Vessel Wall Necrosis Research Articles

Abstract 076: 2023 Fusarium Meningitis Outbreak: Neuroendovascular Outcomes and Observations of the Angioinvasive Disease from South Texas

Introduction The Centers for Disease Control and Prevention (CDC) issued a health advisory in response to an outbreak of Fusarium meningitis from exposure to spinal anesthesia for cosmetic surgery performed in Mexico between Jan 1 to May 13, 2023. This paper outlines the neuroendovascular and neurosurgical observations and management of this outbreak at our Comprehensive Stroke Center with a focus on angio‐invasive disease. Methods A retrospective chart review was performed for fungal meningitis patients that presented between April and July 2023. Results There were a total of 12 patients who were found to have fungal meningitis, 11 of whom were included in the final analysis with angio‐invasive Fusarium solani. The mean age was 31.7 ± 7.15. 92% of patients were female. CT and MRI were initially normal in two‐thirds of patients. No cases demonstrated positive growth on fungal cultures. Only (1→3)‐β‐D‐Glucan assays were positive in all patients who were tested. After several patients in this series developed subarachnoid hemorrhage from a ruptured mycotic aneurysm, we proceeded to institute weekly cerebral angiography protocol. This detected moderate to severe vasospasm in 75%, and aneurysms in 58%, with the most common site being the basilar artery. The aneurysms were seen exclusively in the posterior circulation. The average size of aneurysms when first detected was 5.0 ± 3.8 mm. Patients with brain aneurysms were treated with flow diversion in 57% of cases, primary coiling was performed in 14%, and the remaining expired prior to treatment. 14% in our series actually developed another episode of subarachnoid hemorrhage after treatment from a new angiographically confirmed aneurysm. All patients who presented with subarachnoid hemorrhage from mycotic aneurysms have passed or withdrawn care. With regard to vasospasm treatment, 80% had treatment with intra‐arterial verapamil and 40% underwent mechanical angioplasty. We did not perform balloon angioplasty in any case due to concern for rupture of the weakened compromised vessel walls. Finally with regard to cerebrospinal fluid (CSF) diversion; 67% underwent ventriculostomy, and a minority were converted to ventriculoperitoneal shunts. All but one patient received dual antifungal therapy with Amphotericin B and Voriconazole, and 42% were started on every other day intrathecal Amphotericin B. Conclusion We have found that in patients with fusarium meningitis that weekly angiographic surveillance for aneurysms and vasospasm should be performed. Conventional angiography is preferred to computed tomography angiography due to the smaller size of aneurysms. Aneurysms should be primarily coiled prior before flow diversion is attempted, and vasospastic vessels may be mechanically dilated in the setting of vessel wall necrosis.

PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG TRIAL): FEASIBILITY AND EVALUATION OF TREATMENT RESPONSE IN ENHANCING AND NON-ENHANCING REGIONS

Abstract AIMS Patients with glioblastoma have dismal outcomes and there is an urgent need for new treatment modalities. The POBIG trial is the first to evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma. We report the results from our first dose arm. METHOD POBIG is a phase I radiotherapy dose and volume escalation trial. The first dose arm received 8Gy preoperative radiotherapy to a maximum irradiation volume of 30cm3. The irradiation field included enhancing and non- enhancing FLAIR hyperintense regions judged as highest risk for remaining as postoperative residuum. Part of the tumour remained unirradiated (<2Gy) with a margin for diagnostic sampling. Surgical resection took place within 1 week. Patients underwent diffusion/perfusion MRI scans before/after preoperative radiotherapy. RESULTS Two female and one male patient aged 61, 67 and 45 years, respectively, were enrolled. Preoperative radio- therapy was delivered at a dose of 8Gy to an irradiation volume of 7-30cm3. Near-total surgical resection was performed 2-3 days after preoperative radiotherapy treatment. Pathological examination of irradiated areas showed necrosis including fibrinoid necrosis of vessel walls. There was an increase in Ktrans permeability in both irradiated enhancing tumour (0.097,0.150) and unirradiated enhancing tumour (0.077,0.147) 24-hours after treatment. In contrast, no obvious changes were noted in irradiated (0.002,0.002) and unirradiated (0.002,0.004) non-enhancing FLAIR hyperintense regions or reference unirradiated contralateral white matter (0.000,0.000). CONCLUSIONS Preoperative radiotherapy is feasible in newly diagnosed glioblastoma. Very early radiotherapy changes manifest in enhancing tumour regardless of radiotherapy dose, evident as increased permeability and radiation- induced tumour necrosis.

