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Cold Type Autoimmune Hemolytic Anemia- a Rare Manifestation Of Dematapitiya et al. BMC Infectious Diseases (2019) 19:68 https://doi.org/10.1186/s12879-019-3722-z CASE REPORT Open Access Cold type autoimmune hemolytic anemia- a rare manifestation of infectious mononucleosis; serum ferritin as an important biomarker Chinthana Dematapitiya1*, Chiara Perera2, Wajira Chinthaka1, Solith Senanayaka1, Deshani Tennakoon1, Anfas Ameer1, Dinesh Ranasinghe1, Ushani Warriyapperuma1, Suneth Weerarathna1 and Ravindra Satharasinghe1 Abstract Background: Infectious mononucleosis is one of the main manifestations of Epstein – Barr virus, which is characterized by fever, tonsillar-pharyngitis, lymphadenopathy and atypical lymphocytes. Although 60% of patients with IMN develop cold type antibodies, clinically significant hemolytic anemia with a high ferritin level is very rare and validity of serum ferritin as an important biomarker has not been used frequently. Case presentation: 18-year-old girl presented with fever, malaise and sore throat with asymptomatic anemia, generalized lymphadenopathy, splenomegaly and mild hepatitis. Investigations revealed that she had cold type autoimmune hemolysis, significantly elevated serum ferritin, elevated serum lactate dehydrogenase level with serological evidence of recent Epstein Barr infection. She was managed conservatively and her hemoglobin and serum ferritin levels normalized without any intervention following two weeks of the acute infection. Conclusion: Cold type autoimmune hemolytic anemia is a rare manifestation of infectious mononucleosis and serum ferritin is used very rarely as an important biomarker. Management of cold type anemia is mainly supportive and elevated serum ferritin indicates severe viral disease. Keywords: Infectious mononucleosis (IMN), Hemolytic anemia, Ferritin Background mainly Mycoplasma pneumoniae and infectious mono- Epstein – Barr virus is one of the most ubiquitous human nucleosis (IMN). Diagnosis of cold type AIHA due to viruses, infecting more than 95% the adult population IMN is confirmed by demonstrating red cell aggregates in worldwide. Infectious mononucleosis is the main clinical a peripheral blood smear, presence of high titers of cold syndrome of Epstein – Barr virus infection; this clinical antibodies, positive direct antiglobulin test (IgG negative / syndrome is characterized by fever, tonsillar-pharyngitis, C3d positive) with serological evidence of recent IMN in- lymphadenopathy and atypical lymphocytes. fection [1]. In cold type autoimmune hemolytic anemia (AIHA) Although 60% of patients with IMN develop cold type IgM antibodies are formed against the polysaccharide an- antibodies, clinically significant hemolytic anemia with a tigens of red blood cells, which cause agglutination in low high ferritin level is very rare [2]. There are only few temperatures leading to complement activation and published cases in medical literature; hence we describe hemolysis. Cold type AIHA is mainly caused by lymphoid a case of clinically significant cold type autoimmune malignancies and rarely it can be caused by infections hemolytic anemia associate with significantly high serum ferritin as a rare manifestation of IMN. * Correspondence: [email protected] 1Sri Jayawardanapura General Hospital, Thalapathpitiya, Nugegoda, Western province, Sri Lanka Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dematapitiya et al. BMC Infectious Diseases (2019) 19:68 Page 2 of 4 Case presentation rose up to 10 g/dl and serum ferritin level reduced to Eighteen-year old girl presented to us with sore throat, 925 ng/ml and after six weeks follow up there was no malaise, fatigue and fever for 10 days. She was apparently lymphadenopathy on examination, her hemoglobin rose up well 10 days back where she initially developed a sore to 11.5 g/dl, serum ferritin level normalized to 250 ng/ml throat followed by fever with chills and a non-productive and the repeat (VCA) – IgM was negative but (VCA)-IgG cough. She did not have any abdominal pain, acrocynosis became positive. or exertional dyspnea. She did not have any contact his- tory of similar illness. Discussion and conclusions On examination she was well looking. She was pale but Cold type autoimmune hemolytic anemia (AIHA) is a not icteric. Oral examination revealed inflamed tonsils. rare manifestation of infectious mononucleosis (IMN) She had tender, discrete, mobile bilateral anterior and pos- and serum ferritin is used very rarely as an