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The diagnosis and management of primary autoimmune haemolytic anaemia

2016; Wiley; Volume: 176; Issue: 3 Linguagem: Inglês

10.1111/bjh.14478

1365-2141

Quentin A. Hill, R. Stamps, Edwin Massey, John D. Grainger, Drew Provan, Anita Hill,

Blood disorders and treatments

The objective of this guideline is to provide healthcare professionals with guidance on the management of patients with primary autoimmune haemolytic anaemia (AIHA). The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. Attempts to categorise autoimmune haemolytic anaemia (AIHA) and define its response to treatment vary considerably in the published literature. Author defined criteria have been used in this guideline, but this limits study comparisons and will have contributed to differences in reported outcome. The investigation and diagnosis of adult and paediatric AIHA are considered together. Guidance on the treatment of adult AIHA is then followed by a section on paediatric AIHA. Recommendations are based on the systematic review of published English language literature from January 1960 to October 2015 (see Appendix S1 for further details). Although recommendations are unchanged, an expanded version of this guideline is available as Appendix S2. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the British Committee for Standards in Haematology (BCSH) guidance pack (http://www.bcshguidances.com/BCSH_PROCESS/42_EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION.html) and the GRADE working group website http://www.gradeworkinggroup.org The guideline group was selected to be representative of UK-based experts in the diagnosis and management of AIHA. Review of the manuscript was performed by the BCSH General Haematology Task Force, BCSH Executive Committee and then a sounding board of the British Society for Haematology (BSH). This compromises 50 or more members of the BSH who have reviewed this Guidance and commented on its content and applicability in the UK setting. AIHA is a decompensated acquired haemolysis caused by the host's immune system acting against its own red cell antigens. The incidence is approximately 1 per 100 000/year (Pirofsky, 1975; Klein et al, 2010). It can occur at any age but incidence rises with increasing age. Serologically, cases are divided into warm type (65%), cold type (29% cold haemagglutinin disease [CHAD], 1% paroxysmal cold haemoglobinuria) or mixed AIHA (5%). Approximately half are primary (idiopathic) AIHA and half are secondary to associated disorders (Table 1). Patients with AIHA may present with symptoms of anaemia (weakness 88%, dizziness 50%, dyspnoea 9%), haemolysis (jaundice 21%, dark urine 3%) or symptoms of an underlying disorder (Pirofsky, 1975). Without underlying disease, examination may be unremarkable or reveal mild pallor or splenomegaly. Less often, severe haemolysis leads to hepatosplenomegaly, haemoglobinuria and signs of heart failure (Packman, 2008). Cold haemagglutinin disease (CHAD) can present as a primary chronic clonal disorder, usually occurring in middle age or in the elderly. Cold-induced acrocyanosis (dusky blue appearance of toes, fingers, nose tip or ears) or Raynaud phenomenon occur in 40‒90% of patients (Berentsen et al, 2006; Swiecicki et al, 2013). Secondary CHAD can be self-limiting, for example following childhood infection. With its different natural history, secondary CHAD has also been termed cold agglutinin syndrome (Berentsen & Tjonnfjord, 2012). Paroxysmal cold haemoglobinuria (PCH) is typically transient, presenting 1–2 weeks after an upper respiratory tract infection or other childhood illness with acute fever, abdominal, back or leg pain and haemoglobinuria (Gehrs & Friedberg, 2002). Haemolysis can be severe and intravascular but usually settles over several weeks. When a patient presents with suspected AIHA, three questions should be considered. Is there haemolysis; is the haemolysis autoimmune and what is the type of AIHA? However, there may be confounding factors as these laboratory tests are not highly specific. Some parameters may be normal, especially with mild compensated haemolysis. The differential diagnosis of haemolytic anaemia is shown in Table 2. A positive direct antiglobulin test (DAT) indicates the presence of immunoglobulin (Ig)G, IgM, IgA or complement (usually C3d) bound to the red cell membrane. In the presence of haemolysis, this suggests an immune aetiology but clinical assessment is required before a diagnosis of AIHA can be made. Typically monospecific anti-IgG and anti-C3d antibodies are used in the initial screening and these help to