Case Report
Hemophagocytic lymphohistiocytosis and dengue infection: rare case report A.-S. De Koninck, J. Dierick, S. Steyaert, P. Taelman Laboratory of Hematology and Microbiology, Department of Laboratory Medicine, AZ Maria-Middelares SintJozef, Campus Maria-Middelares, Ghent, Belgium We describe a 21-year-old female patient returning from a journey to Cambodia, who developed dengue fever complicated with hemophagocytic lymphohistiocytosis. Hectic fever, rash, leukopenia, thrombocytopenia, hepatocellular dysfunction, a markedly elevated ferritin level, and a bone marrow demonstrating abundant hemophagocytosis were present. The patient recovered within 14 days. To our knowledge, this is only the second reported case of dengue virus-associated hemophagocytosis in Europe. As dengue is a rising pathogen in tropical import diseases, clinicians must be aware of its rare but serious complications. Keywords: Primary dengue infection, Infection-associated hemophagocytic syndrome, Pancytopenia, Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome
Introduction
Case Report
Dengue fever is an acute infectious disease that is caused by four serotypes of dengue virus (DEN-1, -2, -3, and -4). Dengue virus can be transmitted to humans by the vectors Aedes aegypti and Aedes albopictus. Dengue has a wide spectrum of clinical presentations, many of which are non-specific. The most common manifestations of dengue virus infection are self-limiting high fever, rash, headache, and musculoskeletal pain.1,2 Hemophagocytic lymphohistiocytosis (HLH, also called ‘hemophagocytic syndrome’) is a potentially fatal disorder caused by an aberrant immune response. The mortality of patients with infectionassociated hemophagocytic syndrome (IAHS) is very high.1 Review of the literature in endemic areas (Southeast Asia, India) learns that dengue fever complicated with IAHS is a rather rare association. Although the association is being increasingly reported, it still remains under-recognized. We describe a 21-year-old female patient returning from a journey to Cambodia, who developed dengue fever-associated hemophagocytic syndrome. Our patient is an interesting case of IAHS associated with classic dengue fever and contributes an additional case to the scarce existing literature on this topic. To our knowledge, this is only the second reported case of dengue virus-associated hemophagocytosis in Europe.3
A 21-year-old women recently attended a journey through swampy areas in Cambodia. She took malaria profylaxis in a correct manner (atovaquone and proguanil, ‘MalaroneH’) and actions to reduce human–vector contact were taken during her residence in Cambodia. The night after returning home (day 1), she developed high-grade fever (39.2uC) and abdominal pain. Because she had a known sensitivity for urine bladder infections, her GP prescribed fosfomycin (‘MonurilH’) followed by amoxicillin (361 g), but the high fever remained. Laboratory investigation showed a pyuria of 28 white blood cell count/ml and presence of vaginal contamination. When the patient developed muscular pain in both legs, in the pelvic floor and the lower back (day 3), she was referred to our emergency department. Clinical examination showed abdominal tenderness without diarrhea or nausea. She had occipital and temporal headache, without photophobia or visual impairment. Antipyretics could not adequately control the patient’s hectic fever. Echography of the abdomen and radiography of the thorax revealed no abnormalities. No splenomegaly was found (9.9 cm measured length diameter of the spleen). Acalculous cholecystitis was excluded during echographic examination. Laboratory examination on admission (day 3) showed WBC of 1800/mm3, red blood cell count of 4 600 000/mm3, haemoglobin of 12.6 g/dl, haematocrit of 38%, and platelet count of 95 000/mm3 (Table 1). Differential leukocyte count showed a neutropenia of 1400/mm3, a lymphopenia of 300/
Correspondence to: A.-S. De Koninck, AZ Maria-Middelares, Laboratory of Hematology, Kortrijksesteenweg 1026, 9000 Ghent, Belgium. Email: [email protected]
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ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000019
Acta Clinica Belgica
2014
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De Koninck et al.
