Never say never

This narrative, clinical problem-solving exercise was developed collaboratively with an expert who was unaware of the diagnosis. A 41-year-old presented with recurrent night sweats, purpura, and malaise; his symptoms improved with antibiotics and prednisone, with repeated relapse when these agents were discontinued. Aliquot 1: A 41-year-old man with a history of nephrolithiasis, bicuspid aortic valve, and retroperitoneal lymphangiomatosis presented to his primary care physician with several weeks of purpuric lower extremity lesions, night sweats, and mild malaise. He worked as a welder, smoked cannabis intermittently, had stopped smoking cigarettes a year previously, and consumed minimal alcohol. He was treated with an unspecified antibiotic and a course of prednisone, with resolution of his symptoms. Seven months later, his night sweats and purpuric skin lesions returned. He was treated with an oral antibiotic and prednisone, with complete resolution of his symptoms. However, 3 months later, the lesions and night sweats recurred and progressed over the ensuing 2 months. Discussant: The most specific finding across all three presentations is purpura, which arises either from a bleeding diathesis or vessel injury. Examples of the former include thrombocytopenia or coagulation factor deficiencies. Examples of the latter include vasculitis, infections, scurvy, and amyloidosis. It is possible that the underlying condition resolved spontaneously twice, or that the antibiotic or prednisone was responsible for recovery. His relapsing vascular injury could be explained by intermittent bacteremia originating from his bicuspid aortic valve, with intermittent sterilization by antibiotics. He may have been intermittently exposed to a toxin as a welder, leading to hypersensitivity vasculitis, which regressed with prednisone, although the progressive night sweats suggest an underlying autoimmune, infectious, or malignant driver of vasculitis. Aliquot 2: He presented to a community hospital emergency department, where he was found to have bilateral lower extremity purpura and acute kidney injury (creatinine increase from 1.2 to 1.7 mg/dL). The white blood cell count was 4600/μL, hemoglobin was 10.3 g/dL (93 fL), and the platelet count was 75,000/mL. He was admitted to the hospital. A skin biopsy revealed leukocytoclastic vasculitis (LCV). Multiple sets of blood cultures were sterile. A transthoracic and a transesophageal echocardiogram demonstrated a bicuspid aortic valve with moderate aortic regurgitation and stenosis without valvular vegetations. Serum c-ANCA (antineutrophilic cytoplasmic antibody) titer was 156 U/mL (normal < 20), while p-ANCA, proteinase-3 antibody, and myeloperoxidase antibody testing were negative. The night sweats and rash improved with intravenous methylprednisolone therapy. The creatinine was 1.5 mg/dL. A provisional diagnosis of ANCA-associated vasculitis was made, and he was discharged on a tapering dose of prednisone. Discussant: The histologic finding of LCV confirms the bedside impression of cutaneous vasculitis. Normocytic anemia could arise from chronic inflammation, chronic kidney disease, bone marrow failure syndromes, or brisk blood loss (hemolysis or hemorrhage). Thrombocytopenia develops from decreased production in the marrow, increased consumption/destruction in the circulation, or sequestration in the spleen. Anemia and thrombocytopenia may arise simultaneously in the setting of hypoproliferation, microangiopathic hemolytic anemia, autoimmune cytopenias (Evans syndrome), or bleeding from severe thrombocytopenia. The combination of cutaneous and renal injury is seen in multiple vasculitis syndromes, including IgA vasculitis, polyarteritis nodosa, cryoglobulinemia, and ANCA-associated vasculitis. The latter is plausible given the c-ANCA results, although most such cases have detectable myeloperoxidase or proteinase 3 antibodies. The absence of antibodies against the more targeted antigens does not exclude ANCA-associated vasculitis (granulomatosis with polyangiitis [GPA], microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) but raises the possibility that the immune system has been activated by a different (non-ANCA) immune condition or an infection, cancer, drug, or toxin (e.g., levamisole). The absence of vegetations on a TEE and sterile blood cultures excludes endocarditis with reasonable certainty; if recurrent fever or embolic phenomena develop, however, this would need to be revisited. Aliquot 3: The lower extremity lesions recurred as his prednisone was tapered to less than 15 mg daily, and his malaise and night sweats became more pronounced. After 3 months, he was readmitted to the community hospital with worsening kidney injury (creatinine 2.6 mg/dL) and bicytopenia. The white blood cell count was 6800/μL, hemoglobin 9.3 g/dL (93 fL), and platelet count 99,000/mL. Proteinase-3 antibodies (antibody index 2.2, normal < 1.0) and c-ANCA were positive (no titer reported), while myeloperoxidase antibodies and p-ANCA were negative. A kidney biopsy was performed, though the specimen