- Email: [email protected]
Spontaneous Escherichia coli Meningitis Associated with Hemophagocytic Lymphohistiocytosis
CASE REPORT
Spontaneous Escherichia coli Meningitis Associated with Hemophagocytic Lymphohistiocytosis Kuo-Hsuan Chang, Lok-Ming Tang,1 Rong-Kuo Lyu* Spontaneous Escherichia coli meningitis has not been previously reported in association with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 72-year-old woman was admitted due to fever, nuchal rigidity, disturbed consciousness and splenomegaly. Anemia, thrombocytopenia and hyperferw ritinemia developed on the 8th day of hospitalization. Cultures of cerebrospinal fluid and blood grew E. coli. Abundant macrophages overwhelmed erythrocytes in the bone marrow aspirate, confirming the presence of hemophagocytosis. E. coli meningitis was managed with a 40-day course of antibiotic treatment. However, the severity of anemia and thrombocytopenia progressed despite intensive transfusion therapy. The patient died of HLH on the 60th day of hospitalization. [J Formos Med Assoc 2006;105(9):756–759] Key Words: Escherichia coli, hemophagocytosis, meningitis
Escherichia coli meningitis is rare in adults and generally occurs following head trauma or neurosurgical treatments.1 Spontaneous E. coli meningitis is extraordinarily rare. The complications of E. coli meningitis encompass septic shock, disseminated intravascular coagulopathy, stroke and hydrocephalus.2 Hemophagocytic lymphohistiocytosis (HLH) is known to be associated with several infectious diseases. We report a case of spontaneous E. coli meningitis concurrently complicated by HLH.
Case Report A previously healthy 72-year-old woman was hospitalized due to fever and disturbed consciousness for 1 day. She had no systemic diseases, such as
diabetes mellitus and autoimmune diseases, history of head trauma, alcoholism or major operation. On admission, the patient was drowsy with a body temperature of 39.6°C and a rigid neck. Physical examination showed a palpable spleen in the supine position. The liver was not enlarged. Cervical and inguinal lymph nodes were not palpable. Laboratory findings showed leukocytosis with white blood cell (WBC) count of 23.8 × 109/L (normal, 3.5–11 × 109/L) with 92.5% polymorphonuclear neutrophils. The hemoglobin (Hb) levels and blood platelet count were 92 g/L L 3 (normal, 120–160 g/L) and 163 × 10 /μL (normal, 150–400 × 109/L), respectively. The C-reactive protein level was 3606 mg/L (normal, < 5 mg/L), albumin level was 22 g/L (normal, 35–55 g/L) and alkaline phosphatase level was 120 U/L (normal, 28–94 U/L). The prothrombin time (PT) and
©2006 Elsevier & Formosan Medical Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Section of Neuromuscular Diseases, Department of Neurology, Chang Gung Memorial Hospital and University Medical College, Taipei, and 1Department of Neurology, Lo-Tung Pohai Hospital, Ilan, Taiwan. Received: July 19, 2005 Revised: August 30, 2005 Accepted: October 4, 2005
756
*Correspondence to: Dr Rong-Kuo Lyu, Section of Neuromuscular Diseases, Department of Neurology, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2006 • Vol 105 • No 9
E. coli meningitis associated with hemophagocytosis
partial thromboplastin time (PTT) were normal. The serum levels of electrolytes, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase and total bilirubin were within normal range. Cerebrospinal fluid (CSF) analysis showed a leukocyte count of 5.5 × 109/L (normal, < 5 × 103/L) with 96% neutrophils, raised protein concentration (1.05 g/L; normal, < 0.45 g/L) and diminished glucose (< 0.28 mmol/L; normal, 2.78–4.44 mmol/L). Both CSF and blood cultures grew E. coli. Intravenous penicillin-G, 24 million U, and ceftriaxone, 2 g/day, were administered. Eight days after admission, the Hb levels and platelet count decreased to 67 g/L and 76 × 109/L, respectively. Consequently, serial tests for anemia were arranged. Blood ferritin was elevated at 2917.28 pmol/L (normal, 22.47–653.88 pmol/L). Serum iron levels and total iron binding capacity were normal. Test for Bence–Jones protein in urine was negative. Whole body Tc99m methylene diphosphonate bone scan showed no malignancy. Bone marrow aspirate at 10 days after admission indicated hemophagocytosis (Figure). Six units of packed red blood cells (pRBC) were transfused between the 9th and 20th day of hospitalization. The Hb level returned to 76 g/L, and the platelet count decreased to 49 × 109/L. Four units of pRBC and 24 units of platelets were transfused again. The Hb level increased slightly
