American Journal of Hematology 38:339-340 (1991)
Letter to the Editor: Dengue Virus Infection-Associated Hemophagocytic Syndrome A 53-year-old man presented with maculopapular rash over the trunk, which later progressed to generalized toxic erythema. Systemic steroid was given but was stopped after 2 days because of high swinging fever and hepatosplenomegaly . The hemoglobin level dropped from 13.6 g/dl to 10.6 g/dl, and platelet count from 144 X 109/L to 34 X 109/L over a 6-day period. The leukocyte count remained normal (6.71 X 109/L; normal differential). Marrow examination showed an active marrow with increased reactive histiocytes which accounted for 3% of all nucleated cells. The majority of them exhibited phagocytosis of red cells, leukocytes, platelets and erythroblasts (Fig. 1). A diagnosis of reactive hemophagocytic syndrome (RHS) was made, with an advice to search for an underlying associated disease [I]. The Coombs test was negative and the patient’s coagulation profile remained normal. However, his liver function was impaired: serum bilirubin 48 pmol/L (nor-
mal: 1-18 pmol/L), alkaline phosphatase 291 IU/L (normal: 35-1 15 IU/L), aspartate transaminase 1,251 IU/L (normal: W O IU/L). The disease was complicated by an episode of hypovolemic shock, which was successfully treated by supportive measures. Subsequently, the patient’s condition improved, and the blood counts returned to normal after 1 week. Extensive cultures and serologic studies for bacterial and viral infections were all negative, except for a fourfold rise in the titer of antibodies against Dengue virus type 3. On retrospective questioning, the patient had traveled to the southern provinces of China several weeks before the onset of symptoms. RHS is a clinicopathologic entity characterized by systemic proliferation of reactive histiocytes, fever, cytopenia, and organomegaly [ 11. Many diseases, particularly infection and malignant lymphoma, have been reported to be associated with this syndrome [ 1-31. Among the infective agents, the herpes group of viruses
Fig. 1. A bland-lookinghistiocytewith phagocytosedneutrophiland platelets. (Romanowsky stain.) x600.
0 1991 Wiley-Liss, Inc.
340
Letter to the Editor
is the most commonly implicated. Nonetheless, a literature review shows that dengue virus infection is perhaps one of the earliest diseases reported to be associated with RHS, because previous pathologic descriptions (mostly postmortem findings) of this infection [4,5] have indicated an “increased reticulum cells that phagocytose erythrocytes, normoblasts, lymphocytes, neutrophils, eosinophils, and platelets.” In the absence of disseminated intravascular coagulopathy (DIC) and negative Coombs test, the sudden and significant fall in blood counts in our case appears to result from intramedullary destruction of blood cells by hemophagocytic histiocytes. It is unclear whether the deregulated histiocytic activity results from histiocytic dysfunction (considering the fact that monocyted macrophages serve as the sole or significant target of infection by the virus), stimulation by activated T lymphocytes, or immune complex deposition on the hemopoietic cells (in view of the known occurrence of various immune reactions such as cell-mediated and humoral-mediated immune reactions in dengue hemorrhagic fever) [5,6]. Since dengue virus infection is usually “imported” from neighboring or distant endemic areas [7], the diagnosis may not be suspected until the results of serologic tests are known. Therefore, among other studies (e.g., sepsis workup, antinuclear antibodies, exclusion of lymphoma) [ 1-31, we suggest including serologic tests for dengue virus infection in the workup of patients
with RHS for those with a history of travel to endemic areas.
K.F. Wong J.K.C. Chan J.C.W. Chan W.W.L. Lim W.K. Wong Queen Elizabeth Hospital Kowloon, Hong Kong
REFERENCES 1. Wong KF, Chan JKC: Hemophagocytic disorders-a review. Hematol Rev 1991 (in press). 2. Reiner AP, Spivak JL: Hematophagic histiocytosis: A report of 23 new patients and a review of the literature. Medicine (Baltimore) 67369388, 1988. 3. Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH, Simmons RL: Brunning RD: Virus associated hemophagocytic syndrome. Cancer 44:993-1002, 1979. 4. World Health Organization: Mosquito-borne hemorrhagic fevers of southeast Asia and the Western Pacific. Bull WHO 35:l-103, 1966. 5. Halstead SB: Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade. Rev Infect Dis 1 I (suppl 4):S830-S839, 1989. 6. Halstead SB: Observations related to pathogenesis of dengue hemorrhagic fever. VI. Hypothesis and discussion. Yale J Biol Med 42:35CL 362, 1970 7. Pan HYM, Chow JSF: A case of hemorrhagic dengue without hypovolemia in an adult. Trop Geograph Med 36:305-307, 1984.