PS-R05-3: SEVERE GLOMERULAR MICROANGIOPATHY IN A PATIENT WITH NEPHROTIC SYNDROME FOLLOWING TAKAYASU ARTERITIS

Introduction: Takayasu arteritis (TA) is a large vessel inflammation that predominantly involves aorta and its main arteries. TA-caused kidney injury is known to be mainly due to renal artery stenosis. However, glomerulonephritis including membranous proliferative glomerulonephritis, focal segmental sclerosis, or crescentic nephritis has been histologically identified in some TA cases. Case description: A 69-year-old female presented with leg edema and refractory hypertension with nephrotic range proteinuria (17.0 g/gCr). She exhibited > 10 mmHg blood pressure discrepancy between left and right upper limbs and severe aortic regurgitation. Lab test showed high level of C-reactive protein and high erythrocyte sedimentation rate. Contrast-enhanced computed tomography identified wall thickening of the left subclavian artery, which led to the diagnosis of TA. Renal biopsy demonstrated that double basement membrane, enlarged subendothelial space, and mesangiolysis with no immunoglobulin deposition. Although azilsartan 40 mg QD and nifedipine 30 mg BID had been prescribed, systolic blood pressure (sBP) was still > 160 mmHg. Thus, while oral prednisolone was started to suppress TA-induced inflammation, azilsartan was replaced with sacubitril valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), for treating refractory hypertension. After a few weeks, sBP was decreased to 130 mmHg with sacubitril valsartan 200 mg QD and proteinuria was dramatically improved to 0.5 g/gCr. Discussion: TA commonly involves the renal artery, leading to stenosis and subsequent ischemic nephropathy. However, no stenosis and occlusion were observed in renal artery of this case. In addition, small vessel inflammation in the kidney such as vessel wall necrosis and immune cells infiltration around arterioles was not found. Serum levels of pro-inflammatory cytokines including vascular endothelial growth factor and interleukin-6, a well-known contributors for progression of TA-related inflammation, were within the normal range. The results indicate that TA-caused hypertension, but not vessel inflammation induced by TA, seems to play a pathological role for development of glomerular microangiopathy in this case. A previous study showed that 70% of TA patients presenting with glomerular lesion has severe hypertension and intimal thickening in renal arterioles was observed more frequently in TA patients presenting with glomerular lesion when compared to those without glomerulonephritis, which supports our hypothesis. In the present case, ARNI significantly reduced sBP which might directly contribute to the improvement of proteinuria. ARNI can be potent to control hypertension more effectively than conventional hypertensive agents in TA patients.

Improvement of Outcome for Treatment of ‘Restenosis-prone’ Vascular Lesions? Potential Impact of the Paclitaxel dose on Late Lumen Loss in Porcine Peripheral Arteries

PurposeClinical data indicate that the drug density on drug-coated balloons (DCBs) might have a role on treatment effect and durability. The aim of the current study was to investigate inhibition of neointimal formation and potential adverse effects after treatment with a novel double-dose DCB in swine.Material and methodsA four-week study was performed in peripheral arteries of 12 domestic pigs after vessel injury and stent implantation. The novel double-dose DCB with 6-µg paclitaxel (Ptx)/mm2 balloon surface (1 × 6) was compared to a standard DCB with 3.5 µg Ptx/mm2 (3.5) and uncoated balloons (POBA). Potential adverse effects were stimulated by using three fully overlapping DCBs with 6 µg Ptx/mm2 each (3 × 6). Quantitative angiography, histomorphometry and histopathological analyses were performed.ResultsHigher paclitaxel doses per square millimeter of treated arteries were associated with reduced late lumen loss (LLL) in quantitative angiography 4 weeks after treatment (POBA: 0.91 ± 0.75 mm; 3.5: 0.45 ± 0.53 mm; 1 × 6: 0.21 ± 0.41 mm; 3 × 6: − 0.38 ± 0.65 mm). In histomorphometry, maximal neointimal thickness and neointimal area were the lowest for the 1 × 6 group (0.15 ± 0.06 mm/1.5 ± 0.4 mm2), followed by 3 × 6 (0.20 ± 0.07 mm/1.8 ± 0.4 mm2), 3.5 (0.22 ± 0.12 mm/2.2 ± 1.1 mm2) and POBA (0.30 ± 0.07 mm/3.2 ± 0.7 mm2). Downstream tissue showed histopathological changes in all groups including POBA, in larger number and different quality (e.g., edema, inflammation, vessel wall necrosis, vasculitis and perivasculitis) in the 3 × 6 group, which did not cause clinical or functional abnormalities throughout the study.ConclusionTreatment with the double-dose DCB (6 µg Ptx/mm2) tended to increase inhibition of in-stent neointimal formation and to diminish LLL after peripheral intervention in the porcine model compared to a market-approved DCB with 3.5 µg Ptx/mm2.

