Hemophagocytic syndrome associated with visceral leishmaniasis
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《美国医学杂志》
1 Department of Pathology, Lady Hardinge Medical College and Kalawati Saran Children's Hospital Connought Place, New Delhi, India
2 Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital Connought Place, New Delhi, India
Abstract
The present paper reports a case of 6-year-old male child, suffering from pallor, fever and hepatosplenomegaly. A clinical diagnosis of enteric fever with a second possibility of malaria was considered. Laboratory findings included bicytopenia, hyperbilirubinemia and raised liver enzymes. Bone marrow examination revealed active hemophagocytosis. On extensive search few amastigote forms of Leishmania donovani were seen. Patient was negative for other viral, bacterial and malaria infections. The final diagnosis of hemophagocytic syndrome associated with visceral leishmaniasis was made. There was response of anti-Leishmanial treatment with improvement in clinical condition.
Keywords: Hemophagocytic syndrome; Visceral leishmaniasis
Kala-azar (Visceral leishmaniasis) is caused by Leishmania sp. Out of 22 known species, the majority of cases in India are due to Leishmania donovani.[1] The disease is endemic in north eastern India. Cutaneous, mucocutaneous and visceral leishmaniasis are common manifestations.
Hemophagocytic syndromes are macrophage related histiocytic disorders which are significant in terms of morbidity and mortality. Primary hemophagocytic lymphohistiocytosis (HLH), the prototypical hemophagocytic syndrome is either familial, occurring in obvious familial setting or as a sporadic event.[2] The more common form is seen during infancy and childhood, and is inherited as an autosomal recessive trait. Possible loci for a responsible gene/genes have recently been located on long arms of chromosomes 9 & 10.[3],[4] The disease is invariably fatal with a median survival of two months without therapy. Secondary HLH has been associated with infections, parasitic infestations, malignant disorders, genetic disorders such as Chediak-Higashi disease, Griscelli disease, XLP syndrome, conditions like lipid rich parenteral alimentation and rheumatoid arthritis.[2] Hemophagocytosis as a presentation of visceral leishmaniasis is a very rare event and can cause considerable diagnostic difficulty.
Case Report
A 6-year-old male child, resident of Bihar was admitted to Kalawati Saran Children Hospital with complaints of fever, pallor and loss of appetite for 15 days and yellow discoloration of eyes for 3 days. The child had achieved all developmental milestones at an appropriate age and had been immunized for common diseases. On general examination, the patient was asthenic, had pallor and mild icterus. Systemic examination revealed hepatosplenomegaly of 5 cm and 3 cm below costal margin respectively. Cardiovascular system, respiratory system and central nervous system were within normal limits. A clinical diagnosis of enteric fever with a second possibility of malaria was considered. The child was given cephalosporin and antimalarials but did not respond to therapy.
Laboratory investigations revealed hemoglobin 7.8 g/dl, TLC 12.0 × 10 3/ml, platelets 17.0 × 10 3sub /ml, MCV 71.7 fl, MCH 20.8 pg, MCHC 29.0 g/dl and reticulocyte count 0.2%. Wright stained peripheral smear showed microcytic hypochromic red cells and was negative for malaria parasite. Liver functions were deranged with serum bilirubin3.2mg/dl (direct2.1mg/dl, indirect1.1mg/dl), Aspartate amino transferase 441 IU/L, Alanine amino transferase-221 IU/L, Alkaline phosphatase-1865 IU/L. Serological markers i.e. anti HCV, anti HAV and HBs Ag were negative. Renal function tests were within normal range. Serum Widal was negative. Wright stained bone marrow smears showed hyper cellular marrow with normoblastic erythroid hyperplasia, M:E 1:1. Myeloid and megakaryocytic series were normal in maturatiion and morphology. There was a marked increase in histiocytes with a prominent hemophagocytosis. On extensive search few amastigote forms of L. donovani were seen both intracellularly and extracellularly Figure1. Immunofluorescence test for anti Leishmanial antibody was positive in (1:200) titre. Serology for TORCH, HIV and RAfactor was negative. A final diagnosis of visceral leishmaniasis with secondary hemophagocytic syndrome was made. Patient was given sodium stibogluconate (20 mg/kd body weight) for 20 days after which a repeat bone marrow aspiration was negative for leishmania donovani. Discussion
There are derangements of several metabolic and hematological parameters in hemophagocytic syndrome. The diagnostic criteria is given by Henter et al.[4] includes (a) Clinical criteria of fever and splenomegaly. (b) Laboratory criteria: cytopenias (affecting two of three lineages in the peripheral blood), haemoglobin (<9.0 g/dl), platelets (< 100 × 10 9/l) neutrophils (<1.0 × 10 9/L) hypertrigly-ceridemia and/or hypofibrinogenemia (fasting triglycerides 3 2.0 mmol/l or 33 SD of the normal value for age, fibrinogen 3 1.5 g/l or 3 3 SD of the normal value for age), (c) Histopathological criteria : hemophagocytosis in bone marrow, spleen or lymph nodes with no evidence of malignancy. Certain other associated abnormalities are hyperbilirubinemia, coagulation, derangements, elevated serum transaminases and serum ferritin levels. The pathophysiology is believed to be due to uncontrolled non-malignant proliferation of T lymphocytes and histiocytes leading to increase cytokine production.[5] It is important to differentiate between primary and secondary HLH, as the treatment of primary disease is by cytotoxic drugs and that of secondary is by treating the underlying cause.