determine the type of AIHA. A positive DAT is not specific and is also associated with a wide range of non-haemolytic disease states, possibly through passive deposition of immunoglobulins or immune complexes; examples include liver disease, chronic infection, malignancy, systemic lupus erythematosus (SLE), renal disorders and drugs such as intravenous immunoglobulin (IVIg) or antithymocyte globulin. Rarely, AIHA patients test negative with a tube test DAT, for example due to a low affinity antibody, low levels of red cell bound antibody or an immunoglobulin not tested for (e.g. IgA-only AIHA). A gel column agglutination method is a more sensitive method that is less prone to error than a conventional tube test (Fayek et al, 2012). AIHA can be diagnosed in 3% of patients testing negative with a gel card method by using a red cell elution technique (Sachs et al, 2006). The Donath-Landsteiner test may be considered in children with haematuria and is discussed under investigations. Patients with DAT-negative AIHA generally have a milder anaemia and are steroid responsive. The most relevant tests to investigate for an underlying cause for AIHA are shown in Table 3. Although reticulocytopenia can occur in the acute phase of AIHA; haematinic deficiency, marrow infiltration, aplastic anaemia and parvovirus B19 infection should be considered if it is present. Further serological investigation is required to determine the type of AIHA (e.g. warm, CHAD, PCH) as the approach to treatment differs. Finally, if the patient requires blood, investigations are needed to exclude underlying alloantibodies and identify units suitable for transfusion. In adults, two 7 ml EDTA samples are usually sufficient for initial serological investigation. A clotted sample is also required for investigation of suspected PCH or DIIHA. If DAT is positive for C3 ± IgG and i)DAggT negative or insignificant CAs and ii)age <18 years or haemoglobinuria or cold associated symptoms or atypical serology Typical serological characteristics of AIHA subtypes are shown in Table 4. Although the autoantibody specificity can sometimes be identified, specificity does not help predict the clinical outcome (Issitt, 1985). Is caused by autoantibodies (usually IgG) that bind red cells optimally in vitro at 37°C. When tested with anti-C3 and anti-IgG reagents, the DAT would be positive for: IgG only (35%), IgG + C3 (56%) or C3 only (9%) (Issitt, 1985). AIHA can be considered warm when there is a consistent clinical picture and a DAT positive to IgG, C3 or both, when a clinically significant cold reactive antibody has been excluded (Fig 1). Is caused by autoantibodies (usually IgM) that bind red cells optimally in vitro at 4°C. Although the DAT is usually positive for C3 only, 21–28% are also positive with IgG (Berentsen et al, 2006; Swiecicki et al, 2013). Furthermore, only 7–31% of patients with AIHA and a C3-only positive DAT have CHAD. Marked red cell agglutination on the blood film is classically seen in CHAD but can occur in mixed AIHA and PCH. Milder agglutination sometimes occurs in warm AIHA and clinically insignificant polyclonal cold agglutinins (CAs) can cause agglutination on a blood film spread at room temperature. Up to 35% of patients with warm AIHA have CAs reactive at 20°C (Petz & Garratty, 1980). CHAD must therefore be distinguished from insignificant CAs. The thermal amplitude of CAs (the maximum temperature at which antibody binds red cells in vitro) is usually <25°C. At 4°C, the CA antibody titre is usually only positive with a dilution 1:500 at 4°C and the thermal amplitude ≥30°C (but can be as low as 25°C if red cells are suspended in saline rather than 30% bovine albumin). Defining an absolute cut-off for titre or thermal amplitude is difficult and there are exceptions. CHAD can be diagnosed in patients with AIHA and a DAT positive to C3 ± IgG, with a consistent clinical picture and a high titre cold reactive antibody. The thermal amplitude may be considered as a supportive serological investigation where diagnostic uncertainty exists. The term 'primary' CHAD has been used to describe patients without other systemic autoimmune disease or infective aetiology and who have no clinical or radiological evidence of underlying lymphoma. However, with immunophenotyping, the majority of such cases have evidence of a clonal bone marrow lymphoproliferative disorder and a circulating IgM monoclonal paraprotein (Berentsen, 2011). The paraprotein can be detected by serum electrophoresis and immunofixation in >90% of cases (Berentsen et al, 2006) but the sample must be kept at 37°C until the serum has been separated or the antibody