Clinical update on risks and efficacy of anti-SARS-CoV-2 vaccines in patients with autoimmune hepatitis and summary of reports on post-vaccination liver injury

Authors: Ana Lleo 1Nora Cazzagon 2Cristina Rigamonti 3Giuseppe Cabibbo 4Quirino Lai 5Luigi Muratori 6Marco Carbone 7Italian Association for the Study of the LiverAffiliations expand PMID: 35410851 PMCID: PMC8958090DOI: 10.1016/j.dld.2022.03.014 Published:March 27, 2022DOI:https://doi.org/10.1016/j.dld.2022.03.014

Abstract

Patients with liver diseases, especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 and therefore anti-SARS-CoV-2 vaccine has been recommended by leading Scientific Associations for all patients with chronic liver diseases. However, previous reports have shown a reduced antibody response following the full course of vaccination in immunosuppressed patients, including liver transplant recipients and several rheumatic diseases.This document, drafted by an expert panel of hepatologists appointed by the Italian Association for the Study of the Liver (AISF), aims to present the updated scientific data on the safety and efficacy of anti-SARS-CoV-2 mRNA vaccines in patients with autoimmune hepatitis (AIH). Furthermore, given the recent reports of sporadic cases of AIH-like cases following anti-SARS-CoV-2 mRNA vaccines, we summarize available data. Finally, we provide experts recommendations based on the limited data available.

1. 2022 AISF recommendation on anti-SARS-CoV-2 vaccines for patients with known autoimmune hepatitis

Patients with chronic liver diseases (CLD), especially those with cirrhosis, have an increased mortality risk when infected by SARS-CoV-2 [[1]]. One of the largest international studies currently available, showed an observed mortality of 32% in patients with cirrhosis compared to 8% in those without [[2]]. Therefore, the European Association for the Study of the Liver (EASL) has recommended vaccination against SARS-CoV-2 for all patients with CLD [[3]]. Although contrasting data have been published, patients with AIH with or without cirrhosis under immunosuppressive therapy represent an at-risk category of developing severe COVID-19 when infected [[4],[5]]. Therefore, based on the data available, the benefit of anti-SARS-CoV-2 vaccination outweighs the potential risk for disease exacerbation in AIH.Although the registration trials of mRNA vaccines enrolled patients with CLD (217 patients in Pfizer trial and 196 patients in Moderna trial), subjects under immunosuppressive therapy were excluded. A recent study by Thuluvath and colleagues found that 75% of patients with CLD without cirrhosis and 77% of patients with cirrhosis had adequate antibody response to anti-SARS-CoV2 vaccines [[6]]. The authors included 233 patients with CLD with 61 being affected by immune mediated liver diseases, including AIH, primary biliary cholangitis, and primary sclerosing cholangitis. Also 62 patients were liver transplant (LT) recipients, 79 had cirrhosis, and 92 had CLD without cirrhosis. Antibody levels were undetectable in 11 patients who had LT, 3 with cirrhosis, and 4 without liver cirrhosis. LT and treatment with two or more immunosuppressive drugs were associated with poor antibody responses. However, only 3 patients out of 18 with undetectable antibody were AIH patients on immunosuppression (2 on prednisone plus mycophenolate mofetil (MMF) and 1 on prednisone plus azathioprine).Reports have shown a reduced antibody response following the full course of vaccination in liver transplant recipients [[7]]. It has also been formerly demonstrated that specific drugs (i.e. methotrexate, abatacept, and rituximab) reduced the immune response to influenza or pneumococcal vaccines in a number of different rheumatic diseases [8910]. The efficacy of anti-SARS-CoV-2 vaccination in preventing COVID-19 in patients with AIH on immunosuppressive therapies [[11],[12]], as well as the risk of disease reactivation after anti-SARS-CoV-2 vaccination, have been poorly investigated. Similarly, cellular immunity to SARS-CoV-2 in AIH patients has not been studied.The American College of Rheumatology (ACR) has recently proposed a guidance [[13]] suggesting a short-term withdrawal of methotrexate, JAK inhibitors, abatacept, and MMF, and deferral of rituximab and cyclophosphamide infusion if possible before anti SARS-Cov-2 vaccination, according to rheumatic disease activity. However, there is no solid evidence as to whether it is appropriate or not to suspend or reduce the dose of immunosuppressive drugs immediately before or following the administration of the vaccine in AIH patients. Importantly, this strategy may be potentially associated with an increased risk of AIH reactivation particularly dangerous in patients with cirrhosis. Of interest, high doses of MMF and rituximab remain independent predictors of failure to develop an antibody response after vaccination in rheumatic diseases [[14]]; however, no data are available in AIH. At the present time, the available data do not justify withdraw or reduction of immunosuppression before or immediately after vaccination in patients with AIH.Finally, no clear evidence of reactivation of AIH after anti-SARS-CoV-2 vaccination has been reported in the literature. Interestingly, the presence of significant fibrosis at the liver histology of a small number of newly diagnosed AIH following anti-SARS-CoV-2 vaccination might suggest the possibility of disease reactivation [151617]. However, until new multicenter studies are available there is no current indication for routine testing of transaminases levels in AIH patients after vaccination.

2. 2022 aisf recommendation on autoimmune hepatitis like onset following anti-SARS-CoV-2 vaccination

The COVID-19 pandemics has necessitated the development and registration of several vaccines in record time. The monitoring for safety, side effect and efficacy is ongoing in the post-marketing surveillance. Recent reports inform on the possible occurrence of immune mediated hepatitis or AIH-like disease in predisposed individuals. Autoimmunity is widely accepted to develop in genetically predisposed individuals and some polymorphisms have been identified in AIH [[18]]; unfortunately, they are not yet of clinical use and cannot be of help to identify individuals at risk.Considering that 58% of the world population has received at least one dose of anti-SARS-CoV-2 vaccine, with 9.2 billion doses been administered globally, it is unclear whether this is a pure coincidence rather than a causality.The fact that someone developed immune-mediated acute hepatitis after vaccination does not necessarily mean that this was caused by the vaccine.The European Medicine Agency (EMA)’s Pharmacovigilance Risk Assessment Committee (PRAC) has recently started an assessment following the very small number of cases reported after vaccination with Spikevax and Comirnaty (known as Moderna and Pfizer vaccines, respectively) in the medical literature and EudraVigilance (www.ema.europa.eu). Further data and analyses have been requested from the marketing authorization holder to support the ongoing assessment by PRAC. Given the small number of cases currently reported, the issue seems to be rare; however, specific studies should be performed to define the number and severity of cases.At the time these recommendations are drafted, 17 reports have been published in the medical literature that overall include 31 cases of suspected AIH-like triggered by the vaccine (Table 1). Patients were more often women (F:M 21:10), age ranging from 32 to 89 years old (median 58 years). In eleven cases a pre-existent autoimmune condition (i.e., seven Hashimoto thyroiditis, one primary biliary cholangitis, two rheumatoid arthritis, one systemic lupus erythematosus) is reported. Two patients had experienced COVID-19 infection before the vaccine. All except four presented with an acute onset of AIH-like with jaundice. All patients underwent liver biopsy and in six of them fibrosis was already present, which might suggest that they had a previous liver disease, possibly an undiagnosed AIH. All were treated with steroid therapy, and all improved the liver function tests (LFTs), although details on the biochemical response are not thoroughly reported.Table 1Cases of suspected AIH triggered by the vaccine reported in the literature.

ReferenceVaccinePatient’s characteristicsClinical presentation and laboratory dataTherapyOutcome
Age, genderAutoimmune comorbiditiesPrevious COVID-19 infectionOther comorbidities
Avci & Abasiyanik [15]mRNAPfizer/BioNTech,1 month before61, FHashimoto thyroiditisYes, mild, 8 months beforeHypertensionAcute icteric ANA, ASMA, hyper-IgG, fibrosis F2,Prednisolone + azathioprine add-on35 days follow-up, mild transaminases and bilirubin
Bril et al. [16]mRNAPfizer/BioNTech,7 days before35, FNot reportedNoGestational hypertension and cesarian section 3 months beforeAcute icteric, normal IgG, no fibrosisPrednisone 20 mg/day50 days follow-up, transaminases normalization
Cao et al. [17]Inactivated whole-virion SARS-CoV2 (Coronavac)57, FNot reportedNoNot reportedAcute icteric, pruritus IgG slight elevation, ANA+, Fibrosis F2Methylprednisolone, UDCA + azathioprine add-on5 months follow-up, no relapse
Clayton-Chubb et al. [23]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 26 days before36, MNoNoHypertension, laser eye surgery 2 weeks beforeAcute, sub-icteric, asymptomatic, ANA+, normal IgG, no fibrosisPrednisolone 60 mg/day24 days, normalization of bilirubin, marked reduction of ALT
Garrido et al. [24]mRNA Moderna, 2 weeks before65, FNoNoPolycythemia vera under PEG-IFNAcute icteric severe, ANA, hyper-IgG, no fibrosisPrednisolone 60 mg/day1 month, improvement of LFTs and IgG normalization
Ghielmetti et al. [25]mRNA-1273, 7 days before63, MNoNo, unknown but anti-cardiolipin+Type 2 diabetes, ischemic heart diseaseAcute icteric, hyper-IgG, ANA+, AMA+ (different from PBC) APCA+, no fibrosisPrednisone 40 mg/day, rapidly tapered14 days follow-up
Goulas et al. [26]mRNA Moderna, 2 weeks before52, FNoNoAcute icteric, ANA+, ASMA+, hyper-IgG, no fibrosis reportedPrednisolone 50 mg/day, azathioprine add-onUnknown
Londono et al. [27]mRNA Moderna, 7 days after the II dose41, FNot reportedNoHormonal therapy for premature ovarian failureAcute icteric, ANA, ASMA, anti-SLA/LC+, hyper-IgG, no fibrosisPrednisone 1 mg/KgNormalization of LFTs
Palla et al. [28]mRNAPfizer/BioNTech 1 month after II dose40, FSarcoidosisTransaminases 3–4 x ULN fluctuation, ANA+, hyper-IgG, active hepatitis, fibrosis with septaPrednisolone 40 mg/dayTransaminases decline after 7 days of prednisolone
Rela et al. [29]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 20 days before38, FNo (hypothyroidism?)NoHypothyroidismAcute icteric, ANA+, IgG mildly elevated, multiacinar hepatic necrosis, no fibrosisPrednisolone 30 mg/day and tapering after 4 weeks1 month of follow-up normal LFTs
ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 16 days before62, M2 episodes of jaundice resolved with native medicationAcute severe AIH, autoantibodies negative, mild fibrosisPrednisolone 30 mg/day + plasma exchange 5 cyclesPersistent cholestasis → death in 21 days for economic constraints regarding liver transplantation
Rocco et al. [30]Pfizer/BioNTech 1 week before (II dose)89, FHashimoto thyroiditisNoPrevious acute glomerulonephritis, pravastatin and low-dose aspirin for primary preventionAcute icteric, ANA+, hyper-IgG, no fibrosisPrednisone 1 mg/Kg/day and tapering3 months of follow-up, progressive improvement
Tan et al. [31]mRNA Moderna, 6 weeks before56, FNot reportedNoRosuvastatinAcute icteric, ANA+, ASMA+, hyper-IgG, also eosinophil, early fibrosisBudesonide1 week of follow-up
Tun et al. [32]mRNA Moderna, 3 days before (I dose) and 2 days before (II dose)47, MNot reportedNoNot reportedAcute icteric, ANA+ hyper-IgG, rapidly resolved and then reappeared 2 days after the II dose, minimal fibrosisPrednisolone 40 mg/day2 weeks of follow-up PT normalized
Vuille-Lessard et al. [33]mRNA Moderna, 3 days before76, FHashimoto thyroiditisYes, 3 months before (mild disease)Prior urothelial carcinomaAcute icteric, hyper-IgG, ANA+, ASMA+, ANCA+, steatosis, active AIH, fibrosis not evaluablePrednisolone 40 mg/day + azathioprine add-on 2 weeks after4 months follow-up: LFTs normalization after 4 weeks, stop azathioprine and 6 weeks after no relapse
Suzuki Y et al. [34]mRNA Pfizer/BioNTech 10 days before (II dose)80, FNot reportedNot reportedGastroesophageal reflux esophagitisAcute icteric, ANA+, hyper-IgGPrednisone at an initial dose of 0.8 mg/kg/day, then tapered to 10 mg/week50 days of follow-up: transaminases normalization
mRNA Pfizer/BioNTech 4 days before (II dose)75, FNot reportedNot reportedDyslipidemiaAcute icteric, ANA+, AMA +, hyper-IgGPrednisone at an initial dose of 1 mg/kg/day, then tapered to 10 mg/week105 days of follow-up: transaminases normalization
mRNA Pfizer/BioNTech 7 days before (I dose)78, FPrimary biliary cholangitisNot reportedNoAcute, ANA+, AMA+, hyper IgGPrednisone at an initial dose of 0.6 mg/kg/day, then tapered to 10 mg/week103 days of follow-up: transaminases normalization
Torrente et al. [35]ChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca), 3 weeks before49, FHypothyroidism (?), ANA+NoHypothyroidism treated with levothyroxineAcute AIH, ANA+, hyper-IgG, no fibrosisPrednisone 30 mg/day then tapering and azathioprine add-onTransaminases decrease after 2 weeks
Rigamonti C et al. [36]mRNAPfizer/BioNTech, 7 patientsmRNA Moderna, 2 patientsChAdOx1 nCoV-19 vaccine (Oxford-AstraZeneca),3 patientsmedian age 62 years (range 32–80)6 F, 6 M3 thyroiditis,2 rheumatoid arthritis,1 systemic lupus erythematosus10 acute onset,8 jaundice,8 positive autoantibodies (6 ANA, 1 SMA, 1 LKM-1)Prednisone / prednisolone +/- azathioprinemedian follow-up 3 months: 58% complete biochemical response
Efe C et al. [37]mRNAPfizer/BioNTech, 1 patient53, MNoneNot reportedNoneAcute icteric hepatitis, no ANA, hyper-IgG, no fibrosisprednisolone (40 mg/day) and plasma exchangeLiver transplantation

