Case Report - Report Tuberculosis ... 7 onset and a progressively fatal course with fever,...

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Transcript of Case Report - Report Tuberculosis ... 7 onset and a progressively fatal course with fever,...

  • 1

    Title Page

    Case Report

    Tuberculosis-Associated Hemophagocytic lymphohistiocytosis in adolescent diagnosed

    by PCR

    Ju-Hee Seo, M.D.1, Jun Ah Lee, M.D.

    1, Dong Ho Kim, M.D.

    1, Joongbum Cho, M.D.

    2*, Jung

    Sub Lim, M.D.1

    Department of Pediatrics, Korea Cancer Center Hospital, Seoul1

    Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of


    Running title : Tuberculosis-associated hemophagocytic lymphohistiocytosis

    Correspondence to: Jung Sub Lim, M.D. Ph.D.

    Department of Pediatrics, Korea Cancer Center Hospital,

    Gongneung-dong 215, Nowon-gu, Seoul 139-706, Republic of Korea.

    Tel.: +82 2 970 1224; fax: +82 2 6008 5748; e-mail:

    *Joongbum Cho, M.D. took part in treatment of patient in Korea Cancer Center Hospital and

    moved work to Samsung Medical Center thereafter.

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    We present the case of a 14-year-old female patient diagnosed with tuberculosis-associated

    hemophagocytic lymphohistiocytosis. The patient presented with weight loss, malaise,

    fatigue, prolonged fever, generalized lymphadenopathy. Laboratory investigation revealed

    pancytopenia (white blood cells 2020 cells/L, hemoglobin 10.2 g/dL, platelets 52000

    cells/L), hypertriglyceridemia (229 mg/dL), and hyperferritinemia (1420 ng/mL). Bone

    marrow biopsy showed a hypocellular bone marrow with high numbers of histiocytes and

    marked hemophagocytosis, diagnosed with hemophagocytic lymphohistiocytosis. Polymerase

    chain reaction with both the bone marrow aspiration and sputum samples revealed the

    presence of Mycobacterium tuberculosis. Anti-tubercular therapy with immune modulation

    therapy including dexamethasone and intravenous immunoglobulin was initiated. The results

    of all laboratory tests including bone marrow biopsy and polymerase chain reaction with both

    the bone marrow aspiration and sputum samples were normalized after treatment. Early bone

    marrow biopsy and the use of techniques such as polymerase chain reaction can avoid delays

    in diagnosis and can improve the chance of survival among patients with tuberculosis-

    associated hemophagocytic lymphohistiocytosis.

    Key words: Hemophagocytic lymphohistiocytosis, Adolescent, Tuberculosis, Polymerase

    chain reaction

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    Introduction 1

    Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder characterized by a 2

    dysregulation of the activation and proliferation of macrophages, leading to uncontrolled 3

    phagocytosis of platelets, erythrocytes, lymphocytes, and their hematopoietic precursors 4

    throughout the reticuloendothelial system including in the bone marrow 1, 2)

    . 5

    HLH was first described by Scott and Robb-Smith in 1939. They characterized by an acute 6

    onset and a progressively fatal course with fever, hepatosplenomegaly, lymphadenopathy, 7

    pancytopenia, and widespread histiocytic infiltration. HLH was known to associate with 8

    various stimuli, such as infections, malignant neoplasms, and several other immune disorders. 9

    Of these, infection plays an important role in the etiology of the syndrome, and more than 10

    half of documented pediatric HLH cases occurred in countries in East Asia including Korea 1,


    3). 12

    Mycobacterium tuberculosis is an important pathogen in Asia where the prevalence of 13

    tuberculosis is still high4)

    , although Epstein-Barr virus (EBV) is known to be the most 14

    common cause of HLH among children. Over 50 cases of tuberculosis associated HLH have 15

    been published internationally 5-7)

    . Also several cases of tuberculosis associated HLH 16

    reported in adult, but not children in Korea 8)

    . The scarcity of reports on this condition may 17

    be due to the difficulties associated with diagnosing Mycobacterium tuberculosis in HLH 18

    patients, who exhibit a high mortality rate. Here, we report the successful treatment of a 19

    female adolescent patient with HLH caused by tuberculosis, which was diagnosed early using 20

    polymerase chain reaction (PCR). 21



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    Case report 24

    A 14-year-old girl was admitted to the hospital with fever, chills, malaise, fatigue, and a 25

    dull pain in the right subcostal area. She had lost 5kg in bodyweight in the preceding 3 26

    months. Ten days prior to presentation, she had complained of a remittent feve, with 27

    temperatures of up to 39.5C. Two days prior to presentation, a dry cough and epistaxis had 28

    developed. There was no known history of contact with tuberculosis patients. Physical 29

    examination revealed a temperature of 38.8C, cutaneous pallor, and mild tenderness on the 30

    right upper quadrant of the abdomen. Lymphadenopathy was detected on the both sides of the 31

    neck (a single matted lymph nodes in both side, more than 20 x 10 mm in the size that were 32

    firm with mild tenderness but not erytherma). There was no splenomegaly or hepatomegaly. 33

