In this report we describe a rare presentation of cryoglobulinaemia, and renal impairment in a patient with Bartonella endocarditis.
Bartonella species are small Gram-negative bacilli. The first cases of Bartonella causing infective endocarditis were reported in two separate reports in 1993 [3, 4] and patients typically present similar to that of subacute bacterial endocarditis caused by other bacteria [5]. Bartonella is now considered one of the most common causes of culture-negative endocarditis and the number of cases reported in the literature have been increasing worldwide. The mortality rate in one retrospective study of 101 patients diagnosed with Bartonella endocarditis was found to be 12% [6] which may relate to the difficulty in diagnosis as the organism is difficult to isolate using standard microbiologic culture techniques [5].
Patients with infective endocarditis (IE) irrespective of cause can develop several forms of kidney disease: an infection-related immune complex-mediated glomerulonephritis (GN), renal infarction from septic emboli, a drug-induced acute interstitial nephritis or acute tubular necrosis. One study found that 45% of patients with Bartonella endocarditis have kidney failure [6, 7].
Endocarditis-associated glomerulonephritis can show significant variability in histopathologic appearance with both immune complex–mediated and pauci-immune glomerulonephritis described [6]. Our case is notable as suggests a potential immunological mechanism for the renal injury observed in Bartonella endocarditis via type 3 cryoglobulinaemia. We postulate that the chronic Bartonella infection resulted in polyclonal B cell activation resulting in hyper‐γ‐globulinemia. Whilst this response may be beneficial for early host defence by generating antibodies specific to Bartonella it may also have a deleterious longer-term effect during chronic infection by potentially augmenting anti‐self‐responses resulting in automimmunity and in our case cryoglobulin production. There has only been one other case report of Bartonella infective endocarditis complicated by cryoglobulinemia and renal failure reported in a middle-aged male. There were similarities between the two cases: the presence of a Type 3 mixed cryoglobulin associated with an acute kidney injury with haemoproteinuria in the setting of negative blood cultures [7], a background of cardiac surgery (bioprosthetic aortic valve replacement) and exposure to cats. However, the initial presentations of both cases were different; our patient presented insidiously over a year whereas in the case previously described the patient presented acutely. Moreover, the patient was ANCA negative in the previous case making our case unique.
There are case reports of bartonella infective endocarditis with ANCA and glomerulonephritis reported [8]. Unlike these and the case described above, which had bartonella IE and cryoglobulins, our case had both cryoglobulins and PR3 positivity.
One of the differentials in our patient was an ANCA associated vasculitis given her weakly positive PR3. Positive ANCA/PR3 testing has been reported in some cases of IE, which may lead to diagnostic confusion as in our case. Bartonella endocarditis appears to be associated with particularly high rates of ANCA/PR3 positivity. In a literature review of 54 cases of Bartonella IE-associated glomerulonephritis, 78 percent were ANCA positive by indirect immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA), and 67 percent were positive for proteinase 3 (PR3) [9]. ANCA associated vasculitides are rare, potentially life and organ threatening diseases in children and young people. However, the sensitivity and positive predictive value of a positive ANCA is poor, particularly in low titres, with a retrospective case series identifying that ANCA testing has a positive predictive value of 54% for diagnosis and concluded that a positive result is not a definitive diagnostic indicator of ANCA-associated vasculitis [10]. Expert correlation of the presence of ANCA antibodies with clinical features is needed to confirm a diagnosis of ANCA associated vasculitis.
In terms of the management, our patient and the case reported in the literature were initially treated with steroids and antibiotics empirically. In the previously reported case, the patient underwent additional plasmapheresis as well as required intermittent haemodialysis. Plasmapheresis was considered in our case but deferred as her renal function improved with the introduction of steroids and correct antimicrobial treatment once a unifying diagnosis was made. Rituximab was also considered but given the requirement for conduit revision surgery, held.
Our case describes the association between Bartonella infection and Type 3 cryoglobulinemia and highlights a potential important immune-mediated mechanism for renal injury in such cases. In patients with an unexplained cryoglobulinaemia assessment for Bartonella infection may reveal an under-recognised cause. As cryoglobulin related disease is relative rare in children and young people, patients presenting with Bartonella, and renal impairment would benefit from testing for cryoglobulins to allow early recognition and allow informed management decisions.
We acknowledge that infection in isolation can cause many of the features seen in this case but given the degree of immune activation seen with the low complement, positive RhF, and Type 3 cryoglobulinaemia we feel it is more likely that the infection triggered an aberrant immune response resulting in cryoglobulin production and thus initial immunosuppression and antibiotic/ fungal treatment were both indicated. Moreover, a Type 3 cryoglobulin can be part of an autoimmune process [11].
In summary, this is the first case of Bartonella endocarditis causing a secondary cryoglobulinemia and renal failure reported in the UK. There are a number of key learning points from this case which include that Bartonella endocarditis can present as a cryoglobulinaemic vasculitis and should be considered in any differential when the cause of cryoglobulinaemia is not clear, patients with intracardiac surgical repairs/tissue have high risk of IE therefore high index of suspicion is required in patients presenting with systemic symptoms/vasculitis, complex multi-modality cardiac imaging is helpful in evaluating congenital cardiac IE and the importance of enquiring about relevant exposure especially when culture-negative endocarditis is suspected.