s cells is \210\222ve, a conventional cross- match is unnecessary. Sm all-volume replacement transfusions can be given repeatedly during the fi rst 4 months of l ife without further sero- logical testing. Transfusion centers may specifi cally designate a supply of low anti-A, B titre group O Rh (D) \210\222ve blood for use in neonatal transf usions. 2After the fi rst 4 months, compatibility testing should conform to requirements for adults . Exchange transfusions \200 To prevent kernicterus caused by rapidly rising bilirubin. \200 Most commonly needed in haemolytic disease of the newborn. \200 Plasma-reduced red cells (Hct 0.50 \200\2230.60). 563 RED CELL TRANSFUSION AND BLOOD COMPONENT THERAPY For small-volume transfusions, age of red cells does not matter. For exchange transfusions within 5d of collection ([K+] levels rise in older blood). Transfusion should not take >5h/U due to risk of bacterial proliferation. Volumes of 5mL/kg/h usually safe. Special hazards \200 GvHD: in congenitally immunodefi cient neonates immunocompetent donor T lymphocytes can cause GvHD \200\224rare. Need to irradiate all blood products in these children. Also irradiate if 1st-degree relatives used as donors. CMV infection: particular risk in low birth weight babies, or immuno- compromised children undergoing transplantation. CMV seronegative donations should be used. Alternatively use (modern) leucodepletion fi lter to reduce risk. Hypocalcaemia \200\224rare now, due to change of additive. \200 Citrate toxicity, also ra re nowadays due to improvements in additive. \200 Rebound hypoglycaemia, induced by high glucose levels of blood transfusion anticoagulants. Thrombocytopenia \200\224dilution, DIC. \200 Volume overload. \200 Haemolytic transfusi on reactions in necrotizing enterocolitis. Thought to be due to the \200\230T \200\231 ant igen on baby \200\231s RBCs becoming exposed due to action of bacterial toxin entering the blood from diseased gut. Anti \200\230T \200\231 is present in almost all donor plasma. Use of 4.5% albumin Use controversial, but may be helpful after large-volume paracentesis, as fl uid replacement in therapeutic plasma exchange, or in nephrotic syn- drome resistant to diuretics. There are better products for resuscitation and volume expansion. Should not be used in nutritional protein defi ciency or chronic hypoalbuminaemia (e.g. cirrhosis or p rotein-losing enterop- athy). Risk of infection transmission minimal but not zero. Use of immunoglobulin IV polyvalent immunoglobulin widely used as replacement therapy in im munodefi ciencies, for Kawasaki disease to prevent the formation of coronary microaneurysms , and also as non-specifi c agent for reticuloen- dothelial blockade in immune cytopenias, chiefl y (and usually unneces- sarily) in childhood ITP. Can get immunoglobulin with partic ularly high titre against RSV, HZV, and hepatitis B. Usually this is for intramuscular use only and should not be given IV due to risk of complement activa- tion. IVIg has transmitte d hepatitis C in the past due to poor virus inacti- vation procedures, so should not be use d in trivial conditions. 564 CHAPTER 12 Pediatric hematology Use of FFP Available in aliquots of 50mL. Must be ABO and Rh compatible. Infused via fi lte r. Main indication \200\224DIC. No need for CMV screening, or irra- diation. Dose: 10 \200 \22315mL/kg. Check PT and APTT. Repeat as necessary. May need cryoprecipitate also (E Massi ve blood transfusion, p.658; Cryoprecipitate, p.771), if evidence of d Fgn (<1.0g/L). Both contain untreated plasma, so potential infection risk, though FFP should be virus- inactiva ted in future. For this reason methylene blue treated FFP now rec- ommended for children <1 6 years. Use of platelets \200 Thrombocytopenia more hazardous in neonates, so prophylactic transfusion if count <30 \227 109/L. Reserve for children with marrow failure and counts <10 \227 109/L otherwise: \200 Only use in immune thrombocytopenia for life-threatening bleeding. Then use massive \200\230swamping \200\231 dose to overwhelm antibody. \200 1 dose (1 pe diatric platelet concentrate) contained in 750mL \200\230fresh \200\231 plasma, available either from apheresis or buff y coat derived. Check increment 1h later if no clinical response. \200 Care with volume overload (give 10 \200\22320mL/kg). \200 Must be administered within 2h of receipt on ward. \200 Irradia te for immunosuppressed children. \200 Refractoriness can arise due to alloimmune antibod ies. \200 For children <16 years use platelets collected by apheresis from single donor. Use of granulocytes \200 Severely infected neonates may develop profound neutropenia. \200 Usually respond to antibiotic therapy. \200 Granulocyte transfusions very rarely gi ven because of lack of eff ect, risk of CMV and toxoplasmosis, and respiratory distress syn drome. \200 Blood products now routinely leucodepleted to reduce risk of CMV transmission. Granulocytes may be useful in patients with prolonged pancytopenia (e.g. in patients with a plastic anemia or post-BMT) unresponsive to broad-spectrum IV antibiotics. 565 RED CELL TRANSFUSION AND BLOOD COMPONENT THERAPY 566 CHAPTER 12 Pediatric hematology Polycythaemia in newborn and childhood As in adults, polycythaemia in children may be relat ive or absolute (E Polycythaemia vera (PV), p.264). The condition is usually 2 and most c ommonly seen as a clinical problem in neonates or older children with congenital cyanotic h eart disease or high-affi nity abnormal haemo- globins. 1 polycythaemia is very unusual i n childhood; benign familial erythrocytosis is a very rare autosomal dominant self-limiting condition of unknown etiology. Pathophysiology Polycythaemia is physiological in the neonatal period with i Hct (range 42 \200\22360% in cord blood) persisting in the fi rst few days of life. Pathological polycyth aemia is defi ned 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 \200 Relative (or \200\230pseudo \200\231): dehyd ration, reduced plasma volume. \200 Hypertransfusion: delayed cord clamping, maternofetal , twin to twin. \200 Hypoxia: placental insuffi ciency, intrauterine growth retardation. \200 Endocrine: congenital adrenal hyperplasia, thyrotoxicosis. \200 Maternal disease; toxemia of pregnancy, DM, heart disease, drugs, e.g. propranolol. Other miscellaneous conditions such as Down syndrome. Clinical features \200 Hyperviscosity may give rise to vomiting, poor feeding, hypotonia, hypoglycaemia, lethargy, irritability, and tremulousness. On examination \200\224 plethora, cyanosis, jaundice, hepatomegaly. \200 Complications in clude intracranial hemorrhage, respiratory distress, cardiac failure, necrotizing enterocol itis, and neonatal thrombosis. Diagnosis \200 Clinical presentation may suggest the diagnosis, e.g. anemic twin. \200 FBC (free-fl owing venous sample) i neonatal Hct >65%. \200 Hypoglycaemia, hypocalcaemia, unconjugated hyperbilirubinaemia. \200 Hb studies for excess HbA \200\224?maternal hemor rhage. \200 Radiology: CXR shows i vascularity, infi ltrates, cardiomegaly. Management \200 Supportive \200\224IV fl uids, close observation for complications. \200 Exchange transfusion \200\224partial with FFP/albumin to d Hct <60%. (See Box 12.1.) 567 POLYCYTHAEMIA IN NEWBORN AND CHILDHOOD Box 12.1 Blood vol. \227 (observed \210\222 desired Hct) Observed Hct Vol. of exchange (mL) = Treatment As required for associated abnormalities. Outcome Provided the condition is identifi ed early and appropriate measures taken to reduc e the hyperviscosity, the outcome should be good. 568 CHAPTER 12 Pediatric hematology 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 ra pidly after birth (E Table A3.3, p.812) and by end of the neonatal period (4 weeks in a ter m baby), the mean Hb may be as low as 10.0g/dL. With i RBC destruction, there is a con- com itant i in serum bilirubin. Thus complex changes occur in this period making distinction be tween physiology and pathology diffi cult. Pathophysiology In normal full-term babies, red cell