TL;DR: Acuteaortic dissection (AAD) and accelerated atherosclerosis are bad, AAD with IgG4 infiltration is worse. IgG4-RD is “insidiously progressive”, and there is no cure.
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Although Wiki isn’t the most reliable source available it provides a great introduction to immunoglobulins (antibodies):
An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous.[1] Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules.[2] Each antibody recognizes one or more specific antigens.[3][4] Antigen literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly (for example, by blocking a part of a virus that is essential for its invasion).
Each antibody binds to a specific antigen in a highly specific interaction analogous to a lock and key.
Each antibody binds to a specific antigen in a highly specific interaction analogous to a lock and key.
To allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is relatively generic. In humans, antibodies occur in five classes, sometimes called isotypes: IgA, IgD, IgE, IgG, and IgM. Human IgG and IgA antibodies are also divided into discrete subclasses (IgG1, IgG2, IgG3, IgG4; IgA1 and IgA2). The class refers to the functions triggered by the antibody (also known as effector functions), in addition to some other structural features. Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Importantly, while classes and subclasses of antibodies may be shared between species (at least in name), their functions and distribution throughout the body may be different. For example, mouse IgG1 is closer to human IgG2 than human IgG1 in terms of its function.
The term humoral immunity is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors (fluids) in the form of soluble proteins, as distinct from cell-mediated immunity, which generally describes the responses of T cells (especially cytotoxic T cells). In general, antibodies are considered part of the adaptive immune system, though this classification can become complicated.
In the course of an immune response, B cells can progressively differentiate into antibody-secreting cells or memory B cells.[6] Antibody-secreting cells comprise plasmablasts and plasma cells, which differ mainly in the degree to which they secrete antibody, their lifespan, metabolic adaptations, and surface markers.[7] Plasmablasts are rapidly proliferating, short-lived cells produced in the early phases of the immune response (classically described as arising extrafollicularly rather than from the germinal center) which have the potential to differentiate further into plasma cells.
There are four IgG subclasses (IgG1, 2, 3, and 4) in humans, named in order of their abundance in serum (IgG1 being the most abundant).
Note: IgG affinity to Fc receptors on phagocytic cells is specific to individual species from which the antibody comes as well as the class. The structure of the hinge regions (region 6 in the diagram) contributes to the unique biological properties of each of the four IgG classes. Even though there is about 95% similarity between their Fc regions, the structure of the hinge regions is relatively different.[citation needed]
Given the opposing properties of the IgG subclasses (fixing and failing to fix complement; binding and failing to bind FcR), and the fact that the immune response to most antigens includes a mix of all four subclasses, it has been difficult to understand how IgG subclasses can work together to provide protective immunity. In 2013, the Temporal Model of human IgE and IgG function was proposed.[15] This model suggests that IgG3 (and IgE) appear early in a response. The IgG3, though of relatively low affinity, allows IgG-mediated defences to join IgM-mediated defences in clearing foreign antigens. Subsequently, higher affinity IgG1 and IgG2 are produced. The relative balance of these subclasses, in any immune complexes that form, helps determine the strength of the inflammatory processes that follow. Finally, if antigen persists, high affinity IgG4 is produced, which dampens down inflammation by helping to curtail FcR-mediated processes.
Since then at least 15 papers have been published, discussing the link between receiving 2 or more doses of synthetic mRNA gene agent shots and class switching of the dominant immunoglobulin isotype to IgG4.123456789101112131415
Our review paper discussed a possible link between class switching and cancer.16 I worked through the Gal-3 hypothesis on this Substack, which later contributed to the discussion.
As if the elevated risk of cancer wasn’t grave enough, my colleague Dr. Alberto Rubio-Casillas forwarded three case studies linking IgG4-related disease to cardiovascular disease. More specifically, IgG4 positive plasma cell infiltration, fibrosis, and inflammation of the aorta (aortitis), or IgG4-RA. This Substack will review these cases, which have potential implications for the class switched.
Medical professionals need to be aware of this to make accurate diagnoses, with an improved prognosis. Treatments for aortic aneurysms caused by atherosclerotic plaques differ from those caused by IgG4 plasma cell infiltration.
As we shall see, the two types of AA are not mutually exclusive. Many of the mechanisms are shared or similar at the point of endothelial damage, and I discussed these at length:
This post is a follow-up to the discussion. It is of relevance because, after a lag (latency) of about 3 years post-vaccination, cases of sudden adult (and child) death (SAD) are not abating yet. If anything, they appear to be increasing. Is the steady progression of IgG4-RD-associated fibrosis contributing to these latency effects?