Recurrent Carotid artery blow out in a head & neck patient

Introduction and importanceCarotid artery blowout syndrome is a rare complication of head and neck cancer treatment. It defines a rupture of the carotid artery wall through vessel wall necrosis. This is typically precipitated by radiotherapy, direct tumour invasion, or a combination of these factors. We describe a rare case of three consecutive carotid artery blowouts in a head and neck cancer patient.Case presentationA 58-year-old man with a history of T3NO hypopharyngeal squamous cell carcinoma (SCC) treated with chemotherapy and radiation presented with a four-month history of progressive dysphagia and right sided neck pain. Flexible nasendoscopy revealed laryngeal oedema and slough. A panendoscopy and biopsy showed no evidence of tumour recurrence. The patient was discharged and represented with worsening dyspnoea. He subsequently experienced a large volume hemorrhage necessitating ligation of his right external carotid artery. He underwent pharyngolaryngectomy indicated due to the extent of laryngeal radiation necrosis. Thereafter he suffered two additional acute carotid bleeds from his right common carotid necessitating ligation in theatre.Clinical discussion and conclusionThis case report illustrates the key issues to be considered in patients with locally advanced hypopharyngeal squamous cell carcinoma and subsequent management of acute carotid blowout syndrome, which without prompt management, can be fatal.

Acute haemorrhagic leukoencephalitis (AHLE) – our experience and a short review

BackgroundAcute haemorrhagic leukoencephalitis (AHLE), a rare variant of acute disseminated encephalomyelitis (ADEM), often presents differently from classical ADEM, thereby posing a diagnostic challenge to the clinician. AimTo report AHLE, its clinic-radiological manifestations, process of diagnosis and prognosis. Method and resultsEight patients presented with altered sensorium, acute focal deficits with or without seizures. Initial workup showed evidence of haemorrhagic lobar or thalamic lesions in seven patients. All patients underwent extensive evaluation for collagen vascular disease and vasculitis profile, autoimmune encephalitis panel and aquaporin-4 antibody, which were found to be normal. Cerebrospinal fluid (CSF) biochemistry and microscopy was non-contributory and CSF viral PCRs, toxoplasma antibodies, cryptococcal antigen were also negative. All patients had progressively worsening sensorium and neurological deficits. Repeat MRIs showed increase in oedema in the lesions and appearance/expansion of haemorrhage in the thalamic/hemispherical lesions. All patients received intravenous methylprednisolone (IVMP) without any benefit. Four patients underwent plasmapheresis (PLEX), one received intravenous immunoglobulin (IVIG) and one received both second line immunotherapies, without significant improvement. Brain biopsy (performed in three patients) showed inflammatory demyelination and areas of haemorrhage, thus confirming the diagnosis. Six patients succumbed in 7–30 days of the illness, despite aggressive treatment and only two survived, albeit with a significant disability. ConclusionAHLE is a rare, yet very severe variant of ADEM. MRI shows lesions with haemorrhages, oedema and mass effect and histology findings reveal inflammatory infiltrates, haemorrhagic foci and fibrinoid necrosis of vessel walls. Prognosis is worse as compared to the classic ADEM, with a high mortality rate. To the best of our knowledge, this is one of the largest series of AHLE to have been reported anywhere in the world. KeymessageAcute encephalopathy, multifocal deficits accompanied by haemorrhagic CNS demyelinating lesions with oedema and mass effect are the key features of AHLE. It is a rare, yet very severe form of ADEM with very high morbidity and mortality.

AB020. A case report on cutaneous necrotizing vasculitis treated with colchicine in a Filipino adult male

Cutaneous necrotizing vasculitis is a condition characterized by vessel wall necrosis secondary to neutrophil infiltration classically presenting as palpable purpura on the lower extremities. Several etiologic agents have been identified but, literature showed that majority of cases have an unidentifiable cause. First-line pharmacologic management consists of systemic glucocorticoids with colchicine being used merely as second-line therapy. We report a case of a 59-year-old male with cutaneous necrotizing vasculitis treated with colchicine as monotherapy. This is the case of a 59-year-old male with a ten-day history of multiple discrete to confluent well-defined vesicles and bullae, some eroded with hemorrhagic exudates on the bilateral lower extremities, with accompanying round palpable purpura seen on the abdomen extending to the bilateral upper extremities. Skin biopsy was consistent with leukocystoclastic vasculitis. The patient completed 3-month treatment with colchicine 500 mcg twice daily with adjunct therapy of prednisone 20 mg once a day for 2 weeks tapered down by 5 mg. By 4th week of treatment, 50% improvement over the lesions were observed. By 3rd month of treatment, complete clearance was noted. This case highlights the effectiveness of colchicine as monotherapy for cases of cutaneous necrotizing vasculitis due to its action in suppressing granulocytic inflammatory reaction. Moreover, relative safety of colchicine is more favorable compared to the possible long-term side effects of systemic glucocorticoids. Especially for patients at risk for developing adverse effects to glucocorticoids, colchicine is a feasible yet often overlooked alternative treatment option compared to the conventional treatment with systemic glucocorticoids.

