12-Pediatric.qxd 10.12.2003 04.28 PM Page 484 or spinal cord, causing pressure symptoms and mimicking non-haemic solid tumors. They are m ore common in AML with t(8;21). Peri-orbital chloromas are also not unusual in infants with M4/M5 AML. Treatment and outlook Outcome of therapy for childhood AML has shown a dramatic improve- me nt over the last 15 years. From a dismal outlook in the 1970s through around 30% EFS in the 1980s we have now achieved >50% EFS at the turn of the 21st century. This has been due to increasingly intensive chemotherapy and parallel improvements in supportive treatment for t he secondary marrow failure it produces. The principle of treatment is to ablate marrow with chemotherapy to the point that endogeno us recovery occurs within 4 \200\2236 weeks and to repeat the process with different drug c ombinations 4 or 5 times, giving a total treatment time of around 6 months. Results using t his approach have improved for children in the best risk groups to the point where allo- ge neic BMT is no longer considered the consolidation treatment of choice even if a matched do nor is available. 2 Drugs used in remission induction include daunorubicin, etoposide, cytarabine and mitoxantrone (mitozantrone). 2 Drugs used in post induction and consolidation treatment include amsacrine, high-dose cytarabine, L-asparaginase, etoposide and mitox- antrone (mitozantrone ). 2 Good risk patients are those with t(8;21), t(15;17) and inv (16) \200\224 together accounting for around 20 \200\22325% overall; standard risk patients are those wit hout good risk genetic changes but that respond well and remit after one course of chemothe rapy (65% overall), and poor risk are those without good genetics who have residual disease at the start of course 2 of treatment (around 10% of the total). 484 2 Long term EFS for good risk children is around 75 \200\22380%, for standard risk around 60 \200\22365%, and for poor risk around 15%. 2 Allogeneic BMT as consolidation therapy of first remission is reserved for children in standard and poor risk groups. It is also used as a salvage strategy for go od risk patients who relapse. 2 The role of autologous stem cell rescue following myeloablative condi- tioning in children with AML has not been established. 2 The need for skilled supportive therapy confines AML therapy to spe- cialist units. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 485 Pediatric hematology 485 12-Pediatric.qxd 10.12.2003 04.28 PM Page 486 Childhood myelodysplastic syndromes and chronic leukaemias Myelodysplastic syndromes of childhood present a different spectrum of disease from that se en in adults. All are rare. The FAB classification of adult MDS ((cid:9) p220) has been tra nslated to pediatric disease, but sits uncomfortably and is of limited use clinically or in understanding the complex biology of this diverse group of clonal disorders of marrow func - tion. The proportion that map to the various adult categories is shown below. Adult vs. childhood MDS based on the FAB classification Category % Adults % Children Refractory anemia (RA) Refractory anemia with ring sideroblasts (RARS) Refractory anemia wi th excess blasts (RAEB) Refractory anemia with excess blasts in transformation (RAEB-t) Chr onic myelomonocytic leukemia (CMML) Unclassifiable 28 24 23 9 24 <1 16 5 16 0 50 4 2 Many children with MDS have a monocytosis which results in their being classified as CMML , also the clinical features and outlook for childhood CMML are quite different. 2 RARS is virtually never seen in children. 486 Individual disorders Refractory anemia: Children with a clonal genetic marker in the marrow who present with refractory anemia usually progress to RAEB and AML. Those without such a marker probably do not have MDS but some other cause of erythropoietic failure. RAEB and RAEB-t: Many of the RAEB syndromes in children arise in those with pre-existing di sease like Down syndrome, trisomy 8, neurofibro- matosis type 1, Fanconi \200\231s anemia, Kostmann \200\231s syndrome, Diamond \200\223 Blackfan anemia and Shwachman \200\223Diamond syndrome (see previous section). All these diseases predispose to leukemia, and RAEB is me rely part of the evolution of AML. A substantial proportion of childhood MDS in the RA or R AEB category is also induced by previous chemotherapy as a prodrome to secondary AML. In ot her words all pediatric cases of RAEB/RAEB-t are best regarded as AML and treated as such i f the diagnosis is not in any doubt. 2 Down syndrome children have a particular predisposition to develop M7 (megakaryoblastic) AML in the first few years of life. This is com- monly preceded by a RAEB prodrome where th e marrow is hard to aspirate through secondary sclerosis. The decision when to start therap y is difficult, but the overall outlook is potentially good with EFS >50%. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 487 Pediatric hematology Transient abnormal myelopoiesis (TAM): Down children also have a predisposition to develop a transient blast cell overgrowth in infancy that looks like frank leukemia with blasts in the peripheral blood. It is completely self-limiting within days or weeks and is not associ ated with marrow failure, arising alongside normal haemopoiesis. There is no genetic abnorm ality in the marrow apart from trisomy 21. It is important that chemotherapy is withheld in what is regarded as a temporary stem cell instability. Rarely the problem can arise in non -Down children, where trisomy 21 is found in the bone marrow only. JCMML (juvenile chronic myelomonocytic leukemia): Originally called juvenile chronic myeloi d leukemia to distinguish it from adult type chronic myeloid leukemia (see below), this per nicious disease still has a high mortality. It is now recognized to be a clonal disorder, w ith all marrow cell lines involved. It has several distinctive clinical and hematological f eatures. 2 Stigmata of fetal erythropoiesis; high HbF, 4 red cell i antigen expres- sion and carbonic anhydrase activity, 4 MCV. 2 Modest 4 WBC; average 30 \200\22340 109/L, with evident monocytosis, blasts 5 \200\22310%, and occasionally a basophilia. 2 Marrow appearances unremarkable; modest 4 blasts. 2 Thrombocytopenia; sometimes profound. 2 Skin rashes; butterfly distribution on face. 2 Increasing hepatosplenomegaly. 2 Associat ed with neurofibromatosis type 1. May be present in >10% of 487 cases. 2 Poor outlook with progression associated with wasting, fever, infec- tions, bleeding and pulmonary infiltrations. Monosomy 7 syndrome: Conventional cytogenetic analysis of the marrow in JCMML shows no abno rmality in the classic syndrome, though there is a subvariety (or similar condition that ma y nevertheless be biologically distinct) where monosomy 7 is found. Whether this is a diffe rent disorder is not clear. Apart from the different genetics, monosomy 7 syndrome and JCMM L have several features in common. However, monosomy 7 children may have: 2 A longer prodrome with RA or RAEB and no monocytosis. 2 They may respond to AML chemother apy (JCMML responds poorly and seldom remits). 2 They may remain stable for years without therapy. 2 They respond better to BMT (JCMML ach ieve <40% EFS even with BMT). Adult-type chronic myeloid (granulocytic) leukemia (ATCML, see Adult CML p164): More common than JCMML, though still rare, ATCML arises in around 1 in 500,000 children per year (20 i n whole of UK). Tends to 12-Pediatric.qxd 10.12.2003 04.28 PM Page 488 affect older children (60% >6 years) though it has been reported in a 3 month old infant. 2 Associated with Ph chromosome and t(9;22) BCR-ABL fusion gene in all haemopoietic cells exactly as seen in adults. 2 Natural history exactly the same as the disease in adults with benign phase and eventual progression to accelerated acute phase. 2 Only curative therapy is allogeneic BMT, but impressive remissions of so far unknown leng th are now being achieved with novel tyrosine kinase inhibitor, STI571 (imatinib). This is set to replace the conven- tional management of the chronic phase with a-interferon or hydr ox- yurea, but at present is reserved for those who fail to respond to IFN or those enterin g the accelerated phase. 488 12-Pediatric.qxd 10.12.2003 04.28 PM Page 489 Pediatric hematology 489 12-Pediatric.qxd 10.12.2003 04.28 PM Page 490 Histiocytic syndromes Monocytes are formed in the marrow and move through the peripheral blood into the tissues w here they become histiocytes, either in the mononuclear phagocytic system (MPS) or the dend ritic cell system (DCS). MPS cells are antigen processing, are predominantly phagocytic and include many organ-specific cells such as Kupffer cells and pulmonary alveolar macrophages . DCS cells include tissue-based Langerhans cells (LC) which are antigen presenting. There is a variety of syndromes where histiocytes proliferate and malfunction and some of these c arry a high mortality. A few are clonal neoplasms but most are produced by cytokine distur- bances. In 1991 a new classification of histiocytic syndromes was set out as shown: Histiocytic syndromes Class I Disorders of dendritic cells Langerhans cell histiocytosis (previously known as histiocytosis X) Class II Disorders of macrophages Haemophagocytic syndromes Haemophagocytic lymphohistiocytosis (HLH) Primary (genetic) Secondary (to infection or malignant