was very limited. No glomeruli were present for routine light microscopy or for immunofluorescence. Eight glomeruli were present for electron microscopy, which demonstrated mesangial hypercellularity and mesangial electron dense deposits. While crescents were not present in this limited biopsy, plasmapheresis was initiated in conjunction with high-dose methylprednisolone for suspected ANCA-associated vasculitis. The creatinine remained at 2.6 mg/dL. The platelet count increased to 84,000/mL. The patient was discharged on prednisone 40 mg daily. He was readmitted 2 weeks later, with a creatinine of 4.1 mg/dL, anasarca, and lower extremity skin lesions. The white blood cell count was 3500/µL, hemoglobin 9.9 gm/dL, and platelet count 39,000/mL. After one hemodialysis treatment, the patient was transferred to an academic medical center. Discussant: The temporary responsiveness to prednisone and plasma exchange, the absence of an infection after extended steroid exposure, the specific autoantigen, and progressive multisystem disease all favor an autoimmune condition. The proteinase-3 antibodies in conjunction with c-ANCA are characteristic of GPA. Conversely, he does not have any sinopulmonary symptoms that are characteristic of GPA. A peripheral blood smear, urine microscopy, head and chest computed tomography (CT), and antinuclear antigen antibodies would help confirm or reject GPA as the working diagnosis. Glomerular crescents result from glomerular basement membrane rupture by activated neutrophils, which causes cellular proliferation in Bowman′s space. Crescent formation is a catastrophic form of glomerular injury, and their absence implies some chance of renal recovery. The electron dense deposits suggest some degree of immune complex deposition in the glomeruli, but immunofluorescence studies would be needed to determine their composition. Aliquot 4: On arrival, he appeared comfortable. He was afebrile with a blood pressure of 131/63 mmHg, heart rate of 62 beats per minute, and a normal respiratory rate and oxygen saturation. He had no oral lesions. Systolic and diastolic murmurs were heard at the cardiac base. The lung, abdominal, and neurologic exams were normal. Multiple purpuric lesions, petechiae, and ulcerated lesions were present over both lower extremities. (Figure 1) Medications at the time of transfer included prednisone (60 mg daily), pantoprazole, and trimethoprim-sulfamethoxazole; the latter was prescribed for Pneumocystis jirovecii prophylaxis. The white blood cell count was 2800/µL with normal differential, hemoglobin 8.7 mg/dL, and platelet count 30,000/µL. Blood urea nitrogen was 106 mg/dL and creatinine 4.1 mg/dL. Repeat p-ANCA was positive (no titer), c-ANCA was negative, proteinase-3 antibody index was 1.2 (normal < 1.0), and myeloperoxidase antibodies were negative. Anti-nuclear antibody was 1:80, and anticardiolipin IgM was 23.2 antiphospholipid units (normal < 12.5). Anti-double stranded DNA (dsDNA), anti-Smith, and rheumatoid factor antibodies were negative. Complement levels were C3 59 mg/dL (normal > 86 mg/dL) and C4 14 mg/dL (normal > 13 mg/dL). Several sets of blood cultures were sterile. Urinalysis demonstrated 2+ protein, > 25 RBC/hpf (some of which were dysmorphic), and no casts. A peripheral blood smear showed normocytic anemia, leukopenia with absolute lymphopenia, and thrombocytopenia with normal cell morphologies. Discussant: The dysmorphic urinary red cells confirm glomerulonephritis and are compatible with the working diagnosis of GPA. So too are the positive ANCA results, although a switch from c-ANCA to p-ANCA positivity is unusual as is the pairing of the positive p-ANCA and proteinase-3 antibody results, as opposed to the more common association of p-ANCA and myeloperoxidase antibodies. The greatest discrepancy with GPA, however, is the marked pancytopenia. The blood smear does not provide morphological clues, and the low counts predate all the medicines he is now taking. After exclusion of metabolic causes of pancytopenia (e.g., B12, copper) and viral infections (e.g. human immunodeficiency virus [HIV], Epstein–Barr virus [EBV], and cytomegalovirus [CMV]), a bone marrow biopsy is necessary to exclude an aplastic or myelophthisic process. There are no signs of portal hypertension to suggest that hypersplenism is responsible for pancytopenia. There are several nonspecific lab results, including low-grade antinuclear antibody positivity, the positive anticardiolipin antibody, and hypocomplementemia. The latter is uncharacteristic of GPA, which is pauci-immune and, therefore, less likely to activate and consume complement. The aforementioned trio is compatible with systemic lupus erythematosus (SLE), as are glomerulonephritis and pancytopenia, but the absent anti-dsDNA and anti-Smith antibodies are not. Repeat examination of renal histopathology with a pathologist to see whether the findings are more suggestive of SLE or GPA could be helpful. The cardiac exam is consistent with the known aortic regurgitation and stenosis and is a reminder to be vigilant for the interval development of