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.

Worm globalization.

We report the first case of eosinophilic pleural effusion due to Anisakis spp. infection in a 39-years-old European subject hospitalized for worsening dyspnoea and abdominal and thoracic pain. Lung CT scan showed bilateral pleural effusion; thoracentesis revealed significant eosinophilia (45%), with normal eosinophils in the blood. Microbiological tests on pleural effusion were negative for bacteria, SARS-CoV-2, tuberculosis, fungi and parasites. The patient used to eat raw fish; Western blot was positive for Anisakis spp. in blood and pleural effusion. In the era of globalization, unusual parasitic infections should be considered also in nonendemic countries, especially in patients with unexplained eosinophilia.

Novel targeted inhibition of the IL-5 axis for drug reaction with eosinophilia and systemic symptoms syndrome.

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients. Objectives: We hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity. Methods: Herein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases. Results: A review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17-87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection. Conclusion: Current treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.

Colitis with Hypereosinophilia following the Second Dose of the BNT162b2 mRNA COVID-19 Vaccine: A Case Report with a Literature Review.

A 61-year-old man presented with a 7-day history of watery diarrhea and loss of appetite after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. Laboratory studies showed significant eosinophilia and an elevated IgE level (white cell count, 18.4×109/L; eosinophil count, 9.5×109/L; and IgE level, 540 IU/L). Symptoms resolved 10 days after vaccination without any steroids or antiallergic medications, and the eosinophil count had also returned to within normal limits 2 months later. Several cases of eosinophilic disorders following receipt of any type of injectable COVID-19 vaccine have been reported, so the etiology should be examined.

Pulmonary Paragonimiasis: A Case Series.

Paragonimiasis contributes to significant foodborne zoonosis worldwide. The major mode of transmission in humans is by consumption of uncooked or undercooked crabs and crayfish harbouring Paragonimus metacercariae. It begins with symptoms like fever and lower respiratory involvement from a few months to a year, mimicking those of tuberculosis and leading to diagnostic delay. Here, we report two cases of paragonimiasis during a period of nine months. Both cases presented with symptoms of productive cough with rusty sputum, chest pain, along with eosinophilia, and pleural effusion and had a history of consumption of smoked crab from the local river. The diagnosis was established by microscopic demonstration of Paragonimus ova in the sputum. They were treated with praziquantel and recovered. Indeed, it is challenging to diagnose paragonimiasis due to the lack of its specific symptoms but should be considered in the differential diagnosis of eosinophilia and pleural effusion in such lung diseases. Keywords: case reports; eosinophilia; paragonimiasis; pleural effusion.

FIP1L1-PDGFRA fusion gene in T-lymphoblastic lymphoma: A case report.

BACKGROUND: T-lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of T-lymphoid precursors, rarely co-occurring with myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), with consequent rearrangement of tyrosine kinase (TK)-related genes. The FIP1L1-PDGFRA fusion gene is the most frequent molecular abnormality seen in eosinophilia-associated myeloproliferative disorders, but is also present in acute myeloid leukemia (AML), T-lymphoblastic leukemia/lymphoma (TLL), or both simultaneously. T-LBL mainly affects children and young adults, involving lymph node, bone marrow, and thymus. It represents about 85% of all immature lymphoblastic lymphomas, whereas immature B-cell lymphomas comprise approximately 15% of all cases of LBL. CASE: In this case report, we present an example of T cell lymphoblastic lymphoma with coexistent eosinophelia, treated successfully with a tyrosine-kinase inhibitor (TKI). CONCLUSION: FIP1L1-PDGFRA-positive T-LBL and myeloproliferative disorders have excellent response to low-dose treatment with (TKI) imatinib. Most patients achieve rapid and complete hematologic and molecular remission within weeks.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms following nivolumab and ipilimumab in a pediatric patient with melanoma.

Drug-induced hypersensitivity syndrome (DIHS) is a type of severe cutaneous adverse reaction (SCAR). DIHS typically occurs 2-6 weeks after initiation of the offending medication. We report a case of DIHS in a pediatric patient undergoing treatment of metastatic melanoma with nivolumab and ipilimumab.