disease) Sinus histiocytosis with ma ssive lymphadenopathy Histiocytic necrotising lymphadenitis 490 Class III Malignant histiocytic disorders Malignant histiocytosis Monocytic leukaemias Class I: Langerhans cell histiocytosis (LCH) Cellular destructive tissue infiltration with LC. These are well differenti- ated large cells (15 \200\22325 m) with an indented nucleus and inconspicuous nucleolus; they are not phagocytic. Other reactive cells (granulocytes, eosinophils, macrophages) are often present. Diagnostic criteria of LC include the presence of Burbeck granules on electron microscopy and immunochemical positivity for CD1A. The eti ology of LCH remains unclear. Despite some evidence of clonality (not itself evidence of ma lig- nancy), no genetic mutations have been identified and the disorder is not regarded as a form of cancer. Clinical features: LCH is primarily a disease of the very young with a peak incidence of 1 \200\2233 years. It can present in a variety of ways, from a small bone lesion heavily admi xed with eosinophils (eosinophilic granuloma), through multiple lytic bone lesions, exophth almos and diabetes insipidus (Hand \200\223Schuller \200\223Christian disease) to multiple tissue infiltration involving skin, liver, lung bone and bone marrow (Letterer \200\223Siwe disease). The eponymous terms are no longer used for what is now regarded as a common path ology and the overarching term LCH is preferred. This is staged on the basis of the number of organ systems showing infiltration, 12-Pediatric.qxd 10.12.2003 04.28 PM Page 491 Pediatric hematology and virtually any can be involved. The skin rash of LCH is characteristically in skin folds and scaly with red/brown papules. It may be mistaken for nappy rash. Systemic symptoms inc luding fever and weight loss are common in advanced disease. It can be staged as follows: Stage A Stage B Stage C Stage D Multisystem disease with combinations of A, B, C. Involvement of bones local nodes and adjacent soft tissue. Skin mucous membranes invo lvement, related nodes. Soft tissue involvement \200\224not stage A, B or D. Diagnosis Based on tissue biopsy. Skeletal survey to define extent of disease; also bone sc an, MRI. Urine osmolality studies for diabetes insipidus. BM aspi- rate and biopsy if anemi c or other cytopenias present. Treatment Local curettage of any isolated lesion, with or without intra-lesional steroids. Stable and symptomless disease can be simply observed for spontaneous resolution. Options f or widespread disease include steroids and chemotherapy \200\224rarely radiotherapy. Indica tions for chemotherapy include organ dysfunction and/or disease progression/recurrence. Dru gs commonly used include steroids, vinblastine or etoposide, singly or com- bined. Outcome Generally good, but widespread organ involvement with dysfunction and progression i ndicates a poor prognosis. Overall mortality 15 \200\22320%. Long term sequelae include pul monary/liver fibrosis, diabetes insipidus, growth failure. Risk of malignant disease increa sed, chiefly leukaemias and lym- phomas. 491 Class II: macrophage functional disorders \200\224haemophagocytic syndromes Primary (genetic) Primary haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessi vely inherited disease of infants and young children (>50% <1 year) also known as familial erythrophagocytic lymphohistiocytosis (FEL) due to the striking degree of marrow red cell p hagocytosis. The gene defect is not known, and the pathology of the condition is unclear ap art from cytokine dysregulation and high concentrations of IL-1 and 2, GM-CSF and TNF. CNS involvement common. Laboratory investigation shows periph- eral blood cytopenias, hypertrig liceridaemia and hypofibrinogenaemia. Histopathology shows histiocyte/lymphocyte infiltrati on and haemo- phagocytosis in BM, nodes and spleen. Treatment and outcome: Seldom effective, steroids, chemotherapy, ALG, cyclosporin A, BMT. D isease usually rapidly fatal. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 492 Secondary 2 Clinical and laboratory picture is similar to primary (genetic) HLH. Distinction between the two may be difficult. 2 Affects more older patients, often immunocompromised. 2 Commonly associated with underlyi ng viral/bacterial infection when called infection-associated haemophagocytic syndrome (IAH S). 