|Year : 2022 | Volume
| Issue : 4 | Page : 226-229
Plasmodium vivax Malaria Associated with Severe Autoimmune Hemolytic Anemia
Goranti Nishith, Vivek Sharma, Rajiv Sharan
Department of Pediatrics, Tata Motors Hospital, Jamshedpur, Jharkhand, India
|Date of Submission||02-Jun-2022|
|Date of Decision||17-Oct-2022|
|Date of Acceptance||28-Oct-2022|
|Date of Web Publication||29-Nov-2022|
Dr. Goranti Nishith
M-28/5, Telco Colony, Near Tata Motors Hospital, Jamshedpur - 831 004, Jharkhand
Source of Support: None, Conflict of Interest: None
Background: Severe and/or persistent anemia due to autoimmune hemolytic anemia (AIHA) secondary to vivax malaria is a rare association. Very few cases are reported worldwide, and even less from India. AIHA occurs when immunoglobulins and/or complements target red blood cell surface antigens resulting in hemolysis. Awareness of this complication helps in early recognition, investigation, and prompt initiation of treatment. Clinical Description: A 15-year-old boy presented with a history of high fever associated with chills for 2 days. Examination revealed the presence of severe pallor and icterus. Systemic examination was unremarkable. Investigations showed anemia (Hb: 3.6 g/dl) with reticulocytosis (6.6%), malaria (trophozoites of Plasmodium vivax and antigen test positive), and indirect evidence of hemolysis (indirect hyperbilirubinemia and elevated lactate dehydrogenase of 668 U/l). Management and Outcome: Treatment was started with intravenous artesunate and packed cells transfusion was planned. Cross-matching showed autoantibodies which raised suspicion of AIHA. Coomb's test was positive. Least incompatible packed red blood cells were transfused. A repeat peripheral smear was negative for malaria. Posttransfusion, the Hb levels rose to 8.3 g/dl before falling to 5.3 g/dl over the next 2 days. The direct antiglobulin test was positive. High doses of oral prednisolone resulted in progressive improvement in Hb levels to 8 g/dl within a week. He was discharged on oral prednisolone with daily oral folic acid supplements. The steroids were tapered when Hb reached 10.6 g/dl and continued for 3 months. Conclusion: If a patient with malaria (falciparum or vivax) exhibits persistent severe anemia, indirect evidence of hemolysis is found on investigations and/or autoantibodies identified on cross-matching, AIHA should be suspected and investigated accordingly.
Keywords: Autoantibodies, autoimmune hemolytic anemia, malaria
|How to cite this article:|
Nishith G, Sharma V, Sharan R. Plasmodium vivax Malaria Associated with Severe Autoimmune Hemolytic Anemia. Indian Pediatr Case Rep 2022;2:226-9
|How to cite this URL:|
Nishith G, Sharma V, Sharan R. Plasmodium vivax Malaria Associated with Severe Autoimmune Hemolytic Anemia. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Jan 30];2:226-9. Available from: http://www.ipcares.org/text.asp?2022/2/4/226/362232
Anemia is a known complication of malaria, more frequently due to P. falciparum than with Plasmodium vivax or other species of Plasmodium. Its rate of occurrence depends on the regional endemicity of malaria transmission and the age group affected. The underlying causes of anemia in malaria are multiple: due to the invasion and destruction of red blood cells (RBCs) by the malarial parasite, splenic sequestration, ineffective erythropoiesis, and rarely, autoimmune hemolytic anemia (AIHA).
AIHA is characterized by RBC surface antigens being targeted by immunoglobulins and/or complements. An inappropriate immune response to an RBC antigen or to another antigenic epitope that is similar to an RBC antigen, known as molecular mimicry, may result in the production of the autoantibody. The RBC membrane may also be altered by an infectious agent that renders it “foreign” or antigenic to the host. These may be detected by getting a positive result on a direct Coomb's test (DCT).