Quality over quantity; eosinophil activation status will deepen the insight into eosinophilic diseases.

Eosinophil associated diseases have gained much attention recently because of the introduction of specific eosinophil targeted therapies. These diseases range from acute parasitic infections to chronic inflammatory diseases such as eosinophilic asthma. In eosinophilic asthma an increased eosinophil cell count in peripheral blood is the gold standard for determination of the pheno-/endotype and severity of disease. Despite a broad consensus there is concern on validity of this simple measurement, because the eosinophil compartment is far from homogenous. Multiple tissues harbour non-activated cells under homeostatic conditions and other tissues, normally devoid of eosinophils, become infested with these cells under inflammatory conditions. It will, therefore, be clear that eosinophils become differentially (pre)-activated at different tissue sites in homeostatic and inflammatory conditions. This complexity should be investigated in detail as it is 1) far from clear what the long-term side effects are that are caused by application of eosinophil targeted therapies in a "one size fits all" concept and 2) real-world data of eosinophil targeted therapies in asthma shows a broad variety in the treatment response. This review will focus on complex mechanisms of eosinophil activation in vivo to create a better view on the dynamics of the eosinophil compartment in health and disease both to prevent collateral damage caused by aberrant activation of eosinophils ánd to improve effectiveness of eosinophil targeted treatments.

Strongyloidiasis Hyperinfection Syndrome in COVID-19 Positive Migrants Treated with Corticosteroids.

The aim of this study is to highlight the potentially fatal risk of Strongyloidiasis Hyperinfection Syndrome for hospitalized immigrant patients with moderate to severe COVID-19 disease and undiagnosed Strongyloidiasis. We reviewed electronic medical records of immigrants from 2010 to 2022 and extracted the number of patients with eosinophilia, strongyloidiasis and COVID-19 infection, outpatient and hospitalized. While 885 outpatients were diagnosed with eosinophilia, only 356 (40.2%) were tested for strongyloidiasis and 160 (44.9%) yielded a reactive serology. COVID-19 infection was reported in 6,412 patients. 1135 (17.7%) of these patients sought hospital care. Patients with undiagnosed strongyloidiasis are at risk for a potentially fatal parasitosis if treated with systemic corticosteroids for COVID-19. This supports clinical guidelines in hospital settings for those with severe COVID-19. Strongyloidiasis should be considered by taking a thorough travel or migration history and testing before giving immunosuppressive drugs.

mRNA COVID-19 Vaccine-Associated Subserosal Eosinophilic Gastroenteritis: A Case Report.

The World Health Organization declared coronavirus disease 2019 (COVID-19) a global pandemic in March 2020. Several vaccines have been developed to overcome the COVID-19 pandemic, and messenger RNA vaccines, commonly known as mRNA vaccines, were the first COVID-19 vaccines to be authorized in Korea. With the worldwide increase in vaccinations, reports of adverse reactions are increasing. However, to the best of our knowledge, there have been no reports of eosinophilic gastroenteritis (EGE) following mRNA vaccination. Here, we present the first case of EGE in a patient who received a second dose of the mRNA vaccine, BNT162b2 (Pfizer-BioNTech). A previously healthy 34-year-old woman presented to the emergency department with generalized abdominal pain for the preceding 2 weeks. She had received a second dose of the mRNA COVID-19 vaccine 2 weeks prior. Subserosal EGE was diagnosed, oral prednisolone was administered, and she recovered completely.

Eosinophilic cellulitis in response to BNT162b2 COVID-19 vaccination.

A 12-year-old boy presented with a 2-week history of persistent pruritic edematous plaques one day after he received the first dose of the BNT162b2 COVID-19 mRNA vaccine. A skin biopsy showed urticarial dermatitis with tissue eosinophilia consistent with a diagnosis of vaccine-associated eosinophilic cellulitis, with polyethylene glycol as a potential trigger.

Strongyloides stercoralis.