endocarditis. Aliquot 5: Rheumatology, nephrology, and hematology were consulted, and prednisone was continued at a dose of 60 mg daily. Intermittent hemodialysis was continued to manage hypervolemia that did not resolve with diuretics. A transthoracic echocardiogram demonstrated a normal ejection fraction, bicuspid aortic valve, and moderate aortic regurgitation and stenosis without vegetations. Bone marrow aspirate and biopsy showed a slightly hypocellular marrow with normal trilineage maturation. CT of the abdomen and pelvis showed retroperitoneal lymphangiomatosis and modest splenomegaly, both stable in comparison with imaging obtained 9 years earlier. A kidney biopsy was repeated after platelet and desmopressin infusions. Histopathology (Figures 2 and 3) revealed focal necrotizing and crescentic glomerulonephritis, mild tubular atrophy, and interstitial fibrosis. Immunofluorescence staining was positive for C3 (1–2+) and weakly positive for C1q and polyclonal IgM. Testing for culture-negative endocarditis was performed, including serology for Bartonella, Mycoplasma, Brucella, fungal pathogens, and Chlamydia, and polymerase chain reaction (PCR) testing for Tropheryma whipplei. Whole body fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT scanning had no significant areas of FDG avidity. Discussant: The renal biopsy is compatible with a rapidly progressive glomerulonephritis. The moderate C3 deposition and low serum C3 may reflect complement activation which could be seen with an infection, drug reaction, or autoimmune vasculitis. Immune complex deposition and hypocomplementemia is frequently seen in lupus nephritis and infection-related glomerulonephritis but not in ANCA associated vasculitis. Anti-GBM disease can be excluded based on the absence of its characteristic linear IgG deposition pattern. Additionally, anti-GBM disease does not cause skin lesions or hypocomplementemia. The negative PET/CT scan makes an occult cancer unlikely, but there are some tumors that may not be FDG avid, such as indolent lymphomas or lung adenocarcinoma. Elements of both ANCA-vasculitis and SLE persist in this case; these conditions rarely co-exist as an overlap syndrome. Infectious glomerulonephritis can cause immune complex deposition and hypocomplementemia. Culture negative endocarditis (CNE) is an important consideration in this case given the pre-existing valvulopathy. While the negative PET scan and echocardiograms make CNE less likely, false negative test results must be entertained. A thorough evaluation for culture negative infectious endocarditis has been sent. Legionella, Coxiella, and mycobacteria could also be queried. He does not have epidemiologic risk factors for most of the pathogens under consideration, although sometimes these become evident in retrospect, e.g., exposure to animals (Bartonella, Brucella, Coxiella, Chlamydia) or stagnant water (Legionella). Bartonella endocarditis can lead to variable immune-complex deposition, proliferative glomerulonephritis, and ANCA seropositivity. The most recent echo was a transthoracic study, which has limitations for detecting vegetations and should be followed by a transesophageal study when suspicion for endocarditis is moderate or high. Aliquot 6: Bartonella henselae IgG was positive at a titer of > 1:1024 (normal < 1:64), with IgM negative at < 1:16. Bartonella quintana IgG antibodies were elevated at 1:256 (normal < 1:64), with IgM negative at < 1:16. Chlamydia pneumoniae, psittaci, and trachomatis IgG antibodies were all weakly positive (1:128, 1:64, and 1:64, respectively, with normal < 1:64). Discussant: Based on the elevated Bartonella IgG titers, hypocomplementemic glomerulonephritis, cutaneous vasculitis, and predisposing valvular disease, the most likely diagnosis is Bartonella (B. henselae) endocarditis. Inquiry regarding cat exposure is warranted. The modest elevation of the B. quintana titer may reflect cross-reactivity with the B. henselae assay. It would be interesting to know if doxycycline or azithromycin were the antibiotics that were temporally associated with improvement early in the illness. Demonstration of a vegetation on transesophageal echocardiogram remains prudent and if detected, would guide medical or surgical planning. Aliquot 7: Bartonella henselae endocarditis was suspected. The patient subsequently reported having two healthy pet cats. Doxycycline, rifampin, and ceftriaxone were prescribed, and prednisone was tapered off. Transesophageal echocardiography demonstrated moderate aortic regurgitation and stenosis. A mobile 1.8 × 0.6 cm mass was seen on the aortic side of the right and left aortic valve leaflets. Bartonella serum PCR assay was positive. Kidney function improved with antibiotics, and he no longer needed hemodialysis. The patient underwent uneventful aortic valve replacement, with vegetations noted on right and left valve cusps associated with erosion and inflammatory changes of the aortic annulus. Pathologic examination of the valve demonstrated focal calcification of the vegetations, with Warthin-Starry staining suggesting