Table 12.12 Pediatric modifi cation of WHO classifi cation of myelodysplastic disorders Category Diseases Myelodysplastic/ myeloproliferative disease Juvenile myelomonocytic leukemia ( JMML) Down syndrome disease Transient abnormal myelopoiesis Myeloid leukemia of DS Myelodysplastic syndrome Refractory cytopenia (blood blasts <2%, marrow blasts <5%) Refractory anemia with excess blasts (blood blasts <19%, marrow blasts 5 \200\22319%) Refractory anemia with excess blasts in transformation (blood or marrow blasts 20 \200\2232 9%) 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 m arker 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, neurofi bromatosis type 1, Fanconi anemia, dyskeratosi s congenita, Kostmann syndrome, Diamond \200\223Blackfan anemia, and Shwachman \200\223Diam ond syndrome (E see Childhood acute myeloid leukemia, p.620). All these diseases pre- dispo se to leukemia, and RAEB is merely part of the evolution of AML. A substantial proportion o f childhood MDS in the RA or RAEB category is also induced by previous chemotherapy as a pr odrome to 2 AML. In 625 CHILDHOOD MYELODYSPLASTIC SYNDROMES other words all pediatric cases of RAEB/RAEB-t are best regarded as AML and treated as such if the diagnosis is not in any doubt. \200 Down syndrome children have a particular pred isposition to develop M7 (megakaryoblastic) AML in the fi rst few years of life. This is commonly preceded by a R AEB prodrome where the marrow is hard to aspirate through 2 sclerosis. The decision when to start therapy is diffi cult, but the overall outlook is potentially good with EFS >50%. 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 t he peripheral blood. It is completely self-limiting within days or weeks and is not associa ted with marrow failure, arising alongside normal haemopoiesis. It is important that chemot herapy is withheld in what is regarded as a temporary stem cell instability. Rarely the pro blem can arise in non-Down children, where trisomy 21 is found in the BM only. TAM and M7 i n Down syndrome patients has been recently shown to be associated with acquired mutations i n GATA-1. Juvenile chronic myelomonocytic leukemia (JCMML) Originally called juvenile chronic myeloid leukemia to distinguish it from adult type chronic myeloid leukemia (E CML, p.148), this p ernicious disease still has a high mortality. It is now recognized to be a clonal disorder, with all marrow cell lines involved. It has several distinctive clinical and hematological features. \200 Stigmata of fetal erythropoiesis; high HbF, i red cell i antigen expression and carbonic anhydrase activity, i MCV. Modest i WBC; average 30 \200\22340 \227 109/L, with evident monocytosis, blasts 5 \200\22310%, and occasionally a basophilia. Marrow appearances unremarkable; modest i blasts. \200 Thrombocytopenia; sometimes profou nd. \200 Skin rashes; butterfl y distribution on face. \200 Increasing hepatosplenomega ly. \200 Associated with neurofi bromatosis type 1. May be present in >10% of cases. Poor outlook with progression associated with wasting, fever, infections, bleeding, and pulmonary infi ltrations. Monosomy 7 syndrome Conventional cytogenetic analysis of JCMML shows no abnormality in the classic syndrome, though there is a subvariety (or similar condition that may nevertheless be bio- found. Whether this logically distinct) where monosomy 7 from the diff erent is a d iff erent disorder genetics, monosomy 7 several JCMML have features in common. However, mon osomy 7 children may have: \200 A longer prodrome with RA or RAEB and no monocytosis. \200 They may respond to AML chemotherapy (JCMML responds poorly the marrow in is is not clear. Apart syndrome and and seldom remits). They may remain stable for years without therapy. \200 They respond better to BMT (JCMML achieve <40% EFS even with BMT). 626 CHAPTER 12 Pediatric hematology Adult-type chronic myeloid (granulocytic) leukemia (ATCML) ( E see Adult CML p.148.) More c ommon than JCMML, though still rare, ATCML arises in around 1 in 500,000 children per year (20 in whole of UK). Tends to aff ect older children (60% >6 years) though it has been repo rted in a 3-month-old infant. \200 Associated with Ph chromosome and t(9;22) BCR-ABL fusi on gene in all haemopoietic cells exactly as seen in adults. Natural history exactly the same as the disease in adults with chronic phase and eventual progression to accelerated acute phase. Only curative therapy is allogeneic BMT, but impressive remissions of so far unknown length are now being achieved with novel tyrosine kinase inhibitor imatin ib. For patients who lack a compatible SCT donor this is becoming 1st-line therapy in place of interferon alfa or hydroxycarbamide. 