|Year : 2020 | Volume
| Issue : 10 | Page : 467-471
Haemophagocytic lymphohistiocytosis secondary to Plasmodium falciparum malaria: Case report and review of the literature
Fatma Hammami1, Makram Koubaa1, Mourad Chaari2, Rim Chaabouni1, Abrakhom Zeyni1, Khaoula Rekik1, Fatma Smaoui1, Mounir Ben Jemaa1
1 Infectious Diseases Department, Hedi Chaker University Hospital, University of Sfax, Tunisia
2 Hematology Laboratory, Hedi Chaker University Hospital, University of Sfax, Tunisia
|Date of Submission||09-Dec-2019|
|Date of Decision||16-Jun-2020|
|Date of Acceptance||01-Jul-2020|
|Date of Web Publication||14-Aug-2020|
Infectious Diseases Department, Hedi Chaker University Hospital, University of Sfax
Source of Support: None, Conflict of Interest: None
Rationale: Haemophagocytic lymphohistiocytosis is a rare complication of malaria, which is often misdiagnosed.
Patient concerns: A 30-year-old male was admitted to our department for persistent fever, which began after returning from a stay in Guinea-Conakry. The laboratory investigations revealed a pancytopenia and an elevated C-reactive protein. Peripheral smear examination showed Plasmodium falciparum, therefore confirming the diagnosis of malaria. The laboratory tests showed a worsening pancytopenia. Bone marrow aspiration and biopsy revealed images of hemophagocytosis.
Diagnosis: The diagnosis of haemophagocytic lymphohistiocytosis complicating malaria infection was established.
Interventions: The patient was treated with artemether-lumefantrine. No immunosuppressant treatment was delivered to the patient. He received antipyretic and antimalarial treatment only.
Outcomes and lessons: We report a case of haemophagocytic lymphohistiocytosis trigged by malaria infection and we review all reported cases secondary to Plasmodium falciparum malaria by searching PubMed publications till October 2019. Haemophagocytic lymphohistiocytos secondary to malaria should be suspected even in non-severe cases of malaria.
Keywords: Diagnosis; Haemophagocytic lymphohistiocytosis; Malaria; Plasmodium falciparum
|How to cite this article:|
Hammami F, Koubaa M, Chaari M, Chaabouni R, Zeyni A, Rekik K, Smaoui F, Jemaa MB. Haemophagocytic lymphohistiocytosis secondary to Plasmodium falciparum malaria: Case report and review of the literature. Asian Pac J Trop Med 2020;13:467-71
|How to cite this URL:|
Hammami F, Koubaa M, Chaari M, Chaabouni R, Zeyni A, Rekik K, Smaoui F, Jemaa MB. Haemophagocytic lymphohistiocytosis secondary to Plasmodium falciparum malaria: Case report and review of the literature. Asian Pac J Trop Med [serial online] 2020 [cited 2022 Dec 3];13:467-71. Available from: https://www.apjtm.org/text.asp?2020/13/10/467/291041
| 1. Introduction|| |
Malaria, a public health problem, is still endemic in the tropical and subtropical areas, most notably Southeast Asia, the Amazon and Africa. Despite preventive measures, mortality rate related to malaria globally ranges from 0.3% to 2.2% and reaches 11% to 30% in cases of severe forms of malaria in regions with tropical climate. Since 1979, malaria have been eliminated from our country and since then, only imported cases were reported. Fever, in a patient returning from a tropical area, accompanied by malaise and musculoskeletal pain are the symptoms of uncomplicated malaria. However, serious complications may occur such as cerebral malaria, bleeding, severe anemia, liver dysfunction and renal failure. Another rare complication is haemophagocytic lymphohistiocytosis (HLH), which is a systemic disorder caused by an excessive immune reaction. We distinguish primary (familial) HLH, occurring in children with known genetic defects, and secondary (acquired) HLH caused by infection, malignancy or rheumatologic disorders and occurring in patients typically older,.
