EPIDEMIOLOGY AND RISK FACTORS OF WARM AND COLD AUTOIMMUNE HEMOLYTIC ANEMIA

Even though clinical features in autoimmune haemolytic anaemia vary according to the type of AIHA, anaemic syndrome stays common for most of the cases. A positive Coombs test or direct anti-globulin test developed in 1945 by Coombs, Mourant and Race, is the most deciding factor in AIHA diagnosis. Since the immunologic mechanisms causing erythrocyte destruction vary between AIHAs, treatment is also different. Empirical approach with glucocorticoids is the main treatment of AIHA overall, but less effective in CAD. However, the current medical literature is still with gaps concerning the management, presentation and diagnosis of the different types of AIHA altogether.


INTRODUCTION
Autoantibodies directed against erythrocytes cause autoimmune haemolytic anaemia (AIHA), which can be caused by complement activation or not.
Depending on the antibody's thermal amplitude, isotype, and ability to fix complement, as well as bone marrow compensation, the clinical picture can vary availability of next-generation sequencing has enhanced the diagnosis of many related conditions while also the proportion of "secondary" vs. "primary" AIHAs.
All of these recent discoveries about the disease's pathogenesis and therapeutic options have undeniably altered the AIHA landscape [1].
The Coombs test, also known as the direct antiglobulin test ( The most powerful indicator of relapse has been described as the magnitude of anemia at the time of onset. Complement involvement and the autoantibody's thermal characteristics were also significant, with warm IgG + C, mixed, CAD, and atypical types requiring second or additional therapy lines more frequently. Furthermore, the involvement of immune thrombocytopenia (Evans syndrome) is linked to a higher risk of relapse and treatment refractoriness. Furthermore, the presence of reticular fibrosis, dyserythropoietic marrow, and hyper cellularity in the bone marrow has been linked to shorter relapse-free survival and a lower response rate to immunosuppressive therapies. Hb 6 g/dL at onset, Evans' syndrome, multiple lines of treatment, acute renal failure, and infections have all been linked to an increased risk of death by 5-8 fold.

EPIDEMIOLOGY AND RISK FACTORS
AIHA is a relatively rare disease with a currently estimated incidence of 1.77 cases per 100,000 populations per year and 0.2 cases/1,000,000 in individuals under 20 years of age [2]. Old nations which has its age structure changing, having more number of older population like in the U.S., has an estimated incidence of about 2 per 100,000 per year [3]. Incidence is directly proportional with increasing age of population which is given in the figure 1. Thus, AIHA is more in people above 40 years of age. It is also seen more commonly in early childhood due to a relatively weak immune system. According to a French study, incidence of AIHA in children under age 18 was estimated to be 0.81/100,000 per year [4].
In children, there is some evidence of an occurrence of the disease within some families in excess, but no hereditary genetic background has yet been found. The  in Denmark.
The next common AIHA after warm AIHA is CAD. Cold AIHA is reported in 20-25% of AIHA cases. The incidence of chronic cold agglutinin disease (CAD) is estimated to be 1 per million per year, with a female prevalence. The annual incidence of AIHA is estimated at 1/35,000-1/80,000 in North America and Western Europe. A higher incidence of CAD in Northern climates is suggested. It is more common in elderly and it has a chronic course in contrast with warm AIHA.
According to recent study, the incidence and prevalence of cold AIHA in cold climates showed a fourfold increase than incidence and prevalence of cold AIHA in warm climates but with less evidence to confirm the data [11].
Secondary AIHAs account for 40-50% of AIHA cases and the rest is primary AIHA. Secondary AIHA associated with hematologic malignancy accounts about 50% of cases, most frequently reported with chronic lymphocytic leukaemia (5%-10%) in which the female to male ratio is low, non-Hodgkin lymphoma (2%-3%), and Hodgkin lymphoma (0.2%). Secondary AIHAs associated with infections comprise of 35% of all reported cases. AIHAs associated with infection caused by mycoplasma or EBV were reported in 3% of all secondary AIHAs. Other autoimmune conditions were reported in 15% of secondary AIHAs, out of which 5-10% were SLE patients in which female to male ratio is very high [12,13]. 2%-4% of cases of allogeneic hematopoietic stem-cell transplantation also reported secondary AIHA [14].
Genetic background, immunodeficiency, autoimmune disease, infections, medication -especially novel anti-cancer drugs, neoplasia -especially CLL (5-10% cases) or NHL (13-19%) and transplants are common risk factors suggested based on different studies [2,15,16]. One of the main single risk factor for developing AIHA is ageing. A recent study on the association of COVID-19 with autoimmune diseases, showed evidence of onset of AIHA post COVID-19 infection, but still it is rare. It was found that, the RBC structural membrane protein ankyrin (ANK-1) shared an epitope that is 100% identical to the SARS-CoV-2 spike surface glycoprotein. Many studies stated that elderly patients with co-morbidities were having a less efficient adaptive immune system and more prone to develop autoimmunity after getting infected by COVID. Immunosenescence, the gradual deterioration of immune system as we age, and epigenetic abnormalities on haematopoietic stem cells are believed to be the reason behind age related increased risk for AIHA and at the same time increased risk of elderly patients with COVID infection to develop AIHA [17][18][19].