Brucellosis with p-ANCA- associated renal failure and leukocytoclastic vasculitis, endocarditis : a case report.

Brucellosis with p-ANCA- associated renal

failure and leukocytoclastic vasculitis,

endocarditis : a case report.

*, Orhan Küçükşahin*Ali Şahin*

* Ankara University Medical Faculty, Rheumatology Department

ABSTRACT: Brucellosis is a systemic infectious disease

caused by pathogens of the genus Brucella. We report a case of

brucellosis with perinuclear anti-neutrophil cytoplasmic

antibody (p-ANCA) associated renal failure, leukocytoclastic

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vasculitis, and endocarditis. No similar case has been

reported previously in regard to p-ANCA anti-lactoferrin

antibodies associated glomerulonephritis in brusellosis in the

literature.

Key words. Brucellosis, p-ANCA, glomerulonephritis,

leukocytoclastic vasculitis, endocarditis, anti-lactoferrin

antibodies

Orhan Küçükşahin

Ankara Universitesi Tıp Fakültesi,

İbni sina Hastanesi,

Romatoloji Bilim Dalı.

4.kat c-Blok . Sıhhıye 06140

ANKARA/TÜRKİYE

Tlf:+90-312-3103333 / 2658

Fax:+90-312-3097779

e-mail: [email protected]

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Brusellosis is a systemic infectious disease and still a

serious health problem in developing countries. The organism

enter the body by ingestion of contaminated milk products or by

direct contact. The disease can affect virtually any organ

(1). For this reason, Brucellosis shows variability in clinical

presentation.The disease can frequently affect the

musculoskeletal system. Cardiac involvement occurs in less

than 2% of the cases (2,3). Endocarditis is a severe and a

lethal complication and is more frequent in men. There is

usually involvement of the aortic valve (1,3-6,7). During the

course of Brusellosis, microorganism can be isolated from urine

(9), but serious renal involvement is uncommon (2,10,11). Skin

manifestations affect less than 5 % of the patients, and there

are no characteristic skin lesions in association with

brucellosis infection ( 2,12 ). Palpable purpura indicates the

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presence of leucocytoclastic vasculitis related with

accumulation of immune complexes.(14) In this case, a case

with brucellosis who was consulted to our outpatient clinics

for palpable purpura was presented ,endocarditis and ANCA-

related glomerulonephritis was detected. in clinical

evaluation

Case :

A 52 year old male was admitted to the Emergency Department

with a three months history of progressively worsening

fatigue, swelling of the legs, intermittent fever reaching

39°C, night sweating, diffuse arthralgia, myalgia, abdominal

pain, and purpuric rash on his legs. His blood pressure was

140/90 mmHg, body temperature was 38.4°C, pulse was regular,

110 beats /min. Physical examination revealed palpabl purpura

on legs and hips, systolic murmur in the area of the aortic

valve. He had lost 8 kg of weight in three months. He had no

known previous illness and no dyspnea and palpitations on

exertion. Laboratory examination revealed ESR:52 mm/hr,

CRP:20.0 mg/L (N:0-3mg/L), hemoglobine (Hb): 7.8g/dL, white

blood cell count (WBC): 7950 (72% neutrophile, 19% lymphocyte),

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microscopic hematuria and proteinuria (100mg/dl). Occult stool

blood was negative. Hemoptysis or melena was not detected.

After blood cultures were taken and skin biopsy was performed,

methylprednisolone 40mg/d (0.5mg/kg/d) was started.

A week later he was accepted to Rhematology Department

with the diagnosis of leukocytoclastic vasculitis. His physical

examination revealed fever: 37°C, pulse 108 beats /min, blood

pressure 150/100 mmHg, respiratory rate 18/min. An aortic

systolic murmur (grade II/VI), and mitral systolic murmur

( grade I/V ) were audible. Palpabl purpura was most

prominent on the legs and hips , less on the upper arms. His

neurological, respiratuar , gastrointestinal and

musculoskeletal examinations were normal. Laboratory

evaluation revealed: Hb:7.1g/dl, Htc: 22 %, WBC: 5560/mm3

(granulocyte 81%, lymphocyte 12%), platelets 248.000/ mm3,

ESR:34 mm/hr, CRP:11.40mg/dl, blood urea nitrogen :10 mg/dl

(N:6-20 mg/dl), creatinine:1.1g/dL(N:0.7-1.1 mg/dl), total

protein:7.2 g/dL(N:6.6-8.3 g/dl), albumin:2.9g/dl (N:3.5-5.2).