mm3, and a monocytopenia of 100/mm3. Reactive plasmocytosis was present (5% of total blood formula). The coagulation screen showed slightly prolonged prothrombin time (68%, INR 1.3) and activated partial thromboplastin time (43.3 seconds). Kidney function tests, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase were all within normal limits. Mild proteinuria 0.31 g/l (reference value ,0.15 g/l) was found, and serum electrophoresis showed no sign of nephrotic syndrome. The C-reactive protein was elevated to 53.44 mg/l. No data are available regarding serum lipids. The days following admission, the abdominal pain worsened. Further laboratory investigations showed rising transaminases with markedly elevated ferritin levels and descending platelet count (nadir 28 000/ mm3) (Table 1). C-reactive protein remained elevated. The malaria antigen test (Palutop z4 Optima; All.Diag, Strasbourg, France) scored negative and no malarial parasites were found on peripheral blood film. Blood culture results and toxoplasma, hepatitis A, hepatitis B, hepatitis C, malaria, Epstein–Barr virus, and cytomegalovirus serology were all negative. On day 6, the dengue antigen test (SD Bioline Dengue NS1 Ag; Standard Diagnostics, Korea) was performed, showing a positive result. Two days later (day 8), the result of the polymerase chain reaction (PCR) test demonstrated the presence of dengue virus serotype 3 (DEN-3), confirming dengue virus infection. Dengue IgM and IgG (Dengue Virus IgM Capture DxSelect2 and IgG DxSelect2; Focus Diagnostics, Cypress, CA, USA) were also positive (ratio 6.87 and 3.15, respectively; reference value ratio ,1). Because of worsened bicytopenia (WBC 1300/mm3, platelet count 39 000/mm3) and high ferritin level (8208 mg/l), bone marrow biopsy was examined on day 6. The hypercellular bone marrow showed features of marked hemophagocytosis (Fig. 1) and acute viral infection (presence of reactive plasmocytosis
Hemophagocytic lymphohistiocytosis and dengue infection
and reactive lymphocytes). Normal maturation of the erythropoietic, megakaryopoietic, and granulopoietic cell lines was seen. Anatomopathological investigation of bone marrow biopsy (trephine biopsy) also showed a cellularity of 60%, with presence of reactive lymphocytes and reactive plasmocytosis. The highest ferritin level observed was 13 700 mg/l (day 9). The creatine kinase analysis showed elevated levels on days 6–8 (Table 1), during which the patient experienced severe myalgia. She also developed a rash on her legs. CD4z/CD8z inversion was present on immunophenotypic examination (ratio 0.54; reference value 1–4). Diagnosis of dengue fever with infection-associated hemophagocytic syndrome was made according to the diagnostic criteria of the HLH-2004 protocol of the Histiocyte Society, which include clinical, laboratory, and histopathological features.4 Because the GP informed of a similar (undocumented) episode in the medical history of this patient, a genetic screening is ongoing to exclude a predisposing genetic mutation for HLH (primary HLH). She was given immunoglobulin-G therapy (PrivigenH, 1 g/kg body weight) for 2 days. The patient showed resolution of clinical and biochemical markers for hemophagocytosis indicating transient hemophagocytic activity phenomenon in dengue. The patient fully recovered with appropriate supportive care and was dismissed from our hospital on day 14.