All-cause mortality (NOT just cardiovascular) increases in Finland shows that this may not just be a reporting artefact or misperception.
Ilkka Rauvola posted these on 5th June:
From: “Finland's epidemic 5 June 2024: excess deaths for <60 year olds continue to grow. For 5-9 year olds, excess deaths are now at 2.4 times pre-pandemic level. 1/x”. Source: https://x.com/jukka235/status/1798339937303204229
From: “A major change in excess deaths is underway: in terms of years of life lost, >60 year olds peaked more than a year ago, while both 0-59 and 25-59 age groups have taken the lead. 3/x”. Source: https://x.com/jukka235/status/1798357758296879183
From: “Thanks to excellent work done by Finnish public healthcare, deaths of 5-9 year olds have declined really significantly during past decades (yellow regression line). Since 2021, cumulative excess deaths have increased significantly (pink line). 5/x”. Source: https://x.com/jukka235/status/1798434867727995128
From: “Excess deaths of 5-9 year olds reached a new all-pandemic high in March 2024 (using 5-week averages). Overall trend is increasing (blue and red lines), with 53-week average now at 2.4 times normal (blue line). 7/x”. Source: https://x.com/jukka235/status/1798813353969614882
From: “Deaths of children aged 0-4 have declined slightly since peaking in 2022 (BQ.1) but remain 27 percent above normal level (blue line). The peak in November 2023 (yellow line) coincides with the highest weekly number of deaths ever recorded in Finland. 9/x”. SourceL https://x.com/jukka235/status/1798822209227800810
What did they roll out in 2004? Data for “all age groups” weekly deaths:
“… adoption of herd immunity”? I’m thinking more: “adoption of something else”:
From: “Excess deaths of 10-14 year olds are growing. At the time of THL's adoption of herd immunity (25 Aug 2021), excess deaths of 10-14 year olds stood at 6 percent (blue line). Now the figure is 4x higher (23 percent). 13/x”. Source: https://x.com/jukka235/status/1799036437901480229
Alarm bells should be ringing here. There has been no mass immunization for about 3 years, and the current variants should be mild (unless you are immunocompromised):
Re-infection can also back-boost IgG4 antibodies (abs); a vicious circle of reinfection.
Higher highs is not good:
From: “20-24 year olds: deaths are now 1.4 times above normal. It would look that the rise during the past year was significantly affected by the JN.1 wave. The December 2023 peak (2.2 times normal) coincides with the all-time high weekly deaths recorded in Finland. 17/x”. Source: https://x.com/jukka235/status/1799043962508136815
From: “Summary (0-24 year olds): deaths are now at 1.56 times normal level, and rising. During the past 12 months, the rate of excess deaths has more than doubled. 19/x”. Source: https://x.com/jukka235/status/1799192284707111420
Deaths of > 60-year-olds have peaked for now, but are still well above the baseline:
From: “>60 year olds: excess deaths are roughly 40 percent down from the all-pandemic high reached after the BQ.1 wave in late 2022. The AZ vaccine (2021) was given primarily to the 65-69 group. 23/x”. Source: https://x.com/jukka235/status/1799294335084626117
Arch-Physicist 𓅄 😷 #MildZeroCovid @zin_zah
"Population weighted average death rates, calculated for all 5-year age groups, are showing a linear growth trend." [in Finland]. If this doesn't make people concerned, then I don't know what will:
Sadly, we appear to be well past the “I hope we are wrong in our analysis” stage.
No, we are there, in the fire, and we all need to react accordingly. The MSM appears to be, somewhat begrudgingly, acknowledging this reality. But the politicians and medical profession are still lodged in the 2021 “safe ‘n effective La La Land” of deniability. This approach grows more and more absurd by the day. If you aren’t speaking out by now then you are complicit.
There were significant improvements in ambulance performance last month compared to the year before, with urgent incidents like heart attacks and strokes (Category 2) receiving an ambulance on average 47 minutes faster than in Dec 2022. This is despite much higher demand, with 43,000 more Category 2 callouts than the same period the previous year (410,747 in Dec 2023 vs 367,985 in Dec 2022).
From “Waiting list falls again as NHS staff treat more patients than ever before in one month 11 January 2024“ (2024)
The president of the Royal College of Emergency Medicine has written to the main political parties, calling for action to reduce the dangers in A&E.