Adverse effects of the vaccine are possible, and abnormal liver function tests following vaccination represent an important clinical issue. AIH is a relatively rare, chronic immune-mediated liver disease, which develops in genetically predisposed individuals following environmental triggers; viral infections and drug exposures have been suggested to trigger the disease, but not definitive evidence is available [[19],[20]]. AIH-like onset after vaccination – other than anti-SARS-CoV-2 – has been also previously reported [[21]]. However, even if it can be speculated that the vaccines can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells, it might be hard to definitively state that AIH is induced by a vaccine. Considering the reported AIH-like cases following SARS-CoV-2 vaccination, timing of occurrence of acute hepatitis from vaccination in some of them is very short (less than 7 days), suggesting that a dysregulation of immune system has already occurred before vaccination in those cases. So far, given the availability of only observational literature without a structured collection of AIH-like cases after anti-SARS-CoV-2 vaccines, no definitive conclusions can be drawn. There is a need for population-based studies to gather data on the incidence, severity, and clinical features of anti-SARS-Cov-2 vaccination-induced AIH under the umbrella of the national and European Scientific Societies.In the meantime, while intensive vaccination against SARS-CoV-2 continues, healthcare providers should include the diagnosis of AIH triggered by vaccines in the differential diagnosis in cases of acute hepatitis of unexplained etiology and manage them as drug-induced AIH or AIH-like liver injury as recommended by current guidelines [[22]].

3. RECOMMENDATIONS

*These recommendations will be reviewed periodically as further information becomes available.

  • •AIH patients should receive anti-SARS-CoV-2 vaccination consistent with the age restriction of the local approval. In Italy, as recommended by the Italian Ministry of Health for all immunosuppressed patients, mRNA vaccines should be used. Based on the data for the mRNA vaccines available, there is no preference for one vaccine over another.
  • Patients with AIH are suggested to undergo vaccination when the disease activity is controlled by immunosuppressive therapy. To date there are no data available to establish variations on the interval between doses of anti-SARS-Cov2 vaccine.
  • There is no current evidence to recommend suspension or reduction of immunosuppressive drugs in AIH patients before or immediately after anti-SARS-CoV-2 vaccination.
  • The risk of AIH flare or disease worsening following anti-SARS-Cov-2 vaccination has not been assessed to date and specific studies are required before defining a line of recommendation. Based on available data routine testing of transaminases levels in AIH patients after vaccination could be suggested in selected patients although the timing needs to be defined.
  • •Testing of antibody levels for IgM and/or IgG to spike or nucleocapsid proteins to assess immunity to SARS-Cov2 after vaccination in AIH patients is not recommended, nor to assess the need for vaccination in an unvaccinated AIH patients.
  • Patients with new acute onset of liver injury following anti-SARS-Cov-2 vaccine should be managed as suggested by current guidelines and known clinical algorithms, including the indication to liver biopsy. Considering the lack of evidence currently available to exclude drug induced AIH in this setting, immunosuppressive therapy should be carefully considered and used if AIH diagnosis is confirmed; long-term immunosuppressive therapy needs to be assessed on a patient-by-patient basis.
  • Patients with newly diagnosed AIH or AIH flare after anti-SARS-Cov-2 vaccine should be consider for vaccine booster; however, the timing of the booster could be personalised based on the disease activity and ongoing therapy and discussed case-by-case with an expert center in autoimmune liver diseases.
  • Given the limited number of cases compared to the number of vaccinated subjects, extended testing of transaminases level after vaccination in the general population is not sustainable nor suggested.
  • EMA’s PRAC encourages all healthcare professionals and patients to report any cases of autoimmune hepatitis and other adverse events in people after vaccination.

Autoimmune hepatitis after SARS-CoV-2 vaccine: New-onset or flare-up?

Authors: Enver Avci 1Fatma Abasiyanik 2

Autoimmune 2021 Dec;125: 102745. doi: 10.1016/j.jaut.2021.102745  Epub 2021 Nov 11. PMID:  34781161PMCID: PMC8580815DOI: 10.1016/j.jaut.2021.102745

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported to trigger several autoimmune diseases. There are also recent reports of autoimmune diseases that develop after SARS-CoV-2 vaccines. Autoimmune hepatitis is a polygenic multifactorial disease, which is diagnosed using a scoring system. A 61-year-old woman presented with malaise, fatigue, loss of appetite, nausea and yellow eyes. She had a Pfizer/BioNTech BNT162b2 mRNA vaccine a month ago. Her physical examination revealed jaundice all over the body, especially in the sclera. The laboratory tests showed elevated liver enzymes and bilirubin levels. Antinuclear antibody and anti-smooth muscle antibody were positive and immunoglobulin G was markedly elevated. The liver biopsy revealed histopathological findings consistent with autoimmune hepatitis (AIH). The patient was diagnosed with AIH and initiated on steroid therapy. She rapidly responded to steroid therapy. A few cases of AIH have been reported after the COVID-19 vaccine so far. Although the exact cause of autoimmune reactions is unknown, an abnormal immune response and bystander activation induced by molecular mimicry is considered a potential mechanism, especially in susceptible individuals. As intensive vaccination against SARS-CoV-2 continues, we would like to emphasize that clinicians should be cautious and consider AIH in patients presenting with similar signs and symptoms.

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Autoimmune Hepatitis Following Vaccination for SARS-CoV-2 in Korea: Coincidence or Autoimmunity?

Authors: Seong Hee Kang 1 2Moon Young Kim 1 3Mee Yon Cho 4Soon Koo Baik 1 5Affiliations expandPMID: 35437965PMCID: PMC9015903DOI: 10.3346/jkms.2022.37.e116

J Korean Med Sci 2022 Apr 18;37(15):e116. doi: 10.3346/jkms.2022.37.e116.

Abstract

Autoimmune hepatitis (AIH) is a chronic, autoimmune disease of the liver that occurs when the body’s immune system attacks liver cells, causing the liver to be inflamed. AIH is one of the manifestations of a coronavirus disease 2019 (COVID-19), as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Few cases of AIH have been described after vaccination with two messenger RNA (mRNA)-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of AIH occurring after Pfizer-BioNTech COVID-19 vaccine. A 27-year-old female presented with jaundice and hepatomegaly, appearing 14 days after receiving the second dose of Pfizer-BioNTech vaccine. Her laboratory results showed abnormal liver function with high total immunoglobulin G level. She was diagnosed with AIH with histologic finding and successfully treated with oral prednisolone. We report an AIH case after COVID-19 vaccination in Korea.
Go to:Graphical Abstract

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic, putatively caused by the widespread transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in 257,469,528 laboratory-confirmed cases of infection and 5,158,211 deaths globally as of November 28, 2021.1 Rapid vaccine development, however, has significantly mitigated severe COVID-19 illness. Two messenger RNA (mRNA) COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech, New York, NY, USA/Mainz, Germany) and mRNA-1273 (Moderna, Cambridge, MA, USA), were granted emergency use authorization by the United States Food and Drug Administration in December 2020. SARS-CoV-2 infection has been associated with the development of autoimmune processes.2 Because SARS-CoV-2 harbors the same protein motif the mRNA vaccine codes for, it is plausible that these vaccines could trigger autoimmune diseases in predisposed patients.34 Autoimmune hepatitis (AIH) is a polygenic multifactorial disease that may be triggered by specific environmental factors, such as viral infections, resulting in the loss of self-tolerance to autoantigens in genetically susceptible individuals.5

Go to:CASE DESCRIPTION

We treated a 27-year-old female nurse who developed AIH after COVID-19 vaccination. She had no known history of liver disease and did not use herbal remedies or alcohol. She received a second dose of the Pfizer-BioNTech COVID-19 vaccine on March 30, 2021, and, since April 6, 2021, symptoms of nausea, vomiting, headache, fever, and dark urine continued. Accordingly, she was hospitalized via the emergency room 14 days after COVID-19 vaccination. A COVID-19 polymerase chain reaction test, performed at the local hospital on April 7 and 12, 2021, was negative. The physical examination was unremarkable, except for scleral icterus, jaundice, and palpable hepatomegaly. In the emergency room, laboratory investigations were significant for the following: bilirubin, 8.6 mg/dL; aspartate aminotransferase (AST), 1,004 U/L; alanine aminotransferase (ALT), 1,478 U/L; alkaline phosphatase, 182 U/L, white blood cell count, 6,720/μL (neutrophils, 46.8%); hemoglobin, 13.0 g/dL; platelet count 373,000/μL; blood urea nitrogen/creatinine, < 5.0/0.54 mg/dL (estimated glomerular filtration rate, 145.0 mL/min/1.73 m2); and prothrombin international normalized ratio, 1.1. Laboratory results were negative for hepatitis A, B, C, and E, Epstein-Barr virus, cytomegalovirus, herpes simplex virus types 1 and 2, and human immunodeficiency virus. Antinuclear antibody (ANA) was positive (1:80; mixed pattern). Other antibodies (including anti-mitochondrial, anti-smooth muscle, liver-kidney microsomal, and antineutrophil cytoplasmic antibodies) were negative. Total immunoglobulin G (IgG) level was 1,641 mg/dL (normal range, 549–1,584 mg/dL). Ceruloplasmin, transferrin saturation, thyroid function test, and serum protein electrophoresis were all normal. Abdominal ultrasound revealed splenomegaly (12.5 cm) without cirrhosis and gallbladder wall thickening.

Liver dynamic computed tomography revealed no evidence of biliary lithiasis or biliary dilation, and ultrasound-guided transabdominal liver biopsies were obtained. In microscopic examination, 17 portal tracts were identified. Although there was a focal bridging, the overall lobular architecture was preserved in the low magnification. Some portal tracts were widened by moderate inflammation with periportal fibrosis (Fig. 1). The portal inflammation was composed of mainly lymphocytes, clusters of plasma cells and few eosinophils, extending into proto-lobular interface (interface hepatitis) (Fig. 2A). The immunohistochemical staining for plasma cell markers, MUM1 and CD138 confirmed significant plasma cell infiltration in portal tracts as well as in lobules (Fig. 2B). Diffuse moderate necroinflammatory damage in lobules, associated with perivenular hepatocytes degeneration, mild cholestasis with hepatocytic rosettes (Fig. 2C) and sinusoidal inflammation were found. Other than COVID-19 vaccination, no other drug, herbal supplement, or toxin use were reported by the patient. The revised original score for AIH pretreatment was 18 (results > 15 suggest definite AIH). Treatment with oral prednisolone (40 mg daily) was initiated. Plasma ALT, AST, and total bilirubin levels over time, and before and after treatment, are summarized in Fig. 3. After three weeks of treatment, diarrhea and fever developed, and she was transferred to the hospital’s emergency room. Treatment with prednisolone (20 mg daily) was discontinued with the diagnosis of enteritis. Four days after admission, symptoms were relieved, and she was discharged from hospital with steroid discontinuation. Two weeks after stopping therapy, there were biochemical signs of an AIH relapse; therefore, treatment with oral prednisolone (10 mg daily) was restarted. Liver enzyme levels were completely normalized and the patient’s symptoms significantly improved.


Fig. 1
The microphotograph of low magnification of liver biopsy shows portal widening with periportal fibrosis (A) hematoxylin and eosin ×100, (B) Masson trichrome ×100.Click for larger imageDownload as PowerPoint slide

Fig. 2
Histological finding. (A) The porto-lobular interface shows severe inflammation composed of lymphocytes, clausters of plasma cells (circle) and a few eosinophils. Bile ducts (closed arrow) are not damaged (H&E, ×400). (B) The photomicrography of MUM1 immunohistochemical stain demonstrates numerous plasma cell infiltration (×400). (C) The lobules show diffuse degeneration of hepatocytes, mild cholestasis in hepatocytic rosettes (opened arrow) and sinusoidal lymphoplasma cells infiltration (H&E ×400).
H&E = hematoxylin and eosin.Click for larger imageDownload as PowerPoint slide

Fig. 3
Trends of serum ALT, AST and total bilirubin over time.
ALT = alanine aminotransferase, AST = aspartate aminotransferase.Click for larger imageDownload as PowerPoint slide

We described a case of AIH that developed in a patient after vaccination with the Pfizer-BioNTech COVID-19 vaccine, which was resolved with steroid treatment. To date, four cases of AIH have been reported after Pfizer-BioNTech COVID-19 vaccination in the literature (Table 1)678, the first of which was reported by Bril et al.3 The patient was a 35-year-old woman in her third month postpartum who developed AIH after COVID-19 vaccination. In this case, AIH exhibited some atypical features: autoantibodies other than ANA were negative and eosinophils were present on liver histology. Similarly, Lodato et al.6 reported a case of AIH occurring after vaccination, with no development of autoantibodies and eosinophil infiltrate in liver histology. Thereafter, two patients had a history of Hashimoto’s disease, high IgG levels, and typical findings on biopsy, unlike the above cases.78 Although our patient had no autoimmune disease, autoantibodies were positive, and IgG level was high. In addition, our case had typical findings on biopsy and responded well to steroid therapy. It is thought to be a new-onset AIH triggered by COVID-19 vaccination, but periportal fibrosis was observed in histological examination. However, in case with acute onset, there may be minimal fibrosis. Moreover, symptoms developed after the second vaccination in this patient, but there is a possibility that inflammation may have occurred even though there were no symptoms after the first vaccination.