will remain bound to red cells. All cases of suspected primary CHAD should be reviewed by an appropriately constituted haemato-oncology multidisciplinary team (National Institute for Clinical Excellence, 2003). PCH is caused by a biphasic IgG antibody that binds to red cells at low temperature and causes complement-mediated lysis as the temperature is raised. The DAT is usually positive to C3 only. There may be agglutination, spherocytes or erythrophagocytosis by neutrophils on the blood film. Reticulocytopenia is common early in PCH, evolving into reticulocytosis with recovery. PCH can be diagnosed in patients with AIHA and a positive Donath-Landsteiner test. The test can be technically difficult (Sokol et al, 1999) and false negative results can be avoided by using an indirect method. Testing should be performed by a specialist laboratory and a warm separated serum sample is required. Testing should be considered in patients with AIHA and a DAT positive for C3 ± IgG, when CHAD has been excluded, and there is either haemoglobinuria, cold-associated symptoms, atypical serological features or if the patient is <18 years old. The DAT is negative in some cases of PCH. The Donath-Landsteiner test should therefore also be considered in children with haemolysis, haemoglobinuria and a negative DAT. Mixed AIHA is caused by a combination of a warm IgG antibody and a cold IgM antibody with a thermal amplitude of at least 30°C. The DAT is usually positive with IgG and C3. The cold antibody may have a low antibody titre (e.g. <1:64). Cold-induced haemolysis, Raynaud phenomenon or acrocyanosis do not appear to be features of mixed AIHA (Sokol et al, 1983; Shulman et al, 1985). Mixed AIHA can be diagnosed in patients with AIHA, a DAT positive for IgG and C3, a cold antibody with a thermal amplitude ≥30°C, evidence of a warm IgG antibody and the absence of typical features of CHAD. A diagnostic pathway is illustrated in Fig 1. Patients with AIHA and a DAT positive for C3 ± IgG should be screened for a cold antibody. A direct agglutination test (DAggT) can be performed as a screening test in the local transfusion laboratory; a clinically significant cold haemagglutinin can be excluded if saline-suspended normal red cells are not agglutinated by the patient's serum after incubation at room temperature for 30–60 min (Petz, 2008). If this screening is positive, further testing is needed to distinguish insignificant CAs from CHAD. Samples for titres and thermal amplitude should be kept at 37°C for transportation. As this can be challenging, received ethylenediaminetetra-acetic acid (EDTA)-anticoagulated samples should be warmed to 37°C in a water bath for 1 h before testing (Issitt, 1985). The diagnostic algorithm (Fig 1) is a guide and the diagnosis is not always straightforward. The clinical picture should be considered and the advice of a reference laboratory may be required before a final diagnosis is made. A limitation of serological testing (cold antibody titres, thermal amplitude and the Donath-Landsteiner test) is the current absence of a UK External Quality Assurance (EQA) scheme. Testing should therefore be conducted in laboratories performing these tests on a regular basis. Investigation should be guided by sections 6·5 and 7·13 of recent BCSH guidelines on pre-transfusion compatibility procedures (Milkins et al, 2013). The main aims of the investigation are to determine ABO, Rh and K status of the patient and identify alloantibodies, if present. Full compatibility testing can take 4–6 h or more (Petz, 2004). Approximately 30% of patients with AIHA have an underlying alloantibody (most commonly Rh or K) but these are rare if there is no history of previous transfusion or pregnancy (Petz, 2004). If anaemia is life threatening, transfusion with ABO, Rh and K matched blood is more appropriate than delaying until full serological investigations have been completed. In patients with a clinically significant cold type antibody, the use of a blood warmer and ensuring a warm environment for transfusion is rational although the evidence of benefit is limited. These are the options available in an emergency situation: Evidence from case series suggests that 40% of patients respond to IVIg 0·4–0·5 g/kg/day for 5 days and most responders maintained their Hb for ≥3 weeks (Flores et al, 1993). Response was predicted by low pre-treatment Hb; and IVIg is accepted in the UK Department of Health guidelines as a short term treatment when the Hb is <60 g/l (but higher in patients with co-morbidities) or as a temporising measure prior to splenectomy (Wimperis et al, 2011). The evidence for plasma exchange is