The letter, by Dr Adrian Boyle, comes alongside a survey which shows nine in 10 heads of casualty departments say patients were “coming to harm” because of the quality of care that can currently be delivered.
Some 87 per cent said they had patients being treated in corridors and 68 per cent said they had patients waiting in ambulances outside their A&E.
One of the 63 emergency department leaders polled said that one of their patients this week waited more than 19 hours for a hospital bed to become available after a decision was made to admit them. Overall, the patient spent more than 25 hours in A&E.
Dr Boyle said the survey shows “the level of harm and risk our patients are being exposed to, as recently as yesterday”.
He added: “These responses reveal the true and shameful reality of the state of emergency care in the UK”, describing the situation as “nothing short of a national scandal”.
“Last year the deaths of more than 250 people a week were associated with long waits in emergency departments – that’s the equivalent of an aeroplane full of people every seven days.
From: “A&E waits causing ‘plane-load of deaths every week’”
Aortitis is a form of vasculitis of the aorta. This can lead to restricted blood flow, damaged vital organs and tissues. Possible presentations of IgG4-RA may include:
Arteritis: an inflammation of the lining of the arteries.
Periaortitis: an inflammatory condition which typically involves the infrarenal portion of the abdominal aorta, just below the kidneys.
Periarteritis:“Periarteritis nodosa; PAN; Systemic necrotizing vasculitis. Polyarteritis nodosa is a serious inflammatory blood vessel disease. The small and medium-sized arteries become swollen and damaged.”17
Inflammatory aortic aneurysm:“In contrast to atherosclerotic AA, the inflammatory variant is characterised - pathologically - by 1) marked thickening of the aneurysm wall, 2) fibrosis of the adjacent retroperitoneum, and 3) adherence of the adjacent structures. Furthermore, the triad of abdominal or back pain, weight loss, elevated systemic inflammatory markers in patients with abdominal aortic aneurysms is highly suggestive of inflammatory aneurysm. Surgical treatment of IAA appears prudent once the diameter of the aneurysm exceeds 5.5 cm. However, it is related to a three-times higher perioperative morbidity and mortality rate than in noninflammatory aneurysms.”18
Stenosis: Narrowing of an artery.
Aortic dissection:“AD occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart.[3] In most cases, this is associated with a sudden onset of severe chest or back pain, often described as "tearing" in character.[1][2] Vomiting, sweating, and lightheadedness may also occur.[2] Damage to other organs may result from the decreased blood supply, such as stroke, lower extremity ischemia, or mesenteric ischemia.[2] Aortic dissection can quickly lead to death from insufficient blood flow to the heart or complete rupture of the aorta.”19
From: “Fig. 20.1. Normal anatomy of the aorta, including major branch vessels.”Aneurysms in this section of the aorta are called “abdominal aortic aneurysms.” Source: https://radiologykey.com/abdominal-aorta-5/
From inside to outside you have a layer of endothelium surrounded by an elastic membrane, then a thick layer of smooth muscle, collagen, another elastic membrane and finally the nerves and blood vessels in the outer layer of the artery:
“Multifocal IgG4-related aortitis and periaortitis simulating aortic dissection”20 (2021) by Valluri et al.
The first case report concerns a 47-year-old male. He first noted chest pain a month before, and shortness of breath two months before admission, and was admitted with left-sided chest pain and shortness of breath. The pain was described as “a focal, sharp, intermittent pain localized under the left nipple, which worsened with movement and deep inspiration.” The patient noted that before the symptoms his functional capacity was optimal. In other words, his health declined fairly quickly from asymptomatic to life-threatening in just a few weeks (although many get little warning).
They did some lab checks which didn’t indicate heart damage (negative troponin), but were positive for clotting (D-dimer, a fibrin degradation product, or FDP, after a clot is degraded) and inflammatory markers.