Figure. i Results l off b bone marrow biopsy b (hematoxylin (h l & eosin, 400×) show phagocytized mature erythrocytes displacing the nucleus to the edge of the macrophage (arrows). These changes suggest hemophagocytosis. J Formos Med Assoc | 2006 • Vol 105 • No 9
to 85 g/L following transfusion. However, the platelet count further reduced to 35 × 109/L. PT T and PTT remained normal. Shortness of breath and fever up to 39°C developed 30 days after admission. Chest roentgenography showed right lower lobe pneumonia. Sputum culture grew oxacillin-resistant Staphylococcus aureus. The WBC count was 9.1 × 109/L with 58% polymorphonuclear neutrophils and 6% bands. Penicillin-G was replaced with teicoplanin 400 mg/day. CSF analysis was normal att the end of 40 days of antibiotic treatment. Overr the next 20 days, Hb and platelet count decreased to 59 g/L and 10 × 109/L, respectively, despite continuous blood transfusion (40 units of pRBC and 240 units of platelets in total). The PT and PTT T levels remained normal. Massive bleeding of genitourinary, upper and lower gastrointestinal tractt developed 55 days after admission. The patientt died of severe hypovolemic shock on the 60th day of hospitalization.
Discussion E. coli meningitis is common in neonates. It affected less than 1.5% of cases of acute bacterial meningitis in adults.3 Clinical manifestations off meningitis, such as fever, nuchal rigidity and disturbed consciousness, are easily noticed in mostt patients with E. coli meningitis. This patient had acute onset of illness, which was characterized byy fever, nuchal rigidity and disturbed consciousness. CSF characteristics including decreased glucose level, elevated protein concentration and pleocytosis with predominant polymorphonuclear cells implied bacterial meningitis. The presence of E. coli in both CSF and blood cultures confirmed the diagnosis of E. coli meningitis. Up to 80% of E. coli meningitis arise following penetrating procedures or trauma of the skull or the spine.1 The other 20% of cases, known as spontaneous meningitis, are often communityacquired.1 Spontaneous E. coli meningitis has been reported in patients with chronic liver diseases, chronic alcohol abuse, diabetes mellitus, human 757
K.H. Chang, et al
immunodeficiency virus infection, spinal congenital malformation, malignant diseases, abortion, and urinary tract infection.4–6 Most instances of spontaneous E. coli meningitis, including the present case, were associated with bacteremia, indicating the hematogenous route of bacterial dispersal.2 The mortality rate of adult E. coli meningitis continues to be around 40% even in the era of a new generation of antibiotics.3 Unfavorable aspects of prognosis for E. coli meningitis include nosocomial acquisition, improper antibiotic treatment, presence of bacteremia and shock.2,5,7 Complications of E. coli meningitis have been reported in 55% of adult patients, comprising hydrocephalus, stroke, cerebral herniation, hearing impairment, septic shock and disseminated intravascular coagulopathy.3 In this patient, bacteremia was the sole factor linked with poor response. Nevertheless, HLH, an infrequent complication of bacterial meningitis, developed during the following illness. Clinical diagnosis of HLH should fulfill five out of the following eight criteria: fever, splenomegaly, cytopenias (affecting more than two of three lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen, or lymph nodes, ferritin > 500 ng/mL, low or absent NK-cell activity, soluble CD25 > 2400 U/mL.8 In this patient, hemophagocytosis in the bone marrow, fever, splenomegaly, anemia, thrombocytopenia and hyperferritinemia verified the diagnosis of HLH. Other causes of cytopenia, such as disseminated intravascular coagulopathy, autoimmune diseases and drugs (penicillin-G, ceftrixone), were considered unlikely because of normal PT and PTT, advanced age and continuous deterioration after drug withdrawal. HLH has been reported to be connected with infection, malignancy, autoimmune diseases and drugs.9 Infection-associated HLH is known to be caused by virus, whereas other pathogens, such as Mycobacteria tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Gram-negative bacteria, rickettsiae and fungi, have also been observed.10–12 The clinical features of HLH induced by viral infections and those 758