627 CHILDHOOD MYELODYSPLASTIC SYNDROMES 628 CHAPTER 12 Pediatric hematology Histiocytic syndromes Monocytes are formed in the marrow and move through the peripheral bl ood into the tissues where they become histiocytes, either in the mono- nuclear phagocytic system (MPS) or the dendritic cell system (DCS). MPS cells are antigen processing, are pred ominantly phagocytic, and include many organ-specifi c cells such as Kupff er cells and pul monary alveolar macrophages. DCS cells include tissue-based Langerhan cells (LC) which are antigen presenting. There is a variety of syndromes where histiocytes proliferate and malfu nction and some of these carry a high mortality. A few are clonal neoplasms but most are pr oduced by cytokine distur- bances. In 1991 a new classifi cation of histiocytic syndromes w as set out as shown in Table 12.13. Table 12.13 Histiocytic syndromes Disorders of dendritic cells \200 Langerhan cell histiocytosis (LCH) Class I (previously known as histiocytosis X) Disorders of macrophages \200 Haemophagocytic syndromes \200 Haemophagocytic lymphohist iocytosis (HLH): Class II 1 (genetic) \200 2 (to infection or malignant disease) Sinus histiocytosis with massive lymphadenopathy \200 Histiocytic necrotising lymphadenit is \200 Malignant histiocytic disorders: \200 Malignant histiocytosis \200 Monocytic leukaemias Class III Class I: Langerhan cell histiocytosis (LCH) Cellular destructive tissue infi ltration with LC. These are well-dif- ferentiated large cells (15 \200\22325microm) with an indented nucl eus and inconspicuous nucleolus; they are not phagocytic. Other reactive cells (granulocyte s, eosinophils, macrophages) are often present. Diagnostic criteria of LC include the prese nce of Burbeck granules on electron microscopy and immunochemical positivity for CD1A. The etiology of LCH remains unclear. Despite some evidence of clonality (not itself evi- dence of malignancy), no genetic mutations have been identifi ed 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\223 Schuller \200\223Christian disease) to multipl e tissue infi ltration involving skin, liver, lung, bone, and BM (Letterer \200\223Siwe dis ease). The eponymous terms are no longer used for what is now regarded as a common patholog y and the overarching term LCH is preferred. This is staged on 629 HISTIOCYTIC SYNDROMES the basis of the number of organ systems showing infi ltration, and virtu- ally 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 including fever and weight l oss are common in advanced disease. It can be staged as follows: \200 Stage A \200 Stag e B Skin mucous membranes involvement, related nodes. \200 Stage C Soft tissue invo lvement \200\224not stage A, B or D. \200 Stage D Multisystem disease with combinations o f A, B, C. Involvement of bones local nodes and adjacent soft tissue. Diagnosis Based on tissue biopsy. Skeletal survey to defi ne extent of disease; also bone s can, MRI. Urine osmolality studies for diabetes insipidus. BM aspirate and biopsy if anemic or other cytopenias present. Treatment Local curettage of any isolated lesion, with or without intralesional steroids. S table and symptomless disease can be simply observed for spontaneous resolution. Options fo r widespread disease include steroids and chemotherapy \200\224rarely radiotherapy. Indicat ions for chemotherapy include organ dysfunction and/or disease progression/recurrence. Drug s commonly used include steroids, vinblastine, or etoposide, singly or combined. 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 fi brosis, diabetes insip- idus, growth failure. Risk of malignant disease i, chiefl y leukaemias and lymphomas. Class II: macrophage functional disorders \200\224 haemophagocytic syndromes 1 (genetic) 1 haemophagocytic is an autosomal recessively inherited disease of infants and young child ren (>50% <1 year) also known as familial erythrophagocytic lymphohistiocy- tosis (FEL) due to the striking degree of marrow red cell phagocy- tosis. Genetic HLH is a heterogeneous d isorder with at least 4 genetic subtypes (FHLH1-4). 4 genes (Perforin, PRF1, on 10q21; Munc 13-4 on 17q25; Syntaxin 11 on 6q24; STXBP2) have been identifi ed and account for 750% of p atients. Defects in these genes lead to cytokine dysregulation (high concentrations of IL-1 and 2, GM-CSF, and TNF) and \200\230activated \200\231 T cells and histiocytes prompting haemophago- cytosis. CNS involvement is common. Laboratory investigation shows peripheral b lood cytopenias, hypertrigliceridaemia, and hypofi brinoge- naemia. Histopathology shows hi stiocyte/lymphocyte infi ltration and haemophagocytosis in BM, nodes and spleen. Genetic te sting possible in 7 50%. lymphohistiocytosis (HLH) 630 CHAPTER 12 Pediatric hematology Treatment and outcome The use of ALG and CSA in the \200\230HLH \200\231 protocol enables the disease to be brought under control. If this is followed by a SCT survival can be good. Otherwise the disease is usually rapidly fatal. 