Glomerulonephritis caused by Actinobacillus actinomycetemcomitans mimicking c-ANCA-positive vasculitis. Jean-François Viallard1, Stéphane Bonnet1, ...
Nephrol Dial Transplant (2002) 17: 663–665
Case Report
Glomerulonephritis caused by Actinobacillus actinomycetemcomitans mimicking c-ANCA-positive vasculitis Jean-Franc¸ois Viallard1, Ste´phane Bonnet1, Lionnel Couzi1, Colette Deminie`re2, Ve´ronique Miossec3, Patrick Mercie´1, Michel Aparicio4 and Jean-Luc Pellegrin1 1
Clinique de Me´decine Interne et Maladies Infectieuses, Hoˆpital Haut-Le´veˆque, avenue de Magellan, F-33604 Pessac Cedex, 2Laboratoire d’Anatomopathologie, 3Laboratoire d’Immunologie and 4 Service de Ne´phrologie, Hoˆpital Pellegrin, place Ame´lie Rabat-Le´on, F-33076 Bordeaux Cedex, France
Keywords: Actinobacillus actinomycetemcomitans; c-ANCA, endocarditis; glomerulonephritis
Introduction Actinobacillus actinomycetemcomitans (Aa) is a fastidious Gram-negative coccobacillus that belongs to the HACEK group w1x. It grows slowly and optimally at 378C as small colonies on blood or chocolate agar, and blood cultures need to be incubated in CO2 and maintained for 2–3 weeks. These characteristics of Aa may retard the diagnosis. Aa is well known as the causative agent of localized juvenile periodontal disease, but the most common severe infections caused by Aa are endocarditis and soft-tissue abscesses w1x. Less common are Aa brain abscesses, pneumonia, osteomyelitis and urinary tract infections. We describe a patient who developed Aa septicaemia mimicking c-ANCA (cytoplasm-labelling anti-neutrophil cytoplasm antibodies)-positive small-vessel vasculitis with kidney and nerve damage.
Case A 66-year-old man was hospitalized for fever (408C), anorexia and 12-kg weight loss over 3 months. His past medical history was remarkable only for bradycardiaparoxysmal atrial fibrillation syndrome requiring a pacemaker and cholecystectomy for biliary pancreatitis. Physical examination at admission detected isolated splenomegaly and no skin lesions. He complained
Correspondence and offprint requests to: Dr Jean-Franc¸ois Viallard, Clinique de Me´decine Interne et Maladies Infectieuses, Hoˆpital Haut-Le´veˆque, Centre Franc¸ois-Magendie, avenue de Magellan, F-33604 Pessac Cedex, France. Email: jean-francois.viallard@ chu-bordeaux.fr #
of right lower limb weakness and paresthesia. Results of laboratory analyses were: haemoglobin 10.7 gudl, white blood cell count 6.02 3 109ul with 4.71 3 109ul neutrophils, platelet count 189 3 109ul, erythrocyte sedimentation rate 73 mmu1st hour, C-reactive protein 68 mgul, respective serum urea and creatinine of 8.6 mmolul and 146 mmolul, and 24-h urinary protein excretion 3 g. Microscopic haematuria (5000 000 red cellsumin) and leukocyturia (175 000 leukocytesumin) were present. Three blood cultures were all negative for pathogens. Cryoglobulins and antinuclear and anti-DNA antibodies were not detected. c-ANCA were positive at 1u320 dilution (indirect immunofluorescence). ANCA subspecificities were then ascertained by enzyme-linked immunosorbent assay (ELISA). No anti-myeloperoxidase (MPO) or anti-proteinase 3 (PR3) activity was detected, but that against bactericidalupermeability-increasing protein (BPI) was positive. No hypocomplementaemia was found: C3 0.92 gul and C4 0.32 gul (respective normal values: 0.80–1.60 gul and 0.20–0.4 gul). Electromyography confirmed the clinical diagnosis of mononeuropathy multiplex with mixed sensorimotor neuropathy of the right superficial peroneal nerve and sensory neuropathy of the right saphenous nerve. Within 4 days he developed acute renal failure and serum creatinine rose to 410 mmolul. He was immediately transferred to the Nephrology Department, which refused a neuromuscular biopsy. A percutaneous renal biopsy was performed and by light microscopy, all seven glomeruli examined had an aspect of diffuse mesangial cell proliferation with endocapillary hypercellularity (Figure 1A); the capillary lumens were full of neutrophils. The glomerular capillary walls were finely stained with periodic acidSchiff (PAS). Mild fibrosis with focal inflammatory lesions and tubular atrophy were also seen (Figure 1B). Neither fibrinoid necrosis nor extracapillary proliferation was found. Interstitial vessels had no fibrinoid necrosis and were not surrounded by inflammatory cells. Immunofluorescence studies revealed parietal