Strongyloidiasis has been estimated to affect over 600 million people worldwide. It is caused by Strongyloides stercoralis, a roundworm endemic to the tropics and subtropics, especially areas where sanitation is suboptimal Autochthonous transmission has been documented in rural areas of the USA and Europe. Humans are infected when larvae penetrate the skin or are ingested. Autoinfection, in which larvae generated in the host go on to re-infect the host, leads to a state of chronic asymptomatic infection often with eosinophilia. Hyperinfection syndrome may develop when patients develop immune suppression, due to medications such as corticosteroids or following solid-organ transplantation. Hyperinfection is characterized by exponential increase in parasitic burden, leading to tissue invasion and life-threatening disease and associated bloodstream infections due to enteric organisms. Cases following use of corticosteroids for COVID-19 pneumonia have been described. Strongyloidiasis can be diagnosed by direct visualization of larvae in stool or other body fluids, or by serology. Ivermectin is highly effective in treating the disease. Patients with exposure to endemic areas and those expected to become immune suppressed should be screened and treated before starting immune suppressive agents. Empiric treatment should be considered when timely testing is not readily available.

Three cases of drug-induced hypersensitivity syndrome associated with mRNA-based coronavirus disease 2019 vaccines.

Drug-induced hypersensitivity syndrome (DiHS) is a severe drug eruption that can induce reactivation of herpesviruses such as human herpesvirus 6, resulting in symptom flare-up and organ damage. DiHS is known as drug reaction with eosinophilia and systemic symptoms (DRESS) in Europe. We report three cases of DiHS that could have been triggered by mRNA-based coronavirus disease 2019 (COVID-19) vaccines. In these three patients, symptoms of DiHS developed 2-6 days after the first dose of an mRNA-based COVID-19 vaccine. Although there have been no reports of DiHS/DRESS induced by mRNA-based COVID-19 vaccines in domestic and international journals despite the progress in vaccination worldwide, we speculate that mRNA-based COVID-19 vaccines might have triggered the development of DiHS/DRESS in our patients. In the current coronavirus epidemic, it might be important to assess mRNA-based COVID-19 vaccination status and date of vaccination when evaluating a patient with DiHS/DRESS.

Eosinophilia Is Associated with Improved COVID-19 Outcomes in Inhaled Corticosteroid-Treated Patients.

BACKGROUND: In addition to their proinflammatory effect, eosinophils have antiviral properties. Similarly, inhaled corticosteroids (ICS) were found to suppress coronavirus replication in vitro and were associated with improved outcomes in coronavirus disease 2019 (COVID-19). However, the interplay between the two and its effect on COVID-19 needs further evaluation. OBJECTIVE: To determine the associations among preexisting blood absolute eosinophil counts, ICS, and COVID-19-related outcomes. METHODS: We analyzed data from the Cleveland Clinic COVID-19 Research Registry (April 1, 2020 to March 31, 2021). Of the 82,096 individuals who tested positive, 46,397 had blood differential cell counts obtained before severe acute respiratory syndrome coronavirus 2 testing dates. Our end points included the need for hospitalization, admission to the intensive care unit (ICU), and in-hospital mortality. The effect of eosinophilia on outcomes was estimated after propensity weighting and adjustment. RESULTS: Of the 46,397 patients included in the final analyses, 19,506 had preexisting eosinophilia (>0.15 × 103 cells/µL), 5,011 received ICS, 9,096 (19.6%) were hospitalized, 2,129 required ICU admission (4.6%) and 1,402 died during index hospitalization (3.0%). Adjusted analysis associated eosinophilia with lower odds for hospitalization (odds ratio [OR] [95% confidence interval (CI)]: 0.86 [0.79-0.93]), ICU admission (OR [95% CI]: 0.79 [0.69-0.90]), and mortality (OR [95% CI]: 0.80 [0.68-0.95]) among ICS-treated patients but not untreated ones. The correlation between absolute eosinophil count and the estimated probability of hospitalization, ICU admission, and death was nonlinear (U-shaped) among patients not treated with ICS, and negative in treated patients. CONCLUSIONS: The association between eosinophilia and improved COVID-19 outcomes depends on ICS. Future randomized controlled trials are needed to determine the role of ICS and its interaction with eosinophilia in COVID-19 therapy.