Salmonella Typhi Associated Hemophagocytic Lymphohistiocytosis in a Previously Healthy 23 Years Old Woman

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1 Article ID: WMC ISSN Salmonella Typhi Associated Hemophagocytic Lymphohistiocytosis in a Previously Healthy 23 Years Old Woman Author(s):Dr. Dina Khalaf, Dr. Bassem Toema, Dr. Shaker Al-sadadi, Dr. Fathi Al-jehani, Dr. Mohamed Sammak Corresponding Author: Dr. Dina Khalaf, MBChB, MSc, Department of Hematology and Oncology, Saad Specialist Hospital - Saudi Arabia Submitting Author: Dr. Bassem Toema, M.Sc., M.B.Ch.B, Department Of Clinical Pharmacology, University Of Oxford - United Kingdom Article ID: WMC Article Type: My opinion Submitted on:12-mar-2011, 06:22:03 AM GMT Article URL: Subject Categories:INFECTIOUS DISEASES Published on: 12-Mar-2011, 01:49:40 PM GMT Keywords:Salmonella Typhi, Hemophagocytic Lymphohistiocytosis, Pancyotpenia, Typhoid Fever, Sepsis, Bacterial Immunogenicity How to cite the article:khalaf D, Toema B, Al-sadadi S, Al-jehani F, Sammak M. Salmonella Typhi Associated Hemophagocytic Lymphohistiocytosis in a Previously Healthy 23 Years Old Woman. WebmedCentral INFECTIOUS DISEASES 2011;2(3):WMC Source(s) of Funding: On behalf of all the contributors, I declare that there is no support in financial or other manner. Competing Interests: On behalf of all the contributors, I declare that we have no conflict of interests?. Additional Files: References Cover letter WebmedCentral > My opinion Page 1 of 9

2 Salmonella Typhi Associated Hemophagocytic Lymphohistiocytosis in a Previously Healthy 23 Years Old Woman My opinion A previously healthy 23 years old female was admitted with fever. All the clinical and laboratory findings of the patient are summarized in Table 1. Blood culture revealed Salmonella typhi. Bone marrow aspirate showed hemophagocytosis (figures 1 and 2). The patient received fluoroquinolone, intravenous pentaglobulins for 4 days and intravenous dexamethasone for 8 days. There was marked clinical and biochemical improvement (graphs 1, 2 and 3). Suggestive evidence linking Hemophagocytic Lymphohistiocytosis (HLH) to Typhoid fever include: 1. Differentiating HLH from similar blood diseases According to the Histiocyte Society guidelines, five out of eight criteria should be fulfilled for establishing diagnosis of HLH. The history of persistent high grade fever, physical examination and CT scans that revealed hepatosplenomegaly, pancytopenia, associated transaminitis, hypofibrinogenemia and elevated Lactate dehydrogenase and ferritin levels supported the evidence for HLH besides the histopathological confirmation of hemophagocytosis by bone marrow examination. Peripheral smear didn t show fragmentation or schistocytes excluding thrombotic thrombocytopenic purpura. [1] 2. Exploring other possible causes of HLH Complete viral screen for Cytomegalovirus, Epstein Barr virus, Hepatitis B and C Viruses, and Human Immunodeficiency Viruses 1 and 2 was negative. Antinuclear antibody, Double stranded DNA antibody, Rheumatoid Factor and Anti Neutrophil Cytoplasmic Antibody were negative ruling out the macrophage activation syndrome. 3. Positive temporal relationship and biological plausibility Hemophagocytosis is non-specific frequent pathologic finding in the active proliferative stage of typhoid fever which coincides with the second week of infection. [2] 4. Recognized association with Gram negative aerobic bacilli Brucella is a genus of Gram negative, non motile, non spore-forming bacilli. In a pivotal case-control study, 16 patients (5.8%) out of 276 pediatric cases of brucellosis seen over a 7-year period were found to have pancytopenia. Fourteen out of these 16 patients (87.5%) had positive blood and / or bone marrow cultures for Brucella melitensis. Also hemophagocytosis was observed in 14 out of these 16 patients (87.5%). [3] Typhoid fever is rarely associated with HLH. In one study the bone marrow of four cases (out of fifteen cases of culture proven typhoid fever) was examined and showed infection associated Hemophagocytic syndrome. In another study, the bone marrow examinations of five patients with Typhoid fever associated with pancytopenia revealed histiocytic hyperplasia with marked phagocytosis of platelets, leukocytes and red blood cells in those affected individuals. [4][5] 5. Identification of Salmonella typhi with blood culture. In conclusion, in areas where typhoid fever prevalence is high, hemophagocytic findings should be considered Salmonella typhi associated HLH until proven otherwise. References 1.Janka Gritta. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166: B. Frisch, S.M. Lewis, R. Burkhardt, R. Barti. Biopsy Pathology of Bone and Bone Marrow - Biopsy Pathology Series Chapman and Hall Medical. 1985; Al-Eissa YA, Assuhaimi SA, Al-Fawaz IM, Higgy KE, Al-Nasser MN, Al-Mobaireek KF. Pancytopenia in children with brucellosis: clinical manifestations and bone marrow findings. Acta Haematol. 1993; 89: WebmedCentral > My opinion Page 2 of 9