2 Triggered by a wide variety of infections including (especially) EBV and malaria. Also as sociated with some malignancies (usually involving T cells) and lipid infusions. Treatment and outcome: Good survival rates if underlying infection easily treatable. Otherw ise has high mortality. Class III: Malignant histiocytosis Monocyte-derived acute leukaemias account for 10% of AML s arising in children. What used to be called \200\230malignant histiocytosis \200\231 wit h hepatosplenomegaly, fever, wasting and pancytopenia and tissue infiltra- tion with large monocytoid cells is now recognized as a lymphocyte- derived lymphoma (large cell anaplastic , CD30+, (cid:9) p198). It is doubtful whether true histiocyte-derived malignancies other t han AML occur in children. 492 12-Pediatric.qxd 10.12.2003 04.28 PM Page 493 Pediatric hematology 493 12-Pediatric.qxd 10.12.2003 04.28 PM Page 494 Hematological effects of systemic disease in children Non-hematological disease in children can produce a variety of haemato- logical effects spe cific to the disease, to childhood, or both. Some of the more striking examples are listed below. Wilson \200\231s disease: Genetic defect in copper metabolism that occasionally presents as a brisk non-immune haemolytic anemia without specific features. More commonly presents wit h liver dysfunction, neurological symptoms or renal disease. Cyanotic congenital heart disease: Commonly associated with mild thrombocytopenia for ill-u nderstood reasons. Mast cell disease: Abnormal accumulations of mast cells in the skin or internal organs. Mas t cell leukemia does not occur in children. Commonest manifestation is urticaria pigmentosa in infants. Bullous or urticarial lesions eventually become infiltrated with mast cells. M arrow involvement rare. The cells produce histamine and cause itching. Condition resolves b y adulthood. Juvenile rheumatoid arthritis: Classically the anemia of chronic inflammatory disease \200 \224a defective marrow response to anemia in a variety of chronic inflammatory disorders pr imarily due to cytokine mediated than deficiency of erythropoietin. True iron deficiency al so occurs due to NSAID therapy. Neutropenia may arise, either immune mediated or due to hyp ersplenism. inhibition of erythropoiesis rather 494 Systemic lupus erythematosus: Commonly associated with immune cytopenias (all cell lines) a nd anticardiolipin antibodies. May also produce marrow hypoplasia. Epstein \200\223Barr virus infection: Infects CD21 positive B lymphocytes and other tissues including nasopharyngeal epithelium. Primary infection in the immunocompetent may be asymp tomatic in the early years of childhood but in adolescence produces the syndrome of infecti ous mononucleosis ( \200\230glandular fever \200\231) associated with a striking atypical l ymphocytosis. Occasionally there are associated self-limiting immune cytopenias \200\224 es pecially thrombocytopenia. The majority of adults harbor the latent virus in B cells. EBV i n some cellular immune deficiency states (such as X- linked lymphoproliferative disease als o known as Purtilo \200\231s or Duncan \200\231s syndrome) infection with uncontrolled fata l lymphoproliferation and infection associated haemophagocytosis ((cid:9) HLH, p491). can produce a Parvovirus B19 infection: Causes \200\230fifth disease \200\231 in infants and young child ren with the characteristic \200\230slapped cheek \200\231 rash on the face. More importan tly shows trophism for marrow erythroblasts and causes temporary red cell hypoplasia. This causes very low Hb concentrations in 12-Pediatric.qxd 10.12.2003 04.28 PM Page 495 Pediatric hematology children with chronic haemolysis. Persistent viraemia can arise in the immunosuppressed and can cause transfusion dependency. TORCH infections: A miscellaneous group of congenital infections \200\224 TOxoplasmosis, Ru bella, Cytomegalovirus, Herpes simplex and syphilis. All can cause neonatal anemia and thro mbocytopenia. Leishmaniasis: The Mediterranean type of visceral leismaniasis primarily affects young chil dren under 5. Infected sand flies transmit parasites that develop in macrophages and the ch ild presents often several weeks or months and hepatosplenomegaly. Fatal if untreated but r esponds well to pentavalent antimony or amphotericin B. later with fever and progressive pancytopenia Hookworms (ankylostoma): Are a common cause of iron deficiency in tropical underdeveloped c ountries. Infestations may be heavy with each worm consuming up to 0.2mL blood per day. Tapeworms: A rare cause of vitamin B12 deficiency in societies that eat raw fish \200\224Ba ltic states, Japan and Scandinavia, due to infestation by Diphyllobothrium latum. Kawasaki disease: An acute multisystem disease of young children, presumed to be infective but no organism has so far been identified. Presents with conjunctivitis, rashes, reddening of the mucous membranes, hands and feet with desquamation and lymphadenopathy. Coronary ar tery aneurysms develop in 20%; fatal in 3%. Hematological