Mimics of Vasculitis

Ernest Maningding; Tanaz A. Kermani

Disclosures

Rheumatology. 2021;60(1):34-47. 

In This Article

Infections

Chronic infections like HBV and HCV have been associated with vasculitis (secondary causes), while other infections can mimic features of vasculitis, leading to a misdiagnosis. Infection remains a problematic mimic of vasculitis since it can affect any vessel size. Infectious endocarditis (IE), like vasculitis, can present with constitutional symptoms, cause laboratory abnormalities including elevated ESR and CRP, cause hypocomplementemia and result in multi-organ damage (Figure 1). Other infections, like HIV and syphilis, can cause aortitis, mycotic aneurysms, vasculopathy and stroke.[6,7] Vasculopathies from the novel coronavirus disease 2019 (COVID-19) are also important to recognize during the current pandemic.[8–11] IE and other infections can also induce ANCAs, including MPO and PR3 antibodies (Table 2).[12–23]

Figure 1.

Bacterial endocarditis digital infarction (a) from an embolic phenomenon from infectious endocarditis of a bioprosthetic porcine aortic valve caused by vancomycin-resistant Enterococcus fecalis. The patient died from overwhelming sepsis. (b) At autopsy, numerous vegetations were noted on the porcine aortic valve.

Culture-negative Endocarditis With Bartonella

Bartonella species is an important cause of culture-negative IE. In a retrospective study of 47 patients with bacterial endocarditis, positive ANCA was noted in 43% (all cytoplasmic c pattern, i.e. c-ANCA) with positive PR3 in 23% and positive MPO in 2% (Table 2).[12] A higher proportion of patients with culture-negative IE from Bartonella had a positive c-ANCA (60% vs 23%) and PR3 positivity (40% vs 5%) compared with patients with IE from Gram-positive organisms (Table 2).[12]

There are also reports of glomerulonephritis, a feature of ANCA vasculitis, in association with IE with Bartonella.[24–28] In most cases, glomerulonephritis from Bartonella was in association with immune complex deposition, whereas renal involvement from ANCA vasculitis is pauci-immune, a potentially helpful distinguishing feature.[24–28] There are rare reports of pauci-immune crescentic glomerulonephritis (with positive c-ANCA and PR3) in Bartonella infection, making it indistinguishable from the primary form of ANCA vasculitis.[25,29,30] Other manifestations of IE from Bartonella that can mimic vasculitis include skin involvement with purpura and pulmonary manifestations.[24,29,31]

IE With Gram-positive Organisms

In a French study of 109 patients with IE from Staphylococcus aureus, Streptococcus viridans or Streptococcus bovis (60% of all cases of IE), 18% had a positive ANCA (70% c-ANCA), with MPO and PR3 specificity in 4% each[13] (Table 2). Furthermore, the pair of c-ANCA/PR3 or p-ANCA/MPO was present in 6%.[13] Other antibodies such as RF (35%), ANAs (16%) and aCL antibodies (23%) were also present.[13] Patients with IE and positive ANCA had more ischaemic lesions on cerebral MRI (78% compared with 53% who were ANCA negative, P = 0.05), but renal function was similar and there were no manifestations of ANCA vasculitis.[13]

Another study reported ANCA positivity in 24% of 50 patients with IE (Staphylococcus or Streptococcus in 68%), including positive c-ANCA in 50% and p-ANCA in 42% (Table 2).[14] Positive PR3 was present in 8%, positive MPO in 2% and dual MPO/PR3 positivity in 4%.[14] In this cohort, patients with IE and ANCA positivity had more renal impairment [odds ratio 3.9 (95% CIs 1.01, 15.2)], but there were no differences in cutaneous, musculoskeletal, pulmonary or neurologic manifestations.[14]

Other Infections That can Induce ANCA

Other infectious agents that can cause positive ANCA testing are summarized in Table 2. This includes Mycobacterium tuberculosis, with prevalence estimates of 0–44% depending on the geographic population studied.[15–21] A Turkish study comparing patients with chronic HBV infection to healthy controls found positive ANCA in 31% with infection and 26% in controls, but inclusion of 'borderline' results may have skewed the findings.[22] Parvovirus B19 infection has been associated with ANCA positivity in 3 of 50 patients (6%) with acute parvovirus (positive IgM antibodies), including PR3 positivity (1 case) and dual MPO/PR3 positivity (2 cases).[23] These patients presented with macular rash and inflammatory arthritis and, once clinical symptoms abated, ANCAs were no longer detectable.[23] In the same study, one of 51 patients with a positive IgM antibody for Epstein Barr virus had a positive p-ANCA.[23]