The present case had fever, hepatosplenomegaly, bicytopenia (anemia and thrombocytopenia). There was hyperbilirubinemia and raised liver enzymes. Bone marrow examination revealed active hemophagocytosis. These findings were concordant with the diagnostic criteria defined by HLH study group of the Histiocyte Society in 1991.[2] A vigorous hunt for the cause of hemophagocytosis showed that the patient was negative for viral markers (herpes virus, cytomegalovirus, hepatotropic viruses and rubella virus), bacterial infections, toxoplasmosis and malaria. However on extensive search few amastigotes froms of Leishmania donovani could be domonstrated in the bone marrow aspirate. The patient responded to anti Leishmanial treatment with regression of hepatosplenomegaly, fever and improvement of blood parameters.
Conclusion
This case is presented because of rare association of hemophagocytic syndrome with visceral leishmaniasis of which only few cases have been reported.[6],[7],[8],[9] Moreover due to varied clinicohematological profile there can be an undue delay in diagnosis. Thus a meticulous search for amastigotes of Leishmania should be made in patients presenting with HLH especially those coming from endemic areas.
References
1. Pearson RD, Sousa AQ. A clinical spectrum of Leishmaniasis. Clinical Infectious Diseases 1996; 22 : 1-3.
2. Favara BE, Feller AC, Pauli M, Jaffe ES, Arico M et al. Contemporary classification of Histiocytic disorders. The WHO committee on Histiocyte/Reticulum cell proliferations. Reclassification working group of histiocyte society. Medical and Pediatric Oncology. 1997; 29 : 157-166.
3. Sineidi KA, Wali YA, Pathare AV, Lamki ZA, Visceral leishmaniasis and hemophagocytic syndrome in an Omani child. Squ. Journal for Scientific Research : Medical Sciences 2002; 4(1-2) : 45-48.
4. Henter JI, Elander G, Ost A. Diagnostic guidelines for Hemophagocytic lymphohistiocytosis. The FHL study group of histiocyte society. Semin Oncol 1991; 18 : 29-33.
5. Garnet C, Elander G, Ost A, Henter JI. Kala Azar in a one year old swedish child. Diagnostic difficulties because of active hemophagocytosis. Acta Pediatr 1993; 82 : 794-796.
6. Ornvold K, Carstensen H, Magnussen P, Neilsen MH, Pedersen FK. Kala Azar in a four year old child 18 months after a brief exposure in Malta. Acta Pediatr Scand 1989; 78 : 650-652.
7. Kocak N, Eren M, Yuce A, Gumruk F. Hemophagocytic syndrome associated with visceral leishmaniasis. Indian Pediatrics 2004; 41 : 605-607.
8. Matzner Y, Behar A, Gunders A, Hershko C. Systemic leishmaniasis mimicking malignant histiocytosis. Cancer 1979; 43 : 398-402.