Discussion Dengue is the most rapidly spreading mosquitoborne viral disease in the world. The WHO has estimated that 50 million cases of dengue fever occur each year. The epidemiology in different regions is distinct. Cambodia is considered as one of the four countries (Cambodia, Malaysia, Philippines, and Vietnam) in the Western Pacific Region with the highest numbers of cases and deaths.2 Dengue is endemic in Cambodia, a country with poor health and economic indicators and with a tropical climate.1 Dengue is not endemic in the WHO European
Table 1 Patient’s laboratory investigation results
WBC PLT AST ALT LDH CK CRP Ferritin
Day 2*
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 14
Reference values
4250 167 16 13 307 … 20.00 …
1800 … 30 16 402 61 53.44 …
1500 95 45 24 449 … 32.05 …
1100 83 168 106 709 … 15.23 …
1300 39 563 347 1107 486 7.42 8208
1800 32 724 447 1169 614 6.05 12 764
3500 28 574 392 … 320 5.55 11 917
4200 29 … … 1926 145 14.60 13 700
4600 52 390 285 2307 79 32.23 8626
3700 76 256 209 2193 … 20.16 7276
4500 174 85 107 1175 33 4,16 1976
4000–10 000 140–440 ,32 ,31 240–480 ,170 ,5 15–150
*Results from external laboratory, before hospitalization of the patient. Results exceeding the reference interval are marked in bold. WBC: total white blood cell count (/mm3); PLT: platelet count (6103/mm3); AST: aspartate aminotransferase (IU/l); ALT: alanine aminotransferase (IU/l); LDH: lactate dehydrogenase (IU/l); CK: creatine kinase (IU/l); CRP: C-reactive protein (mg/l); ferritin (mg/l). Proposal: Maybe add the following to the subscript? …: no result available.
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De Koninck et al.
Hemophagocytic lymphohistiocytosis and dengue infection
Figure 1 Group of macrophages engulfing erythrocytes, normoblasts, thrombocytes, and leukocytes.
Region, whereby most cases in the region have been reported either as incidents in overseas territories or importation from endemic countries.2 Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. In the early febrile phase, dengue fever can easily be confused with non-dengue illnesses, particularly in non-epidemic situations. Depending on the geographical origin of the patient, other aetiologies should be ruled out. These include flu-like syndromes (influenza, measles, Chikungunyan, infectious mononucleosis, HIV), illnesses with a rash (rubella, measles, scarlet fever, meningococcal infection, Chikungunyan, drug reactions), diarrhoeal diseases (rotavirus, other enteric infections), and illnesses with neurological manifestations (meningoencephalitis, febrile seizures).2 HLH is an aggressive and potentially life-threatening syndrome of excessive immune activation.5,6 It is hypothesized that the disease is caused by impaired lymphocyte-mediated cytotoxicity and defective triggering of apoptosis, resulting in an uncontrolled immune response. In HLH, macrophages become activated and secrete large amounts of pro-inflammatory cytokines. The natural killer cells and/or cytotoxic lymphocytes fail to eliminate these activated macrophages through perforin-dependent cytotoxicity.5,6 This lack of normal feedback regulation
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results in a persistent activation of macrophages, natural killer cells and cytotoxic lymphocytes, leading to excessive cytokine production (cytokine storm) by all of these cells. The excess of pro-inflammatory cytokines causes tissue infiltration by lymphocytes and macrophages and a proliferation of macrophages in the bone marrow, spleen, liver, and lymph nodes, leading to hemophagocytosis.4,5 Clinically, the most typical findings are persistent fever, pancytopenia, and hepatosplenomegaly. Other common findings include liver dysfunction, coagulopathy with hypofibrinogenemia, elevated serum ferritin level, and (highly variable) neurological abnormalities. Other, less common, initial clinical findings include lymphadenopathy, skin rash, jaundice, and oedema.4 The manifestations may be acute or subacute, with the patient exhibiting severe malaise, weight loss, and rapidly developing pancytopenia.5 Marrow examination is often hyperplastic with increased numbers of hemophagocytic macrophages. Prompt initiation of treatment is essential for the survival of the affected patient. The treatment should be primarily aimed at suppressing the hyper-inflammatory response responsible for the life-threatening symptoms.5 The HLH can occur as a primary (genetic) and secondary (related to infections or malignancy)
De Koninck et al.
