Rare Case of Isolated Plasmodium Vivax Malaria Presenting with Pancytopenia: A Case Report

rare cause of pancytopenia which mostly occur with Plasmodium falciparum and very few cases reported with Plasmodium vivax . This is a case of a 17-year-old girl with no previous co-morbids presented with high grade fever, vomiting, loose motions and decrease appetite for 5 days. On examination she was dehydrated and pale with bruising on arms and thighs. Spleen was palpable. Rest of systemic examination was unremarkable. Complete blood picture showed decreased TLC, Low Hemoglobin and Thrombocytopenia. Liver function tests, Renal function tests, Serum electrolytes, Urine routine examination and Erythrocyte sedimentation rate were normal. C-reactive protein, LDH, Ferritin and D-dimers were raised. Peripheral film showed Retic count of 3%. Dengue serology and Covid-19 PCR was negative. Blood and Urine Cultures showed no growth. Ultrasound abdomen showed splenomegaly. Peripheral smear for Malarial Parasite showed early trophozoites of Plasmodium vivax . Patient was started on Intravenous Artesunate as she could not tolerate Oral anti-malarial. Patient became afebrile and blood counts improved after few days and was discharged with follow up test for G6PD assay.


Discussion
Malaria is a worldwide national health problem in many countries, and many occur in tropical and subtropical areas including sub-Saharan Africa, Asia and Latin America [2].
Worldwide approximately 3 billion people resides in areas which have high risk of malaria transmission. 1.1 to 2.7 million deaths occur due to severe malaria every year. Malaria is considered as a 5th leading cause of death due to infectious disease and 2 nd leading causes of death in Africa with 1 million people dying every year in Africa. About 85% of all the malarial cases in the world are due to Plasmodium falciparum with Plasmodium vivax on 2 nd number. 90% of all the malarial deaths occur in Africa [3].
Of all the plasmodium species, the deadliest and the most virulent is P. falciparum which can lead to life threating complications and death if not treated early. Species other than P. falciparum usually cause mild disease with minimal complications [2]. P. vivax malaria is a parasitic infection which is carried by Anopheles mosquito [4].
Life cycle of P. vivax is a unique phase known as hypnozoite stage in which the parasite remains dormant in the liver causing frequent relapses after acute infection is treated. Severe complications due to P. vivax are extremely rare compared to P. falciparum [5].
Hematological changes occurring in malaria include anemia, thrombocytopenia, leucopenia, neutropenia, leukocytosis, atypical leukocytosis and splenomegaly. One study has shown that lymphopenia, leucopenia and thrombocytopenia are the key predictors of malaria infection. Low Hb, High lymphocyte count, low platelets and monocytosis are more severe in chronic malaria compared to acute malaria [6]. Hematologic changes due to malaria depend on various factors including malaria endemicity, background hemoglobin disorders, demographic factors and level of malarial immunity. Thrombocytopenia and anemia are the main blood abnormalities occurring in malaria [3]. Pancytopenia is an uncommon manifestation of malaria and is mostly common with P. falciparum and occur due to both direct and indirect effect of infection on hematopoietic cells in the bone marrow [7]. Two main mechanisms involved in pancytopenia involve direct bone marrow suppression and hemophagocytosis, the latter is mostly reported with P. falciparum malaria.
P. vivax has lesser pyrogenic threshold, marked inflammatory response and very high cytokine production as compared to P.
falciparum. There have been case reports of severe disseminated infection with multi organ failure due to P. vivax. Studies have also shown that P. vivax can lead to acute tubular necrosis and acute interstitial nephritis termed as Malarial Nephropathy [1].
Pancytopenia secondary to P. vivax malaria is extremely rare and has only been reported in 0.9% of the confirmed P. vivax cases.
To the best of author's knowledge, only up to 5 cases of isolated P.
vivax malaria with pancytopenia have been reported in literature without other associated comorbids [2,5]. Key mechanism involved in the development of pancytopenia in P. vivax is microangiopathic hemolytic anemia followed by hemophagocytic syndrome which has rarely been reported with P. vivax [5]. Hemophagocytic syndrome is an unusual clinicopathological syndrome that is characterized by overt immunological responses by T-cells producing high levels of interferon gamma, TNF alpha, IL-1, IL-2 and IL-18 leading to activation of macrophages which in turn causes phagocytosis of hematopoietic cells and bone marrow suppression. It can be fatal if misdiagnosed or diagnosis is delayed.
Hemophagocytic syndrome mainly occurs secondary to many infections including viral, bacterial, fungal and parasitic infections [4]. Estimation of exact prevalence of malaria associated HLH is very difficult because bone marrow biopsy is not routinely performed to diagnose malarial infection and exact mortality rate is also not low. It can be fatal if not treated. Malaria associated phagocytic syndrome can lead to prolong hemophagocytosis which is a very rare complication and can lead to prolong anemia. It has been reported only with P. falciparum and not with P. vivax [2]. Various treatment modalities to treat HLH include treating the causative agent, immunosuppressant, steroids and IV immunoglobulins [8].
Various studies have proven that malaria associated HLH has an excellent response to antimalarials and supportive care without any need for immunosuppressants and steroids [2,8].
Malaria must always be kept in differential diagnosis as a cause of prolong fever with refractory anemia and pancytopenia particularly in endemic areas and asymptomatic patient despite of negative smear and rapid antigen test. Bone marrow biopsy is the key to diagnose P. falciparum malaria in such cases [9,10].

Conclusion
Malaria is one of many infections which can involve any organ of the body especially the bone marrow. Bone marrow involvement causes decrease in all the three cell lines leading to pancytopenia. It is important that malaria should always be included in the differential diagnosis whenever pancytopenia is worked up because it is one of the treatable causes of pancytopenia with excellent prognosis.

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