9. Gagnaire MH, Galambrun C, Stephen JL. Hemophagocytic syndrome : A Misleading Complication of Visceral Leishmaniasis in children-A series of 12 cases. Pediatrics 2000; 106(4) : 1-6.(Agarwal Shilpi, Narayan S)
2 Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital Connought Place, New Delhi, India
Abstract
The present paper reports a case of 6-year-old male child, suffering from pallor, fever and hepatosplenomegaly. A clinical diagnosis of enteric fever with a second possibility of malaria was considered. Laboratory findings included bicytopenia, hyperbilirubinemia and raised liver enzymes. Bone marrow examination revealed active hemophagocytosis. On extensive search few amastigote forms of Leishmania donovani were seen. Patient was negative for other viral, bacterial and malaria infections. The final diagnosis of hemophagocytic syndrome associated with visceral leishmaniasis was made. There was response of anti-Leishmanial treatment with improvement in clinical condition.
Keywords: Hemophagocytic syndrome; Visceral leishmaniasis
Kala-azar (Visceral leishmaniasis) is caused by Leishmania sp. Out of 22 known species, the majority of cases in India are due to Leishmania donovani.[1] The disease is endemic in north eastern India. Cutaneous, mucocutaneous and visceral leishmaniasis are common manifestations.
Hemophagocytic syndromes are macrophage related histiocytic disorders which are significant in terms of morbidity and mortality. Primary hemophagocytic lymphohistiocytosis (HLH), the prototypical hemophagocytic syndrome is either familial, occurring in obvious familial setting or as a sporadic event.[2] The more common form is seen during infancy and childhood, and is inherited as an autosomal recessive trait. Possible loci for a responsible gene/genes have recently been located on long arms of chromosomes 9 & 10.[3],[4] The disease is invariably fatal with a median survival of two months without therapy. Secondary HLH has been associated with infections, parasitic infestations, malignant disorders, genetic disorders such as Chediak-Higashi disease, Griscelli disease, XLP syndrome, conditions like lipid rich parenteral alimentation and rheumatoid arthritis.[2] Hemophagocytosis as a presentation of visceral leishmaniasis is a very rare event and can cause considerable diagnostic difficulty.
Case Report
A 6-year-old male child, resident of Bihar was admitted to Kalawati Saran Children Hospital with complaints of fever, pallor and loss of appetite for 15 days and yellow discoloration of eyes for 3 days. The child had achieved all developmental milestones at an appropriate age and had been immunized for common diseases. On general examination, the patient was asthenic, had pallor and mild icterus. Systemic examination revealed hepatosplenomegaly of 5 cm and 3 cm below costal margin respectively. Cardiovascular system, respiratory system and central nervous system were within normal limits. A clinical diagnosis of enteric fever with a second possibility of malaria was considered. The child was given cephalosporin and antimalarials but did not respond to therapy.
Laboratory investigations revealed hemoglobin 7.8 g/dl, TLC 12.0 × 10 3/ml, platelets 17.0 × 10 3sub /ml, MCV 71.7 fl, MCH 20.8 pg, MCHC 29.0 g/dl and reticulocyte count 0.2%. Wright stained peripheral smear showed microcytic hypochromic red cells and was negative for malaria parasite. Liver functions were deranged with serum bilirubin3.2mg/dl (direct2.1mg/dl, indirect1.1mg/dl), Aspartate amino transferase 441 IU/L, Alanine amino transferase-221 IU/L, Alkaline phosphatase-1865 IU/L. Serological markers i.e. anti HCV, anti HAV and HBs Ag were negative. Renal function tests were within normal range. Serum Widal was negative. Wright stained bone marrow smears showed hyper cellular marrow with normoblastic erythroid hyperplasia, M:E 1:1. Myeloid and megakaryocytic series were normal in maturatiion and morphology. There was a marked increase in histiocytes with a prominent hemophagocytosis. On extensive search few amastigote forms of L. donovani were seen both intracellularly and extracellularly Figure1. Immunofluorescence test for anti Leishmanial antibody was positive in (1:200) titre. Serology for TORCH, HIV and RAfactor was negative. A final diagnosis of visceral leishmaniasis with secondary hemophagocytic syndrome was made. Patient was given sodium stibogluconate (20 mg/kd body weight) for 20 days after which a repeat bone marrow aspiration was negative for leishmania donovani. Discussion
There are derangements of several metabolic and hematological parameters in hemophagocytic syndrome. The diagnostic criteria is given by Henter et al.[4] includes (a) Clinical criteria of fever and splenomegaly. (b) Laboratory criteria: cytopenias (affecting two of three lineages in the peripheral blood), haemoglobin (<9.0 g/dl), platelets (< 100 × 10 9/l) neutrophils (<1.0 × 10 9/L) hypertrigly-ceridemia and/or hypofibrinogenemia (fasting triglycerides 3 2.0 mmol/l or 33 SD of the normal value for age, fibrinogen 3 1.5 g/l or 3 3 SD of the normal value for age), (c) Histopathological criteria : hemophagocytosis in bone marrow, spleen or lymph nodes with no evidence of malignancy. Certain other associated abnormalities are hyperbilirubinemia, coagulation, derangements, elevated serum transaminases and serum ferritin levels. The pathophysiology is believed to be due to uncontrolled non-malignant proliferation of T lymphocytes and histiocytes leading to increase cytokine production.[5] It is important to differentiate between primary and secondary HLH, as the treatment of primary disease is by cytotoxic drugs and that of secondary is by treating the underlying cause.