disorder. The two main subdivisions of the secondary HLH are infection-associated (IAHS) and malignant (MHS) hemophagocytic syndrome. Viral infections mostly implicated in association with IAHS are Epstein–Barr virus infection, cytomegalovirus infection, adenovirus infection, and viral hepatitis.5,6 A review of literature revealed only a handful of case reports that showed evidence of IAHS caused by dengue virus. Efficient and accurate diagnosis of dengue is of primary importance for clinical care (i.e. early detection of severe cases, case confirmation, and differential diagnosis with other infectious diseases).2 Furthermore, clinicians should consider the possibility that pancytopania secondary to hemophagocytosis could be a complication of dengue infection, which requires bone marrow examination and appropriate therapy. Often the great barrier to a successful outcome of IAHS is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.5
Hemophagocytic lymphohistiocytosis and dengue infection
Acknowledgements We would like to thank GP Dr A. Boer and Dr G. De Lombaerde for their support. We are grateful to the Institute of Tropical Medicine (Antwerp, Belgium) for kindly performing the dengue antigen, serology, and molecular tests.
References 1 World Health Organization. Health topics: dengue [document on the Internet]. Geneva: WHO; 2013 [cited 2013 Dec 1]. Available from: http://www.who.int/topics/dengue/en/ 2 World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control [document on the Internet]. New Edition 2009. Geneva: WHO; 2009 [cited 2013 Dec 1]. Available from: http://whqlibdoc.who.int/publications/2009/ 9789241547871_eng.pdf 3 Lai M, Stirnemann J, Bibi-Triki T, Gerin M, Brichler S, Prendki V, et al. Dengue associe´e a` un syndrome ne´phrotique et a` un syndrome d’activation macrophagique (Dengue fever complicated by a nephrotic syndrome and a hemophagocytic syndrome). Med Mal Infect. 2012;42:30–2. 4 Henter JI, Horne AC, Arico´ M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. 5 McClain K. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. Up To Date – Topic 87499 Version 1.0 (updated 2013 Aug 28; cited 2013 Nov). 6 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46.
Acta Clinica Belgica
2014
VOL .
69
NO .
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213
Hemophagocytic lymphohistiocytosis and dengue infection: rare case report A.-S. De Koninck, J. Dierick, S. Steyaert, P. Taelman Laboratory of Hematology and Microbiology, Department of Laboratory Medicine, AZ Maria-Middelares SintJozef, Campus Maria-Middelares, Ghent, Belgium We describe a 21-year-old female patient returning from a journey to Cambodia, who developed dengue fever complicated with hemophagocytic lymphohistiocytosis. Hectic fever, rash, leukopenia, thrombocytopenia, hepatocellular dysfunction, a markedly elevated ferritin level, and a bone marrow demonstrating abundant hemophagocytosis were present. The patient recovered within 14 days. To our knowledge, this is only the second reported case of dengue virus-associated hemophagocytosis in Europe. As dengue is a rising pathogen in tropical import diseases, clinicians must be aware of its rare but serious complications. Keywords: Primary dengue infection, Infection-associated hemophagocytic syndrome, Pancytopenia, Hemophagocytic lymphohistiocytosis, Hemophagocytic syndrome
Introduction
Case Report