Urine analysis revealed proteinuria (100mg/dL), and 20-25/hpf

erythrocytes. Twenty-four hour urinary protein excretion was

1800 milligram, the urine culture was negative. C3 complement

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(C3) was 0.764 g/L (N:0.9-2g/L)), There is no evidence of

monoclonal gammopathy in the protein and urine

immunoelectrophoresis. Rheumatoid factor, antinuclear antibody,

anti-dsDNA, and cryoglobulin were negative. p-ANCA was

positive, and ELISA revealed positive anti-lactoferrin

antibody (16,8 U/ml; N:0-15). Chest X-Ray, and renal

ultrasonography were normal. Electrocardiography revealed

sinusal tachycardia. Brucella serum agglutination test was

positive at a titer of 1/1280. Anti-Brusella lgG and lgM

antibodies by ELISA were positive. He was started rifampin

600mg/d and doxycycline 200mg/d for brucellosis. When we

questioned our patient about entrance of the infection we

noticed that he had intake of nonpasteurized dairy products.

Skin biopsy taken from purpuric lesions revealed

leukocytoclastic vasculitis with vascular deposition of IgM,

IgA and C3 (figure I). Blood cultures were positive for

brucella. After transthoracic and transesophageal

echocardiography revealed vegetation on the aortic valve and

second degree aortic regurgitation (figure II), his medical

therapy was rearranged as doxycycline (200mg/d), rifampin

(600mg/d) and ceftriaxone (2g/d).

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In the clinical follow-up his renal functions detoriated

day by day. He was consulted to the Department of Nephrology.

Renal biopsy was planned due to persistent proteinuria,

hematuria and rapidly detoriating renal functions, but he

refused renal biopsy. BUN and serum creatinine levels were

increased day by day reaching values of 98mg/dl and 4.5

mg/dl respectively. He was accepted as p-ANCA-associated

rapidly progressive glomerulonephritis (RPGN) and given 1gm/d

intravenous pulse methylprednisolone once and then 2mg/kg/d.

Renal function impairment could not be controlled under

medical therapy, so plasmapheresis was applied three times in

the consecutive days. Following plasmapheresis ,his renal

functions started to improve. Fifteen days after the begining

of brucellosis therapy thrombocytopenia (60.000 / mm3 ) was

detected. Brucella associated bone marrow involvement was

excluded by bone marrow biopsy . It was accepted as rifampin –

induced thrombocytopenia. The therapy was switched to

ciprofloxacin (1g/d). After medical therapy for six weeks,he

had aortic valve replacement with no complications , and was

discharged with doxycycline (200mg/d) and ciprofloxacin (1g/d)

therapy for 6 more months.

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Discussion:

Brucellosis is endemic in Türkiye. The incidence of

Brucella infection was 14/100,000 in our country (1). The most

common symptoms are fever, myalgia, arthralgia, low-back pain

and weight loss. Definitive diagnosis is based on recovery of

the organism from the blood, but it is hard to grow in

cultures, and in this case serologic tests are important

(5). The diagnosis mostly depends on the positive brucella

tube agglutination test when the titer is 1/160 or higher (4).

Our patient had fever, arthralgia, myalgia, fatigue,

weight loss, vasculitic purpuric lesions. Blood cultures, tube

agglutination and ELISA results revealed Brucella infection.

Cutaneous manifestations in brucellosis are rare

(2,12,14). Skin lesions were not characteristic. 7 % of these

lesions were extensive purpuric lesions, 11% were diffuse

maculopapular rash (2,9). There were reports of

leukocytoclastic vasculitis (2, 12,13,14). Cutaneous lesions

could be result of direct inoculation, hypersensitivity

phenomena, deposition of immune complexes or direct invasion

by the organism (2). Cryoglobulinemia has been described very

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rarely in brucellosis and may be the cause of cutaneous

vasculitis (13,14).

