Case Discussion < Brief history >      A 51-year-old electrician was referred to our hospital on May 14, 2005 with a two-week history of intermittent high fever, rapidly progressive jaundice and acute hepatomegaly. He was a habitual drinker but was otherwise healthy. On April 28, 2005, he was exposed to dust from bird nests when he repaired electric equipments and circuitry at an abandoned factory. Three days later, high fever and tea-colored urine developed. He took some antipyretics but fever did not resolve. On May 11, he was admitted to an outside hospital where laboratory tests revealed a white cell count of 9.06 x 109/L, C-reactive protein 26.39 mg/dL, serum aspartate aminotransferase 264 IU/L, serum alanine aminotransferase 106 IU/L, total/direct bilirubin (T-bil/d-bil) 5.6/4.5 mg/dL, alkaline phosphatase 490 IU/L, and g -glutamyl-transferase 1054 IU/L. Physical examination revealed a non-tender liver descending 2 cm below the costal margin. The abdominal ultrasound showed hepatomegaly without an obvious focal lesion or biliary tract dilatation. Ceftriaxone (1 g every 12 hours) was given empirically, but spiking fever persisted. In the following days, the jaundice rapidly progressed (T-bil/d-bil = 9.4/9.3 mg/dL), and the liver further enlarged to 6 cm below the costal margin. The urinalysis, chest X-ray, and the blood culture were negative. Disseminated tuberculosis was suspected. However, antituberculous therapy was considered too risky in the presence of rapidly progressive hepatic failure. He was referred to our hospital.      At admission, initial temperature was 39°C, the pulse rate was 100 beats per minute and regular, and the respirations were 22 breaths per minute. The blood pressure was 114/70 mmHg. The oxygen saturation was 96 percent while he was breathing ambient air. His consciousness was clear. The conjunctiva was not pale but the sclera was markedly icteric. The pupils were isocoric and light reflex was prompt. No oral ulcer or thrush was found. The neck was supple without lymphadenopathy or jugular vein engorgement. Spider angioma and a tattoo were noted over the anterior chest wall. Breath sounds showed bilateral basal rales with decreased breath sounds. Heart rhythm was regular without audible murmurs. The abdomen was flat with engorged superficial veins. There was no abdominal tenderness or rebound tenderness. Shifting dullness was noted. The liver was markedly enlarged, which was about 6cm below the costal margin. There was mild pitting edema over legs without petechia. No focal neurological sign was noted. < Laboratory data >   CBC/DC Date RBC Hb Hct MCV  MCH MCHC PLT WBC   106/ul g/dl  % fL pg g/dl 103/ul /ul 940514 3.61 12.4 35.6 98.6   34.8 202 12430 940517 3.18 10.6 31.3 98.4   33.9 235 10160 940524 2.68 8.7 26.5 98.9     326 12030 940602 2.64 8.7 26.7 101.1   32.6 319 11460 940614 2.88 9.2 29.7 101.5   31 241 8670 Date Band Seg Eso Baso Mono Lymph 940514 0 73 0 0 3 24 940517 1.1 88.2 0 0 1.1 9.6 940524 0 74.8 1.0 0.7 4.9 18.6 940602 13.5 67.7 0 0 11.5 7.3 940614  0 59 1.8 0.7 5.2 33.3  Biochemistry & Electrolytes Date  Alb/Glo Bil(T/D)  BUN CRE GOT GPT ALKP GGT CRP   g/dl mg/dl mg/dl mg/dl U/L U/L U/L U/L Mg/dl 940514 2.53/- 9.4/9.38 10.7 0.8 88 53 958 762 17.28 940516   10.50/7.78 15 0.7 75 37 813 506 17 940520 2.9/- 10.04/7.38     84 32 934 492 11.36 940523   6.61/5.72 11.3 0.8 69 29 878   8.66 940602 3.04/4.1 3.24/2.23     71 32 379 430 2.54 940609   1.81/-  8.5 0.5 34 29 508 251 0.59 Date CK LDH Na K Cl Ca P Mg m/dl U/L mM mM mM mM mM mM 940514 39 911 132 4.5 109 1.81 1.04   940609     143 3.7          Urine analysis Date SG PH Protein Sugar Ketone Ob Bilirubin 940514 1.020 6.5 +/- - + - 3+   Date WBC RBC Epi Cast Crystal Bac Urobil 940514 0-1 0-1 0-1 - - - 1.0      Coagulation profile Date PT (sec) INR PTT (sec) 940514 16.1 1.3 43.5      Hepatitis profile IgM-anti-HAV: negative HBsAg (EIA): negative Anti-hepatitis C virus: positive HCV RNA: undetectable IgM-anti-hepatitis E virus: negative Immunological studies Anti-nuclear antibody: 1:40 RA factor (Nephelometry):<20 Serology test S.T.S (VDRL): negative, TPHA: positive Leptospirosis: negative Anti-HIV: positive; Western Blot: negative Proteus: OX19: 1:20 (negative) Proteus: OX2: 1:20 (negative) Proteus: OXK: 1:20 (negative) S. typhi: H: 1:20 (negative) S. typhi: O: 1:20 (negative) S. paratyphi A: 1:20 (negative) S. paratyphi B: 1:20 (negative) Q fever 檢驗項目 收件日期 發病日期 採檢日期 病日 檢體種類 IgG titer IgM titer 判定 phase I phase II phase I phase II Q fever 94/05/31 94/05/16 94/05/17  2 血清 2560 5120 160 >320 Q熱陽性 Q fever 94/06/01 94/05/16 94/05/31 16 血清 2560 >5120* 160 >320 Q熱陽性 Q fever 94/07/19 94/05/16 94/07/15 61 血清  2560 20480 640 1280 Q熱陽性 *備註：雖未做到 end-point，但若以相同之螢光強度之稀釋倍數來看，phsae II之 IgG titer 有4倍以上之上升 (約640=5120) Culture  Negative results of bacteria, mycobacterial, or fungal cultures of blood, pleural effusion, bone marrow, liver tissue and stool       < Image >          CXR (5/14): bilateral blunting CP angles; atelectasis of the right lower lung (Fig.1 ) Chest, abdomen CT (5/14): bilateral pleural effusions and atelectasis of bilateral lower lungs; hepatosplenomegaly; no biliary tract dilation or LAP     < Pathology >  Bone marrow (940516) (Fig.2 ) Diagnosis: hypocellular marrow MICROSCOPIC FINDING There is interstitial infiltration of plasma cells accounting for about 10 % of mononucler cells. Neither dysplasia, nor evidence of excess of blast or myelofibrosis is noted. No evidence of lymphoma/metastasis is noted. Serous degeneration is observed. Focal lipogranuloma is seen. No acid-fast bacillus or PAS (+) fungus is found. A reactive marrow is considered. Liver biopsy (940519) (Fig.3) (Fig. 4) Diagnosis: granulomatous inflammation Microscopically, it shows hepatic tissue with granulomatous inflammation mainly in portal areas and mild hepatocytic damage. No multinuclear giant cells, eosinophils, or doughnut granuloma is found. Focal macrovasicular steatosis and Mallory bodies are seen, which is compatible with an active drinker clinically. < Course and treatment >      After admission, cefotaxime (1 g every six hours) and doxycycline (100 mg twice daily) were given empirically. After coagulopathy (15.9 seconds, INR 1.32) was corrected by infusion of fresh frozen plasma, transjugular liver biopsy and bone marrow biopsy were performed. There were multiple small fibrinoid-ring granulomas in liver parenchyma and bone marrow. No acid-fast bacilli or periodic acid-Schiff-positive fungi were found. Whole body computed tomography demonstrated ascites and a significantly enlarged liver without evidence of tumor or lymphadenopathy. Multiple blood cultures revealed no growth. Anti-hepatitis C antibody was positive. However, the ribonucleic acid of hepatitis C virus was undetectable. Widal test, Weil-Felix test, anti-nuclear antibody, serological tests for hepatitis A, B, E virus, HIV, Leptospirosis, Cryptococcus, and toxoplasmosis were non-reactive. Doxycycline therapy was continued, and the jaundice and fever gradually improved over a two-week period.      Two weeks after admission, high levels of anti-Coxiella burnetii phase II IgM (>1:320) and phase II IgG (1: 5120) were reported, and a four-fold elevation of phase II IgG was noted in the paired serum collected two weeks later. Echocardiography did not show significant findings. The eventual diagnosis was acute Q fever with granulomatous hepatitis and bone marrow involvement. Doxycycline therapy was continued, and hydroxychloroquine (200 mg twice daily) was added to the regimen. After six weeks of treatment, total bilirubin level decreased to 1.56 mg/dL, and liver size decreased to 2 cm below the right costal margin. He received regular follow-up. Doxycycline and hydroxychloroquine were continued. There was no fever. Because of his frequent drinking, serum aspartate aminotransferase was around 50 IU/L, serum alanine aminotransferase was around 25 IU/L, alkaline phosphatase level was around 350 IU/L and g-glutamyl-transferase was around 800 IU/L. No hyperbilirubinemia was noted during follow up. 繼續教育考題 1. (B)  Q fever的病原菌為何？ A  Rickettsia tsutsugamushi B  Coxiella burnetti C  Rickettsia typhi D  Legionella pneumophila 2. (B)  Acute Q fever主要會表現何種antigen的antibody？ A  phase I B  phase II C  phase III D  phase IV 3. (C)  Q fever的granulomatous hepatitis典型會表現何種granuloma？ A  caseating granuloma B  gumma C  doughnut granuloma D  noncaseating granuloma 4. (A)  Acute Q fever的主要臨床表現不包括何者？ A  Skin rash B  fever C  pneumonia D  hepatitis 5. (D)  Chronic Q fever的主要臨床表現為何？ A  meningitis B  cellulitis C  pneumonia D  endocarditis 6. (A)  Q fever的藥物治療以何者為主？ A  Tetracyclines: doxycycline B  Macrolides: clarithromycin C  3rd generation cephalosporins: ceftriaxone D  Penicillin G