The diagnosis, often delayed, remains a significant concern due to the complexity of diagnostic criteria and similarity to other inflammatory disorders. We report herein a case of HLH trigged by malaria infection in a 30-year-old immunocompetent male and we review all reported cases of HLH secondary to Plasmodium (P.) falciparum malaria by searching PubMed publications till October 2019. We excluded from the search cases of non P. falciparum malaria or non documented species of malaria. Written consent to publish the case report has been obtained from the patient.
| 2. Case report|| |
A 30-year-old male with no significant medical history was presented to our department for persistent fever which have been evolving since 8 days, associated with polyarthralgia and myalgia. His symptoms began 5 days after returning from a stay in Guinea- Conakry, which lasted 2 years and a half. On admission, he had a body temperature of 40 °C, his heart rate was 106 beats/min and his blood pressure was 102/60 mmHg. Physical examination showed a conjunctival pallor and a splenomegaly, but with no icterus, nor lymphadenopathy. His laboratory investigations revealed an elevated C-reactive protein (177 mg/L) and a pancytopenia. Blood tests showed low white blood cells count (2 400/mm3) with a neutrophil rate at 1 010/mm3, thrombocytopenia (44 000/mm3) and anemia (8.1 g/dL). He had normal liver and renal functions. Peripheral smear examination showed P. falciparum, therefore confirming the diagnosis of malaria. The patient was treated with artemether-lumefantrine at a dose of 4 tablets twice-daily for 3 days. Although his fever resolved after initiation of the treatment, pancytopenia continued to worsen. Ferritin level was elevated at 891 μg/L and triglyceride rate was high at 2.7 mmol/L. Blood tests also showed a fibrinogen level of 1.16 g/L and a serum lactate dehydrogenase (LDH) level at 236 UI/L.
Bone marrow aspiration and biopsy revealed images of hemophagocytosis [Figure 1] and [Figure 2]. Satisfying six out of eight criteria including fever, splenomegaly, pancytopenia, hypofibrinogenemia, hyperferritinemia and images of hemophagocytosis, the diagnosis of HLH complicating malaria infection was confirmed. No immunosuppressant treatment was delivered to our patient. He received antipyretic and antimalarial treatment only.
|Figure 1: Bone marrow biopsy of a 30-year-old male with persistent fever showing macrophage (arrow) phagocyting platelets (Wright-Giemsa stain ×100).|
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|Figure 2: Bone marrow biopsy of a 30-year-old male with persistent fever showing macrophage (arrow) phagocyting erythroblasts and platelets (Wright-Giemsa stain ×100).|
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The disease evolution was favourable. His general condition improved. There were no more episodes of fever. His blood tests showed an improvement. The white blood cells count was 4 000/mm3 with a neutrophil rate at 2 330/mm3, platelets rate was 148 000/mm3 and hemoglobin level was 10.9 g/dL after 5 days of treatment. Control peripheral smear examination at day 3 and day 7 were both negative. The patient was discharged after one week. His follow-up visit a week later showed normal blood tests.
| 3. Discussion|| |
HLH trigged by malaria was a rare disease. The literature search yielded 22 cases with HLH secondary to P. falciparum malaria, including our case,,,,,,,,,,,,,,,,,,, [Table 1]. The majority of the cases reported in the literature were trigged by severe malaria and the diagnosis of HLH was mostly considered after the deterioration of the clinical condition of the patient. Our patient had no signs of severe malaria. The diagnosis of HLH was suspected and confirmed in front of a worsening cytopenia during the resolution phase of malaria. The majority of the described cases had 5 of the 8 criteria used for HLH. Neither the evaluation of the interleukin-2 (IL-2) receptor, nor the natural killer cell activity were performed, except for one case of a 5-year-old boy who had an elevated IL-2 receptor at 4 352 U/mL. All patients recovered. No death due to malaria-associated HLH was reported,,,,,,,,,,,,,,,,,,,. All patients received antimalarial therapy. Eleven patients received specific treatment for HLH represented by corticosteroids in 7 cases,,,,,, and intravenous immunoglobulin in 4 cases,,.
|Table 1: Clinical characteristics and management of malaria-related haemophagocytic lymphohistiocytosis reported in the literature.|
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The real incidence of HLH complicating malaria infection might be underestimated in front of the low index of suspicion. For example, cytopenia and splenomegaly which can be seen during HLH, can be associated to malaria. However, for our patient, a worsening cytopenia during the resolution phase of malaria, and the association with hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia, were alarming signs which indicated the bone marrow biopsy.