Table 1
Characteristics of patients with autoimmune hepatitis after Pfizer-BioNTech COVID-19 vaccineClick for larger imageClick for full tableDownload as Excel file

Because causality cannot be definitively confirmed, it is possible that this association was coincidental. However, severe cases of SARS-CoV-2 infection are characterized by autoinflammatory dysregulation.9 Because the viral spike protein appears to be responsible, it is plausible that spike-directed antibodies induced by vaccination may also trigger autoimmune conditions in predisposed individuals.10 In support of this, several cases of immune thrombocytopenia have been reported days after COVID-19 vaccination. Vaccines protect the host from the virus by inducing antibody generation against viral peptides.11 Autoimmunity can develop due to cross-reactivity to the generated antibodies. The epitopes used for induction of the host immune system may mimic the structure of self-peptides, and antibodies that develop after vaccination may cause cross-reactivity directed to the self.12

Given the close temporal relationship between vaccination and onset of symptoms, we hypothesized that vaccination against COVID-19 could have triggered the development of AIH in our patient. To the best of our knowledge, this is the first reported episode of AIH that developed post-COVID-19 vaccination in Korea. Whether a causal relationship exists between COVID-19 vaccination and the development of AIH remains to be determined. Nevertheless, it is necessary to raise awareness about potential side effects that will likely emerge as more individuals are vaccinated.

1. World Health Organization. Global surveillance for COVID-19 caused by human infection with COVID-19 virus: interim guidance 2020. [Updated 2020]. [Accessed November 28, 2021].https://apps.who.int/iris/handle/10665/331506.2. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol 2021;33(2):155–162.

3. Bril F, Al Diffalha S, Dean M, Fettig DM. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J Hepatol 2021;75(1):222–224.

4. Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol 2021;96(5):534–537.

5. Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol 2004;20(3):231–240.

6. Lodato F, Larocca A, D’Errico A, Cennamo V. An unusual case of acute cholestatic hepatitis after m-RNABNT162b2 (Comirnaty) SARS-CoV-2 vaccine: coincidence, autoimmunity or drug-related liver injury. J Hepatol 2021;75(5):1254–1256.

7. Rocco A, Sgamato C, Compare D, Nardone G. Autoimmune hepatitis following SARS-CoV-2 vaccine: may not be a casuality. J Hepatol 2021;75(3):728–729.

8. Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J Autoimmun 2021;125:102745

9. Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A, Kanduc D, et al. COVID-19 and autoimmunity. Autoimmun Rev 2020;19(8):102597

10. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 2020;217:108480

11. Sadarangani M, Marchant A, Kollmann TR. Immunological mechanisms of vaccine-induced protection against COVID-19 in humans. Nat Rev Immunol 2021;21(8):475–484.

12. Malonis RJ, Lai JR, Vergnolle O. Peptide-based vaccines: current progress and future challenges. Chem Rev 2020;120(6):3210–3229.

Acute hepatitis with autoimmune features after COVID-19 vaccine: coincidence or vaccine-induced phenomenon?

Authors: José M Pinazo-Bandera 1Alicia Hernández-Albújar 1Ana Isabel García-Salguero 2Isabel Arranz-Salas 2Raúl J Andrade 1 3Mercedes Robles-Díaz 1 3

Gastroenterol Rep (Oxf) 2022 Apr 27;10:goac014. doi: 10.1093/gastro/goac014. eCollection 2022.

Introduction

Autoimmune diseases result from a breach of immunological self-tolerance and tissue damage by autoreactive T lymphocytes. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is characterized by an inflammatory dysregulation that has been associated with the development of autoimmune processes [1].

Molecular mimicry has been suggested as a potential mechanism for these associations as well as ‘bystander activation’ where the infection may lead to activation of antigen presenting cells that may activate autoreactive T-cells, with the production of pro-inflammatory mediators and tissue damage [1].

There is a potential antigenic cross-reactivity between SARS-CoV-2 and human tissue possibly linked to an increase in autoimmune diseases. A recent study showed that antibodies against the spike protein S1 of SARS-CoV-2 had high affinity against some human tissue proteins such as transglutaminase 2 and 3, or myelin basic protein, among others [2].

As both mRNA vaccine (Comirnaty BioNTech BNT162b2 and Spikevax ARNm-1273) and vectorial vaccine (ChAdOx1nCoV-19 Vaxzevria/Covishield) give rise to the production of protein S, the antibodies produced against this protein after vaccination may also trigger autoimmune conditions in predisposed individuals.

Thirteen case reports (including 16 patients) have recently reported an association between COVID-19 vaccines and acute hepatitis development [3–15].

Here we report two new cases of liver injury possibly related to COVID-19 vaccination.

Case 1

A 77-year-old woman developed intense malaise, vomiting and disorientation 2 days after receiving the second dose of Comirnaty vaccine and was hospitalized the following day. She did not have a history of autoimmune disorders. She denied alcohol drinking and was on long-term therapy with bromazepam, losartan, and omeprazole. Her previous liver tests back in 2020 were normal.

Physical examination was normal except for scleral icterus. Liver test showed acute hepatocellular injury: total bilirubin (TB) 3.1 mg/dL (reference, <1 mg/dL), aspartate aminotransferase (AST) 474 U/L (reference, <40 UI/L), alanine aminotransferase (ALT) 552 U/L (reference, <40 U/L), and alkaline phosphatase (ALP) 159 U/L (reference, <117 U/L). Immunoglobulin G levels were within normal ranges (reference, 800–1,600 mg/dL), while anti-nuclear antibody and anti-mitochondrial antibody M2 were detected with 1/160 and 1/40 titre, respectively. Human leukocyte antigen (HLA) testing was positive for HLA-DR4. All the other possible aetiologies were ruled out.

The patient was discharged and closely monitored. Due to increased transaminase levels, she underwent a liver biopsy (Supplementary Figure 1.1), which showed findings compatible with autoimmune hepatitis (AIH).

Prednisone 60 mg/day on tapering dose was initiated and 3 weeks later liver test had markedly improved. Azathioprine was added 2 months later, but it had to be withdrawn due to rash. Prednisone was then replaced by budesonide 9 mg/day. Five months after onset, transaminases were within the normal range; however, the subject was hospitalized with neurologic symptoms in relation to brain lesions in both hemispheres of probable infectious origin and died 1 month later.

Case 2

A 23-year-old man presented with mononucleosis syndrome-like symptoms and jaundice at the emergency room, 10 days after receiving the second dose of Spikevax vaccine. He did not suffer from previous autoimmune disorders. He denied having taken any conventional drug treatments as well as alcohol consumption.

Physical examination was unremarkable except for scleral icterus. Liver tests showed acute hepatocellular injury: TB 2.3 mg/dL, AST 702 U/L, ALT 587 U/L, and ALP 202 U/L. Immunoglobulin G levels were minimally elevated (1,647 mg/dL), while autoantibodies resulted as negative. HLA testing was positive for HLA-DR3. Serology ruled out viral causes and abdominal ultrasonography was normal. After admission to the hospital, a thoracic-abdominal scan was performed and revealed generalized lymphadenopathy.

He underwent a liver biopsy (Supplementary Figure 1.2), which showed findings compatible with AIH.

Prednisone 60 mg/day on tapering dose was initiated and 1 month later lymphadenopathies were undetectable and liver test had significantly improved. Three months after onset, transaminases were within the normal range and he is still on low-dose prednisone 10 mg/day.

Discussion

These new cases of liver injury compatible with AIH, which developed post COVID-19 vaccination, along with 13 prior published case reports (16 patients) reinforce that this association could be more than coincidental. In the previously published case reports, all the patients, except three, were females and their age ranged from 35 to 80 years [3–15]. Twelve of these patients received one of the mRNA vaccines [35–121415], while four patients received vectorial vaccines [41213]. In 6 of the 16 patients, liver biopsy revealed infiltration with eosinophils [347914] and IgG levels were increased in 12 cases [4–1215].

Fourteen reported patients were successfully treated with prednisolone whereas two died due to acute liver failure [412] (Table 1).

Table 1.

Characteristics of patients with liver injury after SARS-CoV-2 vaccine (published cases and two new cases)

AuthorVaccineDoseDays until clinical onsetGenderAgeLiver-injury patternAutoimmune disease historyAuto- antibodiesIgGBiopsySteroid responseDeath
Compatible (Yes/No)Eosinophils infiltration (Yes/No)
Bril et al. [3Comirnaty BioNTech BNT162b2 1st 13 35 Hep None ANAAnti-dsDNA Normal Yes Yes Yes No 
Rela et al. [4(2 cases) ChAdOx1nCoV-19 Covishield (both patients) NA 20 38 NAa None ANA High Yes Yes Yes No 
NA 16 65 NAa None NA NA Yes Yes No Yes 
Rocco et al. [5Comirnaty BioNTech BNT162b2 2nd 80 Hep Hashimoto disease ANA High Yes No Yes No 
Londoño et al. [6Spikevax, ARNm-1273 2nd 41 Hep None ANASMASLALC-1 High Yes No Yes No 
Tan et al. [7Spikevax, ARNm-1273 1st 35 56 Hep None ANASMA High Yes Yes Yes No 
McShane et al. [8Spikevax, ARNm-1273 1st 71 Hep None SMA High Yes No Yes No 
Ghielmet-ti et al. [9Spikevax, ARNm-1273 1st 63 Hep None ASMAANCAANA High Yes Yes Yes No 
Garrido et al. [10Spikevax, ARNm-1273 1st 14 65 Hep None ANA High Yes No Yes No 
Avci et al. [11Comirnaty BioNTech BNT162b2 NA 14 61 Mix Hashimoto disease ANASMA High Yes No Yes No 
Erard et al. [12(3 cases) Spikevax, ARNm-1273(two first patients)ChAdOx1nCoV-19 Vaxzevria(third one) 2nd 10 80 NAa None Negative High Yes No Yes No 
1st 21 73 NAa None Negative High Yes No Yes No 
1st 20 68 NAa None Negative High Yes No No Yes 
Clayton-Chubb et al. [13ChAdOx1nCoV-19 Vaxzevria 1st 26 36 Hep None ANA Normal Yes No Yes No 
Lodato et al. [14Comirnaty BioNTech BNT162b2 1st 15 43 NAa None Negative Normal Yes Yes Yes No 
Vuille-Lessard et al. [15Spikevax, ARNm-1273 1st 76 Hep Hashimoto disease ANA High Yes No Yes No 
Pinazo et al. (2 cases) Comirnaty BioNTech BNT162b2(First one)Spikevax, ARNm-1273(second one) 2nd 77 Hep None ANAAMANegative Normal Yes Yes Yes Yesb 
2nd 10 23 Hep None High Yes No Yes No 

M, male; F, female; NA, not available; Hep, hepatocellular; Mix, mixed; IgG, immunoglobulin G; ANA, anti-nuclear antikor; SMA, smooth muscle antibodies; dsDNA, double-stranded DNA antibodies; LC1, liver sitozol antibody; anti-SLA, soluble liver antigen antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; AMA, anti-mitochondrial antibodies.a

ALP (alkaline phosphatase) not available.b

The patient died due to an extrahepatic cause (brain lesions in both hemispheres of probable infectious origin).Open in new tab

In both cases of the present study, a number of laboratory (including HLA testing) and histological features supported the autoimmune nature of the liver injury. In our first case, the short period elapsed after vaccine administration, the laboratory and histopathological findings (showing moderate liver fibrosis), the positive HLA-DR4, and the response to therapy suggest unmasking of AIH by the vaccine. However, in our second case, the medical history negative for liver and autoimmune diseases, the short time interval after vaccination, the typical onset of symptoms to which was added generalized lymphadenopathy, the elevated immunoglobulin G levels, the positive HLA-DR3, histopathological findings with absence of liver fibrosis, and the response to therapy reinforce the hypothesis of SARS-CoV-2 vaccine as a trigger of an autoimmune liver injury debut. We realize that there are no pathognomonic (laboratory or histological) features of AIH, but the appropriate exclusion of viral and metabolic causes of liver injury makes the autoimmune mechanisms the more likely explanation for both cases.