induced by bacterial infections are indiscriminate.4,11 In this case, the clinical characteristics of HLH were demonstrated in the early phase off E. coli meningitis. Staphylococcal pneumonia developed 20 days after the diagnosis of HLH. Hence, E. coli meningitis was considered the most likely possible infection provoking HLH. Only five cases of E. coli infection associated with HLH have been reported so far, and all five had either urosepsis or pneumonia.10,11,13 Meningitisassociated HLH has been rarely reported, and E. coli meningitis-associated hemophagocytic syndrome remains unreported. Pathologic features of HLH include proliferation of benign histiocytes with marked hemophagocytosis in the bone marrow, spleen or lymph nodes. The pathogenesis of infection-associated HLH remains unclear. Whether HLH associated with viral infection and bacterial infection shares similar pathogenesis also remains unclear.4,11 Augmented cytokines such as IFN-γ, TNF-α and IL-6 may exert a major influence on hemophagocytosis.14 Recently, some mutations associated with HLH were identified in genes involved in the granule exocytosis pathway (e.g. PRF1, UNC13D, RAB27A, SH2D1A, CHS1), which controls immune responses to infection.15–18 This patient may have been a carrier of such geneticc mutations, which can raise the susceptibility to HLH after infections. The only successful treatment of HLH is treating the underlying infection. Blood transfusion may be the most significant supportive therapyy during the acute illness.19 The effects of steroid, intravenous immunoglobulin, plasmapheresis and immunosuppressants remain controversial.20–22 Despite appropriate treatment, the mortality rate of HLH is as high as 38.5%.23 Negative prognostic factors include age > 30 years, worseningg anemia and thrombocytopenia, absence of lymphadenopathy, raised alkaline phosphatase and total bilirubin levels, presence of disseminated intravascular coagulopathy and hyperferritinemia.24 In this patient, aspects linked to a poorr outcome included old age, deteriorating anemia, thrombocytopenia and hyperferritinemia. J Formos Med Assoc | 2006 • Vol 105 • No 9
E. coli meningitis associated with hemophagocytosis
Subsequent development of nosocomial pneumonia might trigger hypercytokinemia and thereby aggravate hemophagocytosis. These clinical developments led to the poor outcome in this patient. In conclusion, our review of the literature found no previously reported cases of HLH associated with spontaneous E. coli meningitis. While bacterial meningitis was successfully treated by antibiotics, this patient died due to reactive hemophagocytosis. Invasion of the blood brain barrier by E. coli may have led to the spontaneous E. coli meningitis. Unidentified mutations related to the granule exocytosis pathway may have contributed to this case of infection-associated HLH.
References 1. Christopher GW. Escherichia coli bacteremia, meningitis, and hemochromatosis. Arch Intern Med 1985;145:1908. 2. Crane LR, Lerner AM. Non-traumatic Gram-negative bacillary meningitis in the Detroit Medical Center, 1964–1974. Medicine 1978;57:197–209. 3. Harder E, Moller K, Skinhoj P. Enterobacteriaceae meningitis in adults: a review of 20 consecutive cases 1977–97. Scand J Infect Dis 1999;31:287–91. 4. Risdall RJ, McKenna RW, Nesbit ME, et al. Virusassociated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. 5. Lu CH, Chang WN, Chuang YC, et al. The prognostic factors of adult Gram-negative bacillary meningitis. J Hosp Infect 1998;40:27–34. 6. Hsu GJ, Young TG, Chou JW, et al. Gram-negative bacillary meningitis in adults. J Formos Med Assoc 1993;92:317–23. 7. Jang TN, Wang FD, Wang LS, et al. Gram-negative bacillary meningitis in adults: a recent six-year experience. J Formos Med Assoc 1993;92:540–6. 8. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29–33. 9. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 1997;66:135–51. 10. Bruch LA, Jefferson RJ, Pike MG, et al. Mycoplasma pneumoniae infection, meningoencephalitis, and hemophagocytosis. Pediatr Neurol 2001;25:67–70.
