The diagnosis and management of primary autoimmune haemolytic anaemia (2016)

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 <1:64 and it rarely exceeds 1:256. In CHAD, the titre is usually >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 insignificant CAs from CHAD. for and thermal amplitude should be kept at 37°C for this can be samples should be to 37°C in a for 1 before testing (Issitt, 1985). The diagnostic (Fig is a and the diagnosis is not The clinical picture should be considered and the of a laboratory may be required before a diagnosis is made. A of serological testing antibody thermal amplitude and the Donath-Landsteiner is the absence of a UK Testing should therefore be in these tests on a should be by and of BCSH on et al, 2013). The of the investigation are to determine and of the patient and identify if present. testing can or more (Petz, Approximately 30% of patients with AIHA have an underlying or but these are if there is no of transfusion or (Petz, If anaemia is transfusion with and blood is more appropriate than until serological investigations have been In patients with a clinically significant cold type antibody, the of a blood and a warm for transfusion is the evidence of is are the available in an from suggests that of patients to for and most for weeks et al, was by low and is in the UK of as a term treatment when the is (but in patients with or as a to et al, 2011). The evidence for is to and any is has been used in patients with severe haemolysis with other such as et al, 2010). The of high intravenous is to may have a in cases but the of may also et al, 2006; et al, Patients with severe haemolysis who have not to may If the patient is not weeks to this should be until as antibody are et al, 2011). In patients with warm AIHA for (e.g. of anaemia or of available blood to have with are the available in an The response of CHAD to can be with response of in are and be without an high steroid However, a of 1 may be considered as a seen in 2003). However, are (Petz, and warm AIHA, its may be in patients with severe disease in with alternative can occur the cell and its especially if the agglutinin is at 37°C and the room and may a high temperature setting. or alternative of with has been et al, 2010). is an cause of and in AIHA and is more when haemolysis is In study of patients with severe AIHA as in and was more if no was 2003). In in haemolysis range and et al, to the of cases of anaemia and reported in patients with chronic haemolytic The incidence of disease in the is approximately with of upper increasing to with factors include increasing and In patients the is in drugs or of may also occurs in to of term et al, 2012). and and units bone and are for all patients et al, 2012). In bone was by and years with an at a of are considered high for and treatment such as a is et al, et al, et al, 2012). are in Fig 2. AIHA is a chronic and the of is disease with Patients with mild compensated haemolysis may not and are but from haemolysis can the of infection in patients on is Approximately of patients to at a to and approximately The initial response may several weeks but absence of response by should be considered a steroid In an can for example or after a maximum of to over and then by every In a of primary AIHA was more common if to in less than and if in less than et al, 2010). Approximately of patients remain in after are Although a further can an on due to the term of should be considered. are but do not that is to et al, et al, 2010). The and most used are and Approximately of cases to but response are reported with or patients and the of infection et al, et al, et al, the of infection and chronic of AIHA, most patients will from an to of of have been reported following for primary warm AIHA et al, et al, et al, In primary and secondary warm AIHA, with in et al, does not outcome is associated with of AIHA. In the only and was to et al, 2013). At to response is approximately weeks The term is but occurs in after a of et al, et al, and in by et al, 2013). is severe et al, or have been of is a and screening with serology for and antibody is 1 is a et al, The is for weeks but low cell when used for autoimmune disorders et al, 100 for weeks with or et al, response However, was used at an disease than of and of response and further The treatment are as to no for a Approximately of AIHA patients to et al, with (Pirofsky, or et al, et al, However, the steroid and the of response is and should be excluded to and some in AIHA. the was typically of 7 patients with primary warm AIHA to to et al, 1985). The was expanded to with a response In a further patients with secondary AIHA to three and some in primary and secondary AIHA. patients and with to 1 typically of patients with AIHA of patients or to appear in primary secondary AIHA. If the are of primary warm AIHA cases to & & & & et al, 1999) with a of occur the of but have been Approximately a of patients after Although early that high would predict a response to this was not by and has from clinical and the should be based on the of or should be and a of for at et al, 2011). Approximately of patients of with in with haemolytic anaemia et al, 2010). or is also more common in with haemolytic occurring in of et al, low has been on of et al, but evidence of is term is also by AIHA and some in AIHA have (see Appendix Although some has been reported with low (e.g. with or without there are on or its be over intravenous also appear for example 50 for et al, or 1 for & that and is should be to selected patients with disease following multidisciplinary than patients for AIHA have been reported to the for and Some have been with & 2008). should be performed in Committee of and with