Lethal Pediatric Cerebral Vasculitis Triggered by Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. PATIENT DESCRIPTION: A previously healthy, eight-year-old Hispanic girl presented with subacute left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurological decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Postmortem brain autopsy remained consistent with vasculitis. CONCLUSION: This is the first pediatric presentation to suggest that SARS-CoV-2 can lead to a fatal, postinfectious, inflammatory small-vessel cerebral vasculitis. Our patient uniquely included supportive cerebrospinal fluid and postmortem tissue analysis. While most children recover from the neurological complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Rituximab Versus Cyclophosphamide for Central Nervous System Involvement of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Series.

OBJECTIVE: To compare the effectiveness of rituximab (RTX) with cyclophosphamide (CYC) in patients who have central nervous system (CNS) involvement in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: A computer-assisted search was conducted to identify all adults who received a diagnosis of AAV with CNS involvement from January 1, 1997, through July 1, 2017, at our institution. RESULTS: Of the 17 patients identified, 11 had received RTX, and 6 had received CYC. Age at diagnosis of CNS involvement was similar in both groups. In the RTX group, 91% of the patients were women; in the CYC group, 33% were women (p = 0.03). At the time of CNS presentation, orbital involvement had occurred in 6 patients in the RTX group and in none of the patients in the CYC group. Initial remission of induction was achieved in all patients (100%) in the CYC group and in 10 patients (91%) in the RTX group. Two patients had no response to RTX: 1 patient when RTX was used for remission induction at the time of diagnosis and the second patient when RTX was used for remission induction after relapse. The median follow-up was 38 months (range, 9-127 months). Central nervous system relapse occurred in 4 patients in the RTX group and in 1 patient in the CYC group. Of the 4 patients in the RTX group with relapse, 3 had marked ocular involvement. Both nonresponder patients in the RTX group had ocular involvement. CONCLUSION: Rituximab is as effective as CYC in remission induction in patients with CNS involvement in AAV.

Certified reference material against PR3 ANCA IgG autoantibodies. From development to certification.

Background The importance of the standardisation of immunoassays for autoantibodies has been widely discussed. The appropriate use of certified reference materials (CRM) could contribute to a more accurate diagnosis and follow-up of a series of diseases such as small vessel-associated vasculitis. This is a systemic autoimmune disorder during which two autoantibodies can be present, MPO ANCA IgG and PR3 ANCA IgG. Results from different commercially available immunoassays used for PR3 ANCA IgG measurement can vary significantly. Therefore the potential for improvement using a suitable certified reference material was assessed and led to the development of a CRM. Methods Thirty clinical samples were evaluated using 10 immunoassays. The correlation between results from these assays was assessed in a pairwise manner. Feasibility studies were conducted in order to find a reference material format most suitable for the preparation of a CRM. Results The evaluation of two sets of 30 clinical samples with 10 assays showed that differences between assays can result in different interpretations for individual clinical samples. Most of the samples had the same result classification in all assays. However, six of the samples tested led to inconsistent results. Conclusions The correlation between results from clinical samples was systematically good for combinations of eight of those assays. Therefore, it should be possible to improve the comparability of results using a commutable CRM for calibration. Based on these studies, a final format for the CRM was selected and eventually produced and certified for its PR3 ANCA IgG content.

Immune cell profiling in the cerebrospinal fluid of patients with primary angiitis of the central nervous system reflects the heterogeneity of the disease.

Primary angiitis of the central nervous system (PACNS) is a rare and heterogeneous inflammatory disease of the CNS vasculature with poorly understood pathophysiology. Comprehensive immune-cell phenotyping revealed increased frequencies of leukocytes in the cerebrospinal fluid (CSF) of PACNS patients compared to patients with multiple sclerosis, ischemic stroke, and somatoform disorders (n = 18 per group). Changes in the intrathecal immune-cell profile were heterogeneous in PACNS. While proportions of T-cell subsets remained unaltered, some PACNS patients showed a shift toward NK- or B cells. Intrathecal immunoglobulin synthesis was observed in a subgroup of PACNS patients with an increased frequency of antibody producing plasma cells.

[Primary central nervous system vasculitis]. / Primäre Vaskulitis des Zentralnervensystems.