Taking into account the large number of vaccinated subjects worldwide, the suspicion of vaccine-related AIH carries important clinical implications. It is unknown whether prolonged immunosuppression would be required in these cases or whether re-exposure to a new dose of COVID-19 vaccine might trigger fulminant liver injury. Nevertheless, the risk of receiving another dose must be balanced against the risk of contracting SARS-CoV-2 infection. In addition, it remains unclear whether patients who have developed liver injury after vaccination with one type of vaccine can receive other COVID-19 vaccine with a different mechanism of action.

Post COVID-19 vaccination, AIH has been rarely reported so far [3–15], which might be due to either minimal awareness of this disease or because patients without jaundice often do not seek medical attention. However, given the growing number of cases compatible with AIH reported after SARS-CoV-2 vaccination, regulators should consider the inclusion of this potential adverse event in the label of COVID-19 vaccines.

In conclusion, clinicians should be aware of the potential association between the vaccines and the onset of immune mediated disorders such as AIH. However, this rare complication should not discourage people from getting vaccinated.

References

1 Ehrenfeld M, Tincani A, Andreoli L et al.  Covid-19 and autoimmunity. Autoimmun Rev 2020;19:102597.

2 Google ScholarCrossrefPubMed2Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Inmunol 2020;217:108480.

3 Google ScholarCrossref3Bril F, Al Diffalha S, Dean M et al.  Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J. Hepatol 2021; 2021 Jul;75:222–224.

4 Google ScholarCrossrefPubMed4Rela M, Jothimani D, Vij M et al.  Auto-immune hepatitis following COVID vaccination. J Autoimmun 2021;123:102688.

5 Google ScholarCrossrefPubMed5Rocco A, Sgamato C, Compare D et al.  Autoimmune hepatitis following SARS-CoV-2 VACCINE: MAY not be a casualty. J Hepatol 2021;75:728–9.

6 Google ScholarCrossrefPubMed6Londoño MC, Gratacós-Ginès J, Sáez-Peñataro J. Another case of autoimmune hepatitis after SARS-CoV-2 vaccination: still casualty. J Hepatol 2021;75:1248–1249.

7 Google ScholarCrossrefPubMed7Tan CK, Wong YJ, Wang LM et al.  Autoimmune hepatitis following COVID-19 vaccination: true causality or mere association? J Hepatol 2021;S0168-8278(21)00424-4.

8 Google Scholar8McShane C, Kiat C, Rigby J et al.  The mRNA COVID-19 vaccine—a rare trigger of autoimmune hepatitis? J Hepatol 2021;S0168-8278(21)01896-1.

9 Google Scholar9Ghielmetti M, Schaufelberger HD, Mieli-Vergan G et al.  Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination: a novel clinical entity? J Autoimmun 2021;123:102706.

10 Google ScholarCrossrefPubMed10Garrido I, Lopes S, Sobrinho Simões M et al.  Autoimmune hepatitis after COVID-19 vaccine—more than a coincidence. J Autoimmun 2021;125:102741.

11 Google ScholarCrossrefPubMed11Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: new-onset or flare-up? J Autoimmun 2021;125:102745.

12 Google ScholarCrossrefPubMed12Erard D, Villeret F, Lavrut PM et al.  Autoimmune hepatitis developing after COVID 19 vaccine: presumed guilty? Clin Res Hepatol Gastroenterol 2022;46:101841.

13 Google ScholarCrossrefPubMed13Clayton-Chubb D, Schneider D, Freeman E et al. ; Comment to the letter of Bril F. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: causality or casualty? J Hepatol 2021;75:1249–1250.

14 Google ScholarCrossrefPubMed14Lodato F, Larocca A, D’Errico A et al.  An unusual case of acute cholestatic hepatitis after m-RNABNT162b2 (comirnaty) SARS-COV-2 vaccine: coincidence, autoimmunity or drug related liver injury? J Hepatol 2021;75:1254–6.

14Google ScholarCrossrefPubMed15Lessard EV, Montani M, Bosch J et al.  Autoimmune hepatitis triggered by SARS-CoV-2 vaccination. J Autoimmun 2021;123:102710.

At least 58% of U.S. population has natural antibodies from previous Covid infection, CDC says

Authors: Spencer Kimball PUBLISHED TUE, APR 26 2022 CNBC

KEY POINTS

  • Three out of every 5 people in the U.S. now have antibodies from a previous Covid-19 infection, according to a new CDC analysis.
  • The proportion is even higher among children, demonstrating how widespread the virus was during the winter omicron surge.
  • CDC officials told reporters on a call Tuesday that the study did not measure whether people with prior infections had high enough antibody levels to protect against reinfection and severe illness.
  • However, CDC Director Dr. Rochelle Walensky said health officials believe there is a lot of protection against the virus in communities from vaccination, boosting and infection taken together.

Three out of every 5 people in the U.S. now have antibodies from a previous Covid-19 infection with the proportion even higher among children, demonstrating how widespread the virus was during the winter omicron surge, according to data from the Centers for Disease Control and Prevention.

The proportion of people with natural Covid antibodies increased substantially from about 34% of the population in December to about 58% in February during the unprecedent wave of infection driven by the highly contagious omicron variant. The CDC’s analysis didn’t factor in people who had antibodies from vaccination.

The CDC published the data in its Morbidity and Mortality Weekly Report on Tuesday.

The increase in antibody prevalence was most pronounced among children, indicating a high rate of infection among kids during the winter omicron wave. About 75% of children and teenagers now have antibodies from past Covid infections, up from about 45% in December.

The high rate of infection among children is likely due to lower vaccination rates than adults. Only 28% of children 5- to 11-years-old and 59% of teens 12- to 17-years-old were fully vaccinated as of April. Children under 5-years-old are not yet eligible for vaccination.

About 33% of people ages 65 and older, the group with the highest vaccination rate, had antibodies from infection. Roughly 64% of adults ages 18 to 49 and 50% of people 50 to 64 had the antibodies.

The CDC analyzed about 74,000 blood samples every month from September through January from a national commercial lab network. The sample size decreased to about 46,000 in February. The CDC tested the samples for a specific type of antibody that is produced in response to Covid infection, not from vaccination.

CDC officials told reporters on a call Tuesday that the study did not measure whether people with prior infections had high enough antibody levels to protect against reinfection and severe illness. However, CDC Director Dr. Rochelle Walensky said health officials believe there is a lot of protection in communities across the country from vaccination, boosting and infection taken together, while cautioning that vaccination is the safest strategy to protect yourself against the virus.

“Those who have detectable antibody from prior infection, we still continue to encourage them to get vaccinated,” Walensky told reporters during the call. “We don’t know when that infection was. We don’t know whether that protection has waned. We don’t know as much about that level of protection than we do about the protection we get from both vaccines and boosters.”

Scientists in Qatar affiliated with Cornell University found that natural infection provides about 73% protection against hospitalization if a person is reinfected with BA.2. However, three doses of Pfizer’s vaccine provided much higher protection against hospitalization at 98%. The study, published in March, has not undergone peer-review.

About 66% of the U.S. population is fully vaccinated and 77% have received at least one dose, according to data from the CDC.

Infections and hospitalizations have dropped more than 90% from the peak of the omicron wave in January when infections in the U.S. soared to an average of more than 800,000 a day. New cases are rising again due to the BA.2 subvariant. Another subvariant, BA.2.12.1, is now gaining ground in the U.S., representing about 29% of new infections, according to CDC data. Walensky said the public health agency believes BA.2.12.1 spreads about 25% faster than BA.2. However, she said the CDC does not expect to see more severe disease from BA.2.12.1though studies are ongoing.

More than 98% of the U.S. population lives in areas where they do not need to wear masks indoors under CDC guidance due to low Covid community levels, which takes into account both infections and hospitalizations. A U.S. district judge last week struck down the CDC’s mask mandate for public transportation, though the Justice Department has filed an appeal. Walensky said the CDC continues to recommend that people wear masks on public transportation.

Counties With Highest Vaccination Rates See More COVID-19 Cases Than Least Vaccinated

Authors: Petr Svab April 4, 2022 Updated: April 5, 2022 THE EPOCH TIMES

U.S. counties with the highest rates of vaccination against COVID-19 are currently experiencing more cases than those with the lowest vaccination rates, according to data collected by the Centers for Disease Control and Prevention (CDC).

The 500 counties where 62 to 95 percent of the population has been vaccinated detected more than 75 cases per 100,000 residents on average in the past week. Meanwhile, the 500 counties where 11 to 40 percent of the population has been vaccinated averaged about 58 cases per 100,000 residents.

The data is skewed by the fact that the CDC suppresses figures for counties with very low numbers of detected cases (one to nine) for privacy purposes. The Epoch Times calculated the average case rates by assuming the counties with the suppressed numbers had five cases each on average.

The least vaccinated counties tended to be much smaller, averaging less than 20,000 in population. The most vaccinated counties had an average population of over 330,000. More populous counties, however, weren’t more likely to have higher case rates.

Even when comparing counties of similar population, the ones with the most vaccinations tended to have higher case rates than those that reported the least vaccinations.

Among counties with populations of 1 million or more, the 10 most vaccinated had a case rate more than 27 percent higher than the 10 least vaccinated. In counties with populations of 500,000 to 1 million, the 10 most vaccinated had a case rate almost 19 percent higher than the 10 least vaccinated.

In counties with populations of 200,000 to 500,000, the 10 most vaccinated had case rates around 55 percent higher than the 10 least vaccinated.

The difference was more than 200 percent for counties with populations of 100,000 to 200,000.

For counties with smaller populations, the comparison becomes increasingly difficult because so much of the data is suppressed.

Another problem is that the prevalence of testing for COVID-19 infections isn’t uniform. A county may have a low case number on paper because its residents are tested less often.

The massive spike in infections during the winter appears to have abated in recent weeks. Detected infections are down to less than 30,000 per day from a high of over 800,000 per day in mid-January, according to CDC data. The seven-day average of currently hospitalized dropped to about 11,000 on April 1, from nearly 150,000 in January.

The most recent wave of COVID-19 has been attributed to the Omicron virus variant, which is more transmissible but less virulent. The variant also seems more capable of overcoming any protection offered by the vaccines, though, according to the CDC, the vaccines still reduce the risk of severe disease.

Bone Marrow Suppression Secondary to the COVID-19 Booster Vaccine: A Case Report

TAuthors: oral Shastri 1Navkiran Randhawa 2Ragia Aly 3Masood Ghouse 3 PMID: 35210894PMCID: PMC8863340DOI: 10.2147/JBM.S350290 J Blood Med.  2022; 13: 69–74.Published online 2022 Feb 18. doi: 10.2147/JBM.S350290

Abstract

As of September 2021, SARS-CoV-2 booster shots became widely available in the US to ensure continued protection against the virus. A temporal relationship has been previously reported between the first or second dose of the COVID-19 vaccine and the development of thrombocytopenia. However, adverse events related to the third COVID-19 vaccine are still being reported and studied. We report a 74-year-old male who developed bone marrow suppression and pancytopenia recorded seven days after receiving the Pfizer SARS-CoV-2 vaccine. During his hospital stay, the patient’s hemoglobin, white blood cell, and platelet levels continued to trend downwards. However, all three levels showed improvement one week after discharge without robust intervention. Global vaccination is of utmost importance, as is understanding and documenting post-vaccination reactions including bone marrow suppression. Prompt evaluation and patient education are imperative to improve patient outcomes and combat hesitancy against vaccine administration.

Introduction

Since its emergence in December of 2019, the rapid spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has quickly affected millions of lives across every continent.1 This highly transmittable and pathogenic viral infection has led to massive mitigation efforts and allocation of resources to prevent the spread of transmission and high mortality related to complications.2 The establishment of higher levels of community (herd) immunity and protection against SARS-CoV-2 via the widespread deployment of effective vaccines has become a global effort.3 In December of 2020, the FDA issued an Emergency use Authorization for the Pfizer-BioNTech and Moderna COVID-19 Vaccine as a two-dose series.4 In September 2021, booster vaccines became widely administered in the US due to waning immunity of the COVID-19 vaccines against variants of SARS-CoV-2 along with ensuring continued protection against the virus.5

Serious adverse events such as anaphylaxis, Guillain-Barre Syndrome, myocarditis, pericarditis, thrombocytopenia, and death have been previously reported following the first and/or second dose of vaccine.6 To our knowledge, no cases have been reported regarding bone marrow suppression related to the third COVID-19 vaccine. Adverse events reported between August 12-September 19, 2021 from the COVID-19 booster vaccine supported similar reactions to those after dose two.7 According to the Centers for Disease Control and Prevention (CDC), these initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccination.7 However, adverse events related to the COVID-19 booster are still being reported and studied.6 This report presents a case of bone marrow suppression occurring after the third COVID-19 vaccine without a similar reaction after the first or second dose.Go to:

Case Report

A 74-year-old male with a history of polychondritis and hypothyroidism presented to the hospital after falling out of his chair and inability to ambulate. The patient was found to be mildly confused upon arrival to the emergency room, limiting our ability to obtain a full verbal history. Chart review revealed the patient had received his third Pfizer Covid vaccine shot seven days before admission followed by fatigue, decreased appetite, fever, and chills. The patient had received the second Pfizer Covid-19 shot nine months before the booster. No reactions to the previous two shots were noted.