largely limited to case reports and any benefit is temporary. Plasma exchange has been used in patients with severe haemolysis while attempting control with other therapies, such as immunosuppression (Von Baeyer, 2003; Szczepiorkowski et al, 2010). The experience of high dose intravenous methylprednisolone is limited to case reports. Methylprednisolone may have a role in fulminant cases but the risk of serious infections may also increase (Everett et al, 2006; Bay et al, 2007). Patients with severe transfusion-dependent haemolysis who have not responded to immunosuppression may require urgent splenectomy. If the patient is not vaccinated 2 weeks prior to splenectomy, this should be deferred until 14 days post-splenectomy as functional antibody responses are improved (Davies et al, 2011). In critically ill patients with warm AIHA deemed unfit for splenectomy (e.g. severity of anaemia or lack of available blood to transfuse), case reports have documented success with partial splenic embolisation. These are the options available in an emergency situation: The overall response of CHAD to steroids can be disappointing with response rates of 14–69% in larger series. Responses are often partial, and cannot be sustained without an unacceptably high steroid dose. However, given limited therapeutic options, a trial of prednisolone 1 mg/kg/day may be considered as a rescue therapy. Responses were seen in 4/6 case reports (Von Baeyer, 2003). However, responses are often transient (Petz, 2008) and like warm AIHA, its role may be in stabilising patients with severe disease in conjunction with alternative therapy. Agglutination can occur within the cell separator and its tubing, especially if the agglutinin is active at 37°C and the room and extracorporeal circuit may need a high temperature setting. Daily or alternative day exchange of 1–1·5 times plasma volume with albumin has been recommended (Szczepiorkowski et al, 2010). VTE is an important cause of morbidity and mortality in AIHA and is more likely when haemolysis is active. In one study of patients with severe AIHA (defined as Hb 100 g/l or after a maximum of 3 weeks, reducing to 20–30 mg over 4–6 weeks, and then by 5 mg every month. In a series of 33 primary AIHA cases, relapse was more common if steroids were tapered to ≤10 mg in less than 2 months and if stopped in less than 6 months (Dussadee et al, 2010). Approximately 20% of patients remain in remission after steroids are discontinued. Although a further 40% can maintain an acceptable Hb on maintenance prednisolone 66 months although 44% had grade 3–4 haematological toxicity (Berentsen et al, 2010). Iatrogenic cooling, such as peri- and post-operative hypothermia, can precipitate haemolysis in CHAD patients. Surgery can proceed safely by careful maintenance of body temperature. Knowing the antibodies thermal amplitude may help define a minimum temperature threshold. Elective surgery should be deferred if a transient post-infective CHAD is suspected. Cardiothoracic surgery on cardiopulmonary bypass (CPB) may involve paralysis and cooling of the heart to 8–12°C (cold cardioplegia). Clinically insignificant CAs might then become significant. In patients with CHAD or CAs identified pre-operatively, a number of successful strategies, such as warm cardioplegia with systemic normothermia have been employed. Agglutination can also present intraoperatively with increased pressure in the cardioplegia line (Bracken et al, 1993; Fischer et al, 1997) or with visible agglutination in the cardioplegia system. However, complications appear rare in patients with CAs undergoing CPB, even without modifications to reduce hypothermia (Jain et al, 2013) and although serological screening prior to cold cardioplegia is recommended by some, it is not currently routine practice. AIHA can occur at any age during childhood from infancy through to adolescence but with a peak incidence <5 years. In up to 77% of cases it is a self-limiting illness, requiring only short term therapy (Buchanan et al, 1976). Warm AIHA predominates in children followed in frequency by PCH, typically triggered by a viral infection. CHAD is less common in children compared to adults, and often follows a mycoplasma infection. Immunological disease (most commonly Evans syndrome or CVID) is associated with approximately 50% of cases. Most children present with pallor, jaundice, tiredness or dark urine. Less commonly, there will be fever or abdominal pain and 3% presented with collapse, coma or acute renal insufficiency due to sudden, severe anaemia (Aladjidi et al, 2011). The laboratory investigations and differential diagnosis are describ