Primary angiitis of the central nervous system (PACNS) is a rare disorder. However, it is often considered in the differential diagnosis of vascular or inflammatory CNS diseases. Diagnosis is challenging, as specific biomarkers are lacking and the clinical presentation can be variable. A definitive diagnosis can only be established by biopsy of the inflammatory changes in the vascular wall. Alternatively, the diagnosis of PACNS can also be based on the synopsis of clinical, radiological, and laboratory findings. Different subtypes of PACNS have been described in recent years, depending on the size of the affected vessels or histopathological patterns. Based on selective literature research in the database PubMed on the subject of CNS vasculitis, this article reviews the diagnostic characteristics and differential diagnosis of the condition. We suggest a diagnostic algorithm customized to the size of the affected vessels. Lastly, therapeutic options and the outcome of PACNS are briefly outlined.

Cerebral arteriostenosis associated with elevated serum-immunoglobulin E level in young adults without risk factors for ischemic stroke: a possible manifestation of cerebral vasculitis?

We report a series of young adults with symptomatic cerebral arteriostenosis characterized by elevated serum immunoglobulin (Ig) E levels. All patients had no definite risk factors for cerebral vascular diseases. The clinical data of 26 young adults (age 18-50 years) with ischemic stroke, characterized only by increased serum IgE levels and without risk factors for cerebral vascular disease, were retrospectively reviewed. Arteriostenosis was surveyed and followed-up by digital subtraction angiography (DSA), and the stenosis rate was estimated using the warfarin-aspirin symptomatic intracranial disease technique. All patients were treated with corticosteroids according to the common strategy for vasculitis. There was no recurrent stroke during follow-up. The mean degree of stenosis before and after treatment was 69.3±29.8% and 47.9±45.1%, respectively. The difference of stenosis rates between initial and follow-up DSA evaluation was significant using a paired samples test (21.31±26.88, 95% confidence interval [CI] 13.58-29.03, t=5.55, p<0.001). Kaplan-Meier survival analysis revealed that the 13-month cumulative improved lesion rate was 40.3±8.7%. This remained the same at 18 months. The mean time to lesion improvement was 12.58 ± 0.96 months (95% CI 10.70-14.46) and median time was 13±3.88 months (95% CI 5.39-20.61). To our knowledge, cerebral arteriostenosis with only elevated IgE serum levels has not been reported. Our data showed that corticosteroid treatment can achieve clinical and artery improvement. This suggests that the cerebral arteriostenosis seen in our study might be caused by some specific type of vessel inflammation.

Cholestatic liver disease after rituximab and adalimumab and the possible role of cross-reacting antibodies to Fab 2 fragments.

BACKGROUND: Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. METHODS: Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. RESULTS: Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients' sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. CONCLUSION: This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug clearance in patients on Tmab therapy.

Comparative proteomic analysis of neutrophils from patients with microscopic polyangiitis and granulomatosis with polyangiitis.

Both microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils play a key role in their pathology. In this study, in order to discriminate between MPA and GPA, protein profiles of peripheral blood polymorphonuclear cells (PMNs) of 11 MPA patients and 9 GPA patients and 10 healthy controls (HC) were analyzed by 2D-DIGE. In all the 864 spots detected, intensity of 55 spots was significantly different (p<0.05) among the three groups by ANOVA. 31 out of the 55 spots were identified by mass spectrometry. Orthogonal partial-least-squares-discriminate analysis revealed that the abundance profile of the protein spots discriminated the AAV group from the HC group, and the MPA group from the GPA group completely. 13 protein spots were considered as biomarker candidates to distinguish between MPA and GPA. In those, spots whose intensity was higher in MPA than in GPA included actin with various pI values, while a considerable part of spots whose intensity was higher in GPA were proteins related with the activity of neutrophils. Among the candidate proteins, ROC analysis showed that a combination of neutrophil gelatinase-associated lipocalin and a-kinase anchor protein 7 isoforms beta had a high diagnostic potential. BIOLOGICAL SIGNIFICANCE: In this study, protein profiles of polymorphonuclear cells (PMNs) of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) patients and healthy controls (HC) were investigated by 2D-DIGE, and MS analysis. As a result, we found that the protein profiles of PMNs were useful for distinguishing between patients (MPA and GPA) and HC, and between patients with MPA and patients with GPA. Especially, we found that the 13 protein spots that consisted of 10 proteins considerably contributed to the discrimination between MPA and GPA. This is the first to demonstrate that protein profiles of PMNs are different among MPA, GPA and healthy control. The 10 proteins we identified in this study would be new biomarkers for the diagnosis of the diseases, and may be reflect the pathology difference between MPA and GPA.