3 4.Shin BM, Paik IK, Cho HI. Bone marrow pathology of culture proven typhoid fever. J Korean Med Sci. 1994; 9: Udden MM, Bañez E, Sears DA. Bone marrow histiocytic hyperplasia and hemophagocytosis with pancytopenia in typhoid fever. Am J Med Sci. 1986; 291: WebmedCentral > My opinion Page 3 of 9

4 Illustrations Illustration 1 Clinical / Laboratory Findings Table 1. Clinical and Laboratory manifestations High grade fever of one week duration associated Fever with chills, rigors, nausea, vomiting and asthenia Splenomegaly Hepatomegaly Computerized tomography (CT) scan of the abdomen Physical examination and CT scan of the abdomen Leucopenia Total white cell count 2170 / microliter (reference: ,000) Neutropenia Absolute neutrophilic count 1800 / microliter (reference: ) Anemia Hemoglobin level 8.7 gram / deciliter (reference: ) Thrombocytopenia Platelet count 44,000 / microliter (reference: 140, ,000) Prothrombin time 18.4 seconds (reference: ) Coagulopathy International Normalized Ratio 1.4 (reference: ) Partial thromboplastin time 46.2 seconds (reference: ) Hypofibrinogenemia Fibrinogen level 135 milligrams / liter (reference: ) Renal impairment Creatinine level 248 micromol / liter (reference: 53-97) Aspartate Transaminase level 170 International Unit / liter (reference: Transaminitis 14-36) Alanine Transaminase level 54 International Unit / liter (reference: 9-52) WebmedCentral > My opinion Page 4 of 9 Serum lactate dehydrogenase level 934 units / liter (reference: )

5 Illustration 2 Figure 1: Histopathological examination of bone marrow aspiration showing Macrophage engulfing blood cells Illustration 3 Figure 2: Histopathological examination of bone marrow aspiration showing Macrophage engulfing blood cells WebmedCentral > My opinion Page 5 of 9

6 Illustration 4 Graph 1: Line graph of total white cell count and absolute neutrophilic count versus time from day 1 intravenous immunoglobulins to day 8 intravenous immunoglobulins Illustration 5 Graph 2: Line graph of hemoglobin level versus time from day 1 intravenous immunoglobulins to day 8 intravenous immunoglobulins WebmedCentral > My opinion Page 6 of 9

7 Illustration 6 Graph 3: Line graph of platelet count versus time from day 1 intravenous immunoglobulins to day 8 intravenous immunoglobulins WebmedCentral > My opinion Page 7 of 9

8 Illustration 7 Table 1. Clinical and Laboratory manifestations Clinical / Laboratory Findings High grade fever of one week duration associated Fever with chills, rigors, nausea, vomiting and asthenia Splenomegaly Hepatomegaly Computerized tomography (CT) scan of the abdomen Physical examination and CT scan of the abdomen Leucopenia Total white cell count 2170 / microliter (reference: ,000) Neutropenia Absolute neutrophilic count 1800 / microliter (reference: ) Anemia Hemoglobin level 8.7 gram / deciliter (reference: ) Thrombocytopenia Platelet count 44,000 / microliter (reference: 140, ,000) Prothrombin time 18.4 seconds (reference: ) Coagulopathy International Normalized Ratio 1.4 (reference: ) Partial thromboplastin time 46.2 seconds (reference: ) Hypofibrinogenemia Fibrinogen level 135 milligrams / liter (reference: ) Renal impairment Creatinine level 248 micromol / liter (reference: 53-97) Aspartate Transaminase level 170 International Unit / liter (reference: 14-36) Transaminitis Alanine Transaminase level 54 International Unit / liter (reference: 9-52) Serum lactate dehydrogenase level 934 units / liter (reference: ) Haemolysis Haptoglobin level less than 0.28 gram / liter (reference: ) Hyperferritinemia Ferritin level 6485 nanograms / milliliter (reference: 7-83) WebmedCentral Acute Inflammatory > My opinion Page 8 of 9 C-reactive protein level 264 milligrams / liter (reference: ) response

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