production d in the fi rst 2 \200\2233 months of life. RBC survival shortens; reticulocytes and EPO production d; Fe, folate and vitamin B12 stores are normal. Anemia in the neonate may be due either to impaired producti on of RBCs or to i destruction or loss (Table 12.2). Blood loss during delivery is common, in 71% severe enough to produce anemia. Infection is also a signifi cant cause of anemia; 1 haematolog- ical disorders are rare. Anemia in pre mature infant is almost invariably present, induced, and multifactorial. Jaundice arises in 90% healthy infants making interpretation of a raised bilirubin (E Haemolytic disease of t he newborn, p.578) 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 stetric history, maternal and family history. Non-specifi c symptoms \200\224 lethargy, rel uctance to feed, failure to thrive \200\224all may indicate anemia. Clinical features may b e helpful in picking up inherited disorders such as Fanconi anemia. Laboratory tests \200 FBC and reticulocytes. \200 MCV and RBC morphology, bilirubin, an d Kleihauer (on mother). \200 Special tests may be necessary if cause not apparent (e.g. red cell enzyme defects, inherited BM failure syndromes). Glutathione peroxidase defi ciency due to acquired selenium defi ciency can present transie ntly with anemia in neonates. Interpret as follows: Reticulocyte count normally very low in fi rst 6 weeks of life. \200 i haemolysis, blood loss. \200 +ve Kleihauer suggests fetomaternal bleed (quantitate amount). \200 Bilirubi n i (unconjugated). \200 Check DAT: +ve in immune haemolytic anemia (except ABO HDN). \210\222ve in other haemolytic anaemias, including ABO HDN. \200 Bilirubin i (conjugated /mixed look for hepatobiliary obstruction/ dysfunction). Blood fi lm: Note: i polychromasia, occasional NRBC, poikilocytes and spherocytes days 1 \200\2234 in healthy babies. 569 NEONATAL anemia RBC morphology may suggest congenital spherocytosis, other RBC membrane disorders or HDN. d MCV \200\224 thalassaemia syndromes. \200 i WBC \200\224reactive, congenital leukemia . \200 Neutropenia \200\224sepsis, marrow failure. Table 12.2 Causes of neonatal anemia i destruction of RBCs Impaired production of RBCs Anemia of prematurity Overt or concealed hemorrhage; repeated venepuncture Infection thalassaemia DBA Haemolytic anemia Non-immune Immune Fanconi anemia TORCH infection Rh/ABOHDN CDA Congenital RBC abn. Maternal autoimmune haemolytic anemia Drugs, MAHA CDA, congenital dyserythropoietic anemia; DBA, Diamond \200\223Blackfan anemia; MAHA, micro angiopathic haemolytic anemia; Rh/ABO HDN, rhesus/ABO haemolytic disease of the newborn; TO RCH, toxoplasmosis, rubella, CMV, herpes simplex. 570 CHAPTER 12 Pediatric hematology Anemia of prematurity Anemia is an almost invariable fi nding in the premature infant. By w eek 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 transfusion. A number of factors are causal. Pathogenesis \200 RBC production and survival are d. \200 EPO production very low in th e fi rst few weeks. \200 Iatrogenic from repeated blood sampling (depletes the RBC mass a nd Fe stores \200\224by 4 weeks the premature baby may have had its total blood volume remo ved). Clinical features The i O2 needs and metabolic demand of the premature baby makes them less able to tolerate d Hb. Over 50% infants <30 weeks \200\231 gestation develop tachycardia, tachypnoea, feeding diffi culties and d activity when anemic. High HbF level and i O2 affi nity exaggerates the hypoxia. Treatment \200 Delayed cord clamping i Fe stores. \200 Close control of blood sampling is important. \200 Transfusion indications will vary in neonatal units \200\224decide on clinical grounds, particularly if ventilated. The following are guidelines only: \200 Pre ms <2 week with Hb <14.0g/dL, Hct <40%. \200 Prems >2 week, Hb <11.0g/dL, Hct <32%. A rising reticulocyte count in some centers is used as a sign to with- hold transfusion. So me studies have shown better weight gain in transfused infants (not confi rmed by