C-ANCA/proteinase 3-positive colitis in children: a distinctive form of inflammatory bowel disease or vasculitis with colitis as initial presentation?

AIM: Anti-neutrophil cytoplasmic antibodies (ANCAs) detected by indirect immunofluorescence have been found in patients with inflammatory bowel disease (IBD). Nevertheless, specific antibodies against proteinase-3 (PR3) are rare in this context. METHODS: Sera from 30 consecutive pediatric patients with IBD were evaluated for ANCA-indirect immunofluorescence and its specific antibodies to investigate whether PR3-ANCA positivity (PR3-ANCA+) identifies a distinct IBD subtype. RESULTS: The 5 PR3-ANCA+ patients (17%) showed significantly more concomitant biliary disease and severe anal blood loss (P < 0.05). None had vasculitis features at diagnosis nor during follow-up. CONCLUSIONS: This pilot study demonstrates significant clinical differences between the PR3-ANCA-positive and -negative IBD subset.

Occurrence of relapsing polychondritis with a rising cANCA titre in a cANCA-positive systemic and cerebral vasculitis patient.

Relapsing polychondritis (RP) is a relatively rare disorder, with a high death rate that affects cartilaginous structures. RP can be either primary or secondary as part of autoimmune syndromes. We present a case of RP in a 49-year-old man suffering from cytoplasmic antineurophil cytoplasmic antibodies (cANCA) positive vasculitis, admitted to our hospital with red swollen left ear and painful sternoclavicular joint and larynx. The patient was in remission from the vasculitis but manifested a high cANCA titre indicating vasculitis activity. With his high cANCA titre vasculitis, full manifestation of RP concomitantly occurred. After a successful cortisone treatment for RP, the patient received cyclophosphamide treatment for his vasculitis that resulted in a decrease in cANCA titre and full remission of his RP symptoms.

Circulating endothelial cells as potential diagnostic biomarkers in primary central nervous system vasculitis.

OBJECTIVE: Histological evidence is considered the only proof of primary central nervous system vasculitis (PCNSV). However, brain biopsy is often omitted or delayed because of the invasiveness and possible complications of the procedure. Circulating endothelial cells (CEC) were shown to be elevated in patients with active antineutrophil cytoplasmic antibody-associated vasculitis. We hypothesise that CEC are also elevated in patients with active PCNSV and may contribute to the diagnosis. METHODS: CEC were assessed in 18 patients, 3 of whom had biopsy-proven PCNSV and 15 clinical, cerebrospinal fluid and imaging data, highly suggestive of PCNSV. In 3 of these 15 patients CEC assessment was performed after initiation of successful immunosuppressive therapy. CEC numbers of all patients were compared to those of 16 healthy volunteers and 123 subjects with cerebrovascular risk factors and/or ischaemic stroke, who had been studied in our group before. CEC were assessed by immunomagnetic isolation from peripheral blood. RESULTS: In patients with proven and suspected active PCNSV, CEC were extremely elevated (>400 cells/ml in most of the patients) and significantly higher than in healthy and disease controls (p≤0.01 for each group). CEC significantly decreased with immunosuppressive treatment. CONCLUSIONS: For the first time it is shown that CEC are significantly elevated in patients with active PCNSV in contrast to other pathologies associated with brain infarction and correlate with disease activity. Sensitivity and specificity of the method for diagnosing PCNSV and the use of the method for treatment monitoring should be addressed in future prospective studies with a larger patient group.

von Willebrand factor antigen--a possible biomarker of disease activity in childhood central nervous system vasculitis?

OBJECTIVE: The main objective was to develop a trajectory for von Willebrand factor (vWF) antigen in childhood primary CNS vasculitis (cPACNS) after treatment and compare this with disease activity and other inflammatory markers. METHODS: A single-centre cohort study of consecutive children diagnosed with cPACNS was performed. Demographic, clinical, laboratory, imaging and histological data were collected at diagnosis and during standardized clinic visits. Outcome measures included disease activity measured by physician global assessment and serial measures of vWF antigen. Analysis included descriptive statistics and parametric methods. RESULTS: The study cohort consisted of 39 children diagnosed with cPACNS: 25 with angiography-negative cPACNS and 14 with angiography-positive disease. Twenty-one patients were female, median age at diagnosis was 9.8 years, and median follow-up was 18 months. All patients presented with neurological deficits. Disease activity and neurological outcome improved significantly during follow-up. vWF antigen levels were increased at diagnosis in 65% of children with cPACNS and were decreased significantly after treatment. In contrast, levels of CRP and ESR fluctuated over time. Higher vWF antigen levels at diagnosis were associated with lower measures of disease activity at 12 months. CONCLUSION: In our study, all children with cPACNS improved over time. Changes in CRP and ESR, other laboratory tests, and MRI did not consistently reflect altered disease activity. However, vWF antigen may help clinicians to identify changes in disease activity during follow-up and predict treatment response. Controlled studies are necessary to evaluate the sensitivity and specificity of vWF antigen as a biomarker of disease activity.