J Formos Med Assoc | 2006 • Vol 105 • No 9
11. Risdall RJ, Brunning RD, Hernandez JI, et al. Bacteriaassociated hemophagocytic syndrome. Cancer 1984;54: 2968–72. 12. Wong KF, Chan JK. Reactive hemophagocytic syndrome–– a clinicopathologic study of 40 patients in an Oriental population. Am J Med 1992;93:177–80. 13. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine 1988;67:369–88. 14. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol 1993;15:92–8. 15. Allen M, De Fusco C, Legrand F, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica 2001;86:499–503. 16. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;115:461–73. 17. Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000;25: 173–76. 18. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957–9. 19. Gauvin F, Toledano B, Champagne J, et al. Reactive hemophagocytic syndrome presenting as a component of multiple organ dysfunction syndrome. Crit Care Med 2000; 28:3341–5. 20. Matsumoto Y, Naniwa D, Banno S, et al. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apherr 1998;2:300–4. 21. Imashuku S, Hibi S, Ohara T, et al. Effective control off Epstein–Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood 1999;93:1869–74. 22. Larroche C, Bruneel F, Andre MH, et al. Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP. Ann Med Interne 2000;151: 533–9. 23. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003;49: 633–9. 24. Kaito K, Kobayashi M, Katayama T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247–53.
759
Spontaneous Escherichia coli Meningitis Associated with Hemophagocytic Lymphohistiocytosis Kuo-Hsuan Chang, Lok-Ming Tang,1 Rong-Kuo Lyu* Spontaneous Escherichia coli meningitis has not been previously reported in association with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 72-year-old woman was admitted due to fever, nuchal rigidity, disturbed consciousness and splenomegaly. Anemia, thrombocytopenia and hyperferw ritinemia developed on the 8th day of hospitalization. Cultures of cerebrospinal fluid and blood grew E. coli. Abundant macrophages overwhelmed erythrocytes in the bone marrow aspirate, confirming the presence of hemophagocytosis. E. coli meningitis was managed with a 40-day course of antibiotic treatment. However, the severity of anemia and thrombocytopenia progressed despite intensive transfusion therapy. The patient died of HLH on the 60th day of hospitalization. [J Formos Med Assoc 2006;105(9):756–759] Key Words: Escherichia coli, hemophagocytosis, meningitis
Escherichia coli meningitis is rare in adults and generally occurs following head trauma or neurosurgical treatments.1 Spontaneous E. coli meningitis is extraordinarily rare. The complications of E. coli meningitis encompass septic shock, disseminated intravascular coagulopathy, stroke and hydrocephalus.2 Hemophagocytic lymphohistiocytosis (HLH) is known to be associated with several infectious diseases. We report a case of spontaneous E. coli meningitis concurrently complicated by HLH.