Our patient had palpabl purpura and skin biopsy revealed

leukocytoclastic vasculitis. He had no medication use before

the lesions developed, and no eosinophilia. Cryoglobulin was

negative in our case. Therefore it was accepted as the

cutaneous manifestation of brucellosis, and lesions were

healed under therapy. The presence of brucella endocarditis

make us think that the reason of leucocytoclastic vasculitis

might be related with immune complex accumulation.

Hematologic alterations are common in brucellosis, mostly

leukopenia, relative lymphocytosis, and thrombocytopenia.

Pancytopenia occurs in 5-20% (2,15). Our patient developed

thrombocytopenia after rifampin use and bone marrow

examination was normal. After ciprofloxacin was started

instead of rifampin , thrombocyte count was normalized.

Therefore thrombocytopenia was accepted as drug- related side

effect.

During the course of brucellosis mild proteinuria is

common, but biopsy-proven glomerulonephritis is very rare

(2,9,10,11). The mechanisms for renal involvement is multiple.

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Interstitial nephritis caused by directly invasion of bacteria

is most frequently. Therefore, glomerulonephritis due to

accumulation of circulating immune complexes may occur. In our

case, co-existance with endocarditis was present.

Rapidly progressive glomerülonefrit is a clinical syndrome

with an abrupt onset or an insidious onset of hematuria,

proteinuria, anemia, and rapidly progressing renal failure .

Yamagata et al. reported benficial effects of apheresis in

RPGN (11,16). Infections induce glomerulonephritis by

formation of immune complexes and their deposition in the

kidney (11,14,17). Our patient had microscopic hematuria,

proteinuria, p-ANCA positivity , decreased C3 level, and

rapidly detoriating renal functions, therefore RPGN was

diagnosed. Clinical improvement was not observed under

medical therapy, and plasmapheresis was applied. Renal

functions started to return to normal levels following

plasmapheresis. Serum C3 level returned to normal limits, and

proteinüria regressed to 600mg/d. The improvement in renal

functions , hypocomplementemia, and the decrease in the

level of proteinuria together with the resolution of

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clinical findings after therapy led us to believe that

Brucella infection was the cause of glomerulonephritis.

Lactoferrin is one of the targets for ANCA. Lactoferrin

exerts antimicrobial activity, immune-modulatory and anti-

inflamatory functions, and may contribute to neutrophil

activation by the organisms (18,19) .Anti-lactoferrin

antibodies may hamper these functions , leading to an

increased inflammatory condition. Anti-lactoferrin antibodies

may be detectable in patients with infections (18). Our

patient had p-ANCA , and anti-lactoferrin antibody positivity

with RPGN . After 6 week of therapy, ANCA was negative. This

was another indication for brucella infection as the cause

of RPGN.

Brusella endocarditis is an uncommon but a serious and

lethal complication (3,6,7). The aortic valve is the most

frequently affected cardiac valve (3,5,6,7). In Türkiye, the

rate of endocarditis was 0.7% (1). Blood cultures are usually

negative in uncomplicated chronic brucellosis and positive

blood cultures indicate probability of endocarditis (6). Cure

of brucella endocarditis with medical treatment alone has

been reported occasionally (3,6,8). Antibiotic therapy

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followed by surgery seems to be the most effective treatment

(1,4,6,7). After six weeks of medical therapy , our patient

had aortic valve replacement .And he was discharged with

doxycycline (200mg/d) and ciprofloxacin (1g/d) therapy for 6

more months.

We present a patient with brucella and p-ANCA associted

renal failure, endocarditis, and leukocytoclastic

vasculitis . Clinical and laboratory evidence of vasculitis

and ANCA-associated renal failure disappeared after

corticosteroid and antibiotic treatment combined with

plasmapheresis. No similar case has been reported previously

in regard to brucellosis with p-ANCA associated

glomerulonephritis in the literature.

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Figure 2: Transthoracic echocardiography revealed second

degree aortic regurgitation and 1x0.8 cm mobile vegetation

over the aortic valve

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Figure 1: Skin biopsy revealed small dermal vessels with infiltration of polymorphonucleer leukocytes. The endothelial lining is reactive and the walls are thickened.There is scattered nuclear fragment in the vascular wall. H&Ex400

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Figure 1: Skin biopsy revealed small dermal vessels with infiltration of polymorphonucleer leukocytes. The endothelial lining is reactive and the walls are thickened.There is scattered nuclear fragment in the vascular wall. H&Ex400

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