[Post-varicella cerebral thrombophlebitis with anti-protein S: report of a pediatric case]. / Thrombophlébite cérébrale post-varicelle avec anticorps anti-protéine S : à propos d'un cas pédiatrique.

Purpura fulminans and venous thrombosis are rare complications of chickenpox. We report the case of a 6 year old with no history individuals who experienced cerebral thrombophlebitis, 3 weeks after varicella. MRI, performed at admission, has objectified longitudinal sinus thrombosis and a frontal parenchymal hematoma law. Meanwhile, a recent varicella seroconversion was demonstrated. The assessment of thrombophilia, meanwhile, has objectified a significant decrease in free protein S and activity, without associated DIC. Origin acquired this deficit was confirmed by the detection of antibodies (IgG and IgM) against the total protein S by ELISA. After evaluation of the benefit/risk only anticoagulation was initiated. The clinical and biological evolution was favorable, with rapid normalization of the S protein and decrease of anti-protein S. Many studies report the presence of anti-protein S in young children at the waning of chickenpox, without their exact frequency is determined. The decrease in protein S they cause leads to a transient hypercoagulable state may result in different clinical pictures. Cases of purpura fulminans seem more frequent when venous thrombosis isolated post chickenpox, sometimes atypical, appear rare.

Isolated angiitis of the CNS and bacterial endocarditis: similarities and differences.

Both isolated angiitis of the central nervous system (IAN) and bacterial endocarditis (BE) may present with similar clinical and auxiliary findings. The differentiation is extremely important because of the different treatment regimens. We compared the findings of six patients with biopsy-proven IAN with the data of six patients with BE. Patients with IAN were younger (27-62 years) and presented with multiple strokes (n = 4), intracerebral hemorrhage (n = 1), epileptic seizures (n = 2), or encephalopathy (n = 1). All IAN patients had pathologic cerebrospinal fluid (CSF) findings (pleocytosis n = 5; protein elevation n = 4), and angiography revealed multilocular stenoses in two cases while digital subtraction angiography was normal in four. BE patients (32-77 years) presented multiple (n = 3) or single ischemic strokes (n = 2) or encephalopathy and headache (n = 2). While all patients showed inflammatory serum findings (C-reactive protein n = 6, leucocytosis n = 4), CSF-pleocytosis was present in two cases only. Angiography revealed a vasculitic pattern in two patients. The diagnosis of BE was established based on transesophageal echocardiography and blood cultures. Leptomeningeal and brain biopsies performed in two cases were normal. Both IAN and BE may present multiple strokes and encephalopathy. The frequency of a vasculitic pattern in angiography is similar in both conditions. While inflammatory serum findings are the rule in BE, pathologic CSF findings were present in all IAN patients. Transesophageal echocardiography and blood cultures should be performed in order to diagnose or exclude BE. Without brain biopsy, immunosuppressive therapy may be dangerous in suspected IAN.

Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis.

BACKGROUND AND PURPOSE: The molecular pathways involved in the progression of intracranial large artery atherosclerosis (ILA) are largely unknown. Our objective was to prospectively study the relationship between circulating levels of inflammatory markers and fibrinolysis inhibitors, and the risk of progression of symptomatic ILA. METHODS: Seventy-five consecutive patients with first-ever symptomatic intracranial atherostenosis were studied. Blood levels of C-reactive protein (CRP), E-selectin, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinases 1, 2, 3, 8, 9, 10, and 13, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) were measured 3 months after the qualifying stroke or transient ischemic attack. Thereafter, patients underwent long-term transcranial Doppler follow-up to detect progression of ILA. RESULTS: During a median follow-up time of 23 months, 25 (33%) patients showed ILA progression. Multivariable adjusted Cox regression models and Kaplan-Meier curves showed that high baseline level of CRP, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase 9, PAI-1, and lipoprotein(a) predicted ILA progression independently of vascular risk factors. Of them, only CRP (CRP>5.5 mg/L; HR, 5.4 [2.3 to 12.7]; P=0.0001) and PAI-1 (PAI-1>23.1 ng/mL; HR, 2.4 [1.0 to 5.8]; P=0.05) predicted ILA progression also independently of the other studied molecules. CONCLUSIONS: Progression of symptomatic ILA is associated with a proinflammatory state, as reflected by high levels of inflammatory markers, and with defective fibrinolysis, as indicated by raised concentrations of endogenous fibrinolysis inhibitors.