Globally, the annual incidence of AIHA in children is reported to be 1–3 cases per 100,000 patients. Besides the fact that it is rare in malaria, the low numbers may also be due to the low index of suspicion of clinicians (and thus failure to look for supportive evidence), as well as underreporting of the cases that are diagnosed. Very few cases have been reported from India [Table 1].
|Table 1: Case reports of post malaria autoimmune hemolytic anemia from India|
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Severe anemia is a complication associated with Plasmodium falciparum which is not usually found in P. vivax. Therefore, a thorough examination and proper investigations are necessary not only to find the etiology of severe anemia but also to prevent further complications. We present this case to highlight the association of AIHA with P. vivax and sensitize clinicians to consider this entity in malaria complicated with anemia, since its prompt diagnosis and management results in favorable outcomes.
| Clinical Description|| |
A 15-year-old boy from a tribal area presented with high-grade fever associated with chills for 2 days, and yellowish discoloration of eyes for the same duration. There was a history of two episodes of nonprojectile and nonbilious vomiting. There was no history of dark/high-colored urine, gastrointestinal bleeding, or passing worms in stools. A history of pedal or facial swelling, oliguria/anuria, cough, chest pain, breathlessness, headache, or seizures was not elicited. He had not received any blood transfusion in the immediate past. He was diagnosed with P. vivax malaria on the basis of a positive lactate dehydrogenase (LDH) antigen test during a routine work-up for fever at another center and had been prescribed oral doxycycline, primaquine, and paracetamol. The child was brought to our hospital when the fever persisted and he developed severe prostration and severe pallor despite this treatment. There was no family history of any other cases of malaria or of bleeding tendencies and blood transfusions. His immunization status was appropriate for his age.
On examination, the child was sick and displayed severe prostration. He was severely pale and icteric. There was no cyanosis, petechiae, ecchymoses, pedal edema, lymphadenopathy, or dysmorphic features. He was febrile (axillary temperature: 102°F) with a pulse rate of 110 beats per min (regular, normovolemic, and all peripheral pulses palpable), respiratory rate of 24 per min, blood pressure 100/70 mmHg, and saturation of 97% in room air. His weight was 40 kg, height was 142 cm, and body mass index was 19.9 kg/m2 (normal for his age). Salient systemic examination findings were normal vesicular breath sounds (no respiratory involvement), a hemic murmur at the apex of the heart (not in congestive heart failure), and the absence of hepatosplenomegaly.
Since the clinical history and investigations were suggestive, the primary diagnosis was severe anemia and jaundice due to complicated vivax malaria. However, hemolytic anemia due to G6PD deficiency was also considered he was from a tribal area and had received primaquine. Therefore, baseline investigations were ordered at admission to explore these possibilities and also rule out other organ dysfunction and septicemia.
Management and outcome
The hemogram showed hemoglobin (Hb) – 3.6 g/dl, total leukocyte counts – 7530/uL, platelets of 4.61 lakh/ul, with the peripheral blood smear showing trophozoites of P. vivax, normocytic normochromic red blood cells, occasional anisocytosis, and teardrop cells. The corrected reticulocyte count was 6.6%. The antigen test was positive for P. vivax and negative for P. falciparum. The liver function test demonstrated indirect hyperbilirubinemia without transaminitis (total bilirubin was 5.41 mg/dl, direct bilirubin – 0.82 mg/dl, indirect bilirubin – 4.59 mg/dl, serum alkaline phosphatase – 142 U/L, serum glutamic-oxaloacetic transaminase (SGOT) – 31 U/L, and serum glutamic-pyruvic transaminase (SGPT) – 10 U/L. An elevated LDH (668 U/l, normal 105–333U/l) indicated the possibility of hemolysis. The renal function tests were normal (blood urea: 30 mg/dl and creatinine: 0.77 mg/dl). Sepsis was ruled out as the C-reactive protein was negative, and cultures (blood and urine) were sterile. The PCR for the SARS-Cov-2 virus was also negative.
Treatment with isotonic intravenous (IV) fluids, IV artesunate (2.4mg/kg/dose) was started and 2 units of packed cells transfusion was planned. However, during cross-matching, autoantibodies were identified, raising suspicion of AIHA. This was supported by a positive DCT. Direct antiglobulin test (DAT) could not be done at this point of time to categorize the subclass. In these circumstances, the child was transfused with 2 aliquots of best-matched (least incompatible) packed red cells. The posttransfusion period was uneventful, and the Hb increased to 8.3 g/dl.
The fever persisted till the 5th day of admission even though there was no evidence of parasitemia on the peripheral smear. The Hb further dropped to 6.5 g/dl favoring the possibility of ongoing autoimmune hemolysis. Therefore, he was started on tablet prednisolone (40 mg/day orally in two divided doses) on the 6th day of admission. Although the fever subsided within 24 h, the Hb continued to decrease further requiring another transfusion of the least incompatible packed red blood cells. The dose of oral prednisolone was increased to 80 mg/day. Subsequent serial daily Hb estimations showed a gradual rise and the total bilirubin decreased to 2.06 mg/dl [Table 2]. Getting the DAT done became feasible and it was positive. The patient was discharged after 8 days with a Hb of 8 g/dl, with the advice to continue prednisolone for 3 months, along with oral folic acid supplementation (5 mg once daily).