2 \200 Clinical and laboratory picture is similar to 1 (genetic) HLH. \200 Distinct ion between the 2 may be diffi cult. \200 Aff ects more older patients, often immunocompr omised. \200 Commonly associated with underlying viral/bacterial infection when called infection-associated haemophagocytic syndrome (IAHS). \200 Triggered by a wide var iety of infections including (especially) EBV and malaria. Also associated with some malignancies (usually involving T cells) and lipid i nfusions. Treatment and outcome Good survival rates if underlying infection easily treatable. Otherwi se 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 hepatos- plenomegaly, fever, wasting, and pancytopenia and tissue infi ltration with larg e monocytoid cells is now recognized as a lymphocyte-derived lym- phoma (large cell anaplas tic, CD30+, E 1 p.199). It is doubtful whether true histiocyte-derived malignancies other than AML occur in children. 631 HISTIOCYTIC SYNDROMES 632 CHAPTER 12 Pediatric hematology Hematological eff ects of systemic disease in children Non-hematological disease in childre n can produce a variety of haema- tological eff ects specifi c to the disease, to childhood , or both. Some of the more striking examples are listed here. \200 Wilson disease: genet ic defect in copper metabolism that occasionally presents as a brisk non-immune haemolytic anemia without specifi c features. More commonly presents with liver dysfunction, neurological symptoms, or renal disease. Cyanotic congenital heart disease: commonly associated with mild thrombocytopenia for ill-understood 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 infi ltrated with mast cells. Marrow involvement rare. The cells produce histamine and cause itching. Condition resolves by adulthood. Juvenile rheumatoid arthritis: classically the anemia of chronic infl ammatory disease \200\224a defective marrow response to anemia in a variety of chronic infl ammatory disorders primarily due to cytokine mediated inhibition of erythropoiesis ra ther than defi ciency of EPO. True Fe defi ciency also occurs due to NSAID therapy. Neutrop enia may arise, either immune mediated or due to hypersplenism. \200 Systemic lupus eryth ematosus: commonly associated with immune cytopenias (all cell lines) and anticardiolipin a ntibodies. May also produce marrow hypoplasia. Epstein \200\223Barr virus infection: infects CD21 +ve B lymphocytes and other tissues incl uding nasopharyngeal epithelium. 1 infection in the immunocompetent may be asymptomatic i n the early years of childhood but in adolescence produces the syndrome of infectious monon ucleosis ( \200\230glandular fever \200\231) associated with a striking atypical lymphocyto sis. Occasionally there are associated self-limiting immune cytopenias \200\224especially t hrombocytopenia. The majority of adults harbor the latent virus in B cells. EBV in some cel lular immune defi ciency states (such as X-linked LPD also known as Purtilo \200\231s or Du ncan syndrome) can produce a fatal infection with uncontrolled lymphoproliferation and infe ction-associated haemophagocytosis (E HLH, p.629). Parvovirus B19 infection: causes \200\230fi fth disease \200\231 in infants and young chil dren with the characteristic \200\230slapped cheek \200\231 rash on the face. More importa ntly shows trophism for marrow erythroblasts and causes temporary red cell hypoplasia. This causes very low Hb concentrations in children with chronic haemolysis (e.g. sickle cell di sease). Persistent viraemia can arise in the immunosuppressed and can cause transfusion dep endency. TORCH infections: a miscellaneous group of congenital infections \200\224 toxoplasmosis, rubella, cytomegalovirus, herpes simplex and syphilis. All can cause neonata l anemia and thrombocytopenia. 