microorganisms; universal PCR testing on the valve tissue was positive for Bartonella. He was discharged from the hospital 1 week after the surgery, with a serum creatinine of 1.6 mg/dL, hemoglobin 9.1 mg/dL, and platelet count 172,000/mL. His lower extremity purpura and ulcers had significantly improved. After 6 weeks of combined antibiotic therapy and an additional 6 weeks of doxycycline, he was doing well at his follow-up visit. Culture-negative endocarditis, endocarditis with no microbiologic etiology identified by usual blood culture techniques, remains a formidable challenge to diagnose. Expanded molecular and serologic diagnostic techniques have led to enhanced ability to identify the responsible microorganism in an increasing percentage of patients. A prospective study of 759 patients in France with CNE identified a pathogen in 476 (63%). Of these, Coxiella burnetii was responsible for 229 cases, while Bartonella species were identified in 86.1 More recent data suggest that Bartonella species are responsible for 20-30% of CNE.2 Bartonella (formerly Rochalimaea) quintana was first identified as a cause of infective endocarditis in 1993,3 and both B. quintana and B. henselae have since been increasingly recognized as agents of multiple disease processes, including bacillary angiomatosis, cat scratch disease, and endocarditis. B. quintana is associated with unhoused status, alcohol use disorder, and louse infestation, while B. henselae infection is strongly associated with cat exposure.4 Patients with Bartonella IE often experience delayed diagnosis; a study reviewing 16 years of data from the Mayo Clinic reported a mean of 24 weeks of symptoms before diagnosis.5 Bartonella IE has features common to all forms of endocarditis including fever (in 90%),6 malaise, weight loss, and anemia. A distinguishing feature of Bartonella IE is the prevalence of significant valvular destruction at the time of diagnosis, reflecting at least in part the long period of undetected disease, with 60% to 90% of patients requiring valvular surgery.2, 5, 6 Other features of Bartonella IE include cutaneous vasculitis and glomerulonephritis; Bartonella appears to have a stronger association with glomerulonephritis than other etiologies of IE.7 Multiple data points, including leukocytoclastic vasculitis, recurrent prednisone responsiveness, and no evidence of infection on blood cultures, echocardiograms, and PET scan, pointed to an autoimmune condition. The crescentic glomerulonephritis and ANCA seropositivity further supported that conclusion. The latter features, however, are also seen in Bartonella IE. Such patients manifesting acute or subacute kidney injury often demonstrate evidence of immunologic disease, including diffuse or, more often, focal crescentic glomerulonephritis. Pauci-immune glomerulonephritis has also been reported, although less frequently.8-10 Up to 60% of Bartonella IE patients are positive for anti-proteinase 3 (PR3) antibodies.11 A small case series of Bartonella IE patients presenting with necrotizing glomerulonephritis described findings on biopsy nearly identical to this patient, including diffuse or segmental necrotizing crescentic glomerulonephritis, and IgM/C3 positivity on immunofluorescent staining.12 Findings of cutaneous vasculitis have been less frequently observed, 13, 14 In a series of 24 patients with Bartonella infection, 83% of cases mimicked ANCA-associated vasculitis with PR3-ANCA positivity and kidney injury.8 Diagnosis of Bartonella IE is typically made by serology and is confirmed by polymerase chain reaction (PCR). Serology is usually positive, with IgG titer often >1:1024. IgM is often negative, and cross-reactivity with both Coxiella and Chlamydia species is well recognized. Blood and serum PCR results are variably positive, with heart valve PCR positive in 70%–90% of cases.2, 8 Blood cultures are rarely positive. Current evidence is insufficient to make definitive recommendations for the treatment of Bartonella IE, although observational evidence supports treating with the combination of doxycycline and rifampin; many patients will require valve replacement to achieve cure.15 At the highest-level abstraction, this patient had chronic and systemic inflammation manifesting as vascular injury in the skin and kidneys and the elaboration of autoantibodies. The latter are characteristic of autoimmune but not to and infections are all of the immune system in a that and recognized forms of The CNE for an extended period at least in part to multiple negative blood cultures, three negative echocardiograms, and a negative PET This case is a reminder to given the of endocarditis. Culture negative endocarditis should be in the setting of and inflammatory or embolic of evidence of vegetations on features of Bartonella endocarditis to other forms of infectious endocarditis are an increased prevalence of cutaneous vasculitis, glomerulonephritis, and autoimmune seropositivity and significant valvular destruction requiring valvular are of the immune system in that and recognized forms of vasculitis. The for his on the The no of