manifestations include anemia (n ormochromic normocytic), neutrophilia, and a striking secondary thrombocytosis that may lin ger after the acute phase has passed. Treatment is with aspirin and high dose IVIg. 495 Nutritional disorders Iron deficiency: Occurs in apparently healthy children (cf. adults where main cause is bloo d loss). Linked to rapid growth and poor intake the first 2 years of life and again at adol escence. Cows \200\231 milk is a poor source of iron. Cereals inhibit its absorption Premat ure infants run out of iron by 2 months of age. Protein-calorie malnutrition: Covers adequate calories with protein lack (kwashiorkor) and simple calorie lack (marasmus) \200\224or both. Chiefly in undeveloped countries, but also occasionally in vegan families, with gastrointestinal disease or other chronic illness. Con comitant iron or folate deficiency may be present. Normochromic normocytic anemia is usual. Scurvy: Occasionally seen in infants due to poor intake with fruit juices being boiled. Pse udoparalysis due to painful legs. Petechial, periorbital or subdural hemorrhages can arise. Bleeding tendency due to loss of vascular integrity with collagen deficiency. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 496 Poisons Lead poisoning: Inhibits haem synthesis and the activity of pyrimidine-5 -nucleotidase, cau sing hypochromic anemia with basophilic stippling of red cells and ring sideroblasts in the bone marrow. Also causes abdominal pain. Commonest in toddlers eating flakes of old lead-b ased paint. Sodium chlorate: A common weedkiller, also a powerful oxidizing substance causing acute int ravascular haemolysis and renal failure if ingested. Nitrates, aniline dyes, nitrobenzene and azo compounds: Can all cause methaemoglobinaemia. If >20% metHb formed, exchange transfusion may be needed. Storage disorders Gaucher \200\231s disease: Inherited (autosomal recessive) disorder resulting in deficiency of the enzyme glucocerebrosidase (b-glucosidase) Most common form has accumulated glycolip id in macrophages of spleen, liver and bone marrow. May be diagnosed at any time during lif e depending on severity. Some cases are not identified until adulthood. Rarer type 2 diseas e has severe progressive neurological deterioration from birth, usually fatal within 1 year due to glycolipid accumulation in the CNS. Diagnosis by assay of deficient enzyme, but cha racteristic (not diagnostic, see below) Gaucher cells evident in bone marrow (laden macroph ages with appearance of crumpled tissue paper). Neimann \200\223Pick (N-P) disease: Though rare, commonest cause of foamy macrophages in ma rrow of affected patients. Caused by the inherited deficiency of sphingomyelinase resulting in accumulation of sphingomyelin. Four types of Niemann \200\223Pick disease have been def ined, type A (classic N- P disease) presents in the first year of life with developmental d elay, neurodegeneration and death within 3 years; type B with visceral rather than CNS invo lvement also presents in infancy and is also progressive and fatal but spares the CNS; type C presents later in childhood but then shows neurodegeneration with death in the 2nd or 3r d decade; and type 4 patients simply store sphingomyelin in viscera without ill health and live to adulthood. 496 Marrow and blood cells in storage disorders: The foamy macrophages seen in the marrow of N- P patients vary between types and are not in any way diagnostic or specific. Foamy macropha ges are also seen in several other storage disorders and a variety of other clinical circum stances. Pseudo-Gaucher cells are seen in chronic granulocytic leukemia, thalassaemia and s ome atypical mycobacterial infections. Several storage disorders produce vacuolation of per ipheral blood leucocytes, particularly lymphocytes, and this is also a non-specific finding . Diagnosis always rests on the appropriate enzyme assay. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 497 Pediatric hematology 497 12-Pediatric.qxd 10.12.2003 04.28 PM Page 498 This page intentionally left blank 498 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 499 Hematological emergencies 13 Septic shock/neutropenic fever 500 Transfusion reactions 502 Immediate-type hypersensitivity reactions 504 Febrile transfusion reactions 504 Delayed tr ansfusion reaction 504 Bacterial contamination of blood products 506 Post-transfusion purpura 506 Hypercalcaemia 508 Hyperviscosity 510 Disseminated intravascular coagulation 512 Overdosage of thrombolytic therapy 516 Heparin overdosage 518 Heparin-induced thrombocy topenia (HIT) 520 Warfarin overdosa ge 522 Massive blood transfusion 524 Paraparesis/spinal collapse 526 Leucostasis 528 Thr ombotic thrombocytopenic purpura 530 Sickle crisis 532 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 500 Septic shock/neutropenic fever (cid:2)(cid:2) One of the commonest haemato-oncological emergencies. 