    Examination of the other systems revealed no abnormalities. 34

    Laboratory investigations undertaken at the initial assessment revealed microcytic 35

    hypochromic anemia (hemoglobin 10.2 g/dL), leukocytopenia (2020 cells/L), 36

    thrombocytopenia (52000 cells/L) with poikilocytosis and atypical lymphocytosis identified 37

    in the peripheral smears. The erythrocyte sedimentation rate was increased to 26 mm/h and 38

    the C-reactive protein level was slightly increased to 0.86 mg/L (normal range

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    evaluated the potential causes of the fever of unknown origin (FUO). We started treatment 48

    with cefepime for neutropenic fever on the second day. Further laboratory tests revealed 49

    elevated levels of lactate dehydrogenase (1690 IU/L), hypertriglyceridemia (229 mg/dL), and 50

    hyperferritinemia (1420 ng/mL). Multiple lymph node enlargements were detected on 51

    abdominal computed tomography (CT). We noted a hypocellular bone marrow with high 52

    numbers of histiocytes and marked hemophagocytosis on the bone marrow biopsy performed 53

    on day 7 after hospitalization (Fig. 1A, B). The ratio of CD3CD4/CD3CD8 was reduced to 54

    0.53 (normal range, 0.93.6) while CD16+CD56+ (NK cell activity) was within the normal 55

    range. However, caseous granuloma was not noted in the bone marrow specimen. The 56

    Mantoux test, acid-fast bacterium (AFB) stain and culture of sputum revealed negative at that 57

    time. Results of several virus tests, including hepatitis A virus(negative for IgM and IgG) , 58

    cytomegalovirus (negative for IgM, positive for IgG), EBV (negative for VCA IgM, EA IgM 59

    and IgG, positive for VCA IgG and EBNA IgG), and human immunodeficiency virus tests 60

    (negative for Anti-HIV), didnt suggest acute infection. Only the venereal disease research 61

    laboratory (VDRL) test result was positive. However, the Treponema pallidum 62

    Hemagglutination Assay (TPHA) and fluorescent treponemal antibody-absorption (FTA-ABS) 63

    test results were both negative. Results of fluorescent antinuclear antibody (FANA) test was 64

    positive (1:1280) but those of the rheumatoid arthritis factor test and anti-smith antibody 65

    assay were both negative. 66

    On the basis of these findings, a diagnosis of HLH was made and treatment with high-dose 67

    dexamethasone (0.3 mg/kg/day for 7 days and tapering thereafter) and intravenous 68

    immunoglobulin (0.5 g/kg/day for 2days) began on day 8 after hospitalization. At that time, 69

    the patients activated partial thromboplastin time began to prolong to 44.3 s (normal range, 70

    29.042.0 s) and fibrin degradation product was positive. After immune modulation, the fever 71

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    subsided on day 9 after hospitalization, pancytopenia improved and ferritin level decreased to 72

    within the normal range. The PCR tests (AdvanSure TM

    TB/NTM real-time PCR using 73

    Mycobacterium tuberculosis comlex specific IS6110 and ITS specific primer) with both the 74

    bone marrow aspiration and sputum samples were reported to be positive for tuberculosis on 75

    day 10 after hospitalization. An anti-tubercular therapy regimen including 4 drugsisoniazid 76

    300/day, rifampicin 450/day, ethambutol 500/day, and pyrazinamide 100/daywas 77

    immediately started. 78

    On day 17 after hospitalization, the results of all laboratory tests were normalized. After 3 79

    weeks of follow-up, cellularity was restored to normal level and no hemophagocytosis was 80

    observed at bone marrow biopsy (Fig.2). Results of PCR with both the bone marrow 81

    aspiration and sputum samples were also negative for tuberculosis. The previously detected 82

    multiple lymph node enlargements were decreased in size on the follow-up abdominal CT. 83

    After 6 months of anti-tubercular therapy, the patient was healthy with no signs of disease. 84



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    Discussion 87

    Here, we report a rare case of tuberculosis-associated HLH in a female adolescent diagnosed 88

    using PCR performed with both the bone marrow and sputum samples. The patient was 89

    successfully treated with immune modulation and anti-tubercular therapy. 90

    In this case, we suspected disseminated tuberculosis based on clinical findings. Tuberculosis 91

    is widespread in Asian countries, including Korea, and is one of the important causes of FUO 92

    4, 5, 9). The clinica