633 hematological EFFECTS OF SYSTEMIC DISEASE IN CHILDREN Leishmaniasis: the Mediterranean type of visceral leismaniasis primarily aff ects young children under 5 years. Infected sand fl ies transmit parasites th at develop in macrophages and the child presents often several weeks or months later with f ever and progressive pancytopenia and hepatosplenomegaly. Fatal if untreated but responds w ell to pentavalent antimony or amphotericin B. Hookworms (ankylostoma): are a common cause of Fe defi ciency in tropical underdeveloped co untries. Infestations may be heavy with each worm consuming up to 0.2mL blood per day. Tapeworms: a rare cause of vitamin B12 defi ciency in societies that eat raw fi sh \200\224Baltic states, Japan, and Scandinavia, due to infestation by Diphyllo bothrium latum. Kawasaki disease: an acute multisystem disease of young children, presumed to be infective but no organism has so far been identifi ed. Presents with conjunc tivitis, rashes, reddening of the mucous membranes, hands and feet with desquamation and ly mphadenopathy. Coronary artery aneurysms develop in 720%; fatal in 3%. Hematological manife stations include anemia (normochromic normocytic), neutrophilia, and a striking 2 thrombo cytosis that may linger after the acute phase has passed. Treatment is with aspirin and hig h-dose IVIg. Nutritional disorders Fe de \201 ciency Occurs in apparently healthy children (cf. adults where main cause is blood loss). Linked to rapid growth and poor intake the fi rst 2 years of life and again at adolescence. Cows \200\231 milk is a poor source of iron. Cereals inhi bit its absorption. Premature infants run out of Fe by 2 months of age. Protein-calorie malnutrition Covers adequate calories with protein lack (kwashiorkor) and s imple calorie lack (marasmus) \200\224or both. Chiefl y in undeveloped coun- tries, but als o occasionally in vegan families, with GI disease or other chronic illness. Concomitant Fe or folate defi ciency may be present. Normochromic normocytic anemia is usual. Scurvy Occasionally seen in infants due to poor intake with fruit juices being boiled. Pseu doparalysis due to painful legs. Petechial, periorbital, or sub- dural hemorrhages can aris e. Bleeding tendency due to loss of vascular integrity with collagen defi ciency. Poisons Lead poisoning Inhibits haem synthesis and the activity of pyrimidine-5 \200 -nucle otidase, causing hypochromic anemia with basophilic stippling of red cells and ring siderob lasts in the BM. Also causes abdominal pain. Commonest in toddlers eating fl akes of old le ad-based paint. 634 CHAPTER 12 Pediatric hematology Sodium chlorate A common weedkiller, also a powerful oxidizing substance causing acute intr avascular 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 disease Inherited (autosomal recessive) disorder resulting in def i ciency of the enzyme glucocerebrosidase ( -glucosidase). Most common form has accumulate d glycolipid in macrophages of spleen, liver, and BM. May be diagnosed at any time during l ife depending on severity. Some cases are not identifi ed until adulthood. Rarer type 2 dis ease has severe progres- sive neurological deterioration from birth, usually fatal within 1 year due to glycolipid accumulation in the CNS. Diagnosis by assay of defi cient enzyme, b ut characteristic E see Chapter 18, Rare diseases. Gaucher cells evident in BM (laden macro phages with appearance of crumpled tissue paper). Niemann \200\223Pick (N-P) disease Though rare, commonest cause of foamy macrophages in mar row of aff ected patients. Caused by the inherited defi ciency of sphingomyeli- nase result ing in accumulation of sphingomyelin. 4 types of N-P disease have been defi ned: type A (cl assic N-P disease) presents in the 1st year of life with developmental delay, neurodegenera tion, and death within 3 years; type B with visceral rather than CNS involvement also prese nts in infancy and is also progressive and fatal but spares the CNS; type C pre- sents late r in childhood but then shows neurodegeneration with death in the 2nd or 3rd decade; and ty pe D patients simply store sphingomyelin in viscera without ill health and live to adulthoo d. Marrow and blood cells in storage disorders E see Chapter 18, Rare diseases The foamy ma crophages seen in the marrow of N-P patients vary between types and are not in any way diag nostic or specifi c. Foamy macrophages are also seen in several other storage disorders and a variety of other clinical circumstances. Pseudo-Gaucher cells are seen in chronic granu- locytic leukemia, thalassaemia, and some atypical mycobacterial infec- tions. Several stor age disorders produce vacuolation of peripheral blood leucocytes, particularly lymphocytes, and this is also a non-specifi c fi nding. Diagnosis always rests on the appropriate enzym e assay. 635 Chapter 13 Hematological emergencies Septic shock/neutropenic fever 636 Acute transfusion reactions 638 Delayed transfusion reac tion 642 Post-transfusion purpura 643 Hypercalcaemia 644 Hyperviscosity 646 Disseminated in travascular coagulation 648 Overdosage of thrombolytic therapy 651 Heparin overdosage 652 H eparin-induced thrombocytopenia 654 Warfarin overdosage 656 Massive blood transfusion 658 P araparesis/spinal collapse 662 Leucostasis 663 Thrombotic thrombocytopenic purpura 664 Sick le crisis 666 636 CHAPTER 13 Hematological emergencies Septic shock/neutropenic fever 3One of the commonest haemato-oncological emergencies. \200 May be defi ned as the presence of symptoms or signs of infection in a patient with an ab solute neutrophil count of <1.0 \227 109/L. In practice, the neutrophil count is often <0. 