COVID-19 vaccination was a rare potential etiology for cause of death after medicolegal autopsy. A Finnish nationwide study. (preprint)

COVID-19 vaccinations began globally at the end of 2020. By the end of 2021, 9.8 million doses were given in Finland. Regarding safety, most vaccine-related adverse reactions have been mild, but serious and lethal ones have also occurred. Autopsies in post vaccination deaths may give insight to the extent of fatal health conditions with potential COVID-19 vaccine etiology and provide new hypotheses of possible causalities between vaccination and severe health conditions. We searched the complete documentation on all medicolegal autopsies in Finland between December 2020 and December 2021 to assess how often the basis for autopsy was a suspected fatal adverse reaction to COVID-19 vaccination, and whether vaccination remained a potential etiology for any health condition determined as a cause of death after the autopsy. We linked register-based data on individual COVID-19 vaccination course and pre-existing health conditions. We found 428 autopsy cases with a mention of COVID-19 vaccination, and prior to autopsy, vaccination was suspected to play a part in 76 deaths. Post autopsy, a forensic pathologist considered vaccination as a potential etiology in five underlying and seven contributory causes of death. These included seven thromboembolisms, two diabetic ketoacidoses, one myocarditis, one acute pancreatitis, and one eosinophilic granulomatosis with polyangiitis. In relation to the number of vaccinations within Finland, a suspicion of vaccine-related serious adverse reaction was rarely an indication for medicolegal autopsy. Even less frequently was vaccination considered to play a part in the process leading to death, although considerable doubt remains in the accuracy of individual considerations, and autopsy cannot definitively confirm causality between vaccination and death. Regarding vaccination safety, continuing evaluation of suspected vaccine-related deaths is essential, and an autopsy should be part of the investigation when such a suspicion arises.

Eosinophilic Granulomatosis with Polyangiitis after mRNA-1273 SARS-CoV-2 Vaccine (preprint)

During one of the worst global health crises, millions of people were vaccinated against SARS-CoV-2. In rare cases, new onset systemic inflammatory diseases were reported with temporal coincidence to the vaccination. We describe a case of severe Eosinophilic Granulomatosis with Polyangiitis (EGPA) in a young asthmatic woman, occurring after a 2nd dose of mRNA-1273 vaccine. She presented with multisystem EGPA with cardiac and central nervous system involve-ment, complicated by secondary immune thrombocytopenia (ITP). We review the reported cases of EGPA coinciding with SARS-CoV-2 mRNA vaccination. All potentially vaccine-related EGPA cases reported so far occurred within 14 days from immunization. EGPA is very rare with an incidence of 1:1’000’000 inhabitants and the number of reported post-vaccination EGPA cases lies within the expected incidence rate for the period. While we cannot prove a causal relationship between the vaccine and EGPA onset, the temporal relationship with the vaccine immune stimulation is intriguing, in a disease occurring almost always in adults with asthma and/or chronic rhinosinusitis and driven by an aberrant Th2 lym-phocyte activation with hypereosinophilia. Nevertheless, cases of inflammatory diseases emerging in the context of vaccination remain rare and the benefits of preventing severe Covid presentations with SARS-CoV-2 mRNA vaccines remains unquestionable.

Score to assess the probability of relapse in granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: To develop a score assessing the probability of relapse in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Long-term follow-up data from GPA and MPA patients included in five consecutive randomised controlled trials were pooled. Patient characteristics at diagnosis were entered into a competing-risks model, with relapse as the event of interest and death the competing event. Univariate and multivariate analyses were computed to identify variables associated with relapse and build a score, which was then validated in an independent cohort of GPA or MPA patients. RESULTS: Data collected from 427 patients (203 GPA, 224 MPA) at diagnosis were included. Mean±SD follow-up was 80.6±51.3 months; 207 (48.5%) patients experienced ≥1 relapse. Relapse risk was associated with proteinase 3 (PR3) positivity (HR=1.81 (95% CI 1.28 to 2.57); p<0.001), age ≤75 years (HR=1.89 (95% CI 1.15 to 3.13); p=0.012) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (HR=1.67 (95% CI 1.18 to 2.33); p=0.004) at diagnosis. A score, the French Vasculitis Study Group Relapse Score (FRS), from 0 to 3 points was modelised: 1 point each for PR3-antineutrophil cytoplasmic antibody positivity, eGFR ≥30 mL/min/1.73 m² and age ≤75 years. In the validation cohort of 209 patients, the 5-year relapse risk was 8% for a FRS of 0, 30% for 1, 48% for 2 and 76% for 3. CONCLUSION: The FRS can be used at diagnosis to assess the relapse risk in patients with GPA or MPA. Its value for tailoring the duration of maintenance therapy should be evaluated in future prospective trials.