Upon initial evaluation, vital signs were within normal limits and a physical exam revealed significant tenderness in the upper arm and no gross bleeding (Figure 1). Computed tomography (CT) imaging (Figure 2) was significant for enhancement of the left axillary lymph node. The patient’s initial complete blood count (CBC) was remarkable for a hemoglobin count of 9.9 g/dl and platelet count of 84 x 109/L; both values lower than his prior hemoglobin count of 13.7 g/dl and platelet count of 180 x 109/L from December of 2020. His mean corpuscular volume (MCV) was elevated at 101.3 femtolitres from his prior MCV value of 95.8 femtolitres in December of 2020. His white blood cell (WBC) count was recorded at 7.6 x 109/L.

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Figure 1

The patient’s upper arm showed erythema with no gross bleeding near the injection site

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Figure 2

The patient’s CT imaging of the thoracic region showed enhancement of the left axillary lymph node.

The hemoglobin, WBC, and platelet count further down trended from his baseline (Figures 3​5).5). Anemia labs including ferritin levels (554 ng/mL), vitamin B12 (253 pg/mL), total bilirubin (0.5 mg/dL), and reticulocyte count (0.8%) were nonsignificant during the patient’s hospital stay. The patient’s left shoulder presented with extensive bruising, erythema, papular rash, warmth, and tenderness on palpation during the hospitalization. An improvement in WBC and platelet levels was noted on day 4 of hospitalization.

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Figure 3

The patient’s hemoglobin count throughout his hospital course and 6 days after discharge.

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Figure 4

The patient’s WBC count throughout his hospital course and 6 days after discharge.

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Figure 5

The patient’s platelet count throughout his hospital course and 6 days after discharge.

Before discharge, the patient was fully alert and oriented and reported improvement in his symptoms. Examination of his lateral left arm showed decreased erythema and bruising with slight petechiae. The patient was discharged due to stabilization of labs and encouraged to take oral vitamin B12 supplements. During his outpatient follow-up six days after hospitalization, his hemoglobin increased to 10.5 g/dl, WBC count increased to 4.9 x 109/L, and platelets increased to 101 x 109/L.

Discussion

This paper presents a patient with pancytopenia recorded seven days after receiving the Pfizer booster vaccine. Interestingly, this patient did not report any reactions after the first or second dose of the Pfizer vaccine against SARS-CoV-2. Pancytopenia refers to a decrease in all peripheral bloodlines and is present when all three cell lines are below the normal reference range.8 The patient’s physical exam showed no signs of active bleeding along with his labs indicating no evidence of hemolysis. The patient’s hemoglobin, platelet, and white blood cell count presented below baseline followed by a decrease and slight improvement during his hospital stay. Six days after hospitalization, all three cell lines showed improvement. The temporal association with the booster vaccine and negative infectious disease workup raised suspicion for vaccine-induced bone marrow suppression. In addition, the patient’s reticulocyte count and lactate dehydrogenase value were consistent with hypoproliferation within the bone marrow.

Currently, there is a gap in knowledge of adverse events specific to the third vaccine against SARS-CoV-2 due to the recent initiation of administration and ongoing reporting of events.6 To our knowledge, bone marrow suppression after any dose of vaccine against SARS-CoV-2 has not been previously reported. However, a prior case of pancytopenia after the third vaccination with a recombinant hepatitis B vaccine has previously been reported.9 The patient’s bone marrow biopsy within this case displayed a paucity of late myeloid elements and CD8+ T cells.9 It was believed the patient’s CD8+T cells were causing excessive production of IFN-γ; a stimulant of negative regulators of hematopoiesis such as tumor necrosis factor and lymphotoxin.10 IFN-γ has also previously been reported to create immunological effects comprising an upregulation of histocompatibility gene transcription and alteration in class I and II antigen expression at the cell surface.11 It was predicted these changes resulted in an autoimmune reaction causing suppression of maturation of hematopoietic progenitor cells and pancytopenia.9 Via a similar mechanism, we believe that our patient’s pancytopenia was immune-mediated, potentially triggered by the vaccination.

Vaccines against SARS-CoV-2 (first or second dose) and the induction of Idiopathic Thrombocytopenic Purpura (ITP) have also been recently acknowledged in multiple cases.12 Our patient presented with low platelet levels and associated petechiae and purpura at the site of the vaccination. However, the patient’s presentation of low hemoglobin and white blood cells along with normal reticulocyte levels was more indicative of pancytopenia secondary to bone marrow suppression. In patients presenting with pancytopenia, the history and the physical exam should help assess the severity of the pancytopenia and comorbid illnesses that may complicate the disorder.13 In addition, suspicious medications and exposure to toxic agents should be ruled out.13 Initial screening laboratory evaluation should include the patient’s complete blood count, peripheral blood smear examination, reticulocyte count, complete metabolic panel, prothrombin time/partial thromboplastin time, and blood type and screen. Common interventions to alleviate bone marrow suppression and pancytopenia include treating the underlying cause and utilizing supplements to boost red blood cell production if indicated.

Vaccines against SARS-CoV-2 undergo continuous safety monitoring; adverse events are very rare.14 However, vaccine hesitancy remains a barrier towards full population inoculation against SARS-CoV-2 and is influenced by misinformation regarding vaccine safety.15 One study using an anonymous online questionnaire found a person’s trust in the effectiveness of the vaccine was a major facilitative factor affecting willingness to vaccinate.16 The same study also found that 66.7% of unvaccinated participants thought the vaccine’s safety was not enough, making it the main reason for reluctance or hesitance to be vaccinated.16 Therefore, education of adverse events and available interventions post-vaccination is imperative to prevent the spread of misinformation and combat hesitancy towards vaccination.15

As of September 19, 2021, about 2.2 million people in the United States received a third vaccine against SARS-CoV-2.17 Among those who received the vaccine, 22,000 people reported the effects of the vaccine with no unexpected patterns of adverse reactions.17 Our patient demonstrates abnormal pancytopenia first recorded seven days after receiving the booster vaccine, possibly indicating a rare adverse event from the vaccination given the temporal relationship. While additional studies and observations are indicated to verify bone marrow suppression as an adverse reaction, this case report provides an opportunity for patient education and treatment planning before symptoms arise.

Conclusion

Our case report highlights pancytopenia secondary to bone marrow suppression following Pfizer vaccination against SARS-CoV-2. It is important to consider the possibility of bone marrow suppression following the third vaccine against SARS-CoV-2. Although additional studies are indicated to determine the risk factors and pathogenesis of vaccine-induced bone marrow suppression, prompt evaluation and initiation of interventions can improve patient outcomes.

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Never Had Covid? You May Hold KeyTo Beating the Virus

Authors: Madison Muller 02:30 PM IST, 30 Mar 2022 06:48 PM IST, 30 Mar 2022 Read more at:  https://www.bloombergquint.com/onweb/never-had-covid-you-may-hold-key-to-beating-the-virus
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More than half of Americans may have never had Covid, according to U.S. government data, leaving scientists wondering whether those who’ve avoided the novel coronavirus might actually be immune to the virus altogether. This could offer new clues into how to attack Covid. At this stage in the pandemic, people may be immune due to vaccines, a past infection, or a combination of both. There’s also evidence that, in rare instances, some people may be Covid-immune without infection or vaccination at all.

The coronavirus’s frequent mutations and the fact that immunity wanes over time make it difficult to discern how many people are immune at any given moment.  Studies have shown, for example, that while omicron infections offer some immunity against delta, omicron is able to circumvent antibodies from both past infection with other variants and vaccination. Current surveillance techniques have also likely vastly underestimated the number of cases, as more people are taking Covid tests at home and not reporting the results. 

“It’s nearly impossible to gauge protection,” said Andy Pekosz, a virologist at Johns Hopkins Bloomberg School of Public Health.

As cases yet again rise in many regions more than two years into the pandemic, studying those who have not yet caught Covid has become just as critical as studying those who have. Experts say that people with so-called “super” immunity who appear resistant to the virus without vaccination may hold answers to important questions about why certain people get so sick while others don’t. Examining these cases could also help inform the development of vaccines and therapeutics less vulnerable to viral mutations.

“It is essentially defining what a best-case scenario looks like, which can also help to identify what is going wrong in those that don’t control the virus,” said Leo Swadling, an immunologist at the University College of London. 

It may be hard to believe that at this stage of the pandemic so many people have still never gotten sick. Perhaps people were asymptomatic and never knew they were infected, or, despite exposure to the virus, they just never tested positive. But even half of the population getting Covid is actually an extraordinary number of infections. The 1918 Spanish flu is estimated to have only infected 25% of the U.S. population at the time, despite causing a huge number of deaths.

Early in the pandemic, Swadling set out to find out more about the lucky few who weren’t getting sick.

“We were particularly interested in people who are exposed to the virus, but control it very quickly, clearing the virus before it can replicate to detectable levels and before it induces an antibody response,” Swadling said. “It may help us better understand what immunity is best at protection from reinfection.”

Swadling, along with colleagues in London, published a study in the journal Nature last November evaluating a group of U.K. health care workers during the first wave of the pandemic. They found evidence that some of the health care workers exposed to the virus were able to rid their bodies of it even before producing Covid-specific antibodies.

It turned out that for those people, exposure to other human coronaviruses, such as those that cause cold-like symptoms, had helped their bodies to fight off the novel coronavirus. This is because T-cells, a critical part of the body’s immune response, were able to recognize and target genetic elements of prior seasonal coronaviruses that also happened to be present in SARS-CoV-2.  That meant their bodies were able to attack the novel virus without the production of new antibodies specific to it.

Notably, the T-cells that those health care workers produced targeted a different part of the virus than the T-cells did in people who have a detectable Covid infection. Swadling said the while the T-cells produced by both vaccines and a detectable Covid-19 infection attack the frequently mutating spike protein of a virus, these health care workers’ T-cells instead targeted the virus’ internal machinery. Researchers call these T-cells that appear effective against different coronaviruses  “cross-reactive.”

“We identified new parts of the virus that we can put into a vaccine to try to improve it ,” Swadling said. These improvements, he said, could make vaccines better at preventing infection, more effective against new variants and more protective for immunocompromised individuals.

Immunity to a virus occurs when the body is able to recognize a pathogen and effectively fend off infection or disease. Antibodies, such as those acquired from a vaccine or previous infection, attack a virus as soon as it enters the body. T-cells act as another line of defense, working to stop the spread of infection and development of disease once the virus has made it into the body. The mRNA vaccines such as those made by Pfizer and Moderna work by training the body to safely produce antibodies without infection, but they also spur the production of T-cells and B-cells. That’s why the vaccines effectively prevent hospitalization even when they don’t prevent infection altogether — even when antibodies have waned, T-cells are still there to help fight off an infection more quickly.

The study’s authors proposed that T-cells they found— the ones that target the virus’ internal machinery— may offer better protection against emerging variants because of their ability to attack a key part of the virus less vulnerable to mutations than its spike protein. They theorize that targeting those areas of the virus could make the shots more effective.

As labs work to develop a single shot that would offer broader protection against any Covid variant, at least one company, Gritstone Bio Inc., is looking to put Swadling’s theories to the test. Others have reached similar conclusions as Swadling and his colleagues. One study found that in households where some people remained Covid-free despite exposure, those people also appeared protected by T-cells from past exposure to coronaviruses. Another study from January found that some children who did not develop Covid antibodies also had cross-reactive T-cells, which may be part of the reason why children generally have milder symptoms.

Knowing how many people have this heightened immune response is extremely difficult to assess. Some people may have managed to avoid the virus through continued caution or simply luck. But perhaps more important than knowing how many people fall into this category is the information about immunity that can be gathered from studying what sets them apart.

 “T-cells are very long-lived so we may not need repeated vaccination,” Swadling said. 

Studying the super-immune, he said, may help us against omicron — and any future variants of concern.

Read more at: https://www.bloombergquint.com/onweb/never-had-covid-you-may-hold-key-to-beating-the-virus
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Consequences of COVID-19 for the Pancreas

Authors: Urszula Abramczyk,1,*Maciej Nowaczyński,2Adam Słomczyński,2Piotr Wojnicz,2Piotr Zatyka,2 and Aleksandra Kuzan1 Int J Mol Sci. 2022 Jan; 23(2): 864.Published online 2022 Jan 13. doi: 10.3390/ijms23020864

Abstract

Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the pancreas either. This review presents a summary of the molecular mechanisms involved in the development of pancreatic dysfunction during the course of COVID-19, the comparison of the effects of non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic function, and a summary of how drugs used in COVID-19 treatment may affect this organ. It appears that diabetes is not only a condition that predisposes a patient to suffer from more severe COVID-19, but it may also develop as a consequence of infection with this virus. Some SARS-CoV-2 inpatients experience acute pancreatitis due to direct infection of the tissue with the virus or due to systemic multiple organ dysfunction syndrome (MODS) accompanied by elevated levels of amylase and lipase. There are also reports that reveal a relationship between the development and treatment of pancreatic cancer and SARS-CoV-2 infection. It has been postulated that evaluation of pancreatic function should be increased in post-COVID-19 patients, both adults and children.