Malaria remains responsible for significant mortality in endemic areas. Previous studies showed that more than half of the world’s population are at risk of contracting malaria, although a decline in the incidence of malaria in endemic areas over the last decade was reported. As soon as the diagnosis is established, antimalarial treatment is indicated. The treatment choice is based on the patient characteristics and his concomitant medication, the geographic region of infection, the clinical features of malaria, the causative Plasmodium species and the use of chemoprophylaxis and/or previous curative treatment for malaria.
HLH may lead to death if not promptly diagnosed and treated. It is a rare, but a life-threatening syndrome associated with excessive immune activation. Familial HLH is mostly recognized in childhood, whereas the acquired form can occur at any age and is secondary to infections (viral, bacterial, fungal or parasitic infections), autoimmune or neoplastic conditions,.
The secondary HLH treatment strategy includes supportive care, treatment of the underlying etiology and the use of immunosuppressants (steroids, intravenous immunoglobulin and other immunosuppressive drugs such as dexamethasone or etoposide) in unresponsive cases in order to target the hyperinflammatory state ,. However, for HLH associated to infections, patients usually recover with the treatment of the causative infection, like the case of our patient. The prognosis of HLH depends mainly on its early diagnosis and the underlying etiology. The 5-year survival rate was 83% in patients with HLH associated to infections.
HLH secondary to P. falciparum malaria was a rare disease, probably underrecognized and misdiagnosed. Malaria should always be considered in front of an unexplained fever after returning from an endemic country. The diagnosis of HLH secondary to malaria must be bearded in mind even in non-severe cases of malaria. A prompt diagnosis and treatment of malaria associated to HLH may prevent serious complications and improve the prognosis.
Conflict of interest statement
We declare that we have no conflict of interest.
FH, MK and MBJ developed the theoretical formalism. MC, RC, AZ collected the exact data from the patient, and other para-clinical findings. FH and MK wrote the manuscript. FH, MK, KR, FS and MBJ contributed in data analysis and critical revision of the manuscript. All authors approved the manuscript for publication.
| References|| |
Nascimento TL do, Vasconcelos SP, Peres Y, Oliveira MJS de, Taminato M, Souza KMJ de. Prevalence of malaria relapse: Systematic review with meta-analysis. Rev Lat Am Enfermagem
Talapko J, Skrlec I, Alebic T, Jukic M, Vcev A. Malaria: The past and the present. Microorganisms
Gzara Zargouni A, Tej Dellagi R, Ben Alaya N, Ben Jemaa N, Gamara D, Ben Salah A, et al. Indigenous malaria in Tunisia: 4 cases registered in 2013 in Tunisia. Tunis Med
Jiménez-Morillas F, Gil-Mosquera M, García-Lamberechts EJ. Fever in travellers returning from the tropics. Med Clin (Barc)
Amireh S, Shaaban H, Guron G. Severe Plasmodium vivax
cerebral malaria complicated by hemophagocytic lymphohistiocytosis treated with artesunate and doxycycline. Hematol Oncol Stem Cell Ther
Muthu V, Dhooria S, Sehgal IS, Agarwal R, Behera D, Varma N. Malaria-associated secondary haemophagocytic lymphohistiocytosis: Report of two cases & a review of literature. Indian J Med Res
Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer
Harioly Nirina MOM, Raheritiana TM, Harioly Nirina MOJ, Rasolonjatovo AS, Rakoto Alson AO, Rasamindrakotroka A. Hemophagocytic lymphohistiocytosis associated with Plasmodium falciparum. Med Mal Infect
Niang A, Niang SE, Ka EHF, Ka MM, Diouf B. Collapsing glomerulopathy and haemophagocytic syndrome related to malaria: A case report. Nephrol Dial Transplant
Ohnishi K, Mitsui K, Komiya N, Iwasaki N, Akashi A, Hamabe Y. Clinical case report: Falciparum malaria with hemophagocytic syndrome. Am J Trop Med Hyg
Ladeb S, Ben Abdejlil N, Fakhfakh N, Lakhal A, Belloumi D, Ben Hamed L, et al. Plasmodium falciparum
infection transmitted by transfusion: A cause of hemophagocytic syndrome after bone marrow tranplantation in a non-endemic country. Transpl Infect Dis
Selvarajan D, Sundaravel S, Alagusundaramoorthy SS, Jacob A. Hemophagocytic lymphohistiocytosis with concurrent malarial infection. BMJ Case Rep
Weeratunga P, Rathnayake G, Sivashangar A, Karunanayake P, Gnanathasan A, Chang T. Plasmodium falciparum
and Mycoplasma pneumoniae
co-infection presenting with cerebral malaria manifesting orofacial dyskinesia and haemophagocytic lymphohistiocytosis. Malar J
Bhagat M, Kanhere S, Kadakia P, Phadke V, George R, Chaudhari K. Haemophagocytic lymphohistiocytosis: A cause of unresponsive malaria in a 5-year-old girl. Paediatr Int Child Health
Trifi A, Terra A, Abdellatif S, Daly F, Oueslati M, Laamari L, et al. Haemophagocytic lymphohistiocytosis syndrome-related to severe malaria: rare association. Tunis Med
Santos JA, Neves JF, Venâncio P, Gouveia C, Varandas L. Hemophagocytic lymphohistiocytosis secondary to Falciparum malaria
in a 5 year-old boy. Ann Hematol
Vinoth PN, Thomas KA, Selvan SM, Suman DFR, Scott JX. Hemophagocytic syndrome associated with Plasmodium falciparum
infection. Indian J Pathol Microbiol
Dass R, Barman H, Duwarah SG, Choudhury V, Jain P, Deka NM, et al. Macrophage activation syndrome in malaria. Rheumatol Int
Sermet-Gaudelus I, Abadie V, Stambouli F, Hennequin C, Lenoir G, Gendrel D. Haemophagocytic syndrome in Plasmodium falciparum
malaria. Acta Paediatr
Zvulunov A, Tamary H, Gal N. Pancytopenia resulting from hemophagocytosis in malaria. Pediatr Infect Dis J
Sanklecha M, Mehta N, Bagban H. Varied presentation of complicated falciparum malaria in a family. Indian Pediatr
Abdelkefi A, Ben Othman T, Torjman L, Ladeb S, Lakhal A, Belhadj S, et al. Plasmodium falciparum
causing hemophagocytic syndrome after allogeneic blood stem cell transplantation. Hematol J Off J Eur Haematol Assoc
Rehman JU, Bhabri N, Waleed A, Maulawi A, Aslam M. Falciparum malaria in a patient with sickle cell trait with hemophagocytosis and secondary pancytopenia. Ann Hematol
Retornaz F, Seux V, Arnoulet C, Durand JM, Sainty D, Soubeyrand J. Plasmodium falciparum
malaria infection complicated by haemophagocytic syndrome in an old man. Acta Haematol
Anwar M, Saleem M, Malik IA. Severe haemophagocytic syndrome in falciparum malaria. JPak Med Assoc
Ohno T, Shirasaka A, Sugiyama T, Furukawa H. Hemophagocytic syndrome induced by Plasmodium falciparum malaria infection. Int J Hematol
Epelboin L, Rapp C, Faucher JF, Mechai’ F, Bottieau E, Matheron S, et al. Management and treatment of uncomplicated imported malaria in adults. Update of the French malaria clinical guidelines. Med Mal Infect
Tothova Z, Berliner N. Hemophagocytic syndrome and critical illness: New insights into diagnosis and management. J Intensive Care Med
Malinowska I, Machaczka M, Popko K, Siwicka A, Salamonowicz M, Nasilowska-Adamska B. Hemophagocytic syndrome in children and adults. Arch Immunol Ther Exp (Warsz)
[Figure 1], [Figure 2]