They did a chest CT with pulmonary embolism protocol. This revealed diffuse soft tissue thickening around the aortic arch, great vessels, and a significant narrowing of the left common carotid (brain) artery. They also found a large aneurysm of the ascending aorta. This measured up to 6.1 cm diameter:
From: “Fig. 1 Aortitis and aortic aneurysm on initial chest CT. CT angiography of the chest axials (A,B) coronals (C,D), and sagittal (E). There is diffuse wall thickening (blue arrows) of the ascending thoracic aorta, aortic arch, and proximal descending aorta, as well as involvement of the great vessels with significant narrowing of the left common carotid artery (orange arrows). There is an aneurysm of the ascending thoracic aorta measuring up to 6.1 cm that does not spare the sinotubular junction”. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233164/
As these findings weren’t typical for an atherosclerotic aneurysm, they performed a magnetic resonance angiography (MRA). This excluded an aortic intramural haematoma (IMH), where blood leaks through the innermost layer of the aortic wall and flows between the inner and outer walls, but it did indicate severe aortoarteritis and periarteritis, associated with an ascending thoracic aortic aneurysm. You can clearly see the aortic arch in longitudinal section (C) and axial section (D):
From: “Fig. 2. Aortitis Periaortitis and aortic aneurysm on MRA of the chest. MR angiography T1 axials pre-contrast (A) and post-contrast arterial (B) show faint rim enhancement of the adventitia of the aorta in the arterial phase that was T1 hypo-intense pre-contrast (orange arrows). Delayed postcontrast sagittal (C) and axial (D) images demonstrate enhancement involving the circumferential ascending aorta, arch, and proximal descending aorta with extension into the aortopulmonary window and adjacent mediastinum. T2* axial (E) shows no evidence of intramural blood products. Sagittal STIR (F) demonstrates a significant amount of edema (blue arrows) within the ascending arch and proximal descending aorta along the inner and outer margins of the thickened aortic wall.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233164/
The specialist team recommended replacing the aortic arch and hemi-arch. The aortic valve was normal. Once excised, the specimen revealed marked aortitis with lymphoplasmocyticinfiltrate (lymphocytes and plasma) of the vasa vasorum, in a perineural pattern.
Perineural invasion (PNI) is used to describe the involvement of small, unnamed nerves around a tumor.21
Sections of the aortic wall also showed fibrosis, a hallmark of IgG4-RD.
Although they didn’t specifically test for IgG4-RD, the sum of the findings indicated this.
From: “Fig. 3. Lymphoplasmocytic infiltrate. Hematoxylin-eosin stain, original magnification, 10x (A) and 20x (B) of the ascending aortic wall. Photomicrograph of the ascending aorta showing lymphoplasmocytic infiltrate (yellow arrow) around the vessels (black arrow).” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233164/
He was treated with high-dose steroids (glucocorticoids) to suppress the IgG4-RD-associated inflammation and was discharged home four days later, as they caught it early enough.
Our case study doesn’t end here though. Although he was lost to follow-up for two years he later came back to the ER complaining of new-onset stabbing chest pain.
A new chest and abdominal CTA showed that his chest area hadn’t deteriorated, but there were new findings in his abdomen: soft tissue thickening of the infrarenal abdominal aorta, with extension to the common iliac arteries on both sides (bilateral), caused by new areas of inflammation.
From: “Thoracic aorta follow-up and abdominal involvement. CTA of the chest, axial (A), coronal (B), and sagittal (C) views show postsurgical changes of ascending aorta replacement with mild perigraft soft tissue changes. The aortic arch is ecstatic, and there is periaortic soft tissue thickening along the aortic arch measuring up to 8 to 9 mm in thickness. The proximal left common carotid artery demonstrates increased periaortic soft tissue thickening with a similar degree of severe proximal stenosis. CTA of the abdomen axials (D,E) and coronal (F) show increased periaortic soft tissue thickening of the distal abdominal aorta, measuring up to 6 mm, extending along the common iliac arteries. Periarterial soft tissue thickening extends along the bilateral common iliac arteries causing mild luminal irregularities with no significant stenosis. Soft tissue thickening extends along the proximal left internal iliac artery causing focal proximal severe stenosis.“ Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233164/
Key takes:
The clinical progression of IgG4-RD is typically slow with the median age of onset at 58.3 ± 11.1 years [2]. Common risk factors for the development of IgG4-RD are male gender, tobacco exposure, allergic diseases, and a history of malignancy [1,3,4,5].
It’s not so much the inflammation, it’s more the fibrotic mass pressing on something that causes the first symptoms:
Patients usually present with subacute symptoms related to diffuse enlargement or development of a mass in the affected organ. Signs of inflammation and infection are not typically associated with the disease course even as it progresses [1]. Rather, symptoms may manifest due to compression from fibrotic masses [1].