Diffuse alveolar damage (DAD) resulting from coronavirus disease 2019 Infection is Morphologically Indistinguishable from Other Causes of DAD

AimsDiffuse alveolar damage (DAD) is a ubiquitous finding in inpatient coronavirus disease 2019 (COVID‐19)‐related deaths, but recent reports have also described additional atypical findings, including vascular changes. An aim of this study was to assess lung autopsy findings in COVID‐19 inpatients, and in untreated severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐positive individuals who died in the community, in order to understand the relative impact of medical intervention on lung histology. Additionally, we aimed to investigate whether COVID‐19 represents a unique histological variant of DAD by comparing the pathological findings with those of uninfected control patients.Methods and resultsLung sections from autopsy cases were reviewed by three pulmonary pathologists, including two who were blinded to patient cohort. The cohorts included four COVID‐19 inpatients, four cases with postmortem SARS‐CoV‐2 diagnoses who died in the community, and eight SARS‐CoV‐2‐negative control cases. DAD was present in all but one SARS‐CoV‐2‐positive patient, who was asymptomatic and died in the community. Although SARS‐CoV‐2‐positive patients were noted to have more focal perivascular inflammation/endothelialitis than control patients, there were no significant differences in the presence of hyaline membranes, fibrin thrombi, airspace organisation, and ‘acute fibrinous and organising pneumonia’‐like intra‐alveolar fibrin deposition between the cohorts. Fibrinoid vessel wall necrosis, haemorrhage and capillaritis were not features of COVID‐19‐related DAD.ConclusionsDAD is the primary histological manifestation of severe lung disease in COVID‐19 patients who die both in hospital and in the community, suggesting no contribution of hyperoxaemic mechanical ventilation to the histological changes. There are no distinctive morphological features with which to confidently differentiate COVID‐19‐related DAD from DAD due to other causes.

Adrenal Vascular Changes in COVID-19 Autopsies.