1 \227 109/L. Similar clinical picture also seen in neutrophil function disorders such as MDS despite n neutrophil numbers. Beware: can occur without pyrexia, especially patients on steroids. Immediate action 3Urgent clinical assessment. \200 Follow ALS guidelines if cardiorespira tory arrest (rare). \200 More commonly, clinical picture is more like cardiovascular shoc k respiratory embarrassment viz: tachycardia, hypotension, peripheral vasodilatation, an d tachypnoea. Occurs with both Gram +ve (now more common with indwelling central catheters) and Gram \210\222ve organisms (less common but more fulminant). Immediate rapid infusion of albumin 4.5% or Gelofusine to restore BP. \200 Insert central catheter if not in situ and monitor CVP. \200 Start O2 by face mask if pulse oximetry sh ows saturations <95% (common) and consider arterial blood gas measurement \200\224care with platelet counts <20 \227 109/L \200\224manual pressure over puncture site for 30min. Perform full septic screen (E see Guidelines for use of IV antibiotics, p.682). Give the 1st dose of 1st-line antibiotics immediately, e.g. ureidopenicillin and loading dose aminoglycoside (ceftazidime or ciprofl oxacin if pre-existing renal impair ment). Follow established protocols. If the event occurs while patient on 1st-line antibiotics, vancomycin/ ciprofl oxacin or va ncomycin/meropenem are suitable alternatives. Commence full ITU-type monitoring chart. \200 Monitor urine output with urinary catheter if necessary \200\224if renal shutdown has already occurred, give single bolus of IV furosemide. If no response, start re nal dose dopamine. If BP not restored with colloid despite i CVP, consider inotropes. \200 If O2 saturations remain d despite 60% O2 delivered by rebreathing mask, consider ventilation. Alert ITU giving details of current status. Subsequent actions \200 Discuss with senior colleague. \200 Amend antibiotics according to culture results or to suit likely source if cultures \210\222ve (E see Treatment of ne utropenic shock when source unknown, p.684 and Treatment of neutropenic shock when source k nown/suspected, p.686). Check aminoglycoside trough levels after loading dose and before 2nd dose as renal impairment may determine reducing or withholding next dose. Consider swit ch to non-nephrotoxic cover, e.g. ceftazidime/ciprofl oxacin. 637 SEPTIC SHOCK/NEUTROPENIC FEVER Continue antibiotics for 7 \200\22310d minimum and usually until neutrophil recovery. If cultures show central line to be source of sepsis, remove immediately if patient not responding. 638 CHAPTER 13 Hematological emergencies Acute transfusion reactions The diff erential diagnosis of severe, life-threatening transfu sion reaction includes acute haemolytic reactions (usually due to ABO incompatible transfus ion), severe allergic reaction/anaphylaxis, bacterial transfusion- transmitted infection, a naphylaxis, transfusion-related acute lung injury (TRALI), and transfusion-associated circu latory overload (TACO). The British Committee for Standards in Hematology (BCSH) has produc ed a guideline for the investigation and management of acute transfusion reactions (see Fig . 13.1). Acute haemolytic reaction is most commonly due to human error with transfusion of ABO-incompatible red cells which react with the patient \200\231s anti-A or anti-B antibodi es. Activation of complement causes rapid destruction of the transfused red cells in the ci rculation (intravas- cular haemolysis) and triggers the release of infl ammatory cytokines. The patient quickly becomes shocked and develops acute renal failure and disseminated intr avascular coagulation (DIC). See Table 13.1. Transfusion of a blood component contaminated by bac- teria is an uncommon but potentially fatal event seen in particular with platelet c omponents which are stored at 22 \200\22324 C rather than red cells which are stored refri gerated. Implicated organisms include Gram \210\222ve bacteria, including Pseudomonas, Yer sinia, and Flavobacterium. Bacterial screening of platelets is now carried out throughout t he UK which has reduced the risk of such events. The transfusion of a con- taminated pack c an produce rapid onset of fever (usually >2 C above baseline), rigors, and hypotension, wh ich may be initially indistinguish- able from an acute haemolytic reaction or severe