Letter to the Editor: Dengue Virus Infection-Associated Hemophagocytic Syndrome A 53-year-old man presented with maculopapular rash over the trunk, which later progressed to generalized toxic erythema. Systemic steroid was given but was stopped after 2 days because of high swinging fever and hepatosplenomegaly . The hemoglobin level dropped from 13.6 g/dl to 10.6 g/dl, and platelet count from 144 X 109/L to 34 X 109/L over a 6-day period. The leukocyte count remained normal (6.71 X 109/L; normal differential). Marrow examination showed an active marrow with increased reactive histiocytes which accounted for 3% of all nucleated cells. The majority of them exhibited phagocytosis of red cells, leukocytes, platelets and erythroblasts (Fig. 1). A diagnosis of reactive hemophagocytic syndrome (RHS) was made, with an advice to search for an underlying associated disease [I]. The Coombs test was negative and the patient’s coagulation profile remained normal. However, his liver function was impaired: serum bilirubin 48 pmol/L (nor-
mal: 1-18 pmol/L), alkaline phosphatase 291 IU/L (normal: 35-1 15 IU/L), aspartate transaminase 1,251 IU/L (normal: W O IU/L). The disease was complicated by an episode of hypovolemic shock, which was successfully treated by supportive measures. Subsequently, the patient’s condition improved, and the blood counts returned to normal after 1 week. Extensive cultures and serologic studies for bacterial and viral infections were all negative, except for a fourfold rise in the titer of antibodies against Dengue virus type 3. On retrospective questioning, the patient had traveled to the southern provinces of China several weeks before the onset of symptoms. RHS is a clinicopathologic entity characterized by systemic proliferation of reactive histiocytes, fever, cytopenia, and organomegaly [ 11. Many diseases, particularly infection and malignant lymphoma, have been reported to be associated with this syndrome [ 1-31. Among the infective agents, the herpes group of viruses
Fig. 1. A bland-lookinghistiocytewith phagocytosedneutrophiland platelets. (Romanowsky stain.) x600.
0 1991 Wiley-Liss, Inc.
340
Letter to the Editor
is the most commonly implicated. Nonetheless, a literature review shows that dengue virus infection is perhaps one of the earliest diseases reported to be associated with RHS, because previous pathologic descriptions (mostly postmortem findings) of this infection [4,5] have indicated an “increased reticulum cells that phagocytose erythrocytes, normoblasts, lymphocytes, neutrophils, eosinophils, and platelets.” In the absence of disseminated intravascular coagulopathy (DIC) and negative Coombs test, the sudden and significant fall in blood counts in our case appears to result from intramedullary destruction of blood cells by hemophagocytic histiocytes. It is unclear whether the deregulated histiocytic activity results from histiocytic dysfunction (considering the fact that monocyted macrophages serve as the sole or significant target of infection by the virus), stimulation by activated T lymphocytes, or immune complex deposition on the hemopoietic cells (in view of the known occurrence of various immune reactions such as cell-mediated and humoral-mediated immune reactions in dengue hemorrhagic fever) [5,6]. Since dengue virus infection is usually “imported” from neighboring or distant endemic areas [7], the diagnosis may not be suspected until the results of serologic tests are known. Therefore, among other studies (e.g., sepsis workup, antinuclear antibodies, exclusion of lymphoma) [ 1-31, we suggest including serologic tests for dengue virus infection in the workup of patients
with RHS for those with a history of travel to endemic areas.
K.F. Wong J.K.C. Chan J.C.W. Chan W.W.L. Lim W.K. Wong Queen Elizabeth Hospital Kowloon, Hong Kong
REFERENCES 1. Wong KF, Chan JKC: Hemophagocytic disorders-a review. Hematol Rev 1991 (in press). 2. Reiner AP, Spivak JL: Hematophagic histiocytosis: A report of 23 new patients and a review of the literature. Medicine (Baltimore) 67369388, 1988. 3. Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH, Simmons RL: Brunning RD: Virus associated hemophagocytic syndrome. Cancer 44:993-1002, 1979. 4. World Health Organization: Mosquito-borne hemorrhagic fevers of southeast Asia and the Western Pacific. Bull WHO 35:l-103, 1966. 5. Halstead SB: Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade. Rev Infect Dis 1 I (suppl 4):S830-S839, 1989. 6. Halstead SB: Observations related to pathogenesis of dengue hemorrhagic fever. VI. Hypothesis and discussion. Yale J Biol Med 42:35CL 362, 1970 7. Pan HYM, Chow JSF: A case of hemorrhagic dengue without hypovolemia in an adult. Trop Geograph Med 36:305-307, 1984.