Granulomatosis with Polyangiitis following COVID-19 in an Adolescent.

Granulomatosis with polyangiitis (GPA) is a systemic disease that causes vasculitis in various organs. Although the mechanism of pathogenesis remains unclear, infection has been reported to be a causative factor. We herein report a case of GPA that developed following coronavirus disease 2019 (COVID-19) in an adolescent girl. One month after contracting mild COVID-19, the patient had facial allodynia, a fever, and weight loss and was admitted for multiple nodular shadows on a chest roentgenogram. GPA was diagnosed based on pathological findings of the lung and nasal mucosal biopsies. She received methylprednisolone and rituximab, and her symptoms and radiological findings improved.

A case of systemic lupus erythematosus presenting with intestinal lymphangiectasia-associated protein-losing enteropathy accompanying hyperinflammation.

Systemic lupus erythematosus (SLE) has the potential to affect virtually every organ; however, gastrointestinal system manifestations are relatively rare compared to other autoimmune diseases such as systemic sclerosis and inflammatory bowel disease. A 29-year-old female patient attended to the emergency room with abdominal distention, acute onset abdominal pain and constipation. She had watery chronic diarrhea (4-5 times/d) and weight loss (6 kg, 12%) for 4 months. While there was increased intestinal wall thickness, air-liquid levels were shown on abdomen computed tomography scan. The patient underwent abdominal surgery due to diagnosis of ileus. Ileocecal resection was performed and pathologic evaluation revealed intestinal lymphangiectasia. Autoimmune serology was performed with the following resulats: anti-nuclear antibody 1/3200 with homogenous pattern, anti-DNA antibody and anti-Sm/ribonucleoprotein antibodies were positive in addition to low complement levels (C3: 0.28 [0.9-1.8 g/L], C4: 0.06 [0.1-0.4 g/L]) indicating diagnosis of SLE. Development of intestinal involvement in SLE (lupus enteritis) is mainly grouped into 3 headings such as mesenteric vasculitis, pseudo-obstruction, and protein-losing enteropathy. Although the pathogenesis of intestinal lymphangiectasia remains unknown, it has been reported that immune complex-mediated visceral vasculitis may result in bowel wall and mucosal edema. To our knowledge this is the first case report accompanying hyperinflammatory response in addition to intestinal lymphangiectasia in SLE. On the other hand, clinicians should be alert for other reasons for hyperinflammatory syndromes rather than COVID-19, even during the pandemic.

Inflammatory rheumatic diseases developed after COVID-19 vaccination: presentation of a case series and review of the literature.

OBJECTIVE: An increasing number of new on-set autoimmune-inflammatory rheumatic diseases (AIRD) after COVID-19 vaccination has begun to be reported in the literature. In this article, we present our patients with new-onset AIRD after vaccination for COVID-19 and review the literature on the subject. PATIENTS AND METHODS: We investigated the clinical characteristics and laboratory parameters of previously described "newly developed AIRD in individuals recently vaccinated for COVID-19", in 22 cases vaccinated with one of the COVID-19 vaccines (BNT162b2 or CoronaVac) approved in our country. RESULTS: We collected 22 cases (14 female, 63.6%) that developed an AIRD after COVID-19 vaccination. Mean age was 53±14.4 (24-87) years. The interval between the last dose of vaccination and the development of the first complaint was 23.9±19.5 (4-90) days. CoronaVac was administered to four patients, and the BNT162b2 to 18 patients. AIRD-related symptoms developed in 12 patients after the first dose, in 8 patients after the second dose, and in two patients after the third dose. Twelve out of the 22 (54.5%) cases were diagnosed with rheumatoid arthritis, two with SLE, and the remaining eight patients each with leukocytoclastic vasculitis, Sjogren's syndrome, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, mixed connective tissue disease, eosinophilic granulomatosis with polyangiitis, and inflammatory myositis, respectively. Six patients had a history of documented antecedent COVID-19 infection. CONCLUSIONS: Autoimmune/inflammatory rheumatic diseases may develop after COVID-19 vaccinations. In the era of the COVID-19 pandemic, vaccination should be questioned carefully in newly diagnosed AIRD patients.