2 May be defined as th e presence of symptoms or signs of infection in a patient with an absolute neutrophil count of <1.0 109/L. In practice, the neutrophil count is often <0.1 109/L. 2 Similar clinical picture also seen in neutrophil function disorders such as MDS despite normal neutrophil numbers. 2 Beware \200\224can occur without pyrexia, especially patients on steroids. Immediate action (cid:2)(cid:2) Urgent clinical assessment. 2 Follow ALS guidelines if card iorespiratory arrest (rare). 2 More commonly, clinical picture is more like cardiovascular shock respiratory embarrassment viz: tachycardia, hypotension, peripheral vasodilatation and tachypnoea. Occurs with both Gram +ve (now more common with indwelling central cathete rs) and Gram \200\223ve organ- isms (less common but more fulminant). 2 Immediate rapid infusion of albumin 4.5% or Gelofusin to restore BP. 2 Insert central cat heter if not in situ and monitor CVP. 2 Start O2 by face mask if pulse oximetry shows satur ations <95% (common) and consider arterial blood gas measurement \200\224care with platelet counts <20 109/L \200\224manual pressure over puncture site for 30 mins. 2 Perform full septic screen (see guidelines on IV antibiotics, p552). 2 Give the first dos e of first line antibiotics immediately e.g ureidopeni- cillin and loading dose aminoglycos ide (ceftazidime or ciprofloxacin if pre-existing renal impairment). Follow established pro tocols. 2 If the event occurs while patient on first line antibiotics, vancomycin/ ciprofloxacin or vancomycin/meropenem are suitable alternatives. 500 2 Commence full ITU-type monitoring chart. 2 Monitor urine output with urinary catheter if necessary \200\224if renal shut- down has already occurred, give single bolus of IV frusemide (furosemide). If no response, start renal dose dopamine. 2 If BP not restored with colloid despite 4 CVP, consider inotropes. 2 If O2 saturations re main 5 despite 60% O2 delivered by rebreathing mask, consider ventilation. 2 Alert ITU giving details of current status. Subsequent actions 2 Discuss with senior colleague. 2 Amend antibiotics according to cultur e results or to suit likely source if cultures negative (see p554, 556). 2 Check aminoglycoside trough levels after loading dose and before second dose as renal imp airment may determine reducing or with- holding next dose. Consider switch to non-nephrotox ic cover e.g cef- tazidime/ciprofloxacin. 2 Continue antibiotics for 7 \200\22310d minimum and usually until neutrophil recovery. 2 If cultures show central line to be source of sepsis, remove immedi- ately if patient not responding. 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 501 Hematological emergencies 501 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 502 Transfusion reactions Rapid temperature spike (>40 C) at start of transfusion indicates transfu- sion should be stopped (suggests acute intravascular haemolysis). If slow rising temperature (<40 C), providing patient not acutely unwell, slow IVI. Fever often due to antibodies against WBCs (or to cytokines in platelet packs). (cid:2) Immediate transfusion reaction Intravascular haemolysis (7haemoglobinaemia and haem oglobinuria). Usually due to anti-A or anti-B antibodies (in ABO mismatched transfu- sion). Symptoms occur in minutes/hours. Immediate transfusion reaction or bacterial contamination of blood Symptoms Signs Patient restless/agitated Flushing Anxiety Chills Nausea and vomiting Pain at venepuncture site Abdominal, flank or chest pain Diarrhea Fever Hypotension Oozing from wounds or venepuncture sites Haemoglobinaemia Haemoglobinuria If predominantly extravascular may only suffer chills/fever 1h after starting transfusion \200\224commonly due to anti-D. Acute renal failure is not a feature. 502 Mechanism Complement (C3a, C4a, C5a) release into recipient plasma7smooth muscle contractio n. May develop DIC (see p512); oliguria (10% cases) due to profound hypotension. Initial steps in management of acute transfusion reaction 2 Stop blood transfusion immediat ely. 2 Replace giving set, keep IV open with 0.9% saline. 2 Check patient identity against donor unit. 2 Insert urinary catheter and monitor urine output. 2 Give fluids (IV colloids) to maintain urine output >1.5mL/kg/h. 2 If urine output <1.5mL/kg/h insert CVP line and gi ve fluid challenge. 2 If urine output <1.5mL/kg/h and CVP adequate give furosemide (frusemide) 80 \200\223120 mg. 2 If urine output still <1.5mL/kg/h consult senior medical staff for advice. 