allerg ic reaction. Stop transfusion and give IV fl uids. See E p.639 for investigation and manage - ment. Blood cultures should be taken from the patient and the blood unit should be sent b ack to the blood service for microbiological culture with withdrawal of any linked componen ts from the same donation. Start patient on broad-spectrum antibiotics. Severe allergic or anaphylactic reaction can result in severe hypotension or shock associated with wheeze (bro nchospasm), stridor, or swelling of face, limbs, or mucous membranes (angio-oedema) and urt icaria most commonly reported with plasma-rich components such as platelets or FFP but can occur with red cells. This requires immediate inter- vention to ensure the airway is patent and the administration of adrenaline (epinephrine) according to the 2008 UK Resuscitation guidelines. Transfusion-related acute lung injury (TRALI) is caused by antibodies in the do nor blood reacting with the patient \200\231s neutrophils sequestered in the lungs causing leakage of plasma into the alveolar spaces. Most cases present within 2h of transfusion (ma ximum 6h) with severe dyspnoea and cough with frothy pink sputum, often asso- ciated with h ypotension and occasionally fever and rigors. Chest x-ray shows bilateral nodular shadowing . TRALI is often confused with acute heart failure due to circulatory overload. Treatment i s supportive, with high concentration oxygen therapy and ventilatory support and steroid th erapy is not eff ective. 639 ACUTE TRANSFUSION REACTIONS Transfusion-associated circulatory overload (TACO) pre- sents with acute or worsening pulmo nary oedema within 6h of trans- fusion with respiratory distress, tachycardia, raised blood pressure and evidence of positive fl uid balance. TACO is a signifi cant cause of mor- bid ity and mortality due to blood transfusion. The Serious Hazards of Transfusion (SHOT) repor ting scheme received 71 reports of TACO in 2011; contributing to death in two patients and responsible for 24 cases of major morbidity. Elderly patients are at particular risk and many have predisposing medical conditions such as heart failure, renal impairment, hypoalbuni- naemia, and fl uid overload. Treatment incl udes stopping the transfusion and administering oxygen and diuretic therapy with careful mo nitoring and specialist support if required. The risk of TACO is reduced by careful pre-tra nsfusion assessment of predisposing factors, prescription of appropriate volume and fl ow r ate, and adequate monitoring during the procedure. Clinical approach to severe acute transfusion reactions All patients should be transfused i n clinical areas where they can be directly observed to allow prompt detection and immediat e manage- ment of acute reactions. If presumed transfusion reaction the transfu- sion must be stopped with immediate assessment. \200 Stop and disconnect the blood pack and giving- set immediately (but do not discard). Maintain venous access with physiological saline, commence resuscitation. Take samples for FBC, renal and liver function tests, blood cultures, coagulation screen, r epeat compatibility testing, DAT, LDH, and assessment of urine for hemoglobin. Check identifi cation details between the patient, their ID identity band, and the blood component. \200 Consider key/additional features. \200 Fever and sh ock without anaphylaxis: ?ABO mismatched transfusion; ? bacterial sepsis. Dyspnoea without shock: ?TRALI vs TACO \200\224check O2 sats or blood gasses and CXR. Dyspnoea/stridor with shock: ?severe allergic reaction or anaphylaxis. \200 Seek early su pport and advice from critical care and hematology teams. Less severe acute transfusion reactions Include febrile non-haemolytic transfusion reaction s (FNHTR) char- acterized by fever, sometimes accompanied by shivering and myalgia. These a re much less common since leucodepleted blood components were introduced. Mild FNHTR (pyrex ia 38 C but <2 C rise from base- line) can often be managed with an antipyretic such as p aracetamol. The patient should be monitored closely in case these are early signs of a more severe ATR. 640 CHAPTER 13 Hematological emergencies In the case of moderate FNHTR (pyrexia >2 C from baseline or >39 C or rigors and/or myalg ia) consider the possibility of a haemolytic or bac- terial reaction \200\224stop the trans fusion, assess, and investigate as above. Mild allergic reactions result in pruritus and urticarial rash with no change in vital sign s. They are most common in patients receiving plasma-rich components such as FFP or platele ts. These symptoms often improve with an antihistamine, e.g. chlorpheniramine. The patient must, however, be monitored closely