Case Report A previously healthy 72-year-old woman was hospitalized due to fever and disturbed consciousness for 1 day. She had no systemic diseases, such as
diabetes mellitus and autoimmune diseases, history of head trauma, alcoholism or major operation. On admission, the patient was drowsy with a body temperature of 39.6°C and a rigid neck. Physical examination showed a palpable spleen in the supine position. The liver was not enlarged. Cervical and inguinal lymph nodes were not palpable. Laboratory findings showed leukocytosis with white blood cell (WBC) count of 23.8 × 109/L (normal, 3.5–11 × 109/L) with 92.5% polymorphonuclear neutrophils. The hemoglobin (Hb) levels and blood platelet count were 92 g/L L 3 (normal, 120–160 g/L) and 163 × 10 /μL (normal, 150–400 × 109/L), respectively. The C-reactive protein level was 3606 mg/L (normal, < 5 mg/L), albumin level was 22 g/L (normal, 35–55 g/L) and alkaline phosphatase level was 120 U/L (normal, 28–94 U/L). The prothrombin time (PT) and
©2006 Elsevier & Formosan Medical Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Section of Neuromuscular Diseases, Department of Neurology, Chang Gung Memorial Hospital and University Medical College, Taipei, and 1Department of Neurology, Lo-Tung Pohai Hospital, Ilan, Taiwan. Received: July 19, 2005 Revised: August 30, 2005 Accepted: October 4, 2005
756
*Correspondence to: Dr Rong-Kuo Lyu, Section of Neuromuscular Diseases, Department of Neurology, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2006 • Vol 105 • No 9
E. coli meningitis associated with hemophagocytosis
partial thromboplastin time (PTT) were normal. The serum levels of electrolytes, glucose, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase and total bilirubin were within normal range. Cerebrospinal fluid (CSF) analysis showed a leukocyte count of 5.5 × 109/L (normal, < 5 × 103/L) with 96% neutrophils, raised protein concentration (1.05 g/L; normal, < 0.45 g/L) and diminished glucose (< 0.28 mmol/L; normal, 2.78–4.44 mmol/L). Both CSF and blood cultures grew E. coli. Intravenous penicillin-G, 24 million U, and ceftriaxone, 2 g/day, were administered. Eight days after admission, the Hb levels and platelet count decreased to 67 g/L and 76 × 109/L, respectively. Consequently, serial tests for anemia were arranged. Blood ferritin was elevated at 2917.28 pmol/L (normal, 22.47–653.88 pmol/L). Serum iron levels and total iron binding capacity were normal. Test for Bence–Jones protein in urine was negative. Whole body Tc99m methylene diphosphonate bone scan showed no malignancy. Bone marrow aspirate at 10 days after admission indicated hemophagocytosis (Figure). Six units of packed red blood cells (pRBC) were transfused between the 9th and 20th day of hospitalization. The Hb level returned to 76 g/L, and the platelet count decreased to 49 × 109/L. Four units of pRBC and 24 units of platelets were transfused again. The Hb level increased slightly
Figure. i Results l off b bone marrow biopsy b (hematoxylin (h l & eosin, 400×) show phagocytized mature erythrocytes displacing the nucleus to the edge of the macrophage (arrows). These changes suggest hemophagocytosis. J Formos Med Assoc | 2006 • Vol 105 • No 9
to 85 g/L following transfusion. However, the platelet count further reduced to 35 × 109/L. PT T and PTT remained normal. Shortness of breath and fever up to 39°C developed 30 days after admission. Chest roentgenography showed right lower lobe pneumonia. Sputum culture grew oxacillin-resistant Staphylococcus aureus. The WBC count was 9.1 × 109/L with 58% polymorphonuclear neutrophils and 6% bands. Penicillin-G was replaced with teicoplanin 400 mg/day. CSF analysis was normal att the end of 40 days of antibiotic treatment. Overr the next 20 days, Hb and platelet count decreased to 59 g/L and 10 × 109/L, respectively, despite continuous blood transfusion (40 units of pRBC and 240 units of platelets in total). The PT and PTT T levels remained normal. Massive bleeding of genitourinary, upper and lower gastrointestinal tractt developed 55 days after admission. The patientt died of severe hypovolemic shock on the 60th day of hospitalization.