To the Editor.—For the past 2 months, New York City has been the epicenter of the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). The disease (coronavirus disease 2019 [COVID-19]) most acutely and severely affects the lungs, requiring mechanical ventilation in a subset of cases. Other organs, including the heart, kidneys, liver, and gastrointestinal tract, can also be involved. The pathophysiology and the extent of multiorgan involvement is poorly understood. We report pathological findings in the adrenal glands of the first 5 postmortem examinations of patients with COVID-19 diagnosed on clinical grounds with confirmatory real-time polymerase chain reaction testing of nasopharyngeal swab. Two patients were brought to the emergency room in cardiac arrest and could not be resuscitated. Three were briefly hospitalized, 2 for 24 hours and 1 for 72 hours. There were 4 males and 1 female, ranging from 59 to 90 years of age and with the following co-morbidities: hypertension (5 of 5), diabetes (3 of 5), ischemic cardiomyopathy (3 of 5), chronic lung disease (2 of 5, 1 with chronic obstructive pulmonary disease and 1 with interstitial lung disease), prostate carcinoma (2 of 5), and recent spinal surgery (1 of 5). Blood cultures were negative in the 3 patients tested. On microscopic examination, acute fibrinoid necrosis of small vessels, mainly arterioles in adrenal parenchyma, adrenal capsule, and in the immediately adjacent periadrenal adipose tissue, was identified. Subendothelial vacuolization and apoptotic debris were present (Figure, A–C). No significant inflammation, adrenal parenchymal infarcts, or thrombi were appreciated. The vascular pathology was disproportionately conspicuous in adrenal and not as easily identified in other organs examined.Fibrinoid necrosis describes vessel wall necrosis with fibrin and serum protein accumulation conveying an eosinophilic amorphous appearance on histology. With Masson's trichrome stain, the amorphous fibrinoid material is red, unlike collagen that stains blue (Figure, D). Arteriolar hyalinosis is another term used to describe the accumulation of pink amorphous material in vessel walls. This is thought to relate to hypertension, but is not typically associated with vessel necrosis and endothelial apoptosis. Hyalinosis may explain some of the histopathology; however, many of the vessels we observed were either necrotic or associated with apoptosis. It is unclear if the adrenal vasculopathy is because of hypoxia, abnormal vascular reaction and blood flow patterns, direct viral cytopathic effect, an immune-mediated injury, or a combination of events. Acute fibrinoid necrosis is classically described in malignant hypertension (first by Volhard and Fahr1 in 1914), mainly in kidneys, and in immune-mediated vasculitides. While SARS-CoV-2 infection seems to more severely affect patients with a history of hypertension,2 most critically ill patients with COVID-19 need vasopressors for persistent hypotension.3 Two of 3 hospitalized patients described had recorded high blood pressure values and 1 was hypotensive on arrival. Localized fibrinoid necrosis is also mentioned in a report of pathological findings in SARS virus infection.4 SARS-CoV-2 virus gains entry to the cell via the angiotensin-converting enzyme 2 receptor,5 which is most abundant in lung alveolar cells, but also present in endothelia and other tissues, providing a possible mechanism for vascular injury.6Adrenal hormones are involved in modulating inflammatory responses7 and adrenal gland dysfunction has been described in patients with community-acquired pneumonia.8In general, adrenal function is not routinely assessed in an intensive care unit setting. The most common indication for corticosteroid administration in an intensive care unit is refractory hemodynamic shock. According to several critical care societies, acute respiratory distress syndrome management can include corticosteroids, as they may decrease the time on a ventilator and reduce mortality.9 Corticosteroids are also administered if there is suspicion of adrenal insufficiency or if they are indicated because of an underlying condition. Currently, the World Health Organization and major critical care and infectious diseases associations advise against routine corticosteroid use in COVID-19 patients, mainly out of concern for slowing viral clearance. However, early reports from China and Europe suggested that corticosteroids are useful in severe COVID-19 and some experts posit that severe cytokine release syndrome seen in some patients warrants the use of corticosteroids or other targeted immunosuppressants.9–12It is interesting to consider that adrenal insufficiency secondary to the vasculopathy described here may contribute to the cytokine storm observed in patients with severe COVID-19. Clinical studies to further assess adrenal function in COVID-19 may help in understanding the pathogenesis of disease in severely affected patients and hopefully lead to therapeutic protocols that may rescue an increased number of patients.

Inhibitory Effects of a Reengineered Anthrax Toxin on Canine Oral Mucosal Melanomas

Canine oral mucosal melanomas (OMM) are the most common oral malignancy in dogs and few treatments are available. Thus, new treatment modalities are needed for this disease. Bacillus anthracis (anthrax) toxin has been reengineered to target tumor cells that express urokinase plasminogen activator (uPA) and metalloproteinases (MMP-2), and has shown antineoplastic effects both, in vitro and in vivo. This study aimed to evaluate the effects of a reengineered anthrax toxin on canine OMM. Five dogs bearing OMM without lung metastasis were included in the clinical study. Tumor tissue was analyzed by immunohistochemistry for expression of uPA, uPA receptor, MMP-2, MT1-MMP and TIMP-2. Animals received either three or six intratumoral injections of the reengineered anthrax toxin prior to surgical tumor excision. OMM samples from the five dogs were positive for all antibodies. After intratumoral treatment, all dogs showed stable disease according to the canine Response Evaluation Criteria in Solid Tumors (cRECIST), and tumors had decreased bleeding. Histopathology has shown necrosis of tumor cells and blood vessel walls after treatment. No significant systemic side effects were noted. In conclusion, the reengineered anthrax toxin exerted inhibitory effects when administered intratumorally, and systemic administration of this toxin is a promising therapy for canine OMM.

A case of ANCA associated vasculitis presented with mononeuritis multiplex

Mononeuritis multiplex is a common manifestation of many illnesses which includes diabetes, leprosy, malignancy and certain types of systemic vasculitis. The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare diseases which show typical characteristic inflammatory cell infiltration and blood vessel wall necrosis. AAV syndromes include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilicgranulomatosis with polyangiitis (EGPA). Here we present a patient who presented with mononeuritis multiplex and had features ofEGPA. The patient was treated with standard regimen of steroids and pulsed cyclophosphamide and she achieved good clinical response.
 Birdem Med J 2019; 9(3): 257-260

Mast cell chymase degrades fibrinogen and fibrin.