Environmental factors influencing the risk of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of diseases characterized by inflammation and destruction of small and medium-sized blood vessels. Clinical disease phenotypes include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The incidence of AAV has been on the rise in recent years with advances in ANCA testing. The etiology and pathogenesis of AAV are multifactorial and influenced by both genetic and environmental factors, as well as innate and adaptive immune system responses. Multiple case reports have shown that sustained exposure to silica in an occupational environment resulted in a significantly increased risk of ANCA positivity. A meta-analysis involving six case-control studies showed that silica exposure was positively associated with AAV incidence. Additionally, exposure to air pollutants, such as carbon monoxide (CO), is a risk factor for AAV. AAV has seasonal trends. Studies have shown that various environmental factors stimulate the body to activate neutrophils and expose their own antigens, resulting in the release of proteases and neutrophil extracellular traps, which damage vascular endothelial cells. Additionally, the activation of complement replacement pathways may exacerbate vascular inflammation. However, the role of environmental factors in the etiology of AAV remains unclear and has received little attention. In this review, we summarized the recent literature on the study of environmental factors, such as seasons, air pollution, latitude, silica, and microbial infection, in AAV with the aim of exploring the relationship between environmental factors and AAV and possible mechanisms of action to provide a scientific basis for the prevention and treatment of AAV.

Diffuse alveolar hemorrhage as a life threatening manifestation of newly diagnosed granulomatosis with polyangiitis following COVID-19 infection - a case report.

A case report of a patient with newly diagnosed granulomatosis with polyangiitis (GPA) after undergoing COVID-19 (Coronavirus Disease 2019) is discussed. GPA is one of the ANCA-associated vasculitis, which is characterized by the presence of autoantibodies against cytoplasmic enzymes neutrophils (Anti Neutrophil Cytoplasmatic Antibodies). It is a vasculitis that mainly affects small blood vessels, leading to damage to the kidneys, lungs, and upper respiratory tract, including the paranasal sinuses and orbits. This disease can result in an acute life-threatening condition. Such complications include diffuse alveolar hemorrhage (DAH), a condition characterized by blood leakage from the pulmonary vessels into the alveoli, often leading to acute vital signs and even respiratory failure. DAH can have many causes - autoimmune diseases including vasculitides as well as non-immunological causes. Early and adequate comprehensive therapy including immunosuppressive treatment (cyclophosphamide/rituximab and glucocorticoids) can be life-saving.

COVID-19 course in granulomatosis with polyangiitis: single center experience with review of the literature.

BACKGROUND: Coronavirus disease 2019 (COVID-19) shares some clinical features with new-onset granulomatosis with polyangiitis (GPA) or GPA flare that may lead to a challenge in differential diagnosis. To date, little is known whether GPA can be induced by COVID-19. Herein, we aimed to seek the frequency and mortality rates of COVID-19 in our GPA cohort, and along with the literature cases, to evaluate clinical features and treatments of GPA patients with COVID-19. We also tried to identify clinical features of COVID-19 induced GPA. METHODS: As of July 2021, we conducted a systematic literature review using different spelling combinations of "COVID-19 and GPA" in the PUBMED database. In total, 18 cases were found in the literature, 6 of them had COVID-19 induced GPA. The remaining 12 of literature cases and 6 cases in our GPA cohort (n = 81) had a COVID-19 infection while followed-up with GPA. We grouped these 18 patients as GPA+COVID-19. RESULTS: The frequency of COVID-19 was 7.4% in GPA cohort and mortality rate was 33% in GPA patients with COVID-19. The most common symptoms of GPA+COVID-19 patients were fever, cough, arthralgia/myalgia, and malaise. The most frequent treatments for GPA before the COVID-19 infection were steroids (72%) and rituximab (56%). Three patients who received rituximab also had COVID-19 reinfection. In the literature cases, mortality was observed in 4 (22%) of 18 patients with GPA+COVID-19. The most common symptoms of COVID-19 induced GPA were dyspnea, fever and cough. DISCUSSION: In our GPA cohort, we observed a higher mortality rate compared to global WHO data. In patients followed up with GPA, rituximab treatment may be precarious for both COVID-19 disease and reinfection. Our study also provided some clues about the diagnostic challenge of GPA induced by COVID-19.

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications.