HIV

While there are reports of vasculitis in HIV, severe vasculopathy has been increasingly reported.[6,32–39] The exact mechanism remains unclear and may include HIV-mediated changes in the vascular endothelium and smooth muscles, accelerated atherosclerosis and vasculitis.[32,37] HIV vasculopathy primarily affects large and medium vessels and includes arterial aneurysms, arterial occlusions and arterial thrombosis.[6,32,37–39] The majority of the reported cases are in males and aneurysmal manifestations are seen in more severe cases of HIV.[38,39] In a series of 60 patients with HIV and vasculopathy, 48% had occlusive disease, 40% aneurysmal disease and 12% pseudo-aneurysms.[38] Aneurysms affected the abdominal aorta (30%), thoracic aorta (20%) and carotid arteries (20%), while the occlusive disease was most frequently femoro-popliteal (45%) and aorto-iliac (34%).[38] In another series of 226 patients from South Africa with HIV vasculopathy, the most common findings were arterial occlusions (51%) and aneurysms (49%).[39] The most frequent sites of aneurysms were the lower extremities (40%), carotid (25%) and abdominal aorta and branches (20%).[39] Occlusive manifestations included critical limb ischaemia (56%) and acute thrombosis (44%).[39] CNS manifestations from HIV have also been reported.[32] In a study comparing ischaemic stroke in patients with HIV (64 patients) and without HIV (107 patients), those with HIV were more likely to have large artery disease as the cause of stroke (20% vs 10% without HIV).[32] The most common causes for HIV-associated stroke were vasculopathy (38%) followed by opportunistic infection (25%).[32] In 25% of stroke cases with HIV, manifestations of stroke started after the introduction of antiretroviral therapy.[32] It is still unclear whether treatment of HIV can prevent or treat these vascular manifestations.

COVID-19

Pernio-like skin lesions have been commonly reported in COVID-19, although in a study of 375 patients with COVID-19 from Spain, the most common cutaneous manifestations were maculopaular eruptions (47%), pernio-like lesions (19%), urticarial lesions (19%), vesicular eruptions (9%) and livedo/necrosis (6%).[9] Another large series of pernio-like lesions in 318 patients with suspected COVID-19 from eight countries reported isolated pernio-like lesions as the only symptom in 55%, although this is difficult to interpret given that 72% of patients in this series were clinically suspected of COVID-19 and had no confirmatory testing.[8] Thrombotic occlusive vasculopathy and cutaneous vasculitis have also been described.[40–42] Widespread microangiopathy and thrombosis also appear to be distinguishing aspects of this infection, with findings of diffuse alveolar damage, microthrombi and vascular angiogenesis in the lungs on autopsy.[43,44] Finally, there has also been increased recognition of a Kawasaki-like illness in children with COVID-19, with a series from France reporting a higher proportion of gastrointestinal symptoms and shock syndrome and a series from Italy reporting more cardiac involvement and features of macrophage activation syndrome.[10,11]

Mycotic Aneurysms

Mycotic aneurysms develop when infectious organisms directly penetrate and weaken arterial walls. Risk factors include arterial injury (e.g. catheterization), prior infections like IE with septic emboli, periodontal infection, immunocompromised state, atherosclerosis and pre-existing aneurysm.[45–52] The infectious organisms are primarily bacterial (Staphylococcus species, Salmonella species, Streptococcus species, Escherichia coli), although Treponema pallidum (previously a common cause), Mycobacterium and fungal species can also cause mycotic aneurysms.[45–51,53–58] Positive cultures support the diagnosis, but negative cultures do not exclude the possibility. Patients present with fever and a painful, pulsatile, enlarging mass. Laboratory findings include leucocytosis and elevated acute phase reactants. Mycotic aneurysms can occur anywhere, but intracranial arteries are the most frequently affected, followed by visceral arteries and upper or lower extremity arteries.[55,59] Infectious aortitis can also occur.[53,55,57–59] Diagnosis is made with computed tomography angiography, although magnetic resonance angiography is acceptable if intravenous contrast is contraindicated. Imaging findings that may help differentiate mycotic aneurysms from vasculitis include the presence of peri-aortic gas, oedema, mass or stranding.[52]

Summary

Infections are important mimics of vasculitis and can affect any vessel size. IE should be considered in patients presenting with systemic manifestations, elevated acute phase reactants or glomerulonephritis. While ANCA positivity is helpful in diagnosing patients with ANCA vasculitis, it is important to remember that infections can also induce ANCA. Infection with Bartonella has been associated with ANCA positivity and glomerulonephritis (typically with immune complex deposition). Chronic infection with HIV can cause severe vasculopathy. Clinicians should be aware of the association with pernio-like lesions and Kawasaki-like disease with COVID-19.

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