1. Effects of Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-Related Coronavirus (MERS-CoV) on the Pancreas

Coronaviruses are enveloped, single- and positive-stranded RNA viruses that infect birds and mammals. In humans, coronaviruses cause respiratory tract infection, usually the common cold, but they can also cause severe respiratory illness including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), caused by severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), respectively [1]. Coronaviruses tend to cause epidemics and even pandemics. The first coronavirus pandemic was the SARS outbreak in 2002–2003 [2]. With the experience gained during the SARS pandemic, it was possible to more quickly identify subsequent outbreaks of the MERS epidemic in 2012 [3]. The pathomechanism of both viruses is very similar—they even both use transmembrane protease serine 2 (TMPRSS2), except SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as its receptor, whereas MERS uses dipeptidyl peptidase-4 (DPP4) [4,5]. Moreover, there is a difference in terms of the severity and frequency of symptoms, which was observed in MERS patients as more frequent hospitalization in the intensive care unit (ICU) compared to SARS patients [2] (Table 1). Diabetes was one of the significant and independent predictors for developing severe SARS-CoV and MERS-CoV [6,7,8]. In MERS, no viral antigen was detected in any tissue other than pneumocytes [7], despite multiple organ dysfunction syndrome in critically ill patients. In SARS-CoV, the presence of the virus was detected not only in respiratory epithelial cells, but also in small intestinal and colonic epithelial cells, in which it also revealed replication features [9]. It is known that the ACE2 receptor is also present in tissues such as the heart, kidney, and pancreas [8,9]. According to some authors, the presence of the receptor is sufficient for tissue entry and pathogenic activity, although other researchers do not support this thesis [9,10]. Yang et al. were some of the first researchers who hypothesized that SARS coronavirus enters islets using ACE2 as its receptor and damages islets causing acute diabetes [8]. Yang’s study revealed that SARS-CoV had a much higher affinity for pancreatic islet cells than for pancreatic exocrine cells, which was consistent with the hyperglycemia observed in some patients and rarely reported acute pancreatitis (AP) [8]. Furthermore, insulin-dependent diabetes mellitus (IDDM) and high fasting blood glucose values were observed in some inpatients [8]. A 3-year follow-up revealed that both abnormalities were transient, which may be indicative of only temporary damage to the pancreatic islets [8]. However, another reason (different from that given by Young et al.) for high fasting blood glucose value in patients may result from increased stress hormones release. Cortisol, catecholamines, growth hormone, and glucagon, which are released during infection, fever, and trauma, can lead to hyperglycemia to the same degree as SARS-CoV can [11]. No information was found in the literature about a direct impact of the MERS virus on the pancreas or on glycemia during or after infection. This may be due to an insufficiently detailed analysis of the available data during previous studies that oscillated primarily, for laboratory tests, between complete blood count (CBC), lactate dehydrogenase (LDH), urea, and creatinine analysis. A summary of SARS-CoV, MERS, and SARS-CoV-2 is shown in Table 1.Table 1. The summary of characteristics of SARS and MERS coronaviruses. Dipeptidyl peptidase-4 (DPP4), transmembrane protease serine 2 (TMPRSS2), hospitalization in the intensive care unit (ICU), and cathepsin L (CTSL).

Table

In 2019, a new coronavirus named SARS-CoV-2 was identified, causing COVID-19. This virus has many characteristics that are analogous to SARS-CoV, for example, ACE2 is also used as its receptor [12]. Patients with diabetes are among those with the most severe forms of COVID-19 and related mortality; insights from recent experience can guide future management [17], particularly for the consequences on the pancreas. As the COVID-19 pandemic has been ongoing for nearly two years, this study aims to collect data concerning the impact of SARS-CoV-2 on the pancreas and analyze them to estimate the future health consequences of COVID-19 in populations.

2. Pancreatic Damage during Diabetes Mellitus and COVID-19

Pancreas tissue damage may cause to the lack of control over normal blood glucose levels in the body. Type 1 diabetes (T1D) is caused by insulin deficiency due to βcell dysfunction of immunologic or idiopathic cause. In contrast, β pancreatic cells in type 2 diabetes (T2D) become depleted over time due to compensatory insulin secretion caused by insulin resistance. There is also type 3 diabetes (T3D), which is described as diabetes associated with the development of Alzheimer’s disease [18]. It should not be confused with type 3c (pancreatogenic) diabetes, which relates to the exocrine and digestive functions of the pancreas. The issue concerning the impairing effect of hyperglycemia (glucotoxicity) on the secretory function of the islets of Langerhans has also been increasingly raised. In addition to endocrine dysfunction, some diabetic patients may also develop moderate exocrine pancreatic insufficiency (EPI), in which pancreatic enzyme secretion is impaired. EPI can be observed in almost all patients with type 3c (pancreatogenic) diabetes (secondary to pancreatic pathology), whereas the prevalence of this dysfunction in patients with T1D or T2D is 40% and 27%, respectively [19].With the ongoing SARS-CoV-2 pandemic, patients with reduced normal pancreatic function are at high risk for COVID-19 requiring hospitalization. In particular, elevated blood glucose levels in patient with and without diabetes makes them at high risk of mortality [20]. Hyperglycemia impairs the immune response (e.g., by reducing the activity of macrophages and polymorphonuclear leukocytes), which in addition influences the excessive cytokine response, and thus has a strong proinflammatory effect.The receptors for ACE2, which are also present in the pancreas, are a target of SARS-CoV-2 in the body, which may result in acute failure of both the islets of Langerhans and exocrine cells [15]. Infection-induced, transient β cell dysfunction may cause an uncontrolled hyperglycemic state, especially in patients whose pancreas is already affected by diabetes mellitus. Persistent hyperglycemia usually predisposes to severe COVID-19 and to viral infection complicated by secondary infections. The aforementioned risk can be found in T1D, T2D, and gestational diabetes mellitus (GDM). In T2D patients, the much more frequent coexistence of other risk factors such as atherosclerosis, hypertension, and obesity should be taken into consideration, which usually implies a worse prognosis for the course of COVID-19 [21,22]. In GDM, SARS-CoV-2 infection not only increases the risk of more severe course of the disease in a patient, but may also result in diabetic fetopathy or, in more advanced pregnancies, increase the risk of future pathologies involving glucose metabolism (such as T2D) in a child [23].

3. Pancreatic Damage in Patients without Pre-Existing Diabetes Infected with SARS-CoV-2

It has been postulated that, either by direct invasion of pancreatic cells by the virus or by indirect mechanisms described below, SARS-CoV-2 has a destructive effect on the pancreas and can lead to insulin deficiency and development of T1D [24].If the hypothesis that SARS-CoV-2 infection causes hyperglycemia is true, increased statistics of new T1D cases should be observed. Indeed, there are publications that describe such a phenomenon. For instance, Unsworth et al. and Kamrath et al. describe an increase in new-onset T1D in children during the COVID-19 pandemic [16,25]. Although pancreatic β cell damage induced transient hyperglycemia in SARS-CoV, it is still unclear whether β cell damage is transient or permanent in SARS-CoV-2 [22]. This information appears to be of great importance because COVID-19 in children is frequently considered “harmless”. Therefore, it is reasonable to sensitize parents to the fact that the consequences of COVID-19 may be potentially dangerous for their children.Below you will find the proposed molecular mechanisms that may participate in pancreatic damage that causes carbohydrate metabolism disorders.

4. Etiology Associated with ACE2, TMPRSS2, and Na+/H+ Exchanger

As previously mentioned, SARS-CoV infection of host cells is facilitated by ACE2, but also by the transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL) [13].ACE2 is an enzyme that is expressed to varying degrees in most cells of the human body [14,26,27]. This enzyme catalyzes the conversion of angiotensin II to angiotensin 1–7, taking part in the maintenance of body homeostasis by influencing the regulation of blood pressure and water–electrolyte balance through the renin–angiotensin–aldosterone (RAA) system [28]. Moreover, ACE2/angiotensin (1–7) stimulates insulin secretion, reduces insulin resistance, and increases pancreatic βcell survival [27,28].In addition to the key role it plays in maintaining body homeostasis, ACE2 is now also the best-studied target for SARS-CoV-2 S glycoprotein, enabling infection of host cells [27,29]. ACE2 in the pancreas is expressed mainly within the pericytes of pancreatic microvessels and to a lesser extent on the surface of the islets of Langerhans, including pancreatic β cells [30]. SARS-CoV-2 shows 10–20 times more activity against ACE2 than SARS-CoV, which significantly increases the infectivity of SARS-CoV-2 [31,32]. Furthermore, studies indicate that SARS-CoV may also downregulate ACE2 expression in cells. This causes an imbalance between ACE and ACE2, consequently leading to blood pressure disorders and systemic inflammation [27,33,34]. Due to the 79% genetic similarity between SARS-CoV and SARS-CoV-2 [35], it is speculated that ACE2 expression may also be downregulated during SARS-CoV-2 infection, causing i.a. MODS observed in COVID-19 [27].During cell infection by SARS-CoV-2, in addition to the role played by ACE2, it is also appropriate to consider the significant pathogenic role of TMPRSS2 that is necessary for the preparation of S glycoprotein by its cleavage, thereby enabling fusion of the virus with the host cell [36,37]. The S1 and S2 domains can be distinguished in the SARS-CoV-2 S glycoprotein. The S1 domain is involved in binding to the ACE2 receptor and then TMPRSS2 intersects with the S protein, including at the boundary of the S1 and S2 domains and within the S2 domain, which enables the virus–cell fusion [38,39]. According to studies, TMPRSS2 expression is significantly increased in obese patients, which may contribute to the poorer prognosis that is observed during COVID-19 in this patient group [40]. Moreover, obese patients are frequently already burdened with problems such as insulin resistance at baseline, while the presence of ACE2 and TMPRSS2 within the pancreas as a binding site for SARS-CoV-2 may exacerbate insulin resistance causing problems in terms of diabetes management in COVID-19 patients.There are also other mechanisms by which COVID-19 may affect the development of hyperglycemia. It is reported that the virus may also affect the glucose regulation through the Na+/H+ exchanger and lactate pathways. The mechanism is that angiotensin II, which accumulates during infection, contributes to insulin resistance and—by activating the Na+/H+ exchanger in the pancreas—it leads to hypoxia and extracellular acidification, which, through the accumulation of calcium and sodium ions in the cells and the production of reactive oxygen species, damages pancreatic tissue [41]. Simultaneously, the concentration of lactate increases, which in COVID-19 infection is intensively released, among other things, from adipose tissue, and then monocarboxylate transporters transport lactate and H+ ion inward in the cell, which increases Na+/H+ exchanger activation, further disrupting pancreatic homeostasis [41].

5. The Etiology Associated with a Systemic Proinflammatory Environment, Immune System Aggression, and Production of Novel Autoantigens

A broad spectrum of proinflammatory cytokines, such as IL-2, IL-6, IL-7, IL-8, interferon-γ, and Tumor Necrosis Factor α (TNF-α), is released during, in particular severe, COVID-19 infection [42,43,44]. Based on current studies, it is reasonable to suspect that these cytokines are released in response to the binding of the virus to ACE2 receptors that are also located in the pancreas [9,42]. The cause of pancreatic damage during COVID-19 is the cytokine storm that plays a key role in this case, because in both acute pancreatitis (AP) and severe COVID-19, elevated levels of the aforementioned interleukins are associated with the severity of these both disease entities. Particular attention should be paid to IL-6, because it is suspected to play a key role in the pathogenesis of AP as well as acute respiratory distress syndrome (ARDS) that is the most common and most severe clinical manifestation of COVID-19. In COVID-19-induced ARDS, IL-6 levels are correlated with disease-related mortality [45,46,47]. At the same time, high IL-6 levels correlate with an increased risk of developing severe pancreatitis [48,49].The production of neutralizing antibodies is also an important response of the body in the course of COVID-19 [50,51,52]. It has been observed that early seroconversion and very high antibody titers occur in patients with severe SARS-CoV-2 infection [53,54]. The available literature details a mechanism called antibody-dependent enhancement (ADE), which is associated with a pathological response of the immune system [53]. ADE exploits the existence of FcRS receptors located on various cells of the immune system, for example, macrophages and B lymphocytes [53]. This relationship may lead to a likely bypass of the classical viral infection pathway by ACE2, and virus–antibody complexes may stimulate macrophages to overproduce cytokines including significant IL-6 [53,55].Molecular mimicry may be also one of potential causes of pancreatic cell damage [56]. There are similarities in the protein structure of the virus and β-pancreatic cells, which may induce cross-reactivity and lead to autoimmunity [56]. Furthermore, viral infection may also lead to increased cytokine secretion by surrounding dendritic cells and activation of naive T cells in genetically predisposed individuals [56].