Upon follow-up (7 days after discharge), the Hb had increased to 10.6 g/dl and we started tapering prednisolone by 5 mg/week. A repeat DAT done 2 months after the hemolytic crisis was still positive with Hb 10.8 g/dl. A G6PD quantitative enzyme assay by the kinetic method was done just to rule out the possibility of G6PD deficiency. It was 8.59 U/g within the normal range. Thus, the positive malarial smear, severe anemia, reticulocytosis, positive DAT coupled with clinical and hematological improvement after corticosteroid therapy, and the absence of G6PD deficiency established the diagnosis of AIHA secondary to vivax malaria.
| Discussion|| |
Complicated malaria may present with prostration and multiple system involvement: neurological (impaired consciousness seizures), pulmonary (respiratory distress pulmonary edema), jaundice (as a consequence of hepatic dysfunction or hemolysis), hematological (hemoglobinuria, abnormal bleeding, and severe anemia), renal (acute kidney failure), and circulatory (shock).
Anemia in vivax malaria is caused by hemolysis, increased splenic clearance, and a variable degree of bone marrow ineffective erythropoiesis. Vivax, malaria-induced AIHA, is an infrequent condition. It varies in severity in childhood and is self-limited. Immune hemolytic anemia is mediated by antibodies directed against the erythrocyte surface antigens. The demonstration of antibodies to red blood cells (RBCs) by a positive Coombs test is essential. Till date, only a few cases of AIHA in malaria patients are reported worldwide [Table 1]. The exact mechanism of AIHA in vivax malaria is not well understood but, nevertheless, AIHA should be considered and hemolysis looked for in vivax malaria if anemia persists (as in this case).
Typical laboratory findings of malaria include anemia, thrombocytopenia, and a normal or low leukocyte count with a positive smear or malarial antigen test. The erythrocyte sedimentation rate is often elevated. The cause of indirect hyperbilirubinemia and elevated LDH was probably due to the ongoing intravascular hemolysis that was occurring due to the autoimmune antibody-mediated lysis of RBCs. This was evident by the positive DAT test that demonstrates the presence of antibodies or complement on the surface of red blood cells, the hallmark of autoimmune hemolysis. Agglutination of erythrocytes with anti-IgG serum reflects warm AIHA, while a positive anti-C3 DAT occurs in cold AIHA. In this case, subclass testing could not be performed. Direct antiglobulin/Coombs test results may remain positive even after Hb levels normalize.
The disease tends to remit spontaneously within a few weeks or months. A consistent response to glucocorticoid therapy, low mortality rate, and full recovery are characteristics of the acute form of AIHA as seen in this case. Glucocorticoids decrease the rate of hemolysis by blocking macrophage function by downregulating Fcγ receptor expression, decreasing autoantibody production, and enhancing the elution of antibodies from the RBCs. Prednisone or its equivalent is administered at a dose of 2 mg/kg/day that may be increased to 6 mg/kg/day in severe cases to reduce the rate of hemolysis. In severe anemia, transfusions may be lifesaving, but it is critical to check for underlying alloantibodies that can hasten the hemolysis of transfused red blood cells.
Very few cases of AIHA in malaria have been reported from India [Table 1]. Ghosh et al. described a 1-month-old infant who had a similar clinical presentation of high fever with pallor and jaundice but splenomegaly was present. Taneja et al. reported a 6-month-old infant with fever, pallor, and jaundice with a positive smear for P. vivax. He received antimalarial treatment but later presented with severe anemia and hepatosplenomegaly with the clearing of malarial parasitemia. The serum of the recipient was incompatible with all the blood samples of the same group, but DAT was negative. A diagnosis of AIHA was made when he demonstrated a clinical and hematological response to therapy with oral prednisolone. Splenomegaly is not always found in AIHA, as is evident in our case. Hence, AIHA should be suspected even in the absence of splenomegaly. To conclude, if a patient with malaria (falciparum or vivax) exhibits persistent severe anemia, indirect evidence of hemolysis is found on investigations and/or autoantibodies identified on cross-matching, AIHA should be suspected and investigated accordingly.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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