2 Contact Bloo d Transfusion Lab before sending back blood pack and for advice on blood samples required for further investigation. Complications Overall mortality 10%. 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 503 Hematological emergencies 503 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 504 Immediate-type hypersensitivity reactions May occur soon (30 \200\22390min) after transfusion of blood/component. Antibody often unkn own but in some cases is due to antibody directed against IgA (in recipients who have becom e sensitized). 2 Mild reaction: urticaria, erythema, maculopapular rash, periorbital oedema. 2 Severe reaction: bronchospasm. 2 Hypotension. Management 2 Stop transfusion immediately. 2 Change giving set. 2 IV colloids to maintain B P/circulatory volume. 2 Give \200\223 epinephrine (adrenaline) \200\223 hydrocortisone \200\223 chlorphenamine (chlor pheniramine) 10mg IV stat 1:1000 1mL IM stat 100mg IV stat Febrile transfusion reactions Seen in 0.5 \200\2231.0% blood transfusions. Mainly due to anti-HLA antibodies in recipient serum or granulocyte-specific antibodies (e.g. sensitisation during pregnancy or previous blood transfusion). Less common now that all blood is leucodepleted after donation. Treatment 2 Slow down rate of transfusion. 2 Antipyretic. 504 Delayed transfusion reaction Occurs in patients immunized through previous pregnancies or transfu- sions. Antibody weak (so not detected at pretransfusion stage). 2 immune response occurs \200\224antibody titr e 4. Symptoms/signs 2 Occur 7 \200\22310d after blood transfusion. 2 Fever, anemia and jaundice. 2 haemoglobinuria. Management 2 Check DAT and repeat compatibility tests. 2 Transfuse patient with freshly cro ss-matched blood. 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 505 Hematological emergencies 505 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 506 Bacterial contamination of blood products Uncommon but potentially fatal adverse effect of blood transfusion (affects red cells and b lood products e.g. platelet concentrates). Implicated organisms include Gram \200\223ve ba cteria, including Pseudomonas, Yersinia and Flavobacterium. Features 2 Fever. 2 Skin flushing. 2 Rigors. 2 Abdominal pain. 2 DIC. 2 ARF. 2 Shock. 2 Car diac arrest. Management \200\224as per Immediate transfusion reaction 2 Stop transfusion. 2 Urgent resu scitation. 2 IV broad-spectrum antibiotics if bacterial contamination suspected. 506 Post-transfusion purpura Profound thrombocytopenia occurring 5 \200\22310d after blood or platelet transfusion. Usua lly due to high titre of anti-HPA-1a antibody in HPA-1a \200\223ve patient. Features 2 Rare. 2 Multiparous 3 most commonly (previous pregnancies or transfusions). 2 Ca used by platelet-specific alloantibodies (usually anti-HPA-1a). 2 Platelets 55 with associa ted bleeding/bruising \200\224may be severe and even life threatening. Management 2 IVIg if bleeding. 2 Plasma exchange worth considering. 2 If platelet transfusi on needed, use random donor platelets (no evi- dence that HPA-1a superior). 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 507 Hematological emergencies 507 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 508 Hypercalcaemia Clinical symptoms 2 General \200\224weakness, lassitude, weight loss. 2 Men tal changes \200\224impaired concentration, drowsiness, personality change and coma. 2 GIT \200\224anorexia, nausea, vomiting, abdominal pain (peptic ulceration and pancreatitis are rare complications). 2 Genitourinary \200\224polyuria, polydipsia. Clinical effects 2 Cardiovascular \200\2245 QT interval on ECG, cardiac arrhythmias and hypertension. 2 Renal \200\224dehydration, renal failure and renal calculi. Hematological causes 1. Myeloma. 2. High grade lymphoma. 3. Adult T-cell leukemia/lymphoma (ATLL). 4. Acute lymphoblastic leukemia. Hypercalcaemia occurs in other clinical situations including metastatic carcinoma of breast , prostate and lung. Theories for occurrence in hematological malignancy include increased bone resorption mediated by osteoclasts under the influence of locally or systemically rele ased cytokines such as PTH-related peptide, TGF, TNF-a, M-CSF, interleukins and prostagland ins. Increased intestinal absorption of calcium secondary to increased 1,25-hydroxycholecal ciferol. Normal range for plasma [Ca2+] 2.12 \200\2232.65mmol/L. 40% of plasma Ca2+ is bound to albu min. Most laboratories measure the total plasma Ca2+ although only unbound Ca2+ is physiolo gically active. For accurate mea- surement of plasma or serum Ca2+ blood sampling should be taken from an uncuffed arm, i.e. without the use of a tourniquet. 