Ischemic stroke accompanied by anti-PR3 antibody-related cerebral vasculitis and hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection has been found to be strikingly associated with autoimmune phenomena. Autoantibodies are commonly found in patients with HCV infection. PURPOSE: The aim of the present study was to investigate the presence of anti-neutrophil cytoplasmic antibody (ANCA) in patients with ischemic stroke and HCV infection. MATERIAL AND METHODS: ANCA were determined in sera from 36 patients with ischemic stroke and HCV infection (18 females, 18 males, mean age 75+/-10 years) and 44 healthy controls. Assays employed were indirect immunofluorescence for detection of ANCA and ELISA for anti-proteinase 3 (anti-PR3-ANCA). No one of the patients studied received IFN-alpha treatment before blood collection. RESULTS: ANCA were positive in 21 out of 36 (58 %) patients with ischemic stroke and HCV infection. All sera with ANCA showed cANCA patterns and contained anti-PR3 specificity. HCV patients with ANCA showed a higher prevalence of cerebral vasculitis. CONCLUSION: HCV may be regarded as a possible causative factor in ANCA-related vasculitis.

High proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) level measured by the capture enzyme-linked immunosorbent assay method is associated with decreased patient survival in ANCA-associated vasculitis with renal involvement.

Wegener granulomatosis (WG) and microscopic polyangiitis (MP), diseases associated with antineutrophil cytoplasmic antibodies (ANCA), had an extremely poor prognosis before the introduction of cyclophosphamide and corticosteroids for their treatment. However, there is still reduced patient survival, and some studies have documented severe side effects of the immunosuppressants used. This 10-yr follow-up study assessed 117 consecutive patients with WG or MP with biopsy-confirmed renal involvement. The cumulative relative patient survival was lower: 0.664 for women and 0.648 for men. The causes of death (n = 64) were in most cases registered as associated with the vasculitic disease. Analysis of possible predictive factors for patient survival by multiple Cox regression analysis revealed that a very high level of proteinase 3 (PR3)-ANCA measured by the capture ELISA method, a diagnosis of MP, and older age were factors predicting poorer patient survival. High levels of B-thrombocytes at time of diagnosis were associated with a better prognosis. For patients surviving the first year, remission-sustaining therapy with azathioprine for longer than 12 mo was associated with improved patient survival. Thirty-nine patients developed end-stage renal failure. Elevated serum creatinine at time of diagnosis and a very high level of PR3-ANCA by capture ELISA were factors predicting a higher risk for renal failure during follow-up. The epitope on PR3 assessed by capture ELISA needs to be further analyzed and explored: it seemed to implicate poorer patient and renal survival in WG or MP with renal involvement.

Usefulness of indium-111-oxine-labeled leukocyte scintigraphy in diagnosis of inflammation associated with chronic aortic dissection.

BACKGROUND: Patients with chronic aortic dissection require monitoring for indications of disease progression. In present study, inflammation adjacent to associated aortic wall was evaluated by indium-111-oxine-labeled leukocyte scintigraphy, scince inflammation of the blood vessel wall often associates with progression of chronic aortic dissection. METHODS AND RESULTS: Fifteen patients with aortic dissection underwent indium-111-oxine-labeled leukocyte scintigraphy. Seven showed positive images at sites corresponding to the actual sites of the dissociated aorta. Four patients with positive images underwent surgery. Histologic examination revealed inflammatory and necrotic changes of the aortic wall. During a mean follow-up period of 2.3 years, progression of aortic dissection was observed in two of the seven patients with positive intimal imaging. CONCLUSION: Indium-111-oxine-labeled leukocyte scintigraphy may be a useful noninvasive technique to assess the persistent inflammation in patients with chronic aortic dissection.