Discussion E. coli meningitis is common in neonates. It affected less than 1.5% of cases of acute bacterial meningitis in adults.3 Clinical manifestations off meningitis, such as fever, nuchal rigidity and disturbed consciousness, are easily noticed in mostt patients with E. coli meningitis. This patient had acute onset of illness, which was characterized byy fever, nuchal rigidity and disturbed consciousness. CSF characteristics including decreased glucose level, elevated protein concentration and pleocytosis with predominant polymorphonuclear cells implied bacterial meningitis. The presence of E. coli in both CSF and blood cultures confirmed the diagnosis of E. coli meningitis. Up to 80% of E. coli meningitis arise following penetrating procedures or trauma of the skull or the spine.1 The other 20% of cases, known as spontaneous meningitis, are often communityacquired.1 Spontaneous E. coli meningitis has been reported in patients with chronic liver diseases, chronic alcohol abuse, diabetes mellitus, human 757
K.H. Chang, et al
immunodeficiency virus infection, spinal congenital malformation, malignant diseases, abortion, and urinary tract infection.4–6 Most instances of spontaneous E. coli meningitis, including the present case, were associated with bacteremia, indicating the hematogenous route of bacterial dispersal.2 The mortality rate of adult E. coli meningitis continues to be around 40% even in the era of a new generation of antibiotics.3 Unfavorable aspects of prognosis for E. coli meningitis include nosocomial acquisition, improper antibiotic treatment, presence of bacteremia and shock.2,5,7 Complications of E. coli meningitis have been reported in 55% of adult patients, comprising hydrocephalus, stroke, cerebral herniation, hearing impairment, septic shock and disseminated intravascular coagulopathy.3 In this patient, bacteremia was the sole factor linked with poor response. Nevertheless, HLH, an infrequent complication of bacterial meningitis, developed during the following illness. Clinical diagnosis of HLH should fulfill five out of the following eight criteria: fever, splenomegaly, cytopenias (affecting more than two of three lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen, or lymph nodes, ferritin > 500 ng/mL, low or absent NK-cell activity, soluble CD25 > 2400 U/mL.8 In this patient, hemophagocytosis in the bone marrow, fever, splenomegaly, anemia, thrombocytopenia and hyperferritinemia verified the diagnosis of HLH. Other causes of cytopenia, such as disseminated intravascular coagulopathy, autoimmune diseases and drugs (penicillin-G, ceftrixone), were considered unlikely because of normal PT and PTT, advanced age and continuous deterioration after drug withdrawal. HLH has been reported to be connected with infection, malignancy, autoimmune diseases and drugs.9 Infection-associated HLH is known to be caused by virus, whereas other pathogens, such as Mycobacteria tuberculosis, Streptococcus pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae, Gram-negative bacteria, rickettsiae and fungi, have also been observed.10–12 The clinical features of HLH induced by viral infections and those 758
induced by bacterial infections are indiscriminate.4,11 In this case, the clinical characteristics of HLH were demonstrated in the early phase off E. coli meningitis. Staphylococcal pneumonia developed 20 days after the diagnosis of HLH. Hence, E. coli meningitis was considered the most likely possible infection provoking HLH. Only five cases of E. coli infection associated with HLH have been reported so far, and all five had either urosepsis or pneumonia.10,11,13 Meningitisassociated HLH has been rarely reported, and E. coli meningitis-associated hemophagocytic syndrome remains unreported. Pathologic features of HLH include proliferation of benign histiocytes with marked hemophagocytosis in the bone marrow, spleen or lymph nodes. The pathogenesis of infection-associated HLH remains unclear. Whether HLH associated with viral infection and bacterial infection shares similar pathogenesis also remains unclear.4,11 Augmented cytokines such as IFN-γ, TNF-α and IL-6 may exert a major influence on hemophagocytosis.14 Recently, some mutations associated with HLH were identified in genes involved in the granule exocytosis pathway (e.g. PRF1, UNC13D, RAB27A, SH2D1A, CHS1), which controls immune responses to infection.15–18 This patient may have been a carrier of such geneticc mutations, which can raise the susceptibility to HLH after infections. The only successful treatment of HLH is treating the underlying infection. Blood transfusion may be the most significant supportive therapyy during the acute illness.19 The effects of steroid, intravenous immunoglobulin, plasmapheresis and immunosuppressants remain controversial.20–22 Despite appropriate treatment, the mortality rate of HLH is as high as 38.5%.23 Negative prognostic factors include age > 30 years, worseningg anemia and thrombocytopenia, absence of lymphadenopathy, raised alkaline phosphatase and total bilirubin levels, presence of disseminated intravascular coagulopathy and hyperferritinemia.24 In this patient, aspects linked to a poorr outcome included old age, deteriorating anemia, thrombocytopenia and hyperferritinemia. J Formos Med Assoc | 2006 • Vol 105 • No 9
E. coli meningitis associated with hemophagocytosis
Subsequent development of nosocomial pneumonia might trigger hypercytokinemia and thereby aggravate hemophagocytosis. These clinical developments led to the poor outcome in this patient. In conclusion, our review of the literature found no previously reported cases of HLH associated with spontaneous E. coli meningitis. While bacterial meningitis was successfully treated by antibiotics, this patient died due to reactive hemophagocytosis. Invasion of the blood brain barrier by E. coli may have led to the spontaneous E. coli meningitis. Unidentified mutations related to the granule exocytosis pathway may have contributed to this case of infection-associated HLH.