PURPOSE: SARS-CoV-2 infection in immunocompromised hosts is challenging, and prolonged viral shedding can be a common complication in these patients. We describe the clinical, immunological, and virological course of a patient with eosinophilic granulomatosis with polyangiitis, who developed the status of long-term asymptomatic SARS-CoV-2 carrier for more than 7 months. METHODS: Over the study period, the patient underwent 20 RT-PCR tests for SARS-CoV-2 detection on nasopharyngeal swabs. In addition, viral cultures and genetic investigation of SARS-CoV-2 were performed. As for immunological assessment, serological and specific T-cell testing was provided at different time points. RESULTS: Despite the patient showing a deep drug-induced B and T adaptive immunity impairment, he did not experience COVID-19 progression to severe complications, and the infection remained asymptomatic during the follow-up period, but he was not able to achieve viral clearance for more than 7 months. The infection was finally cleared by SARS-CoV-2-specific monoclonal antibody treatment, after that remdesivir and convalescent plasma failed in this scope. The genetic investigations evidenced that the infection was sustained by multiple viral subpopulations that had apparently evolved intra-host during the infection. CONCLUSION: Our case suggests that people with highly impaired B- and T-cell adaptive immunity can prevent COVID-19 progression to severe complications, but they may not be able to clear SARS-CoV-2 infection. Immunocompromised hosts with a long-term infection may play a role in the emergence of viral variants.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and COVID-19: The Clinical Course and Prognosis of 15 Patients From a Tertiary Care Center.

OBJECTIVE: The aim of this study was to evaluate incidence rates, prognoses, and disease-related factors associated with poor outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) who had coronavirus disease (COVID-19). METHODS: Patients with AAV were questioned for a history of COVID-19 in the outpatient setting. Cumulative clinical findings and treatment history were obtained from the patients' medical records. The clinical, laboratory, and imaging findings of inpatients with COVID-19 were recorded. The data of patients who developed symptomatic COVID-19 and/or died of the disease were used for comparison. RESULTS: Eighty-nine patients (47.2% female; mean age, 56 ± 12.5 years) were included. The diagnosis was granulomatosis with polyangiitis in 56 patients (62.9%) and microscopic polyangiitis in 33 (37.1%). Sixty-one (68.2%) and 21 patients (23.6%) had renal and peripheral nerve involvement, respectively. Ten patients had a history of diffuse alveolar hemorrhage. Fifteen patients (16.9%) had COVID-19, including 9 (60%) with severe pneumonia. Twelve patients (85.7%) were hospitalized, 6 (42.9%) were admitted to the intensive care unit, and 5 (35.7%) died. All deceased patients had hypogammaglobulinemia (IgG levels <700 mg/dL) during hospital admission. Symptomatic COVID-19 was associated with higher disease activity, glucocorticoid and rituximab treatments, and glomerular filtration rate <30 mL/min. A history of peripheral nerve involvement, higher organ damage scores, and hypogammaglobulinemia was associated with mortality. CONCLUSIONS: The prognosis was poor in our patients with AAV who had COVID-19, especially those with severe multisystem involvement. Hypogammaglobulinemia was associated with mortality. Serum IgG level monitoring in patients with AAV would be beneficial during the COVID-19 pandemic.

Recrudescence of severe polyneuropathy after receiving Pfizer-BioNTech COVID-19 vaccine in a patient with a history of eosinophilic granulomatosis with polyangiitis.

A middle age man with a history of diabetes mellitus type 2, hypertension, migraine and eosinophilic granulomatosis with polyangiitis (EGPA) with polyneuropathy in remission presented with paresthesia and motor weakness soon after receiving the Pfizer-BioNTech COVID-19 messanger RNA (mRNA) vaccine. The patient had polyneuropathy 10 years ago secondary to EGPA, which had resolved. EGPA was diagnosed on the basis of typical symptoms and positive sural nerve biopsy. Five days after receiving the first dose of COVID-19 vaccine, he developed heaviness and reduced dexterity of both the upper extremities, which progressed to patchy and asymmetric motor weakness of all four extremities. Given the lack of clear alternative explanation after a thorough work up, recrudescence of underlying asymptomatic polyneuropathy due to a possible reaction to COVID-19 mRNA vaccine was considered although a temporal association with vaccine dose does not prove causality. He was treated with corticosteroids with slow improvement of his symptoms.

Acute Myocardial Infarction and COVID-19 in a Known Case of Granulomatosis with Polyangiitis.