The accumulation of immunoreactants and fibrinoid necrosis of postcapillary vessel walls are common pathological features of cutaneous immune complex vasculitis. In more advanced lesions, these immunoreactants are subject to proteolysis. Mast cell chymase is a powerful enzyme that can degrade several substrates including the extracellular matrix. Heparin can influence the catalytic properties of chymase. To study the effects of recombinant human (rh) chymase on fibrinogen, coagulation and fibrinolysis, and to relate these effects to the pathogenesis of vasculitis. The colocalization of chymase and fibrin in vasculitis specimens was analysed by immunohistochemical double staining. Fibrinogen and fibrin were treated with rh-chymase and the effects were studied invitro by sodium dodecylsulfate polyacrylamide gel electrophoresis and a variety of clotting and fibrin gel experiments. The effects of rh-chymase on vasculitis cryosections were analysed by direct immunofluorescence. Chymase-positive mast cells were associated with fibrin-positive vessels in vasculitis cryosections. Rh-chymase degraded the alpha-, beta- and gamma-chains of fibrinogen, while heparin enhanced the degradation of the beta-chain. Rh-chymase pretreatment of fibrinogen prolonged thrombin-induced clotting time. Fibrinogen degradation products induced by rh-chymase increased the clotting time of human plasma. Rh-chymase degraded fibrin gel prepared from fibrinogen or human plasma. Immunofluorescence staining positivity of fibrin in vasculitis cryosections decreased after pretreatment with rh-chymase for 24 h, and heparin enhanced this effect. Mast cell chymase may constitute a previously unrecognized endogenous anticoagulant and fibrinolytic enzyme, and may be involved in the clearance of fibrin from vessel walls in aged vasculitis lesions.

Neutrophilic urticarial dermatosis: A review.

Neutrophilic urticarial dermatosis (NUD) is a rare form of dermatosis. In clinical terms, it consists of a chronic or recurrent eruption comprising slightly elevated, pink to reddish plaques or macules. The elementary lesion lasts 24 to 48hours and resolves without leaving any residual pigmentation. Extra-cutaneous signs are common, particularly fever or arthralgia. At histopathology, the dermis contains dense neutrophilic interstitial infiltrate with leukocytoclasis, but without fibrinoid necrosis of vessel walls. NUD often occurs in a setting of underlying systemic disease. The most commonly associated diseases are adult-onset Still's disease, Schnitzler syndrome, lupus erythematosus and cryopyrin-associated periodic syndromes. Treatment of NUD depends on the clinical context. Dapsone and colchicine are often effective.

Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after CD19 CAR-T Cell Immunotherapy