Dengue fever is an acute infectious disease that is caused by four serotypes of dengue virus (DEN-1, -2, -3, and -4). Dengue virus can be transmitted to humans by the vectors Aedes aegypti and Aedes albopictus. Dengue has a wide spectrum of clinical presentations, many of which are non-specific. The most common manifestations of dengue virus infection are self-limiting high fever, rash, headache, and musculoskeletal pain.1,2 Hemophagocytic lymphohistiocytosis (HLH, also called ‘hemophagocytic syndrome’) is a potentially fatal disorder caused by an aberrant immune response. The mortality of patients with infectionassociated hemophagocytic syndrome (IAHS) is very high.1 Review of the literature in endemic areas (Southeast Asia, India) learns that dengue fever complicated with IAHS is a rather rare association. Although the association is being increasingly reported, it still remains under-recognized. We describe a 21-year-old female patient returning from a journey to Cambodia, who developed dengue fever-associated hemophagocytic syndrome. Our patient is an interesting case of IAHS associated with classic dengue fever and contributes an additional case to the scarce existing literature on this topic. To our knowledge, this is only the second reported case of dengue virus-associated hemophagocytosis in Europe.3
A 21-year-old women recently attended a journey through swampy areas in Cambodia. She took malaria profylaxis in a correct manner (atovaquone and proguanil, ‘MalaroneH’) and actions to reduce human–vector contact were taken during her residence in Cambodia. The night after returning home (day 1), she developed high-grade fever (39.2uC) and abdominal pain. Because she had a known sensitivity for urine bladder infections, her GP prescribed fosfomycin (‘MonurilH’) followed by amoxicillin (361 g), but the high fever remained. Laboratory investigation showed a pyuria of 28 white blood cell count/ml and presence of vaginal contamination. When the patient developed muscular pain in both legs, in the pelvic floor and the lower back (day 3), she was referred to our emergency department. Clinical examination showed abdominal tenderness without diarrhea or nausea. She had occipital and temporal headache, without photophobia or visual impairment. Antipyretics could not adequately control the patient’s hectic fever. Echography of the abdomen and radiography of the thorax revealed no abnormalities. No splenomegaly was found (9.9 cm measured length diameter of the spleen). Acalculous cholecystitis was excluded during echographic examination. Laboratory examination on admission (day 3) showed WBC of 1800/mm3, red blood cell count of 4 600 000/mm3, haemoglobin of 12.6 g/dl, haematocrit of 38%, and platelet count of 95 000/mm3 (Table 1). Differential leukocyte count showed a neutropenia of 1400/mm3, a lymphopenia of 300/
Correspondence to: A.-S. De Koninck, AZ Maria-Middelares, Laboratory of Hematology, Kortrijksesteenweg 1026, 9000 Ghent, Belgium. Email: [email protected]
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ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000019
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2014
VOL.
69
NO.
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De Koninck et al.
mm3, and a monocytopenia of 100/mm3. Reactive plasmocytosis was present (5% of total blood formula). The coagulation screen showed slightly prolonged prothrombin time (68%, INR 1.3) and activated partial thromboplastin time (43.3 seconds). Kidney function tests, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase were all within normal limits. Mild proteinuria 0.31 g/l (reference value ,0.15 g/l) was found, and serum electrophoresis showed no sign of nephrotic syndrome. The C-reactive protein was elevated to 53.44 mg/l. No data are available regarding serum lipids. The days following admission, the abdominal pain worsened. Further laboratory investigations showed rising transaminases with markedly elevated ferritin levels and descending platelet count (nadir 28 000/ mm3) (Table 1). C-reactive protein remained elevated. The malaria antigen test (Palutop z4 Optima; All.Diag, Strasbourg, France) scored negative and no malarial parasites were found on peripheral blood film. Blood culture results and toxoplasma, hepatitis A, hepatitis B, hepatitis C, malaria, Epstein–Barr virus, and cytomegalovirus serology were all negative. On day 6, the dengue antigen test (SD Bioline Dengue NS1 Ag; Standard Diagnostics, Korea) was performed, showing a