154

Chronic Melioidosis: A Report of the First Case in Japan

Michio ARAKAWA1), Teruo MITSUI2, Reiko MIKI3> and Eiko YABUUCHI4)*1)Second Department of Internal Medicine, and 4)Department of Microbiology, Gifu University School of Medicine,

Gifu 500,2)Department of Surgery and 3)Clinical Microbiology Laboratory,Yamanashi Chuo Hospital, Kofu 400

*Present address: Department of Bacteriology, Osaka City University Medical School(Received: October 19, 1992)

(Accepted: November 24, 1992)

Key words: human melioidosis in Japan, chronic form of melioidosis , Pseudo-monas pseudomallei, liver and splenic abscesses, parotid abscess,

prostatic abscess

Abstract

A 41-year-old Japanese male with uncontrolled diabetes mellitus and alcoholicliver dysfunctiondeveloped melioidosis after his business trip to Indonesia and Singapore in 1988 . His disease started withspiked fever on the following day after extraction of a tooth, and a liver abscess developed, followed by

abscesses in the spleen and in the subphrenic space. In spite of splenectomy and intensive antimicrobialtreatments for three months, he developed parotitis, prostatitis , and abscessof the right submandibulargland at 5 to 16-month interval. Pseudomonas pseudomallei was isolated from the blood and pus from eachabscess. The lung was not involved. At present, he has returned to work, withcontinued intravenous

instillation of imipenem/cilastatin.

Introduction

Whitmore and Krishnaswamil) first described the etiologic agent of a new glanders-like disease and

Whitmore2) named this causative organism Bacillus pseudomallei; later on , Stanton and Fletcher3) namedthe disease melioidosis. Since then melioidosis has been recognized as an endemic disease in the tropical

area, especially in Southeast Asia4). A number of patients were reported among the French troops in the

civil war in Indochina5) and among the U.S. troops in Vietnam War6,7). Sakihara8) reported the first

Japanese patient with melioidosis, in the Japanese Army Hospital in Penam Island, Malaya, during WorldWar II. After the end of World War II, however, no cases of melioidosis were reported in Japan , even when anumber of injured or diseased soldiers came home from the endemic areas . One possible explanation forthis fact might be a lack of knowledge of this disease among the medical personnel in Japan . Mitsui et al.reported for the first time a Japanese patient who developed melioidosis in Japan after a trip to Indonesia in

1988 (The 64th Annual Meeting of Japanese Association for Infectious Diseases , 1990). We would like tocall attention to this disease.

Case Report

A 41-year-old Japanese male, living in Kofu City, Yamanashi Prefecture (a central part of Japan) , usedto drink one and a half bottles of whisky and smoke 60 cigarettes every day . He was not aware that he haddiabetes mellitus and liver dysfunction. He traveled to Indonesia, Singapore ,and Batam Island on business

別刷請求先: (〒500) 岐阜市司町40

岐阜大学医学部第2内 科 荒川 迫生

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A Japanese patient with melioidosis in Japan 155

from July 3 to 12, 1988. He spent most of his time in the hotel during his stay in Indonesia and Singapore.

He did not experience any out-door injury during his trip in Batam Island, anundeveloped area. From the

beginning of August 1988, he became slightly febrile, and he noted a loss of appetite and a decrease in

alcoholic capacity, and he lost weight (5 kg). On September 3, a decayed tooth was extracted and he

developed a high fever the next day. On September 9, he visited a private clinic because of a spiked fever,

38-39•Ž. He received fosfomycin (FOM) 2 g, ciprofloxacin (CPFX) 200 mg and predonine 10 mg, but he

showed no improvement. He was admitted to the Yamanashi Chuo Hospital on September 10.

On admission, the white blood cell (WBC) count was 6600/mm3 with 14% band form and 81%

segmented form, 4% lymphocytes, and 1% monocytes. IgG was 2520 mg/dl, IgA 750mg/dl, and IgM 200

mg/dl. C-reactive protein (CRP) level was as high as 24.96 mg/dl, nitroblue tetrazolium (NBT) reduction

test was 2%, which was within normal range. Because of discrepancies in spiked fever, high level of CRP

titer, no leukocytosis, and normal range of NBT test, a viral infection was suspected. On September 15, the

abdominal echogram showed multiple low-density areas in the spleen. On September 16, about 2 ml of

bloody pus was obtained by direct puncture of the spleen under ultrasound guidance. Liver abscess was

suspected at S7 region of the liver as well as multiple splenic abscesses by abdominal echography and

computed tomography (CT) on September 19 (Fig. 1). CT showed a solitary low-density area in the liver and

multiple low-density areas in the spleen, which indicated abscesses. Yellowish white pus was obtained by

percutaneous transhepatic cholangiography drainage (PTCD) on September 20, which smelled differently

from pus due to Escherichia colt or Klebsiella pneumoniae. Pus culture yielded a Gram-negative non-

fermentative rod-shaped organism which was identified as a strain of Pseudomonas pseudomallei. Because

the liver abscess was considered to be discrete, drainage and washing were begun on September 21. The

abscess cavity disappeared on CT on September 30 and fever subsided. Blood sugar level was successfully

controlled and he was discharged on October 13, 35 days after admission.

On February 14, 1989, he again developed fever and a dull pain in the left upper abdomen; he was

readmitted 7 days later. Since CT showed splenic abscess, he was transferred to the surgery department.

High-grade fever declined after antibiotic treatment and drainage, but the outcome was not satisfactory.

Finally, he underwent splenectomy on March 10. In the peritoneal cavity, there was no ascites, the surface

of the liver was grossly smooth, and the pancreas appeared normal. Slight adhesion of the Omentum majus,

and subphrenic abscess were observed. The removed spleen was covered with pusand weighed 570 g after

the blood was drained. The cut surface showed disseminated microabscesses in the parenchymal tissue.

Pus culture yielded P. pseudomallei. After splenectomy, he became afebrile and recovered by March 15.

Soon after the removal of the drainage tube from the surgical wound on March 20, he was again febrile

Fig. 1 CT of the abdomen of the melioidosis

patient on September 19, 1988, showing enlargedliver and spleen. Low-density areas in the liver

and spleen indicate abscesses.

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156 Michio ARAKAWA et al.

and the WBC count remained as high as 14.6 X 103/mm3. Spiked fever, elevated WBC count and CRP titer

(20.12 mg/dl) continued. Ceftizoxime (CZX) and doxycycline (DOXY) were switched to imipenem (IPM) onMarch 27. On March 29, fluid was found in the subphrenic space by CT. Aspoxicillin (ASPC) was added onApril 1. On April 7, drainage tube was reinserted into the subphrenic space. The contrast medium instilledthrough the drainage tube reached the rectovesical pouch, indicating the abscess was not encapsulated.With the continued drainage and antimicrobial treatments, the abscess cavity became localized on April 13and CRP declined to 0.74 mg/dl. However, fever and leukocytosis continued andP. pseudomallei was stillisolated from the pus. Finally, after May 2, the pus culture became negative,the abscess cavity disappearedon CT, and CRP returned to normal. Drainage tube was removed and antimicrobial agents werediscontinued. He was discharged on May 19, 89 days after admission.

On December 14, 1989, he developed fever and pain when chewing in the left temporomandibular joint.He found a hard tumor, 3 cm in diameter, near the left auricle. He also complained of general fatigue andloss of appetite. High-grade fever continued and the WBC count was 16 X 103/mm3. P. pseudomallei wasdetected from the pus of left temporomandibular abscess on December 22 and sputum on December 28. Hewas admitted on December 27. Neither the liver abscess nor subphrenic abscesswas found, and ascites wasnot present on CT on January 5. Intravenous instillation of IPM and cefoperazone (CPZ) was effective, andhe became almost afebrile. However, he was febrile from January 17, 1990, andcomplained of right femoral

pain at urination. Between February 16-28, prostatic abscesses were found, and P. pseudomallei wasisolated from these abscesses. Minocycline (MINO) was used in combination with either one ofcefoperazone (CPZ), ceftazidime (CAZ), or piperacillin (PIPC). In addition tothe antimicrobial treatments,

puncture of abscess for elimination of pus was performed several times. He recovered and was dischargedon March 12.

On July 22, 1991, he was readmitted because of high fever. WBC count was 17.6X 103/mm3. Hard and

painful swelling of the right submandibular gland was noted. Another tumor inthe right preauricularregion appeared, for which parotitis was suspected. A small amount of pus wasobtained from these twolesions and both specimens were positive for P. pseudomallei by culture. The antimicrobial agent

cefotaxime (CTX) was not effective, but IPM was. He was discharged and returned to work on October 7,1991.

Results of hematological and serum biochemical tests are summarized (on the four admissions andtheir respective acute phase period and the period before discharge) in Tables 1 and 2, respectively. Onadmission and in the acute phase period, liver dysfunction was manifested. Contrary to this, hypoalbu-minemia and a high level of CRP continued throughout his four admissions. Respiratory, cardiovascular,and renal functions remained normal (data are not shown).

Histopathology

Macroscopically, yellowish nodules were scattered in the removed spleen. At the center of each nodule,a necrotic mass was found. These nodules histologically consisted of central caseous necrosis and weresurrounded with epitheloid cells. Furthermore, each nodule was surrounded with a hemorrhagic zone (Fig.2-a, b).

Bacteriology

Bacteriological culture records are listed in Table 3. Before the beginning of antibiotic treatment,

specimens for bacteriological examination were collected. However, pathologically significant isolate did

not grow on the cultures of throat swab and midstream urine. All the isolatesof Gram-negative rod-shaped

organism showed remarkable bipolar staining. They produced dried and wrinkledcolonies on blood agar

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A Japanese patient with melioidosis in Japan 157

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A Japanese patient with melioidosis in Japan 159

Table 3 Bacteriological culture record with special reference to Pseudomonas pseudomallei

*Pus from the inside of splenic capsule (at splenectomy)

**Left temporomandibular abscess

***Abscess at right submandibular gland

plates and smelled of putrid wood. Colonies on MacConkey agar plate were pink or red, though the mediumcolor remained unchanged. They were motile with polar tuft of flagella, and they oxidized glucose, maltose,inositol, and other 20 carbohydrates. They were able to grow at 41C, reduced nitrate to nitrogen gas,dihydrolyzed L-arginine in Bacto-decarboxylase base Moeller. Based on these results compared with thoseof the type strain of Pseudomonas pseudomallei EY (Eiko Yabuuchi) 2004, the isolates were identified asstrains of P. pseudomallei. The identifications by API 20NE gave the same results. The minimuminhibitory concentrations (MICs) of 30 antimicrobial drugs are listed in Table 4.

Discussion

Strains of P. pseudomallei are more virulent to mammals than P. aeruginosa and other Pseudomonasspecies. It has been known that P. pseudomallei causes characteristic pathological changes in variousorgans. The histopathological findings of the removed spleen were sufficiently consistent with thosedescribed by Whitmore and Krishnaswamil). In Southeast Asia, the fulminant septicemic form and lung

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160 Michio ARAKAWA et al.

Table 4 Minimum inhibitory concentration (MIC) of 30 antimicrobials

against two isolates in comparison with those of Escherichia coli

*Determined by agar dilution method according to Japanese Association of Chemo-

therapy, EY: Eiko Yabuuchi, Department of Bacteriology, Osaka City University

Medical School, NIHJ : National Institute of Health, Japan

lesions in chronic form are of special importance91. Although an apparent portal of entry of the organism in

our patient is not known, the onset of disease might be associated with tooth caries. Despite the affinity of

P. pseudomallei to the lungs, his lungs appeared to be free of involvement. The patient has been working

since his last discharge on October 7, 1991. However, complete elimination of P. pseudomallei from his

organs or tissues cannot be confirmed. Furthermore, localization of the organism during the interrelapsing

period is not known. Accordingly, unless his underlying diseases such as diabetes mellitus, liverdysfunction, alcoholism, and physical conditions in general are sufficiently controlled, he will suffer from

relapses after short or long latent periods. The activation of melioidosis long after exposure in a known

endemic area has been reported in the literaturel,11).

Although human-to-human transmission of melioidosis has not been known, there is a report in which

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A Japanese patient with melioidosis in Japan 161

a housewife, whose husband had prostatitis due to P. pseudomallei12), develope elevated serum antibodytiter against P. pseudomallei. However, environmental contamination with P. pseudomallei could occur by

pus or other excretions, as reported by a French investigator13). Unfortunately our knowledge of melioidosisis scant14). Recently, many Japanese are in Southeast Asia on bussiness or in the operation of the Peace

Keeping Organization and thus they might be exposed to it. Therefore, we wish to alert doctors, nurses,

and clinical bacteriologists to melioidosis.

Acknowledgment

We are grateful to all doctors who took care of the patient and allowed us to makethis publication.Thanks are also extended to Dr. T. Mochizuki for his histopathological help.

References

1) Whitmore, A. & Krishnaswami, C.S.: An account of the discovery of a hithert undescribed infective diseaseoccurring among the population of Rangoon. Indian Med. Gaz. 47: 262-267, 1912.

2) Whitmore, A.: An account of a glanders-like disease occurring in Rangoon. J. Hyg. 13: 1-34, 1913.3) Stanton, A.T. & Fletcher, W.: Melioidosis, a new disease of the tropics. Trans. 4th Congress Far East Assoc. Trop.

Med. 2: 196-198, 1921.4) Redfearn, M.S., Palleroni, N.J. & Stanier, R.Y.: A comparative study of Pseudomonas pseudomallei and Bacillus

mallei. J. gen. Microbiol. 43: 293-313, 1966.5) Rubin, H.L.K., Alexander, A.D. & Yager, R.H.: Melioidosis—A military medical problem? Milit. Med. 128: 538-542,

1963.6) Brundage, W.G., Thuss, C.J. & Walden, D.C.: Four fatal cases of melioidosis in U.S. soldiers in Vietnam. Am. J.

Trop. Med. Hyg. 17: 183-191, 1968.7) Patterson, M.C., Darling, C.L. & Brumenthal, J.B.: Acute melioidosis in a soldier home from south Vietnam. JAMA

200: 447-451, 1967.8) Sakihara, H.: A case of melioidosis in a Japanese soldier in Malaya. Jap. J. Med. Sci. Biol. 5: 425-432, 1952.9) Watasnachai, S., Auratai, P., Somchao, T. & Yaowalak, E.-A.: Melioidosis: A retrospective analysis of 245 patients

admitted to Khon Kaen Hospital during 1982-1985. In Melioidosis (Sompone, P., Somak, L., Nalinee, A., Prasit, A.,Boonmee, S., Visith, .D and Prawat, N. ed.) p. 9-21. Bangkok Medical Publisher, Bangkok, 1986.

10) Mays, E.E. & Ricketts, E.A.: Melioidosis: Recrudescence associated with bronchogenic carcinoma twenty-six yearsfollowing initial geographic exposure. Chest 68: 261-263, 1975.

11) Mackowiak, P.A. & Smith, J.W.: Septicemic melioidosis. Occurrence following acute influenza A six years afterexposure in Vietnam. JAMA 240: 764-766, 1978.

12) McCormick, J.B., Sexton, D.J., McMurray, J.G., Carey, E., Hayes, P. & Feldman,R.A.: Human-to-humantransmission of Pseudomonas pseudomallei. Ann. Intern. Med. 83: 512-513, 1975.

13) Mollaret, H.H.: "L'affaire du Jardin des Plantes" ou comment la melioidose fit son apparition en France. Med. Mal.Inf. 18: 643-654, 1988.

14) Dance, D.A.B.: Melioidosis: the tip of the iceberg? Clin. Microbiol. Rev. 4: 52-60, 1991.

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162 Michio ARAKAWA et al.

本 邦 初 の 慢 性 メ リオ イ ドー シ ス 症 例 に つ い て

岐阜大学医学部第2内 科1),山 梨県立 中央病院外科2),同 微生物検査科3)

荒 川 迫 生1)三 井 照 夫2)三 木 礼 子3)

岐阜大学医学部微生物学講座4)

薮 内 英 子4)*

*現在の所属:大 阪市立大学医学部細菌学教室

(平成4年10月19日 受付)

(平成4年11月24日 受理)

要 旨

患者は41歳 の日本人男性で洋酒を多飲 し,糖 尿

病 と肝機能障害があったが自覚していなかった.

1988年7月 に商用でイン ドネシア,シ ソガポール

へ渡航 ・帰国した.8月 初旬から微熱などがあ り,

9月 始めに抜歯した翌 日から弛張熱が始まり,肝

膿瘍,脾 膿瘍,横 隔膜下膿瘍の存在が判明し,夫 々

の材料か らPmdomonas psmdomal観 が検 出さ

れた.脾 臓摘出 と化学療法により軽快 ・退院 した

が,そ の後約数箇月の間隔でPPsendomai観 に

よる耳下腺炎,前 立腺炎,顎 下腺炎を再発 し4回

入退院を繰 り返 した.現 在は化学療法を受けなが

ら社会復帰しているが,基 礎疾患の存在から長年

に亘る潜伏期の後の再発が憂慮 される.本 邦では

この疾患に対する医家の認識が低 いが,東 南アジ

アとの交流拡大,PKO活 動などに関連 して注意 と

関心を高める必要がある.

感染症学雑誌 第67巻 第2号