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rapidly became afebrile and improved clinically. After 10 days, ceftriaxone was stopped and oral ofloxacin (400 mguday) and rifampicin (600 mg bid) were prescribed for 2.5 months. Symptoms disappeared completely. Cyclophosphamide was stopped after 7 months and prednisone had been tapered to 7.5 mguday. At the end of the immunosuppressive treatment, serum creatinine was 160 mmolul, blood urea nitrogen was 12.5 mmolul, c-ANCA and 24-h urinary protein excretion were negative. The patient had no recurrence 1 year after antibiotics were discontinued and he had gained 15 kg (weight of 76 kg). However, chronic renal failure persists with serum creatinine at 190 mmolul.
Discussion
Fig. 1. Renal biopsy showing (A) diffuse mesangial cell proliferation and neutrophils in the capillary lumen (Masson’s trichrome stain, 3 400) and (B) mild fibrosis with focal inflammatory lesions and tubular atrophy (Masson’s trichrome stain, 3 250).
granular deposits reacting with anti-C3 serum. A few IgM deposits were noted in the periphery of two sclerotic glomeruli. We advanced a diagnosis of small-vessel vasculitis because of multiorgan damage associated with the presence of c-ANCA. Intravenous (i.v.) prednisolone (1 g pulse for three consecutive days) and cyclophosphamide (1 g pulse on day 1) were administered followed by high-dose oral prednisone (60 mguday). Within 1 week, serum creatinine had returned to 150 mmolul, 24-h urinary protein excretion was -0.3 g, and the patient was no longer febrile but continued to lose weight. Immediately after the second cyclophosphamide pulse (day 15), his temperature rose to 398C but returned to normal within 2 days. Prednisone tapering was started. Blood cultures were established: standard, short-term were negative; those incubated for 2–3 weeks were positive for a Gram-negative bacillus identified as Aa. The third cyclophosphamide pulse was given on day 30 and, again, his temperature rose to 408C for 2 days and normalized thereafter. c-ANCA were again detected (titer of 1u250). No periodontal or sinus disease was found and two transesophageal echocardiographies were negative (neither vegetations nor abscesses were seen on valves or the pacemaker electrodes). Following the diagnosis of Aa septicaemia, the patient was given i.v. ceftriaxone (1 guday) and oral ofloxacin (400 mguday). Under treatment, he
This case report raises the question of whether the patient acquired the Aa infection during immunosuppressive therapy or had a subclinical infection that was responsible for his various symptoms. Initially, we thought the patient had c-ANCApositive small-vessel vasculitis because of the association of systemic lesions (glomerular pathology and peripheral neuropathy) and circulating c-ANCA at a high titer, thereby excluding false-positive interpretation of the results. Indeed, a pathogenic role has been suggested for this class of autoantibodies first found in different vasculitides w2x, such as Wegener’s granulomatosis (WG), microscopic polyangiitis and primary necrotizing glomerulonephritis (GN). Because c-ANCA with anti-PR3 activity in ELISA are highly suggestive of WG, these antibodies are useful for disease diagnosis and monitoring. In our patient, Aa septicaemia was thought to be a consequence of immunosuppressive therapy, as combining cytotoxic agents with corticosteroids is known to weaken host defenses w3x. However, in the light of several observations, we modified our analysis. First, the histological lesions seen in the kidney biopsy did not agree with the diagnosis of primary systemic vasculitis: no fibrinoid necrosis was seen but rather diffuse endocapillary hypercellularity with capillaries full of neutrophils as in infectious GN. Immunofluorescence studies showed a granular glomerular labeling pattern, indicative of immune-complex disease and excluding ‘pauci-immune’ GN. Moreover, Aa infection associated with immunosuppressive therapy has never been reported. Our patient’s fever appeared before renal function became impaired and also before the immunosuppressive therapy began. The fastidious nature and slow growth characteristics of Aa may delay the diagnosis of an infection since blood cultures need to be incubated for 2–3 weeks and they are generally considered to be negative when no growth is seen after 1 week. Finally, Aa endocarditis leading to small-vessel vasculitis involving skin and kidney has been reported w4x, and several cases of the association of endocarditis, vasculitis and GN with ANCA positivity have been published w5,6x.