The present case had fever, hepatosplenomegaly, bicytopenia (anemia and thrombocytopenia). There was hyperbilirubinemia and raised liver enzymes. Bone marrow examination revealed active hemophagocytosis. These findings were concordant with the diagnostic criteria defined by HLH study group of the Histiocyte Society in 1991.[2] A vigorous hunt for the cause of hemophagocytosis showed that the patient was negative for viral markers (herpes virus, cytomegalovirus, hepatotropic viruses and rubella virus), bacterial infections, toxoplasmosis and malaria. However on extensive search few amastigotes froms of Leishmania donovani could be domonstrated in the bone marrow aspirate. The patient responded to anti Leishmanial treatment with regression of hepatosplenomegaly, fever and improvement of blood parameters.
Conclusion
This case is presented because of rare association of hemophagocytic syndrome with visceral leishmaniasis of which only few cases have been reported.[6],[7],[8],[9] Moreover due to varied clinicohematological profile there can be an undue delay in diagnosis. Thus a meticulous search for amastigotes of Leishmania should be made in patients presenting with HLH especially those coming from endemic areas.
References
1. Pearson RD, Sousa AQ. A clinical spectrum of Leishmaniasis. Clinical Infectious Diseases 1996; 22 : 1-3.
2. Favara BE, Feller AC, Pauli M, Jaffe ES, Arico M et al. Contemporary classification of Histiocytic disorders. The WHO committee on Histiocyte/Reticulum cell proliferations. Reclassification working group of histiocyte society. Medical and Pediatric Oncology. 1997; 29 : 157-166.
3. Sineidi KA, Wali YA, Pathare AV, Lamki ZA, Visceral leishmaniasis and hemophagocytic syndrome in an Omani child. Squ. Journal for Scientific Research : Medical Sciences 2002; 4(1-2) : 45-48.
4. Henter JI, Elander G, Ost A. Diagnostic guidelines for Hemophagocytic lymphohistiocytosis. The FHL study group of histiocyte society. Semin Oncol 1991; 18 : 29-33.
5. Garnet C, Elander G, Ost A, Henter JI. Kala Azar in a one year old swedish child. Diagnostic difficulties because of active hemophagocytosis. Acta Pediatr 1993; 82 : 794-796.
6. Ornvold K, Carstensen H, Magnussen P, Neilsen MH, Pedersen FK. Kala Azar in a four year old child 18 months after a brief exposure in Malta. Acta Pediatr Scand 1989; 78 : 650-652.
7. Kocak N, Eren M, Yuce A, Gumruk F. Hemophagocytic syndrome associated with visceral leishmaniasis. Indian Pediatrics 2004; 41 : 605-607.
8. Matzner Y, Behar A, Gunders A, Hershko C. Systemic leishmaniasis mimicking malignant histiocytosis. Cancer 1979; 43 : 398-402.
9. Gagnaire MH, Galambrun C, Stephen JL. Hemophagocytic syndrome : A Misleading Complication of Visceral Leishmaniasis in children-A series of 12 cases. Pediatrics 2000; 106(4) : 1-6.(Agarwal Shilpi, Narayan S)