CD19 chimeric antigen receptor (CAR)-modified T cell therapy has produced impressive results in patients (pts) with CD19+B cell malignancies; however, treatment can be complicated by neurologic adverse events (AEs). The presentation and pathogenesis of neurotoxicity (NT) are incompletely understood.We report a clinical and pathologic study evaluating NT in 133 B-ALL, NHL and CLL pts treated with lymphodepletion chemotherapy and CD19 CAR-T cells (NCT01865617). Neurologic AEs were observed in 53 of 133 pts (40%; 19% grade [gr] 1-2; 16% gr 3; 2% gr 4; 3% gr 5). Most neurologic AEs were reversible. Delirium, headache, and language disturbances were the most frequently observed neurologic AEs, presenting in 66%, 55%, and 34% of pts with NT, respectively. Multivariable analysis showed that higher burden of malignant B cells in marrow, lymphodepletion with cyclophosphamide and fludarabine, and higher infused CAR-T cell dose were associated with increased risk of NT and cytokine release syndrome (CRS).The severity of NT correlated with higher peak concentrations of cytokines that may activate endothelial cells (EC), such as IL-6, IFN-γ, and TNF-α. Pts who developed gr ≥3 NT had more severe CRS with higher CAR-T cell counts in blood and evidence of vascular dysfunction. In severe NT, hypofibrinogenemia with elevated PT, aPTT, and d-dimer were consistent with EC activation. We confirmed in vivo EC activation during NT by demonstrating high concentrations of serum angiopoietin-2 (Ang-2) and von Willebrand Factor (VWF), which are released from Weibel-Palade bodies on EC activation. In vitro, serum from pts with NT induced activation and VWF release from human umbilical vein ECs (HUVECs), which suggests that the finding of a reduced fraction of high molecular weight VWF multimers in vivo during gr ≥4 NT results from consumption on platelets and sequestration on activated EC. Consistent with this explanation, we found reduced activity of the VWF-cleaving protease ADAMTS13 relative to VWF levels and more severe thrombocytopenia in pts with gr ≥4 NT.We considered that cytokine-induced EC activation might alter the integrity of the blood-brain barrier (BBB) during NT. During severe NT, CSF analyses demonstrated increased permeability of the BBB to protein and leukocytes, including CAR-T cells. The gradient between serum and CSF cytokines observed before lymphodepletion was lost during acute NT, consistent with inability of the BBB to shield the CNS from high concentrations of plasma cytokines. Brain vascular pericytes (BVP) play a critical role in vascular and BBB support, and when exposed to high TNF-α or IFN-γ concentrations BVP exhibited stress (increased cleaved caspase-3 and reduced PDGFRβ) and secreted IL-6 and VEGF, further promoting EC activation and BBB permeability.Neuropathologic examination of the brain of a patient with fatal NT demonstrated disrupted endothelium by CD31 immunohistochemistry and EC activation was confirmed by intravascular VWF binding and CD61+ platelet microthrombi. Further evidence of breach of the BBB included red blood cell extravasation from multiple vessels, vascular lesions with karyorrhexis, perivascular CD8+ T cell infiltration, and fibrinoid vessel wall necrosis. CAR-T cells were detected in the CNS.We investigated strategies to reduce the risks of severe NT. Logistic probability curves demonstrated that reduction in CAR-T cell dose to reduce the peak in vivo CAR-T cell blood count was associated with reduced risk of NT, but that the narrow therapeutic index of this approach would lead to loss of anti-tumor efficacy. To maintain CAR-T cell peak counts in blood, we developed a strategy to identify pts early after CAR-T cell infusion who might be at risk of subsequent severe NT and could be candidates for early intervention. Classification tree modeling demonstrated that in the first 36 hours after CAR-T cell infusion pts with fever ≥38.9°C, serum IL-6 ≥16 pg/mL, and MCP-1 ≥1343.5 pg/mL were at high risk of subsequent gr ≥4 NT (sensitivity 100%; specificity 94%). We also investigated whether pts with pre-existing endothelial activation were at higher risk of NT. Before lymphodepletion, pts who developed gr ≥4 NT had higher Ang-2:Ang-1 ratios than those with gr ≤3 NT, indicating that endothelial activation before lymphodepletion or CAR-T cell infusion may be a risk factor for NT that identifies pts who would benefit from a modified treatment regimen. DisclosuresTurtle:Adaptive Biotechnologies: Other: Advisory board; Bluebird Bio: Other: Advisory board; Gilead Sciences: Other: Advisory board; Precision Biosciences: Other: Advisory board; Celgene: Other: Advisory board; Juno Therapeutics: Other: Advisory board, Patents & Royalties, Research Funding. Liles:Juno Therapeutics: Consultancy, Other: Advisory board. Li:Juno Therapeutics: Employment, Equity Ownership. Yeung:Gilead: Research Funding. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Maloney:Celgene: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board.

The changing face of polyarteritis nodosa and necrotizing vasculitis

Polyarteritis nodosa (PAN) is a vasculitic disease characterized primarily by necrotizing vasculitis - inflammatory lesions in blood vessels that lead to vessel wall necrosis. Our understanding of PAN and necrotizing vasculitis has evolved over time. In addition to PAN, necrotizing vasculitis is now a recognized feature of a broad range of diseases with different aetiopathogenesis. For example, necrotizing vasculitis associated with hepatitis B virus infection has a different aetiopathogeneis to PAN and is now classified as a separate disease. Additionally, although 'classic' PAN is not an inherited disease, mutations in specific genes, such as ADA2 (also known as CECR1), can result in a necrotizing vasculopathy similar to PAN. The literature also suggests that the course of PAN differs in childhood-onset disease and in cases confined to the skin (so-called cutaneous PAN). Dissecting PAN and other autoinflammatory diseases with PAN-like features has enabled more-specific therapies and might also help us better understand the pathogenesis of these devastating conditions.

Vasculitis in the Central Nervous System.

Central nervous system (CNS) vasculitides are a heterogeneous group of disorders characterized by an inflammatory cell infiltration and necrosis of blood vessel walls in the brain, spinal cord, and the meninges. The CNS complications are likely to be fatal without judicious use of immunosuppression; thus, early diagnosis may prevent from damage and disability. This chapter updates our knowledge on CNS vasculitis-related immunological mechanisms, neurological complications, diagnosis, and management.

First steps in the standardization of immunoglobulin IgG myeloperoxidase-anti-neutrophil cytoplasmic antibody measurements.