Actinobacillus actinomycetemcomitans glomerulonephritis
Therefore, we think that our patient’s illness is more suggestive of infection-related GN. Although the Duke criteria for diagnosing infective endocarditis could not be applied to our patient, this diagnosis can be based on one major criterion (two separate blood cultures positive for Aa) and two minor criteria (fever P388C and GN) w7x. Moreover, this hypothesis could explain the splenomegaly. All previously reported cases of Aa-related GN occurred during the course of endocarditis w4,8,9x. We postulate that c-ANCA were generated secondarily to the subacute bacterial endocarditis, as was described by Steitz et al. w9x, but not found by Collazos et al. w4x. Indeed, several cases of GN occurring during infectious processes were associated with confusing elevated c-ANCA levels w5,6,10–13x. The kinetics of antibody titers clearly showed a close relationship between the infectious process and ANCA positivity, as previously reported for severe infections or subacute bacterial endocarditis w5,10x. In our patient, c-ANCA disappeared only after antibiotic treatment had begun. Clinicians should be alert to situations other than vasculitides in which ANCA titers may become positive. Elevated ANCA levels in patients without necrotizing vasculitis are most commonly associated with infection, especially human immunodeficiency virus, mycobacteria, severe pneumonia, bacterial endocarditis and cystic fibrosis with secondary sepsis w14x. In these infectious processes, c-ANCA or perinuclear(p)-labelling-ANCA have been detected but our observation supports the notion that, in others, such as subacute bacterial endocarditis, ANCA can be directed against antigens other than PR3 or MPO, e.g. BPI. BPI is a 55-kDa cationic protein involved in host defences against Gram-negative bacteria and endotoxin which acts intracellularly in polymorphonuclear leukocytes. Anti-BPI ANCA have been found in cystic fibrosis, inflammatory bowel disease, vasculitis or primary sclerosing cholangitis but also in patients with rheumatoid arthritis, systemic lupus erythematosus or mixed connective tissue disease w15x. Their presence is associated with higher inflammatory disease activity and more organ damage. Our findings raise the possibility that certain epitopes on Aa may trigger ANCA production by acting as a molecular mimic of BPI, as seen in some viral infections and helper T cells specific to Aa would then induce BPI-committed B cells to synthesize autoantibodies. Alternatively, infection may stimulate the release of BPI, which then serves as an antigen for autoantibody production. Anti-BPI ANCA may exacerbate inflammation non-specifically via extracellular and cell-associated immune complexes or by reducing the ability of BPI to promote clearance of Gram-negative bacteria and bacterial-associated endotoxin. When faced with ANCA positivity in a patient with symptoms evoking systemic vasculitis, physicians
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should take appropriate steps to rule out infectious diseases, like endocarditis, before initiating long-term immunosuppressive therapy, which could promote the infection and produce disastrous consequences. Then, rigorous ANCA testing combining indirect immunofluorescence tests for ANCA and antigen-specific ELISA, not only for antibodies to PR3 and MPO, but also to BPI, elastase or cathepsin G, could improve the specificity of ANCA testing as compared to either method alone. The discovery of ANCA directed against antigens other than MPO or PR3 should signal the need to search for infection as a possible confounding factor.
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