others). Fe supplementation (2mg/kg/d PO) after fi rst 2 weeks and until Fe suffi cient. EPO \200\224controversial. It can be eff ective but its indiscriminate use is not encourage d. Large randomized trials have shown it to have an eff ect, but its expense makes cost-eff ectiveness a concern and modern neonatal practice has already reduced the need for transfu sion making it less necessary. Its best use is probably reserved for transfusion avoidance in infants weighing <1000g. A suitable regimen would be 200 \200\223250U/kg SC \227 3/week between day 3 and week 6. Natural history Despite the growing safety of blood and its ready availability and con- ven ient packaging to reduce donor exposure, blood transfusion carries defi nite risks and is t o be avoided. It is likely that in affl uent societies the use of EPO will increase, despit e its limited eff ect. 571 anemia OF PREMATURITY 572 CHAPTER 12 Pediatric hematology Haemolytic anemia in the neonate Normal red cell life span in term infants is <80d, in pre- term infants <50d. Red cell \200\230cull \200\231 in 1st month with jaundice is physiologi cal. Pathological haemolysis, when present, is most commonly due to iso- immune HDN 2 to fetomaternal blood group incompatibility in Caucasian populations. In other ethnic groups G 6PD defi ciency 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 1st weeks of life. Neonatal RBCs are more susceptible to ox idative stress and there is altered RBC enzyme activity compared to adult RBC and reticuloc ytes. So pathological hae- molysis occurs in the neonatal period more than at any other tim e. Causes of haemolytic anemia Haemolysis may be due to intrinsic defects of the RBC, usually congen- ital, or to acquired extracorpuscular factors which may be immune or non-immune. Clinical features Pathological jaundice may be clinically obvious at birth or within 24h (d istinguishing it from the common physiological anemia which occurs >48h after birth, E Haem olytic disease of the newborn, p.578). \200 Anemia may be severe depending on cause. \200 Infections are common cause of hyperbilirubinaemia (E Haemolytic disease of the newborn, p.578 with specifi c clinical fi ndings. In utero inf ections (TORCH) do not usually cause severe jaundice cf. post-natal bacterial sepsis where jaundice may be striking and associated with MAHA. Splenomegaly at birth indicates a prenatal event; when noted later it may be 2 to splenic clearance of damaged RBC and is non-specifi c. Kernicterus is the major complication of neonatal hyperbilirubinaemia. Family history and drug history may be informative. Laboratory diagnosis of haemolysis \200 i unconjugated bilirubin with anemia is hallmark of haemolytic anemia. i reticulocytes (haptoglobins are unreliable in the newborn). \200 Blood fi lm \200\224ma y show RBC abnormalities, e.g. spherocytes, elliptocytes, fragmented cells. DAT, if +ve indicates immune haemolysis; \210\222ve does not rule this out \200\224 especially consider ABO HDN. Heinz body test \200\224+ve in drug-induced haemolysis, G6PD defi ciency and occasionally other enzyme disorders. Intravascular haemolysis \200\224look for haemoglobinuria/ haemoglobinaemia. 573 HAEMOLYTIC anemia IN THE NEONATE 574 CHAPTER 12 Pediatric hematology Congenital red cell defects Pathophysiology The neonate is uniquely disadvantaged when it c omes to handling patho- logical haemolysis because of hepatic immaturity and altered enzyme activity. Thus congenital defects of the RBC commonly present in the newborn except for de fects involving the globin chain (e.g. SCD, thalassaemia) which become clinically man ifest several weeks after birth but can be diagnosed in utero, or in the neonatal period if suspected. HS is the commonest congenital haemolytic anemia in Caucasian populations; half present in the neonatal period. Worldwide, G6PD defi ciency occurs in 3% population; neona tal presentation is common in Mediterranean and Canton peoples. thalassaemia is incompat ible with life causing hydrops fetalis (all 4 globin genes deleted), or may present as H bH disease (3 of the 4 globin genes deleted) with mild-to-moderate haemolysis in neonate . Hereditary RBC defects in neonatal haemolytic anemia \200 Membrane defects: Hereditary spherocytosis, hereditary elliptocytosis and variants, e.g. stomatocytosis and p yropoikilocytosis (Afro-Americans). Hemoglobin defects: \200 thalassaemia. \200 Unstable haemoglobins (e.g. HbK ln, HbZurich). Enzyme defects: Glycolytic pathway; pyruvate kinase and other enzyme defi ciencies. \200 Hexose monophosp hate shunt; G6PD defi ciency, other enzymes. Clinical features Congenital haemolytic anemia with mild or moderate unconjugated hyperbili rubinaemia. No gross excess of bile pigments in urine (old col- lective name for these dise ases was \200\230acholuric jaundice \200\231), hepatosple- nomegaly. A +ve family histo ry is common but not invariable. Laboratory investigation May be diffi cult to diagnose in neonate, especially if post-trans fusion. Often have to wait until clinically stable some weeks/months later. \200 Exclude acquired disorders, and immune lysis (DAT). \200 RBC morphology is one key to diagnosis a nd further investigation, but spherocytes not specifi c for HS. Further tests for suspected: Membrane defect (osmotic fragility, autohaemolysis, dye binding, membrane chemistry). Hb defect; Hb electrophoresis, HbF, HbA2 measurement. \200 Enzyme defect; Heinz body prep , screening tests for specifi c enzymes, G6PD, PK. Heinz body test +ve: Drug or chemical induced in neonate without hereditary defect. \200 Enzyme defi ciency: G 6PD commonest but consider others. \200 Unstable Hb. \200 thalassaemia. 575 CONGENITAL RED CELL DEFECTS 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 1st weeks and months of life as the infant matures. Where the haemolysis is likely to be chronic folic supplementation should be commenced. 576 CHAPTER 12 Pediatric hematology Acquired red cell defects These may be either immune or non-immune. Main cause of the latte r will be underlying infection either acquired in utero or in the days fol- lowing delivery . Drug-induced haemolysis in the newborn is rare. Pathophysiology Neonatal RBCs have i sensitivity to oxidative stress due to altered enzyme activity, and are more liable to be destroyed by altered phys- ical conditions, mechanical factors, toxins, and drugs than adult RBC. Infection acquired in utero postnatally is a com mon cause of mild-to- moderate haemolytic anemia. The mechanism is multifactorial, and incl udes i reticuloendothelial activity and microangiopathic damage. Drug-induced haemolysis an d Heinz body formation is occasionally noted as a transient phenomenon in normal neonatal R BCs as a result of chemical or drug toxicity but is much more often seen when there is an u nderlying RBC defect such as G6PD defi ciency. Acquired RBC defects causing congenital haemolytic anemia \200 Infection: Congenital TORCH infections also rare but serious are malaria (can cause stillbirth) and syphilis. Post-natal, either viral or (more commonly) bacterial. Microangiopathy \200\2242 to severe infections DIC, also Kasabach \200\223Merritt syndrome (giant haemangioma with haemolysis and thrombocytopenia). \200 Drug or chemically induced. \200 Infantile pyknocytosis. \200 (Rare) metabolic disease such as Wilson disease, galactosaemia. Clinical features Congenital infections: all rare with adequate antenatal care. Most infant s with herpes simplex will be symptomatic with DIC and hepatic dysfunc- tion \200\224haemol ysis is not a major fi nding. Haemolytic anemia is also mild in CMV and rubella infections but 50% infants with toxoplasmosis will be anemic (may be severe). Postnatal infections: viral, bacterial and protozoal (congenital malaria can be delayed for some days or weeks or it can be acquired early in life). Anemia can be severe and associat ed 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 haemolysis, RBC damage and profound thrombocytopenia. 577 ACQUIRED RED CELL DEFECTS