positive result. Two days later (day 8), the result of the polymerase chain reaction (PCR) test demonstrated the presence of dengue virus serotype 3 (DEN-3), confirming dengue virus infection. Dengue IgM and IgG (Dengue Virus IgM Capture DxSelect2 and IgG DxSelect2; Focus Diagnostics, Cypress, CA, USA) were also positive (ratio 6.87 and 3.15, respectively; reference value ratio ,1). Because of worsened bicytopenia (WBC 1300/mm3, platelet count 39 000/mm3) and high ferritin level (8208 mg/l), bone marrow biopsy was examined on day 6. The hypercellular bone marrow showed features of marked hemophagocytosis (Fig. 1) and acute viral infection (presence of reactive plasmocytosis
Hemophagocytic lymphohistiocytosis and dengue infection
and reactive lymphocytes). Normal maturation of the erythropoietic, megakaryopoietic, and granulopoietic cell lines was seen. Anatomopathological investigation of bone marrow biopsy (trephine biopsy) also showed a cellularity of 60%, with presence of reactive lymphocytes and reactive plasmocytosis. The highest ferritin level observed was 13 700 mg/l (day 9). The creatine kinase analysis showed elevated levels on days 6–8 (Table 1), during which the patient experienced severe myalgia. She also developed a rash on her legs. CD4z/CD8z inversion was present on immunophenotypic examination (ratio 0.54; reference value 1–4). Diagnosis of dengue fever with infection-associated hemophagocytic syndrome was made according to the diagnostic criteria of the HLH-2004 protocol of the Histiocyte Society, which include clinical, laboratory, and histopathological features.4 Because the GP informed of a similar (undocumented) episode in the medical history of this patient, a genetic screening is ongoing to exclude a predisposing genetic mutation for HLH (primary HLH). She was given immunoglobulin-G therapy (PrivigenH, 1 g/kg body weight) for 2 days. The patient showed resolution of clinical and biochemical markers for hemophagocytosis indicating transient hemophagocytic activity phenomenon in dengue. The patient fully recovered with appropriate supportive care and was dismissed from our hospital on day 14.
Discussion Dengue is the most rapidly spreading mosquitoborne viral disease in the world. The WHO has estimated that 50 million cases of dengue fever occur each year. The epidemiology in different regions is distinct. Cambodia is considered as one of the four countries (Cambodia, Malaysia, Philippines, and Vietnam) in the Western Pacific Region with the highest numbers of cases and deaths.2 Dengue is endemic in Cambodia, a country with poor health and economic indicators and with a tropical climate.1 Dengue is not endemic in the WHO European
Table 1 Patient’s laboratory investigation results
WBC PLT AST ALT LDH CK CRP Ferritin
Day 2*
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 14
Reference values
4250 167 16 13 307 … 20.00 …
1800 … 30 16 402 61 53.44 …
1500 95 45 24 449 … 32.05 …
1100 83 168 106 709 … 15.23 …
1300 39 563 347 1107 486 7.42 8208
1800 32 724 447 1169 614 6.05 12 764
3500 28 574 392 … 320 5.55 11 917
4200 29 … … 1926 145 14.60 13 700
4600 52 390 285 2307 79 32.23 8626
3700 76 256 209 2193 … 20.16 7276
4500 174 85 107 1175 33 4,16 1976
4000–10 000 140–440 ,32 ,31 240–480 ,170 ,5 15–150
*Results from external laboratory, before hospitalization of the patient. Results exceeding the reference interval are marked in bold. WBC: total white blood cell count (/mm3); PLT: platelet count (6103/mm3); AST: aspartate aminotransferase (IU/l); ALT: alanine aminotransferase (IU/l); LDH: lactate dehydrogenase (IU/l); CK: creatine kinase (IU/l); CRP: C-reactive protein (mg/l); ferritin (mg/l). Proposal: Maybe add the following to the subscript? …: no result available.
Acta Clinica Belgica
2014
VOL .
69
NO .
3
211
De Koninck et al.
Hemophagocytic lymphohistiocytosis and dengue infection
Figure 1 Group of macrophages engulfing erythrocytes, normoblasts, thrombocytes, and leukocytes.