for the development of a more severe reaction. Haemovigilance relates to procedures around monitoring and reporting adverse events in rela tion to blood transfusion. The Blood Safety and Quality Regulations mandate that such adver se incidents must be reported via the Serious Adverse Blood Reactions and Events online sys tem to MHRA. This also includes online reporting to the SHOT reporting scheme. Discuss all suspected transfusion reactions with a member of your Hospital Transfusion Team who can advise about investigation and man- agement together with reporting to haemovigila nce schemes. Table 13.1 Acute haemolytic transfusion reaction Symptoms Signs Patient restless/agitated \200 Flushing \200 Anxiety \200 Chills \200 Nausea and vo miting \200 Pain at venepuncture site \200 Abdominal, fl ank, or chest pain \200 Diar rhea Fever \200 Hypotension \200 Oozing from wounds or venepuncture sites \200 Haemoglobinaemia \200 Haemoglobinuria Further reading Tinegate, H. (2012). Guideline on the investigation and management of acute transfusion reactions. Prepared by the BCSH Blood Transfusion Task Force. Br J Haematol, 1 59, 143 \200\22353. 641 ACUTE TRANSFUSION REACTIONS e r e v e s / e t a r e d o m e s i a a m C 8 3 \211 e r u t a r e p m e t d e t a o s I , e t a r e d o m o n n e s r o w s n g i s / s m o t p m y s T O H S / w e v e r C T H / T T H r o / d n a C 2 \200\223 1 l n o i s u t a h t c i t a m o t p m y s e r o m n o i s u l a r e n e g ) t x e t s e t o n f s n a r T e u n i t n o C y n o h s a r / s u t i r u r P ) t f e l y r a s s e c e n r o t n e i t a p r o t i n o M f s n a r t i t i n u d e t a n m a t n o c e e s ( l f e e s ( , a e s u a n s a n i f t n e m u c o D t i n u s a y t n e m t a e r t o e s i r d n a r e d i s n o C r e d i s n o C s n o i t c a e r l t n e u q e r f n o i t c a e r e g a n a m t r o p e r s s e s s a i , s s e r t s i d y r o t a r i p s e r l D L M f I I ff a t s y l l : a u s i v e d u l c n f o e c n e d v e l a c d e m m r o n c i t a m o t p m y s n o i t a u n i t n o c n o i s u e t a r d e t a e r n u g n y i , l o N e b a i y n o h s a r / s u t i r u r p m o r f l i l r e d n u l n o i s u r e w o l s f s n a r T i y a m h c i h w s \200\231 t n e i t a p w e v e r d n a l y t i l i P, B , ) l a n m o d b a r o / d n a y r o t s i h f s n a r t b i t a p m o c d o o b / D f h t i , R P T t a r e d i s n o c e t a i r p o r p p a d n a I i w r o / d n a C 2 \211 e s i r e h t t n e v e d e t a e r n o i s u n o i s u r o n o i t i d n o c t n e t s i s n o c n e v . g . e n o i s u i t n e m t a e r t f i , t u p t u o y r a n i r u n o i t c a e r n o i s u f s n a r t e t u c a n a f s n a r t i n o i t a n m a t n o c g d o o b g n o r w r o / d n a , t s e h c y f s n a r T y r o t s i h l t n e u q e r f f s n a r t d n a l l e v o b a f l i t r a p a o f I , e c s u m l I t n e i t a p k c e h c ) s / t i n u d e t a c e r o m r o C 9 3 \211 e r u t a r e p m e T s n g i s / s m o t p m y s s a n o i t i d n o c , s n o i t a r u t a s l , a i r e t c a b r e d i s n o C s e s i r e n o b ( e t a i r p o r p p a m r o f r e P t o n o d ( y r o t s i h h t i t n e i t a p r o t i n o M w e r u t a r e p m e t : f o t n e t s i s n o c n a p g n y s n o i t a g i t s e v n s i ) 1 e c n e d i v E i l , t n e m r o n o i t i d n o c m e b o r p y r o t a u c r i e u n i t n o c s i D i p m E T A R E D O M n e g y x o e b a T e e s ( l r e d n u , a i r a c i t r u l l i r e h t O d r a c s i d s s e s s a t o N f o s e r u t a e f e b i s s o p g n i t i b h x e t n e i t a P i , g n h s u fl l a c n l i i i l c d p a r C , s n o i t a r u t a s n e g y x o i r o / d n a y a w h t a p s i x a y h p a n a w o e s p a y r o t a r o b a e d u g o t o t l i e k a t r e d n u l l e c v r e s d o o b t c a t n o c d e t c e p s u s o c \200\224 t o n ) s / t i n u d e t a c t n e m t a e r t i g n h t a e r B r o / d n a , n o i s n e t o p y h i ) y r a s s e c e n l e t a i r p o r p p a n o i s u l f I \200\224 N O I S U F S N A R T E H T P O T S ? n o i s n e t o p y h ) 1 e b a T e e s ( l c i t o b i t n a n o i t a r t s i n m d a f s n a r t o t i , t u p t u o y r a n i r u P, B l i l p m i f i r o - r e p y h i e s i r e t e h t a c ( t n e m l l s a A R H M / T O H S o t d r a c s i d t o n o d ( o \200\224 s t n e n o p m o c d e t a c o s s a y a w r i f i ) t e s t r a t s g n i s u a c s n o i t a g i t s e v n t r a p e d n o i s u y g r e s e Y n o i t a r t s i n m d a A g n n e t a e r h t - e y e k e n , a d r a c y h c a t l l l i i l a e r e v e s / s i x a y h p a n a G N N E T A E R H T - E F I L / E R E V E S a s p e h i l t u p t u o e n i