The standardization of immunoassays for immunoglobulin (Ig)G myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA) could contribute to a more accurate diagnosis and follow-up of small vessels-associated vasculitis, a systemic autoimmune disorder that leads to necrosis of blood vessel walls. Despite significant efforts by different groups, the level of comparability of results from commercially available immunoassays used for IgG MPO-ANCA detection is still poor. Therefore, the potential for improvement using reference materials was assessed. The evaluation of a set of 30 patient samples with 11 assays showed that differences between assays result in different interpretations for individual patients. Only 10 of 30 patient samples had the same clinical interpretation among 11 assays applying the cut-off values provided by each respective manufacturer. The correlation between results from 13 different assays was assessed in a pairwise manner. The correlation between results from patient samples was systematically very good for combinations of seven of those assays. The correlation of results ranged from reasonable to good for combinations with four other assays, therefore it should be possible to improve the comparability of results using a commutable reference material for calibration. Feasibility studies were conducted in order to find a reference material format most suitable for a calibrator. Two sets of candidate reference materials were produced from different raw materials, and assessed according to their suitability. A final format was selected, and a candidate reference material was produced.

Evaluation of percutaneous microwave coagulation therapy for hepatic artery injury.

ObjectivesTo evaluate the in vivo efficacy of 915 MHz percutaneous coagulation in the treatment of hepatic artery injury.MethodsAfter inducing hepatic artery injury, 8 dogs in each group underwent 915 MHz microwave percutaneous coagulation therapy and 8 dogs were injected with batroxobin and α-cyanoacrylate.ResultsThe hemostatic effects of 915 MHz microwave were better than drug injection, and the amount of bleeding was significantly lower (p < 0.05). Pathological examination showed that vessel wall necrosis were greater.ConclusionContrast ultrasound guided 915 MHz microwave percutaneous coagulation treatment has potent hemostatic effects in the repair of in vivo hepatic artery injury.

Cerebral amyloid angiopathy and dementia

Cerebral amyloid angiopathy (CAA) is one of the most frequent causes of intracerebral hemorrhage (ICH). The deposition of beta amyloid leads to vascular fragility due to degeneration of vessel walls, formation of microaneurysms particularly in cortical blood vessels and fibrinoid vessel wall necrosis. The Congo red positive amyloid deposits are biochemically similar to the material comprising senile plaques in Alzheimer's disease. Recurrent or multiple simultaneous hemorrhages particularly in older patients should raise the suspicion of CAA. Gradient echo magnetic resonance imaging (MRI) is a sensitive, non-invasive technique for identifying even very small hemorrhages and superficial siderosis, which may cause transient symptoms in CAA. There is also a correlation between CAA, microbleeding and cognitive decline. Inflammatory variants of CAA must be suspected whenever patients present with progressive dementia, headache and multifocal symptoms in association with CAA findings in MRI. Histopathologically, a distinction is made between CAA-related inflammation (CAA-ri) with perivascular inflammatory infiltrates and amyloid beta-related angiitis (ABRA) with histological detection of transmural vasculitis. Inflammatory variants should be treated with corticosteroids and immunosuppressants.

Lupus erythematosus and neutrophilic urticarial dermatosis: a retrospective study of 7 patients.

Neutrophilic urticarial dermatosis (NUD) resembles urticaria clinically but is a neutrophilic dermatosis histopathologically. The majority of patients with NUD have an underlying systemic condition, mainly, autoinflammatory disorders such as cryopyrin-associated periodic syndromes, Schnitzler syndrome, and adult-onset Still disease, but a few also have systemic lupus erythematosus (LE). Here, we confirm these data and we report relevant clinical and histopathological data of 7 patients with LE and NUD. We retrospectively retrieved the medical records of all patients with LE in whom skin biopsy showed NUD in registers of Strasbourg and Montpellier University hospitals since 2000. All were female and aged between 13 and 45 years. Skin lesions were typically rose or red macules or slightly elevated papules occurring in a wide distribution. Individual lesions resolved within 24 hours and were not or only slightly itchy. Every patient had associated signs, most of the time polyarthritis and/or fever. NUD was the presenting mode of LE in 2 patients. NUD was misdiagnosed as a classic lupus flare and led to therapeutic intensification with the introduction of immunosuppressive drugs in 4 patients. Histopathological findings consisted of intense neutrophilic interstitial and perivascular infiltrate with leukocytoclasia and without fibrinoid necrosis of vessel walls. Direct immunofluorescence testing showed a lupus band in 4 patients. Antinuclear antibodies were always positive, anti-dsDNA antibodies were positive in 5 patients, and anti-Ro/SSA antibodies in 6 patients. Immunosuppressive drugs such as prednisone, hydroxychloroquine, mycophenolate mofetil, and methotrexate were never effective to treat NUD. Antihistamines were effective in 1 patient and dapsone or colchicine was effective in 5 patients. NUD is not exceptional in patients with systemic LE and is easily misdiagnosed as an acute LE flare. Furthermore, we show that conventional immunosuppressive LE treatments are not efficient and we underline the major interest of dapsone and colchicine, classic neutrophil migration inhibitors, in those patients.