6. Pancreatitis in COVID-19

Although the impact of the discussed coronavirus-induced disease on exocrine function is not fully understood, available literature is not able to unambiguously determine whether the tissue damage leading to AP occurs as a result of direct SARS-CoV-2 infection [57] or as a result of systemic MODS with increased levels of amylase and lipase [42]. Liu et al.’s study involving 121 COVID-19 patients with a mean age of 57 years and a variable course of infection proved above-normal levels of amylase and lipase in 1–2% of patients with moderate COVID-19 infection and in 17% of patients with severe COVID-19 infection. This may support the hypothesis that SARS-CoV-2-induced disease has a destructive effect not only on the endocrine portion of this gland, but also on the exocrine one [15].However, elevated levels of pancreatic enzymes in question do not have to mean the destruction of pancreatic cells—after all, such a situation may occur during kidney failure or diarrhea in the course of COVID-19. Furthermore, there remains the question of the effect of drugs administered during SARS-CoV-2 infection on changes in pancreatic function [42], discussed further in this article.According to the International Association of Pancreatology (IAP) and the American Pancreatic Association (APA), the diagnosis of AP is based on meeting two out of three of the following criteria: clinical (epigastric pain), laboratory (serum amylase or lipase > 3 × upper limit of normal), and/or imaging criteria (computed tomography, magnetic resonance imaging, ultrasound) [58]. Pancreatic lipase is considered as a potential marker of SARS-CoV-2 severity with concomitant AP. In Hemant Goyal et al.’s study, as many as 11.7% out of 756 COVID-19 patients had hyperlipidemia and they were three times more likely to have severe COVID-19 [59]. Those with higher lipase levels—17% out of 83 patients—required hospitalization [60]. However, it is difficult to distinguish whether these patients required hospitalization for severe systemic COVID-19 infection or for pancreatitis in the course of COVID-19 infection.AP in the course of COVID-19 was analyzed in different age groups; however, some studies only involve children [61]. Compared to pancreatic islet cells, cells of the exocrine pancreatic ducts are more abundant in ACE2 and TMPRSS2 that are necessary for the virus to penetrate the cell [62]. Infection of these cells may be one of the causes of AP [63]. Infections, both bacterial and viral, are one of the causes of AP. The definitive mechanism of how viral infections affect pancreatic cells is not known; however, a study by Maria K Smatti et al. found that there is infection of pancreatic islet cells and replication of the virus within them, ultimately resulting in autoimmune reactions that eventually affect both diabetes and AP in a negative way [64]. For non-SARS-CoV-2 patients, the etiology of AP is known and confirmed in most cases, although 69% of those undergoing infection do not have definite etiology of AP while meeting the AP-Atlanta criteria for diagnosis [65].Hegyi et al. show the mechanism of MODS formation during COVID-19 infection and AP [66]. This is lipotoxicity, involving an interstitial increase in pancreatic lipase levels, which leads to the breakdown of triacylglycerols contained in adipose tissue cells and the release of unsaturated fatty acids. These in turn exert a toxic effect on mitochondria causing the release of cytokines, which results in a cytokine storm.There is also a hypothesis, which claims that AP can develop because of blood circulatory centralization resulting from uncontrolled cytokine storm created by SARS-CoV-2 infection [67]. There exist reports that say that pancreatic ischemia may be the cause of different degrees of acute pancreatitis [68,69]. This statement can be supported by the reports that state that pancreatic blood reperfusion inhibits the development of AP and accelerate pancreas recovery [70].Another mechanism of developing AP during COVID-19 may be a coagulation cascade activation caused by active inflammatory process due to SARS-CoV-2 infection [71]. The ongoing inflammatory process causes not only hemostasis imbalance for blood clotting, but it also leads to intensification of coagulation by removing epithelial cell protein C receptor (EPCR) from epithelial by the means of inflammatory mediators and thrombin [71]. This means that both processes intensify each other. Simultaneously, it was proved that COVID-19 predisposes patients to venous thromboembolism resulting from excessive inflammation, platelet activation, and endothelial dysfunction [72]. It is also important to notice that AP is inherently connected with a coagulation cascade activation, increased fibrinolysis and, hence, higher level of D-dimers [73]. Acute pancreatitis severity may depend on hemostasis imbalance; local coagulation results in mild AP whereas, in more severe AP cases, the imbalance may lead to development of disseminated intravascular coagulation (DIC) [74]. These observations have been supported by the results of experimental studies showing that the inhibition of coagulation reduces the development of AP [75,76,77] and exhibits therapeutic effect in this disease [78,79]. Additionally it is worth noticing that infection-related hyperglycemia has powerful inflammation-promoting effects on the organism (especially when organism is under stress), thus increasing the number of inflammatory mediators [74]. Unfortunately, it is impossible to decide which process is dominant in causing AP in COVID-19 patients: local inflammation caused by SARS-CoV-2 or systemic hemostasis imbalance.Clinical reports on low molecular weight heparin (LMWH) treatment in AP seem to emphasize a more significant role of hemostasis imbalance in causing AP [74,80,81]. Heparin is extremely significant in the treatment of COVID19 patients due to its properties, mainly its similarity to heparan sulphate, which appears in a respiratory tract, its interactions with SARS-CoV-2 S protein, leading to viral adhesion inhibiting to the cell membrane [82], and its anti-inflammatory effects. Thanks to these properties, heparin may not only show its therapeutic effect as the anticoagulant, but also its protective role in acute pancreatitis or respiratory inflammations [83,84,85].

7. Drugs Used against SARS-CoV-2 Infection (Glucocorticoids, Lopinavir, Ritonavir, Remedesivir, Interferon-β1 (IFN-β1), and Azithromycin) Induce Pancreatic β Cell Damage

Statistical analyses revealed a significantly higher incidence of AP with the concomitant systemic use of glucocorticosteroids (GCS) [86]. In one study analyzing the development of drug-induced AP, dexamethasone, was classified as type IB—there was one case report in which administration of this drug-induced AP occurred; however, other causes of pancreatitis such as alcohol consumption could not be excluded [87]. Other GCS such as hydrocortisone, prednisone, and prednisolone were used in patients with mild to moderate AP; however, they cannot be classified into any group because they are frequently used together with other drugs that cause AP [86,87]. However, it has been determined that GCS independently increase the risk of AP, and patients with residual AP risk factors during GCS treatment should be more monitored for the development of AP [23]. Javier A. Cienfuegos et al. additionally observed that one of mechanisms of AP formation in COVID-19 patients may be GCS administered at the time of admission to the ICU with severe respiratory failure [88]. Because GCS were used in severe COVID-19 cases, it is difficult to say what true reason for AP was—either a severe course of COVID-19 or GCS application or both.GCS are used in the treatment of many diseases due to their immunosuppressive and anti-inflammatory nature. They induce diabetes in previously healthy patients as well as significantly exacerbate diabetes in diabetic patients [89,90]. Diabetes develops in these patients likely due to pancreatic β cell dysfunction, decreased insulin secretion, and increased insulin resistance in other tissues, which may depend on the timing and the dose of GCS used [89,91]. Long-acting or intermediate-acting insulin alone or combined with short-acting insulin should be used during the treatment [90]. At the same time, no advantage was found over the use of oral hypoglycemics [92]. Certainly, patients after long-term GCS therapy will need further observation for diabetes.Lopinavir/ritonavir was classified in the previously mentioned study as a type IV drug—medications reported with little information [87]. Both drugs are included in the group of antiretrovirals that act as protease inhibitors, and they are primarily used for HIV infection. Although Lopinavir is an active drug, it is not used alone. There have been reports about the occurrence of AP during the use of protease inhibitors in question, which is also described in the Summary of Product Characteristics (SmPC) of products approved by Committee for Medicinal Products for Human Use (CHMP). It has been proved that the use of lopinavir/ritonavir causes hyperglycemia [93,94].Remdesivir is an adenosine analogue with antiviral activity. There are single reports about the occurrence of pancreatitis as a result of the use of the aforementioned medication [95,96]. At the same time, it should be noted that other nucleoside-derivative drugs may cause pancreatitis [97].The current state of knowledge does not clearly indicate the therapeutic benefit of interferon-β in the treatment of COVID-19 patients [98,99]. To date, only single cases suggesting induction of pancreatitis by interferon-β have been reported. Based on this, Badalov et al. classified interferon into type III [87].There are few reports about the development of AP due to the use of azithromycin [100]. In the previously mentioned study by Badalov et al., two macrolide antibiotics were classified as type II and III. Unfortunately, there are no direct data concerning azithromycin. Interestingly, there were cases of patients with concomitant symptoms of AP and viral pneumonia caused by SARS-CoV-2 who were treated with azithromycin, which resulted in complete resolution of symptoms for both conditions [96,101]. Based on available data, the risk of azithromycin-induced AP is low.There is no clear evidence that azithromycin affects blood glucose levels in humans. However, it is known for its prokinetic effects, which may be helpful in patients who suffer from diabetic gastroparesis [102]). The incidence of hypo- and hyperglycemic episodes was not proved to be significant for azithromycin [103]; however, the risk of dysglycemia is emphasized [94]. In the SmPC, where azithromycin is the main ingredient, it is not possible to establish a causal relationship between the occurrence of pancreatitis and taking medications (Zithromax) based on the available data. In contrast, glycemic disturbances were not indicated as side effects (Zithromax) [104].Hydroxychloroquine has been extensively promoted for COVID-19 due to its anti-inflammatory and antiviral action; yet, the use of this agent in diabetes deserves particular attention for its documented hypoglycemic action, and its benefit on COVID-19 is controversial, although there is large usage [105].Table 2 shows a comparison of the side effects of medications in question.Table 2. Side effects of medications used in SARS-CoV-2 infection in the area of pancreatic effects and hyperglycemia.

Table

8. COVID-19, Pancreas, and Glycation

In T2D diabetics, oxidative stress leading to pancreatic damage may be stimulated by, among other things, the intense glycation that accompanies hyperglycemia [24]. Glycation is a non-enzymatic process involving reducing sugar and amino groups of proteins, which contributes to the formation of advanced glycation end products (AGEs). These products have significantly altered biochemical properties relative to the substrates, including proteins that have altered conformation, increased rigidity, resistance to proteolysis, etc. [106,107].Part of the pathomechanism involved in facilitating coronavirus infection in diabetics may be due to glycation of ACE2 and SARS-CoV-2 spike protein [108,109].An interesting hypothesis is that COVID-19 has a worse prognosis in patients with intense glycation, and thus high tissue AGE content. Glycated hemoglobin (HbA1c) is a commonly used diagnostic tool that estimates intensity of glycation. The parameter is not only a marker of long-term persistent hyperglycemia, but an active participant in immune processes, as HbA1c levels are associated with NK cell activity [110].Zhang et al.’s retrospective cohort study concerning COVID-19 patients revealed that glycated hemoglobin correlates negatively with saturation (SaO2) and positively with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen (Fbg). It was concluded that determination of HbA1c levels may be helpful in assessing inflammation, hypercoagulability, and prognosis of COVID-19 patients [111].According to the meta-analysis by Chen et al. (2020), Hba1c levels were slightly higher in patients with severe COVID-19 compared to patients with mild COVID-19; however, this correlation was not statistically significant. However, it is of great importance to note that only two studies analyzing HbA1c in COVID-19 patients were included in this analysis because only these studies were available in May 2020 [112].Glycation plays its physiological effects not only directly by changing the properties of various proteins, but also indirectly through various receptors. RAGE is the most common receptor for AGEs. Binding of RAGE to its ligands activates a proinflammatory response primarily by mitogen-activated protein kinase (MAPK) and nuclear factor κβ (NFκβ) pathways. This interaction was proved to be significant in the pathogenesis of cancer, diabetes mellitus, and other inflammatory disorders [113]. RAGE was found to be expressed in the pancreas, and S100P-derived RAGE antagonistic peptide (RAP) reduces pancreatic tumor growth and metastasis [113]. The implications of this fact may also apply to the etiology and treatment of COVID-19. It has been postulated that targeting RAGE by various antagonists of this receptor may inhibit damage to various organs including the pancreas [114].

9. COVID-19 vs. Pancreatic Cancer

Immunosuppression as a treatment effect, elevated cytokine levels, altered expression of receptors for SARS-CoV-2, and a prothrombotic state in patients with various types of cancer may exacerbate the effects of COVID-19 [115].Focusing on pancreatic cancer, it can be observed that the pathomechanism of both diseases—COVID-19 and tumorigenesis in the pancreas—overlap in several molecular mechanisms. As mentioned above, SARS-CoV-2 infection of host cells is facilitated by ACE-2, TMPRSS2, and CTSL. Cathepsin L is upregulated in a wide variety of cancers, including pancreatic adenocarcinoma [13]. TMPRSS2 upregulation in pancreatic cancers is moderate, whereas ACE-2 is overexpressed in some cancers, including pancreatic carcinomas [115]. Interestingly, ACE2 upregulation seems to be associated with favorable survival in pancreatic cancer [116], and it is known that SARS-CoV-2 reduces ACE2 expression [22]. Furthermore, the above-mentioned RAGE may also participate in both pancreatic cancer development and SARS-CoV-2 infection. RAGE facilitates neutrophil extracellular trap (NET) formation in pancreatic cancer [117]. In conclusion, pancreatic cancer predisposes to an increased risk of COVID-19 and its more severe course, and coronavirus infection may contribute to pancreatic cancer.It also seems important how the COVID-19 epidemic has affected the treatment of patients with pancreatic cancer of SARS-CoV-2-independent etiology. According to the study by Pergolini et al., care of patients with pancreatic cancer can be disrupted or delayed, particularly in the context of treatment selection, postoperative course, and outpatient care [118].A separate issue is how patients after pancreatoduodenectomy respond to SARS-CoV-2 infection. A case series reported by Bacalbasa reveal that patients who develop SARS-CoV-2 infection postoperatively require re-admission in the ICU and a longer hospital stay; however, these infections are not fatal [119]. Although the analysis was performed on single cases, it is concluded that these results are an argument to perform elective oncological surgeries [119].There are also reports that chemotherapy in pancreatic cancer patients who become ill between treatment series can be successfully completed after a complete cure of the infection [120]. Guidelines for, e.g., prioritization and treatment regimens regarding pancreatic cancer treatment in the era of the pandemic, are developed and described, for example, by Catanese et al. or Jones et al. [121,122].