important terior cervical lymph nodes with bilateral inguinal lymph- biomarker. In this case our patient had cold type AIHA, adenopathy. On admission she had fever (39.2 °C) with no significantly high levels of serum ferritin with hepatitis evidence of dehydration. She did not have any evidence of and splenomegaly, high levels of lactate dehydrogenase peripheral gangrene or acrocynosis She was found to have (LDH) with fever and generalized lymphadenopathy tachycardia (110 beats/min) with normal blood pressure. caused by infectious mononucleosis. Her cardiovascular and respiratory system examinations The exact pathogenesis of IMN causing cold type were unremarkable. Her abdominal examination revealed AIHA is poorly understood. But according to suggested mild, non-tender splenomegaly with no hepatomegaly. mechanisms initially there is formation of IgM anti- On admission laboratory testing was remarkable for mac- bodies to EBV. Then due to the molecular mimicry, IgM rocyticmoderateanemiawithahemoglobinof8.6g/dl antibodies cross react with RBC polysaccharide antigens (normal 11-16 g/dl), mean corpuscular volume 96.3 fl and result in formation of antigen-antibody complexes. (normal 80-96 fl), mean corpuscular hemoglobin 37.7 pg This will activate the complement (C1) complex. Then it (normal 27-34 pg), red blood cell mass 2.28 × 106/ul (nor- will activate C4/C2 complex forming C3 convertase, mal 3.5–5.5 × 106/ul), white blood cell count 8.27 × 103/ul which produces C3b, which will deposit on the RBC (normal 4–11 × 103), neutrophils 48.4% and lymphocytes membrane. In cold temperatures, when IgM is bound to 45.9%. Her blood pictures revealed macrocytes, sphero- the antigen, C3b will activate C5, forming membrane at- cytes, few polychromatics and lymphocytosis with atypical tack complexes, which will eventually cause intravascular lymphocytes. Her direct anti globulin test (DAT) was posi- hemolysis. But upon warming, IgM antibody dissociates tive and DAT profile revealed positive for C3d and negative from the RBC membrane but C3b will remain attached for IgG. Her monospot test was positive and Epstein Barr to RBC surface. Those RBC will be eventually destroyed in virus (IgM) antibody was positive as well (EBV- viral capsid the reticulo-endothelial system, mainly spleen and causes antigen (VCA)- IgM using ELISA method was positive but extravascular hemolysis [3]. In our patient hemolysis was IgG was negative). Her biochemical tests revealed serum fer- confirmed by an increased total bilirubin with a high indir- ritin > 1650 ng/ml (6.9–282.5 ng/ml), serum iron 12.6 μmol/ ect fraction, increased LDH and decrease level of heptoglo- l (normal 5-33 μmol/l), total iron binding capacity (TIBC) bulin. Since direct antiglobulin test (DAT) became positive 50.1 (normal 52.0–101.0), transferrin saturation 25.15%, with DAT profile revealing positive C3b with a negative serum lactate dehydrogenase (LDH) 1673u/l (normal IgG,weconfirmedshehadcoldtype– autoimmune 200-400u/l), serum heptoglobulin < 9 mg/dl (normal 30– hemolytic anemia. Interestingly our patient did not have 200 mg/dl), Aspartate transaminase (AST) 124.5u/l (normal clinical acrocyanosis, so may be the extravascular hemolysis 0-31u/l), Alanine transferase (ALT) 46.7u/l (normal 7-35u/l), was predominant in her causing the moderate anemia. total bilirubin 1.3 mg/dl(normal 0.3–1.20) with an increased In this case she had significantly high levels of serum indirect fraction, alkaline phosphatase 77.4u/l (normal 30- ferritin with mild hepatitis and mild splenomegaly. 120u/l), serum creatinine 41.1 μmol/l (normal 0-97 μmol/l), Causes for her high serum ferritin may be multifactorial. C reactive protein 24 mg/l (normal < 6.0 mg/l), erythrocyte It can be due to acute phase response following Epstein sediment rate 60 mm/hour (normal 0-10 mm/hour). Her Barr infection. In our patient there was mild elevation of anti-nuclear antibodies and rheumatoid factor was negative. C reactive protein (CRP) but very high levels of serum Her ultrasound scan abdomen showed mild spleno- ferritin. It has been shown that although classical inflam- megaly (11.3 cm × 6.0 cm) and transthoracic echocar- matory parameters such as CRP have proven its useful- diogram was normal. ness in bacterial or fungal infections, when it comes to She was given analgesics and advised to bed rest and viral infection CRP often has very low sensitivity and is avoid cold exposure and started on folic acid 5 mg daily. non-discriminatory. It has
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