508 Correct for albumin corrected calcium = (Ca2+) + 0.02 [40 \200\223(Albumin)] corrected calcium = (Ca2+) \200 \223 0.02 [(Albumin) \200\22345] Albumin <40g/L Albumin >45g/L Management (cid:2) An emergency if Ca2+ >3.0mmol/L. 1. Rehydrate with normal saline 4 \200 \2236L/24h. 2. Beware fluid overload \200\224use loop diuretics and CVP monitoring if nec- essary. 3. Stop thiazide diuretics and consider regular loop diuretics. 4. Give bisphosphonates e.g . disodium pamidronate 60 \200\22390mg IV stat (see table). 5. Treat underlying malignancy. 6. Consider dialysis if complicating factors (CCF, advanced renal failure). 7. Other therapeutic options: \200\223 Calcitonin 200IU 8-hourly. 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 509 Hematological emergencies \200\223 Corticosteroids (e.g. prednisolone 60mg/d PO). \200\223 Mithromycin 25 g/kg IV 3 weekly. \200\223 Plicamycin. Treatment of hypercalcaemia with disodium pamidronate Serum Ca2+ (mmol/L) Up to 3.0 3.0 \200\2233.5 3.5 \200\2234.0 >4.0 Pamidronate (mg) 15-30 30-60 60-90 90 Infuse slowly (see BNF). Response often takes 3 \200\2235d. 509 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 510 Hyperviscosity Common hematological emergency. Defined as increase in whole blood viscosity as a result of an increase in either red cells, white cells or plasma components, usually Ig. Commonest situations arise as a result of 2 4 in red cell volume in polycythaemia rubra ver a. 2 High blast cell numbers in peripheral blood e.g. AML or ALL at presen- tation. 2 Presence of monoclonal Ig e.g. Waldenstr m \200\231s macroglobulinaemia (IgM). Clinical features \200\224polycythaemia (e.g. PRV) 2 Lethargy, itching, headaches, hyperte nsion, plethora, arterial throm- boses viz: MI, CVA and visual loss (central retinal artery occlusion). (cid:2) Emergency treatment Isovolaemic venesection. Remove 500mL blood volume from large b ore vein (antecubital usually) with simultanous replacement into another vein of 500mL 0.9% saline. Repeat daily until PCV <0.45. Clinical features \200\224high WBC (e.g. AML) 2 Dyspnoea and cough (pulmonary leucostasis) ; confusion, 5 conscious level, isolated cranial nerve palsies (cerebral leucostasis), visu al loss (retinal hemorrhage or CRVT). (cid:2) Emergency treatment 2 Unless machine leucapheresis can be obtained immediately, ven esect 500mL blood from large bore vein and replace isovolaemically with packed red cells if Hb <7.0g/dL \200\224otherwise replace with 0.9% saline to avoid increasing whole blood vis cosity. 2 Arrange leucapheresis on cell separator machine. Use white cell inter- face program to ap herese with replacement fluids depending on Hb as above. 2h is usually maximum tolerated. 510 2 Initiate tumor lysis prophylactic protocol (see p560) in preparation for chemotherapy. 2 Start chemotherapy as soon as criteria allow (high urine volume of pH>8 and allopurinol commenced). This is crucial as leucapheresis in this situation is only a holding maneuver while the patient is prepared for chemotherapy. 2 Continue leucapheresis daily until leucostasis symptoms resolved or until WBC <50 109/L. Hypergammaglobulinaemia (e.g. Waldenstr m \200\231s) Lethargy, headaches, memory loss, con fusion, vertigo, visual disturbances from cerebral vessel sludging \200\224rarely MI, CVA. (cid:2) Emergency treatment 2 Unless immediate access to plasma exchange machine available, vene- sect 500mL blood from large bore vein with isovolaemic replacement with 0.9% saline unless Hb <7.0g/dL when use packed red cells. 2 Arrange plasmapheresis on a cell separator machine using plasma exchange program (see p584). Replacement fluids on criteria as above. Aim for 1 \200\2231.5 blood volume exchange (usually 2.5 \200\2234.0L) 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 511 Hematological emergencies starting at lower end of range initially. Repeat daily until symptoms resolved. 2 Maintenance plasma exchanges at 3 \200\2236 weekly intervals may be suffi- cient treatmen t for some forms of Waldenstr m \200\231s macroglobuli- naemia. However, if hyperviscosity due to IgA myeloma or occasionally IgG myeloma, chemotherapy will need to be initiated. Note Diseases in which the abnormal Ig shows activity at lower temperature e.g. cold antibo dies associated with CHAD (see p118) require mainte- nance of plasmapheresis inlet and outl et venous lines and all infusional fluids at 37 C. Polyclonal 4 in Ig (e.g. some forms of cryoglobulinaemia) can also rarely cause hyperviscosity symptoms. Management is as above fo r monoclonal immunoglobulins. 511 13-haem emergencies.qxd 10.12.2003 04.29 PM Page 512 Disseminated intravascular coagulation