Since the emergence of novel coronavirus and the disease named as COVID-19 in late December of 2019 in Wuhan, Hubei province, China, many aspects of this disease have been reported in the literature (mainly pulmonary manifestations). In patients with COVID-19, rheumatic and cardiovascular manifestations and interactions were reported separately, but they were all very rare. This is the report of a 14-year-old teenager with GPA (previously known as Wegner's granulomatosis) who was in remission with immunosuppressive therapy. Post COVID-19 infection, she developed exacerbation of her disease. Besides the rheumatologic manifestations, she developed epigastric pain found to be acute myocardial infarction (MI) that needed primary percutaneous coronary intervention (PCI).

Fulminant granulomatosis with polyangiitis presenting with diffuse alveolar haemorrhage following COVID-19.

A 40-year-old man developed granulomatosis with polyangiitis (GPA) following a mild case of COVID-19. Initially, he experienced mild migrating joint pain for 2 months prior to testing positive for SARS-CoV-2 but dramatically worsened following resolution of his infection. The pain continued to progress until he suddenly develope haemoptysis, prompting him to present to a local hospital. The diagnosis of diffuse alveolar haemorrhage secondary to GPA was confirmed with labs, imaging and histopathology. Precipitous deterioration of GPA with concurrent COVID-19 infection indicates a possible temporal relationship. Since the onset of the pandemic, SARS-CoV-2 has been anecdotally associated with the development of various connective tissue disorders. The overlapping clinical presentations and similar appearance on lung imaging present clinicians with a diagnostic challenge. This underscores the importance of having a high index of suspicion of autoimmune diagnoses in patients who present with new or worsening findings following a COVID-19 infection.

COVID-19 pneumonia in a patient with granulomatosis with polyangiitis on rituximab: case-based review.

A 77-year-old man with past medical history of granulomatosis with polyangiitis (GPA) on rituximab and prednisone, presented to the hospital with worsening cough and shortness of breath. He had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by nasal swab polymerase chain reaction (PCR) while asymptomatic, 6 weeks earlier. He started with cough and shortness of breath 2 weeks after his initial positive test. After developing symptoms, he tested negative twice by nasal swab PCR, but the PCR of his bronchioloalveolar lavage was positive for SARS-CoV-2. He did not develop antibodies against coronavirus. Prednisone 15 mg daily was continued, and he received remdesivir, and convalescent plasma with quick recovery. We reviewed the literature to search for similar cases. Our case suggests that SARS-CoV-2 infection in patients on rituximab may have an atypical presentation and the diagnosis may be delayed due to negative PCR testing in the nasal swab. Patients may benefit from treatment with convalescent plasma.

Eosinophils as Major Player in Type 2 Inflammation: Autoimmunity and Beyond.

Eosinophils are a subset of differentiated granulocytes which circulate in peripheral blood and home in several body tissues. Along with their traditional relevance in helminth immunity and allergy, eosinophils have been progressively attributed important roles in a number of homeostatic and pathologic situations. This review aims at summarizing available evidence about eosinophils functions in homeostasis, infections, allergic and autoimmune disorders, and solid and hematological cancers.Their structural and biological features have been described, along with their physiological behavior. This includes their chemokines, cytokines, granular contents, and extracellular traps. Besides, pathogenic- and eosinophilic-mediated disorders have also been addressed, with the aim of highlighting their role in Th2-driven inflammation. In allergy, eosinophils are implicated in the pathogenesis of atopic dermatitis, allergic rhinitis, and asthma. They are also fundamentally involved in autoimmune disorders such as eosinophilic esophagitis, eosinophilic gastroenteritis, acute and chronic eosinophilic pneumonia, and eosinophilic granulomatosis with polyangiitis. In infections, eosinophils are involved in protection not only from parasites but also from fungi, viruses, and bacteria. In solid cancers, local eosinophilic infiltration is variably associated with an improved or worsened prognosis, depending on the histotype. In hematologic neoplasms, eosinophilia can be the consequence of a dysregulated cytokine production or the result of mutations affecting the myeloid lineage.Recent experimental evidence was thoroughly reviewed, with findings which elicit a complex role for eosinophils, in a tight balance between host defense and tissue damage. Eventually, emerging evidence about eosinophils in COVID-19 infection was also discussed.

COVID-19-induced granulomatosis with polyangiitis.

COVID-19 and granulomatosis with polyangiitis share many clinical and radiological features, making it challenging for clinicians to distinguish between the two. In this case report, we describe a patient who was diagnosed with COVID-19 in October 2020. One month later, she presented with persistent fatigue, shortness of breath and anaemia with worsening renal functions, found to have elevated antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies, and diagnosed with granulomatosis with polyangiitis.