r u C B A \200\224 n o i t a t i c s u s e r e b o t i C T H l n o i t a n m a t n o c n o i t a n m a t n o c , l R P T a c g o o i s y h p s u o n e v a r t n I s s e c c a n o i s u i l i a c d e m i f s n a r t y e k t a w e v e R e t a i r p o r p p a m r o f r e P . g . e i l i l i i , s r o g i r t r o p e R f s n a r t h t i i l s u o n e v : t n e i t a p r o t i n o M f i e g a h r r o m e a h l l i a t i p s o h m r o n w L t n e g r u , e s l u p P, B e s U l l ( a c e r t i n u e u n i t n o c s i d , s l l i l l a i r e t c a b a i r e t c a b n a t n a M h c r o y e k i s s u c s i d n r u t e R e t a i t i n l , r e v e F f l l i i l a C f s I f I f I f I I i I Fig 13.1 Acute transfusion reactions. Reproduced from Tingate, H. et al. Guideline on the i nvestigation and management of acute transfusion reactions, Br J Haem, 159(2), 143 \200\223 53 (26 Aug 2012), with permission from Wiley Blackwell. 642 CHAPTER 13 Hematological emergencies Delayed transfusion reaction Occurs in patients immunized through previous pregnancies or t rans- fusions. Antibody weak (so not detected at pretransfusion stage). 2 immune response occurs \200\224antibody titre i. Certain patient groups such as those with sickle cell anemia are more prone to form red cel l antibodies with risk of delayed haemolytic trans- fusion reaction. Close communication wi th the hematology team and the transfusion laboratory is essential to ensure appropriate ca re of these patients. Symptoms/signs \200 Occur 7 \200\22310d after blood transfusion. \200 Fever, anemia, an d jaundice. \200 haemoglobinuria. Management \200 Check DAT and repeat compatibility tests. \200 Seek hematology advice a nd if needed in complex cases specialist advice from the Red Cell Immunology Team at the Na tional Blood Service regarding further transfusion. 643 POST-TRANSFUSION PURPURA Post-transfusion purpura Profound thrombocytopenia occurring 5 \200\22310d after blood or p latelet transfusion. Usually due to high titre of anti-HPA-1a antibody in HPA-1a \210\222v e patient. Now very rarely seen. Features \200 Rare. \200 Multiparous \231\200 most commonly (previous pregnancies or transfusions). Caused by platelet-specifi c alloantibodies (usually anti-HPA-1a). \200 Platelets dd with associated bleeding/bruising \200\224may be severe and even life-threatening. Management \200 IVIg if bleeding. \200 If platelet transfusion needed, use random donor platelets (no evidence that HPA-1a negative platelets superior). 644 CHAPTER 13 Hematological emergencies Hypercalcaemia Clinical symptoms \200 General: weakness, lassitude, weight loss. \200 Mental changes: impaired concentration, drowsiness, personality change and coma. GIT: anorexia, nausea, vomiting, abdominal pain (peptic ulceration and pancreatitis are rare complications). Genitourinary: polyuria, polydipsia. Clinical eff ects \200 Cardiovascular: d QT interval on ECG, cardiac arrhythmias and hypertension. Renal: dehydration, renal failure, and renal calculi. Hematological causes \200 Myeloma. \200 High-grade lymphoma. \200 Adult T-cell leukem ia/lymphoma (ATLL). \200 Acute lymphoblastic leukemia. Hypercalcaemia occurs in other clinical situations including metastatic car- cinoma of brea st, prostate, and lung. Theories for occurrence in haema- tological malignancy include i bo ne resorption mediated by osteoclasts under the infl uence of locally or systemically relea sed cytokines such as PTH-related peptide, TGF, TNF- , M-CSF, interleukins, and prostaglan - dins. i intestinal absorption of Ca2+ 2 to i 1,25-hydroxycholecalciferol. n range for p lasma [Ca2+] 2.12 \200\2232.65mmol/L. 40% of plasma Ca2+ is bound to albumin. Most laborato ries measure the total plasma Ca2+ although only unbound Ca2+ is physiologically active. Fo r accurate meas- urement of plasma or serum Ca2+ blood sampling should be taken from an unc uff ed arm, i.e. without the use of a tourniquet. (See Table 13.2.) Table 13.2 Correct for albumin Corrected calcium = (Ca2+) + 0.02 [40 \210\222 (albumin)] Corrected calcium = (Ca2+) \210 \222 0.02 [(albumin) \210\222 45] Albumin <40g/L Albumin >45g/L Management 2An emergency if Ca2+ >3.0mmol/L. \200 Rehydrate with normal saline 4 \200\223 6L/24h. \200 Beware fl uid overload \200\224use loop diuretics and CVP monitoring if necessary. Stop thiazide diuretics and consider regular loop diuretics. \200 Give bisphosphonates, e .g. disodium pamidronate 60 \200\22390mg IV stat (E see Table 13.3) or zoledronic acid 4mg IV in 100mL Normal saline over at least 15min. \200 Treat underlying malignancy. \200 C onsider dialysis if complicating factors (CCF, advanced renal failure). 645 HYPERCALCAEMIA Other therapeutic options: