Chronic Brucellosis in Japan.

Human brucellosis, one of the most common zoonoses worldwide, rarely occurs in Japan, and only a few chronic cases have been reported. We herein report the case of a 39-year-old Japanese woman with chronic human brucellosis, considered a Brucella canis infection, that persisted for 19 years. Her medical history and fever pattern suggested chronic brucellosis, and the diagnosis was made based on the results of a serum tube agglutination test (SAT). After undergoing combination therapy with streptomycin and doxycycline, she achieved symptomatic relief and showed negative SAT results. Even in non-endemic areas, chronic brucellosis is an important differential diagnosis in patients with long-term persistent fatigue or a fever.

Introduction

Human brucellosis is one of the most common zoonoses worldwide and is considered a serious public health problem, particularly in low-income countries throughout Africa, South America, Asia, and parts of Europe (1). However, brucellosis is extremely rare in Japan, with only two to four cases reported each year (2). Symptoms of human brucellosis are various and nonspecific; thus, the diagnosis is challenging, especially in non-endemic areas, such as Japan. Patients with acute and chronic brucellosis may present with intermittent fever and, in chronic disease, with general malaise or psychoneurosis (3). We herein report a case of chronic brucellosis in Japan - presumed to be a Brucella canis infection - with a 19-year disease duration.

Case Report

In 2016, a 39-year-old Japanese woman was referred to our hospital with complaints of a persistent high fever for 1 week. Her medical history revealed a long medical narrative.

In 1996, at 18 years of age, she had attended an animal care school and assisted in delivering dogs. In 1998, at 20 years of age, she developed an intermittent nocturnal high fever persisting for 1 month and left arm paralysis and was admitted to our hospital. The paralysis was diagnosed as indeterminate radiculopathy. Her high fever and paralysis spontaneously resolved a few days after admission, so she was discharged on hospital day 10. However, the low-grade fever and slight malaise persisted, and she developed an intermittent night fever (>38℃) at irregular intervals, ranging from 2 weeks to 6 months. At the highest frequency, her fever without focal symptoms occurred every other week for several months. She was usually diagnosed with common colds because her high fever usually resolved spontaneously within a few days and her malaise during the fever was mild. However, upper respiratory symptoms were only rarely observed in any of these febrile episodes.

In May 2014, at 37 years of age, she visited another hospital due to complaints of a high fever for 1 week. Blood cultures were negative; however, whole-body computed tomography (CT) revealed mediastinal and abdominal lymph node swelling (Fig. 1). Symptoms, physical examination results, and blood test results were all nonspecific. In addition, the results of the QuantiFERON TB-3GⓇ test were negative. She was prescribed oral garenoxacin (GRNX) tablets at 400 mg/day without a diagnosis. Her body temperature decreased a few days after taking GRNX. However, the high fever recurred after discontinuing the medication. She was repeatedly prescribed GRNX, and the fever abated each time she took the medication and recurred when she stopped. Finally, after receiving 1 g of oral azithromycin in addition to GRNX, the high fever subsided and did not recur after discontinuing the medication. She discontinued the follow-up visits. Ever after the high fever subsided, she still experienced a low-grade fever and slight malaise, and a high fever recurred at irregular intervals after several months.

Figure 1.

Whole-body computed tomography in 2014 showing mediastinal and abdominal lymph node swelling (arrows).

In August 2016, at 39 years of age, she developed a persistent high fever with general arthralgia, headache, nausea, and vomiting. Subsequently, she was referred and admitted to our hospital. She had a history of cough-variant asthma but was not taking any medications, illegal drugs, or herbal supplements. She had had one pregnancy and delivered the baby via normal birth. She had no history of abortion. She never smoked and only drank occasionally. She worked as a courier delivering bread and had not traveled overseas. She had owned a Pomeranian dog from 1999 to 2015 and another since July 2016. As previously mentioned, her first febrile illness occurred in 1998 while attending an animal care school.

Her vital signs upon admission were as follows: body temperature, 37.5℃; blood pressure, 116/80 mmHg; pulse rate, 109 bpm; respiratory rate, 12/min; and oxygen saturation, 98% (on room air). She was mildly weak but conscious; the results of physical examination were unremarkable. Laboratory tests showed the following results: white blood cell count, 8,120 /μL (77% neutrophils); hemoglobin level, 14.0 g/dL; and platelet count of 271,000 /μL. Her C-reactive protein level was elevated (13.66 mg/dL). HIV screening and T-Spot TBⓇ test results were negative (Table). Results of transthoracic echocardiography and head CT were normal. Results of whole-body CT were also normal; furthermore, the mediastinal and abdominal lymph node swelling noted in 2014 had decreased. Gallium-67 scintigraphy showed no focal uptake. Urinalysis and cerebrospinal fluid test results were normal, and blood culture results were negative.

Table.

Peripheral Blood Test on the Last Admission.

Hematology

Biochemistry

Serology

WBC

8,120

/μL

TP

7.8

g/dL

HBs antigen

Negative

Neutrophils

77.4

%

Alb

3.9

g/dL

HCV antibody

Negative

Lymphocytes

15.0

%

BUN

10

mg/dL

HIV screening test

Negative

Monocytes

6.7

%

Cr

0.70

mg/dL

RPR (Quantitative)

Negative

Eosinophils

0.7

%

UA

4.8

mg/dL

TPHA (Quantitative)

Negative

Basophils

0.2

%

Na

134

mEq/L

T-Spot TB®

Negative

Hb

14.0

g/dL

K

3.9

mEq/L

EBV-VCA IgG (EIA)

4.5

index

Plt

27.1×104

/μL

Ca

8.8

mg/dL

EBV-VCA IgM (EIA)

Negative

index

ESR

52

mm

AST

31

IU/L

EBV-EBNA IgG (EIA)

2.5

index

ALT

55

IU/L

EBV-EA IgG (EIA)

1.4

index

Immunology

LDH

267

IU/L

EBV-DNA

Negative

ANA

≤×20

ALP

135

IU/L

CMV IgG

Negative

RF

6

IU/mL

γ-GTP

31

IU/L

CMV IgM

Negative

CH50

46.3

U/mL

T-Bil

0.7

mg/dL

Toxoplasma IgG

Negative

PR3-ANCA

Negative

CK

50

IU/L

Toxoplasma IgM

Negative

MPO-ANCA

Negative

Glu

134

mg/dL

SAT for Brucella abortus

<1:40

IgG

1,505

mg/dL

HbA1c

6.0

%

SAT for Brucella canis

1:160

IgA

236

mg/dL

CRP

13.66

mg/dL

soluble IL-2 receptor

535

U/mL

IgM

101

mg/dL

Procalcitonin

0.18

ng/mL

IgE

862

IU/mL

Ferritin

211

μg/mL

ESR: erythrocyte sedimentation rate, ANA: antinuclear antibodies, RF: rheumatoid factor, CH50: 50% hemolytic complement activity, MPO: myeloperoxidase, PR3: proteinase-3, ANCA: antineutrophil cytoplasmic antibody, RPR: rapid plasma reagin, TPHA: Treponema pallidum hemagglutination test, EBV: Epstein-Barr virus, VCA: virus capsid antigen, EA: early antigen, CMV: cytomegalovirus, SAT: serum agglutinin test, IL-2: interleukin-2

She frequently experienced a nocturnal fever (Fig. 2). Several days after admission, her fever and other symptoms resolved spontaneously. Her history of close contact with dogs and fever pattern suggested brucellosis. We therefore performed the serum tube agglutination test (SAT) for Brucella. SAT results were positive for B. canis (1:160) and negative for B. abortus (<1:40) (Table). Therefore, a diagnosis of chronic brucellosis almost certainly caused by B. canis was made. However, she refused long-term antibiotic therapy, as she only had mild malaise. Subsequently, we observed her as an outpatient. In January 2017, the high fever recurred. Blood and bone marrow samples were collected, and streptomycin (SM) and doxycycline (DOXY) combination therapy was initiated. Results of culture test and polymerase chain reaction (PCR) for Brucella (target genes; bcsp31, omp2, and omp31) using both blood and bone marrow were negative, while SAT for B. canis remained positive (1:160). In addition, antibodies to Q fever were not detected.

Figure 2.

Fever pattern at the last admission showing an intermittent nocturnal fever. Only cooling treatment was provided. No antipyretic or antibiotics were administered.

After treatment with intramuscular injections of SM (1 g 1×/d; weeks 1-3) and oral DOXY (100 mg 2×/d; weeks 1-12), her symptoms subsided, and the SAT titer decreased to 1:20 (Fig. 3). Pelvic and spinal magnetic resonance imaging findings were normal. The final diagnosis was chronic brucellosis caused by B. canis infection without an obvious focus. Her malaise and fever resolved and had not recurred 18 months after treatment completion. Her Pomeranian dog tested negative for SAT. We concluded that the disease duration was at least two years since 2014. There was a possibility that her disease had been transmitted from the previous dog she had owned between 1999 and 2015. However, we presumed that she had been infected at school, giving a disease duration of 19 years (since 1998), because her medical history suggested completely typical chronic brucellosis.