References 1. Christopher GW. Escherichia coli bacteremia, meningitis, and hemochromatosis. Arch Intern Med 1985;145:1908. 2. Crane LR, Lerner AM. Non-traumatic Gram-negative bacillary meningitis in the Detroit Medical Center, 1964–1974. Medicine 1978;57:197–209. 3. Harder E, Moller K, Skinhoj P. Enterobacteriaceae meningitis in adults: a review of 20 consecutive cases 1977–97. Scand J Infect Dis 1999;31:287–91. 4. Risdall RJ, McKenna RW, Nesbit ME, et al. Virusassociated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44:993–1002. 5. Lu CH, Chang WN, Chuang YC, et al. The prognostic factors of adult Gram-negative bacillary meningitis. J Hosp Infect 1998;40:27–34. 6. Hsu GJ, Young TG, Chou JW, et al. Gram-negative bacillary meningitis in adults. J Formos Med Assoc 1993;92:317–23. 7. Jang TN, Wang FD, Wang LS, et al. Gram-negative bacillary meningitis in adults: a recent six-year experience. J Formos Med Assoc 1993;92:540–6. 8. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29–33. 9. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 1997;66:135–51. 10. Bruch LA, Jefferson RJ, Pike MG, et al. Mycoplasma pneumoniae infection, meningoencephalitis, and hemophagocytosis. Pediatr Neurol 2001;25:67–70.
J Formos Med Assoc | 2006 • Vol 105 • No 9
11. Risdall RJ, Brunning RD, Hernandez JI, et al. Bacteriaassociated hemophagocytic syndrome. Cancer 1984;54: 2968–72. 12. Wong KF, Chan JK. Reactive hemophagocytic syndrome–– a clinicopathologic study of 40 patients in an Oriental population. Am J Med 1992;93:177–80. 13. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine 1988;67:369–88. 14. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hematol Oncol 1993;15:92–8. 15. Allen M, De Fusco C, Legrand F, et al. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? Haematologica 2001;86:499–503. 16. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 2003;115:461–73. 17. Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 2000;25: 173–76. 18. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999;286:1957–9. 19. Gauvin F, Toledano B, Champagne J, et al. Reactive hemophagocytic syndrome presenting as a component of multiple organ dysfunction syndrome. Crit Care Med 2000; 28:3341–5. 20. Matsumoto Y, Naniwa D, Banno S, et al. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apherr 1998;2:300–4. 21. Imashuku S, Hibi S, Ohara T, et al. Effective control off Epstein–Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Histiocyte Society. Blood 1999;93:1869–74. 22. Larroche C, Bruneel F, Andre MH, et al. Intravenously administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP. Ann Med Interne 2000;151: 533–9. 23. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003;49: 633–9. 24. Kaito K, Kobayashi M, Katayama T, et al. Prognostic factors of hemophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol 1997;59:247–53.
759