in for patients with autoimmune AIHA caused by IgA occurs in of cases and usually to conventional treatment and Mixed AIHA is usually as severe haemolysis et al, Approximately are primary secondary cases are associated with Mixed AIHA is steroid but most leads to chronic haemolysis. was in (Sokol et al, and patients et al, 1985). has been reported with and for acute haemolysis, with for underlying and with all cold where to the of severe to the and in cold should be considered for severe symptoms or transfusion (Berentsen & Tjonnfjord, 2012). In patients has usually been avoided IgM red cells are not in the of is therefore and to have a CHAD is less than warm AIHA. or do not the of or was in some but not all also a response to et al, et al, and et al, 2013). In the response to for weeks was (Berentsen et al, (Berentsen et al, and secondary et al, and treatment was with a response of In a study of with the response was and response (Berentsen et al, 2010). such as and can haemolysis in CHAD can by of temperature. the antibodies thermal amplitude may help define a temperature should be if a CHAD is on may and of the heart to insignificant CAs then In patients with CHAD or CAs a of such as warm with systemic have been can also present with in the et al, et al, or with agglutination in the However, appear in patients with CAs without to et al, and serological screening to cold is by it is not AIHA can occur at any age childhood from through to but with a incidence In to of cases it is a only term et al, AIHA in children followed in by PCH, typically by a infection. CHAD is less common in children to adults, and a infection. disease syndrome or is associated with approximately of children present with or dark Less there will be or pain and 3% with or acute renal due to severe anaemia et al, 2011). The laboratory investigations and differential diagnosis are in the adult section and in and 3. In the differential should be to such as of childhood and parvovirus B19 infection. lymphoproliferative syndrome and a primary should be tested for before or should include serum cell and is cell and liver tests should also be et al, 2011). The management of AIHA in children is to that in the adult is typically as at a of et al, & 1983; et al, with in of children with primary or secondary AIHA. children for a blood transfusion can be less until there is evidence of which is when the is & may be a in children to of for et al, The is with response of in children with primary or secondary AIHA. A response to was reported in et al, (Sokol et al, and et al, However, there was on of response in of but three of a of & that childhood AIHA is self-limiting, should usually be considered a treatment and that and may also have some in childhood AIHA. In a children to as treatment for primary AIHA et al, The most common of PCH is acute and transient, following an illness in PCH may for to of AIHA in Although the cases of PCH in patients with or chronic cases are usually or infection. cases in children have a of a upper respiratory infection. include and Clinical features are and diagnostic tests are in the section on investigation of AIHA. to the of PCH, initial management is In the acute intravascular haemolysis can be severe and blood transfusion may be required. blood is not usually required (Sokol et al, should be with but should be avoided due to the of haemolysis. Although cold has been there is no evidence to the of Patients can a without which are for severe or In the of disease, may the haemolysis. AIHA has been to occur in approximately 1 in (Sokol et al, and investigation for underlying causes should be to cases but usually avoided and causes of haemolysis especially if there is a outcome is generally and cases or after IgG autoantibodies can the and cause or haemolysis to haemolytic disease of the In the there or at & Although the majority of have no following the DAT is positive and antibodies may in anaemia and in the or anaemia weeks. patients typically to high may have an on the There is evidence to treatment of Some patients with CHAD with treatment (e.g. warm, and blood Some considered in such as and have been used in AIHA can the in a of who an all with no or et al, 2011). for anaemia can be by of the middle et al, In the of transfusion is to a of anaemia blood is to be negative for the autoantibody and of haemolysis and any underlying cause should be to haemolysis in et al, and may have a in AIHA with to the circulating autoantibody and early also be but are with early anaemia and have been with but sometimes these cases required transfusion. In early of the for transfusion & 2003). anaemia in the mild and in cases of AIHA. In to the BSH and the BSH group reviewed and commented on the and All in and of the All the version of the The would to the BCSH the BSH sounding board and the BCSH for in these All have a of to the BCSH and Task which may be reviewed on The following members of the group have no of to and of the group will the group if any evidence available that would the strength of the recommendations in this or it The will be and from the BCSH website if it If recommendations are an will be published on the BCSH website at If are required due to in of evidence or significant evidence recommendations a version of the guidance will be on the BCSH the and in these is to be and at the of to the the British Committee for Standards in Haematology (BCSH) the any for the content of these Appendix review for the guideline on diagnosis and management of primary autoimmune haemolytic Appendix S2. version of the BSH guideline on the diagnosis and management of primary autoimmune haemolytic The is not for the content or of any by the than should be to the for the