Region, whereby most cases in the region have been reported either as incidents in overseas territories or importation from endemic countries.2 Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. In the early febrile phase, dengue fever can easily be confused with non-dengue illnesses, particularly in non-epidemic situations. Depending on the geographical origin of the patient, other aetiologies should be ruled out. These include flu-like syndromes (influenza, measles, Chikungunyan, infectious mononucleosis, HIV), illnesses with a rash (rubella, measles, scarlet fever, meningococcal infection, Chikungunyan, drug reactions), diarrhoeal diseases (rotavirus, other enteric infections), and illnesses with neurological manifestations (meningoencephalitis, febrile seizures).2 HLH is an aggressive and potentially life-threatening syndrome of excessive immune activation.5,6 It is hypothesized that the disease is caused by impaired lymphocyte-mediated cytotoxicity and defective triggering of apoptosis, resulting in an uncontrolled immune response. In HLH, macrophages become activated and secrete large amounts of pro-inflammatory cytokines. The natural killer cells and/or cytotoxic lymphocytes fail to eliminate these activated macrophages through perforin-dependent cytotoxicity.5,6 This lack of normal feedback regulation
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results in a persistent activation of macrophages, natural killer cells and cytotoxic lymphocytes, leading to excessive cytokine production (cytokine storm) by all of these cells. The excess of pro-inflammatory cytokines causes tissue infiltration by lymphocytes and macrophages and a proliferation of macrophages in the bone marrow, spleen, liver, and lymph nodes, leading to hemophagocytosis.4,5 Clinically, the most typical findings are persistent fever, pancytopenia, and hepatosplenomegaly. Other common findings include liver dysfunction, coagulopathy with hypofibrinogenemia, elevated serum ferritin level, and (highly variable) neurological abnormalities. Other, less common, initial clinical findings include lymphadenopathy, skin rash, jaundice, and oedema.4 The manifestations may be acute or subacute, with the patient exhibiting severe malaise, weight loss, and rapidly developing pancytopenia.5 Marrow examination is often hyperplastic with increased numbers of hemophagocytic macrophages. Prompt initiation of treatment is essential for the survival of the affected patient. The treatment should be primarily aimed at suppressing the hyper-inflammatory response responsible for the life-threatening symptoms.5 The HLH can occur as a primary (genetic) and secondary (related to infections or malignancy)
De Koninck et al.
disorder. The two main subdivisions of the secondary HLH are infection-associated (IAHS) and malignant (MHS) hemophagocytic syndrome. Viral infections mostly implicated in association with IAHS are Epstein–Barr virus infection, cytomegalovirus infection, adenovirus infection, and viral hepatitis.5,6 A review of literature revealed only a handful of case reports that showed evidence of IAHS caused by dengue virus. Efficient and accurate diagnosis of dengue is of primary importance for clinical care (i.e. early detection of severe cases, case confirmation, and differential diagnosis with other infectious diseases).2 Furthermore, clinicians should consider the possibility that pancytopania secondary to hemophagocytosis could be a complication of dengue infection, which requires bone marrow examination and appropriate therapy. Often the great barrier to a successful outcome of IAHS is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.5
Hemophagocytic lymphohistiocytosis and dengue infection
Acknowledgements We would like to thank GP Dr A. Boer and Dr G. De Lombaerde for their support. We are grateful to the Institute of Tropical Medicine (Antwerp, Belgium) for kindly performing the dengue antigen, serology, and molecular tests.
References 1 World Health Organization. Health topics: dengue [document on the Internet]. Geneva: WHO; 2013 [cited 2013 Dec 1]. Available from: http://www.who.int/topics/dengue/en/ 2 World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control [document on the Internet]. New Edition 2009. Geneva: WHO; 2009 [cited 2013 Dec 1]. Available from: http://whqlibdoc.who.int/publications/2009/ 9789241547871_eng.pdf 3 Lai M, Stirnemann J, Bibi-Triki T, Gerin M, Brichler S, Prendki V, et al. Dengue associe´e a` un syndrome ne´phrotique et a` un syndrome d’activation macrophagique (Dengue fever complicated by a nephrotic syndrome and a hemophagocytic syndrome). Med Mal Infect. 2012;42:30–2. 4 Henter JI, Horne AC, Arico´ M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. 5 McClain K. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. Up To Date – Topic 87499 Version 1.0 (updated 2013 Aug 28; cited 2013 Nov). 6 Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46.
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