10. Conclusions

Evidence shows that SARS-CoV-2 infection contributes to damage within the pancreas. The mechanisms that are involved in this include but are not limited to direct cytopathic effect of SARS-CoV-2 replication and systemic and local inflammatory response [123]. At the current state of knowledge, it is certain that the virus attacks the endocrine portion of the pancreas as well as, to a much lesser extent, the exocrine portion. It has been shown that a bidirectional relationship between COVID-19 and diabetes exists; indeed, diabetes is associated with COVID-19 severity and mortality but, at the same time, patients with COVID-19 have shown new onset of diabetes [124]. SARS-CoV-2 virus infection not only directly affects glycemic levels, but also exacerbates already existing hyperglycemia through its negative impact on the functional competence of the islets of Langerhans. It cannot be excluded that the real cause of exocrine dysfunction of this gland is the negative effect of the drugs used for treatment of the infection. As the pandemic progresses, special attention should be given to the evaluation of chronic and acute pancreatic diseases, including pancreatic cancer, so that faster diagnosis enables faster implementation of treatment.

Author Contributions

Conceptualization, A.K.; investigation, U.A., M.N., A.S., P.W., P.Z. and A.K.; resources, U.A., M.N., A.S., P.W., P.Z. and A.K.; writing—original draft preparation, U.A., M.N., A.S., P.W., P.Z. and A.K.; visualization, U.A.; supervision, A.K. All authors have read and agreed to the published version of the manuscript.

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Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence?

Authors: Shotaro Tabata 1Hiroki Hosoi 2Shogo Murata 1Satomi Takeda 1Toshiki Mushino 1Takashi Sonoki 1PMID: 34920343

PMCID: PMC8668346I: 10.1016/j.jaut.2021.102782 J Autoimmun. 2022 Jan; 126: 102782.Published online 2021 Dec 14. doi: 10.1016/j.jaut.2021.102782

Abstract

The development of various autoimmune diseases has been reported after COVID-19 infections or vaccinations. However, no method for assessing the relationships between vaccines and the development of autoimmune diseases has been established. Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. We report a case of severe AA that arose after the administration of a COVID-19 vaccine (the Pfizer-BioNTech mRNA vaccine), which was treated with allogeneic hematopoietic stem cell transplantation (HSCT). In this patient, antibodies against the SARS-CoV-2 spike protein were detected both before and after the HSCT. After the patient’s hematopoietic stem cells were replaced through HSCT, his AA improved despite the presence of anti-SARS-CoV-2 antibodies. In this case, antibodies derived from the COVID-19 vaccine may not have been directly involved in the development of AA. This case suggests that the measurement of vaccine antibody titers before and after allogeneic HSCT may provide clues to the pathogenesis of vaccine-related autoimmune diseases. Although causality was not proven in this case, further evaluations are warranted to assess the associations between vaccines and AA.

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease 2019 (COVID-19). The introduction of SARS-CoV-2 vaccines has drastically reduced the transmission rate of the disease. Studies have confirmed the safety and efficacy of the available SARS-CoV-2 vaccines. However, rare cases of adverse immunological reactions to SARS-CoV-2 vaccines have been reported, including cases involving immune-mediated disease [[1][2][3]]. Although evaluating the associations between SARS-CoV-2 vaccines and the development of autoimmune diseases is important, no method for assessing such relationships has been established. Aplastic anemia (AA), a bone marrow failure syndrome, appears to be immune-mediated [4,5]. In addition to T lymphocytes and cytokines, autoantibodies are involved in the development of AA as immunological factors [4]. Here, we report a case of AA that developed after the administration of a SARS-CoV-2 vaccine and discuss the association between AA and vaccination.

2. Case description

A previously healthy 56-year-old male, who was not taking any medication, was referred to a clinic because of bleeding in the oral cavity after dental therapy. Laboratory tests showed that his white blood cell count (1.6 × 109/l) and platelet count (11 × 109/l) were decreased. Four days before his visit to the clinic, he had received a second dose of the Pfizer-BioNTech mRNA vaccine (three weeks after his first dose). He was admitted to our hospital due to progressive pancytopenia (Supplementary Table 1). He had no history of COVID-19 infection. The Elecsys® anti-SARS-CoV-2 immunoassay (Roche, Basel, Switzerland), which is used to detect anti-SARS-CoV-2 nucleocapsid protein antibodies, produced a negative result. Tests for immunoglobulin G against cytomegalovirus and Epstein-Barr virus produced positive results, but were not indicative of virus reactivation. Serological tests for hepatitis B, hepatitis C, and human immunodeficiency virus produced negative results. A bone marrow biopsy revealed a hypocellular marrow (Fig. 1 ). The patient was diagnosed with very severe AA [6]. Human leukocyte antigen (HLA) testing showed DRB1 04:05 04:05, which is not associated with a high frequency of AA. The administration of granulocyte-colony stimulating factor had no effect on his neutropenia. In spite of the administration of cyclosporine and eltrombopag, his pancytopenia progressed.

Fig. 1

Fig. 1

Histological findings of the bone marrow biopsy specimen at diagnosis. Panel A: Hematoxylin and eosin (H.E.) staining (x40) of the bone marrow after the administration of a SARS-CoV-2 vaccine showed a markedly hypocellular marrow. Panel B: H.E. staining (x400) showed the replacement of hematopoietic cells by fat and a few nucleated cells.

He underwent an allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA haploidentical related donor (Fig. 2 ). The donor had no history of COVID-19 infection and had not received a SARS-CoV-2 vaccine. The conditioning regimen consisted of 120 mg/m2 fludarabine, 100 mg/kg cyclophosphamide, 2.5 mg/kg anti-thymocyte globulin, and 2 Gy of total body irradiation. Tacrolimus and short-term methotrexate were used as a prophylaxis against graft-versus-host disease (GVHD). Post-transplant cyclophosphamide was not administered because the patient’s HLA-A, C, and DR were homologous, which would not increase the risk of GVHD. The transplanted cells collected from the donor’s bone marrow were transfused into the patient after the removal of red blood cells and plasma. Twenty-one days after the HSCT, neutrophil engraftment was achieved. Chimerism analysis performed on day 29 after the HSCT revealed complete chimerism in the peripheral blood. The patient developed acute GVHD (skin grade 1), which was ameliorated with a topical corticosteroid alone.

Fig. 2

Fig. 2

Evaluation of neutrophil count, The X-axis indicates the number of days after the 2nd dose of the COVID-19 vaccine was administered. The allogeneic BMT was conducted at 34 days after the 2nd dose of the COVID-19 vaccine was administered. The gray boxes indicate the titers of antibodies against the SARS-CoV-2 spike protein (log scale). BMT, bone marrow transplantation; COVID-19, coronavirus disease 2019; CyA, cyclosporine A; TAC, tacrolimus.

The titers of antibodies against SARS-CoV-2 were measured before and after the HSCT to examine the association between the SARS-CoV-2 vaccine the patient received and the development of AA. The measurement of anti-SARS-CoV-2 spike protein antibody titers was performed by SRL, Inc. (Tokyo, Japan) using the Elecsys® anti-SARS-CoV-2 S immunoassay (Roche, Basel, Switzerland). The titers of antibodies against SARS-CoV-2 before the conditioning regimen and 63 days after the HSCT were 540 and 34.9 U/mL (reference range, <0.8 U/mL), respectively (Fig. 2). These results suggest that the AA was ameliorated by the allogeneic HSCT even though anti-SARS-CoV-2 spike protein antibodies continued to be detected after the HSCT.Go to:

3. Discussion

We report a case in which AA developed after the administration of a SARS-CoV-2 vaccine. No association between new-onset AA and SARS-CoV-2 vaccines has been reported. The patient in this case underwent allogeneic HSCT. In this patient, antibodies against the SARS-CoV-2 spike protein were detected both before and after the HSCT. After the allogeneic HSCT, the patient’s AA was ameliorated despite the presence of antibodies against SARS-CoV-2. Our results did not reveal a direct association between antibodies derived from the SARS-CoV-2 vaccine and the development of AA. Further studies are needed to investigate the impairment of hematopoiesis induced by immune reactions after SARS-CoV-2 vaccine administration.

One of the most feared adverse reactions to vaccines is the development of autoimmune disease. To the best of our knowledge, only six cases of newly diagnosed acquired AA have been reported after vaccination [[7][8][9][10][11]] (Table 1 ). However, in general, AA is not recognized as a vaccine-related adverse event [12]. The mRNA vaccines against SARS-CoV-2 have a novel mechanism of action. Therefore, it is important to collect information about their adverse events. Various cases of autoimmune disease have been reported after SARS-CoV-2 vaccine administration, including autoimmune hepatitis, type 1 diabetes mellitus, immune thrombocytopenia, and acquired hemophilia [3,[13][14][15]]. Patients with AA after COVID-19 infection were also reported [16,17]. Further epidemiological evaluations of the incidence of AA after COVID-19 infection and SARS-CoV-2 vaccination are warranted.

Table 1

Reported cases of newly diagnosed aplastic anemia after vaccinations.

Age (years)SexVaccineTime to symptom onsetTreatmentOutcomeReference
16FRecombinant hepatitis B3 weeks after 3rd doseCorticosteroidImprovedViallard et al. [7]
19FRecombinant hepatitis B10 days after 3rd doseCorticosteroidImprovedAshok Shenoy et al. [8]
25MHepatitis B7 days after 2nd doseAllogeneic HSCTN.A.Shah et al. [9]
19MAnthrax1 monthAllogeneic HSCTN.A.Shah et al. [9]
1.5FVaricella zoster3 weeksNoneImprovedAngelini et al. [10]
25MH1N1 influenza2 weeksAllogeneic HSCTImprovedDonnini et al. [11]
56MSARS-Cov-24 days after 2nd doseAllogeneic HSCTImprovedThis case

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HSCT, hematopoietic stem cell transplantation; N.A., not applicable; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2.

Various cases of vaccine-related autoimmune disease have been reported. Most of these reports have linked vaccination to the development of autoimmune disease based on clinical observations of temporal associations. There is no established method for examining the relationships between vaccines and the development of autoimmune diseases. The pathogenetic mechanisms by which vaccines cause the development of autoimmune disease are still unclear. The major hypotheses relating to such immunological reactions involve epitope mimicry [18,19]. For example, it has been reported that vaccine-derived antibodies may exhibit structural similarities with autoantibodies [18,19]. There is significant evidence that AA is an immune-mediated condition, mainly based on the effectiveness of immunosuppressive therapy against AA. In addition to T cells and cytokines, autoantibodies are one of the factors that contribute to the pathogenesis of AA [4]. However, autoantibodies specific to AA and the role of autoantibodies for the pathogenesis of AA are unclear. The allogeneic HSCT replaces the recipient’s hematopoietic and associated immune systems with those of the donor. The measurement of vaccine antibody titers before and after allogeneic HSCT may provide a clue to the pathogenesis of vaccine-related autoimmune diseases. The clonal expansion of effector T cells was also reported to occur following vaccination [20]. To understand the link between COVID-19 vaccination and the development of AA, the following needs to be examined: the exploration of autoantibodies against stem cells, the role for molecular mimicry between mRNA vaccine encoded antigens and stem cells, and T-cell subset dynamics after vaccination.

In conclusion, the administered SARS-CoV-2 mRNA vaccine may have contributed to the pathogenesis of AA in this case. However, it is not clear whether antibodies derived from the SARS-CoV-2 vaccine directly contributed to the development of AA because the anti-SARS-CoV-2 antibodies remained after the patient’s pancytopenia had been ameliorated by the allogeneic HSCT. Further evaluations in large cohorts are warranted to elucidate the associations between AA and SARS-CoV-2 vaccines.Go to:

Authors’ contributions

Shotaro Tabata: Data curation, Investigation, Writing – original draft; Hiroki Hosoi: Conceptualization, Data curation, Investigation, Writing – original draft and Review & Editing; Shogo Murata: Investigation, Writing – review & editing; Satomi Takeda: Data curation, Writing – review & editing; Toshiki Mushino: Writing – review & editing; Takashi Sonoki: Writing – review & editing, Supervision.Go to:

Declaration of competing interest

There are no funding sources associated with the writing of this manuscript. Written consent for publication was obtained from the patient.Go to:

Acknowledgements

We thank the patients and clinical staff at Wakayama Medical University Hospital for their participation in this study. We also wish to thank Dr. Takashi Ozaki and Mr. Masaya Morimoto from Kinan Hospital for their helpful diagnostic support.Go to:

Footnotes

Appendix ASupplementary data to this article can be found online at https://doi.org/10.1016/j.jaut.2021.102782.Go to:

Appendix A. Supplementary data

The following is the Supplementary data to this article:Multimedia component 1:Click here to view.(12K, xlsx)Multimedia component 1Go to:

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