Figure 3.

The clinical course and serum agglutination test (SAT) titers for Brucella canis after treatment initiation.

Discussion

We herein report a domestic case of chronic brucellosis presumed to be B. canis infection with a 19-year disease duration. Human brucellosis is most often caused by B. melitensis (major hosts: sheep and goats), B. abortus (cattle), B. suis (swine), and B. canis (dog). Most human cases worldwide are attributed to B. melitensis and B. abortus (1-3). In Japan, B. suis and B. abortus have already been eradicated, and infections caused by B. melitensis have never been observed in domestic animals. Therefore, in recent years, reported brucellosis patients infected with B. melitensis and B. abortus are imported cases from endemic countries.

Regarding B. canis infection, recent cases have been considered domestic (2), as the prevalence of B. canis in dogs in Japan is currently around 3% (4). B. canis is transmitted from dogs to humans mainly via inhalation of contaminated dust or aerosols during delivery or abortion (2,3). As mentioned above, we presumed that our patient had been infected at school. In a 2014 US report, 3.6% of asymptomatic adults with occupational exposure to dogs were seropositive (5). B. canis infection is usually mild or asymptomatic and does not commonly cause chronic disease (3,5). However, our case indicates that it can be persistently symptomatic for long years. Many human chronic cases with mild symptoms may be underdiagnosed.

At the first febrile episode, the patient presented with the left arm paralysis, and at the last, without obvious focus. Symptoms of brucellosis are nonspecific and various, and the severity ranges from asymptomatic to fatal disease. Acute brucellosis is marked by a fever, night sweats, arthralgia, myalgia, low-back pain, weight loss, malaise, headache, anorexia, and, occasionally, cough, chest pain, and abdominal pain. Chronic brucellosis may present without evidence of infection; the patient may only experience a low-grade fever, malaise, back pain, or psychiatric symptoms (2,3,6,7). Osteoarticular, gastrointestinal, genitourinary, hepatobiliary, pulmonary, neurological, cardiovascular, ocular, and dermatologic involvements are observed in brucellosis (2,3,8). In our case, the left arm paralysis that occurred in 1998 was probably a neurological manifestation. Her fever, persisting for years, was undulant, intermittent, and nocturnal. This fever pattern is typical for brucellosis (2,3), providing us with an important diagnostic clue.

The presumptive disease duration of our case was 19 years, which is relatively long, even in endemic countries. Chronic brucellosis is generally defined as clinical symptoms persisting for ≥12 months. The longest commonly reported disease duration is <5 years (9,10). However, one study reported a case with a 57-year duration (11). Brucella is thought to suppress immunity, autophagy, and apoptosis through various mechanisms and can survive long-term intracellularly (12). In Japan, only a few cases of chronic brucellosis have been reported, and none has been reported since 1954 (13-17). To our knowledge, the present case is the first chronic case in 60 years in Japan and the first one to persist for at least 2 years; in addition, it is also the first chronic case presumed to be due to B. canis infection.

Our patient tested negative for both culture and PCR using blood and bone marrow, so the diagnosis was based on the SAT. The diagnosis of brucellosis is established via culture, serology, or molecular testing. Cultures are often negative, especially in patients with chronic disease; the diagnosis is therefore made based on the symptoms and results of serological tests (2,3,8,18). While the SAT is the most useful serological tool, the results may be negative in those with chronic disease or an immunocompromised state (18,19). Molecular tests, such as PCR, are considered highly specific; however, their sensitivities reportedly vary (8,18). For instance, one study reported 100% sensitivity of PCR targeting bscp31, omp2, and bp26 for diagnosing acute disease (20), while another reported only 3% sensitivity of PCR targeting IS711 for diagnosing chronic or relapsed disease (21). Such discrepancies might be due to the use of different DNA detection methods and different types of specimens. In addition, many other factors, such as the disease definition, disease phase (acute, chronic, or relapsed), and history of antibiotic therapy, vary in these studies.

The first-line treatment regimen for uncomplicated brucellosis is DOXY plus SM or gentamycin. The minimum recommended treatment duration is six weeks (2,3). Combination therapy of DOXY, rifampicin, and ceftriaxone is recommended for neurobrucellosis (22). In our case, we chose DOXY plus SM because none of the findings in 2014-2017 suggested neurological involvement.

Conclusion

We encountered a case of presumptive B. canis symptomatic infection persisting for many years. Brucellosis should be suspected in cases of chronic fatigue or a fever, even in non-endemic areas. However, many cases remain underdiagnosed or neglected.

The authors state that they have no Conflict of Interest (COI).