In Part II I will explore this ambiguity:
The role of IgG4 itself in its disease processes is not clear [8]. The antibody typically plays a minimal part in inflammation due to its low affinity to Fc receptors and complement molecules [8,9]. Despite this, IgG4 levels directly correlate with disease severity in the majority of affected patients [8,9].
“Th2 cells encourage 'humoral immunity' directed against extracellular organisms and promote antibody production (especially IgE) and allergic responses.”22
There is an irony here, as IgG4 is associated with gaining tolerance to repeated exposure to allergens, such as bee stings, and yet IgE itself forms part of an allergic response:
Th2 mediated immunity and the production of IgG4 in response to stimulation from IL-4, IL-10, and Treg cells is thought to be the driving force behind IgG4-RD [8,10,11].
High serum levels of IgG4 have been indicated in hypersensitivity conditions such as atopic dermatitis and asthma [12]. Increased IgG4 serum levels and auto-antibodies have also been indicated in certain autoimmune disorders, such as pemphigus vulgaris and membranous nephropathy [12].
Of note, he had no other apparent IgG4-RD associated health conditions apart from aortitis. This could have dire implications for some of the class switched vaccinated, and medics need to be aware of the association:
Our case draws attention to IgG4 related aortitis in the absence of any other health conditions commonly associated with IgG4-RD.
Diagnostic thresholds:
Typical findings in IgG4-RA are 50% of the infiltrate consisting of IgG4 producing plasma cells and a minimum of 50 of these cells visualized at high power magnification exam of three fields [13].
Another defining feature unique to IgG4-RD is storiform fibrosis [11,14]. Storiform fibrosis consists of collagen fibers in a spiral pattern interspersed among lymphoplasmacytic infiltrate [7]. It commonly involves the adventitia, media, and medial elastic fibers of the aorta in IgG4-RA [15].
This characteristic pattern of fibrosis was present in the aortic wall specimen obtained from our patient. Additionally, our patient also had extensive fibrotic involvement of the vasa vasorum within the adventitia.
From: “THE VASA VASORUM”. “… As the vessel thickens, this diffusion eventually becomes insufficient to reach the outermost cells. These outermost cells become hypoxic — that is, they suffer from an insufficient supply of oxygen, as well as other nutrients. To compensate, the VV develop, carrying blood from further up the artery or adjacent arteries and veins to provide a blood supply to these outermost cells. As hypoxia expands throughout the artery (a consequence of further thickening), the VV branch out from single vessels to networks”.“Figure 2”. Source: https://www.crossfit.com/essentials/vasa-vasorum-part-1
Diagnosis is usually by imaging and assessment of vessel wall thickness:
As the clinical symptoms of IgG4- related aortitis are typically nonspecific, a tissue biopsy may not be obtained early in a patient's presentation. Imaging plays a crucial role in diagnosis due to its non-invasiveness and routine use in disease workup.
Typical features of IgG4-related aortitis/arteritis include vessel wall thickening greater than 2 mm [16,17]. Homogenous enhancement of the aortic/arterial wall during the delayed phase of contrast-enhanced CT is characteristic [6].
The arterial and delayed phases of dynamic contrast-enhanced CTA or MRA show soft tissue density and thickening of affected vasculature [2].
Sclerosing: A pathological hardening due to fibrous tissue overgrowth, or an increase in interstitial tissue.
This characteristic IgG4-RA finding is associated with sclerosing inflammation caused by lymphoplasmacytic infiltration mainly involving the adventitia [18].
Although small to medium sized vessels may be narrowed by IgG4-RA, the aorta itself does not undergo stenosis:
Rather, aneurysmal luminal dilation and dissection are potential findings in addition to diffuse periaortic soft tissue thickening [20−22].
Things can escalate quickly:
Radiologists must be aware of these findings typical of IgG4-RA as aortitis and inflammatory aortic aneurysms have the potential to escalate to aortic dissection [19,2].
Pericardium: a double-walled sac containing the heart and the roots of the great vessels.
Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=28761820
Furthermore, the involvement of the pericardium and surrounding cardio-vasculature significantly affects disease prognosis [18]. Thus, careful consideration of IgG4-RD must be taken in the fitting scenarios.
Diagnosis is challenging, as it may present with similarities to other vasculopathies.
Patent: Open, unobstructed, with free passage.
Furthermore, adult males such as our patient are far more at risk for developing IG4-RA than Takayasu arteritis [18,24].
The aorta itself was consistently visualized as widely patent on imaging from the first patient presentation. This is in contrast to Takayasu arteritis where luminal stenosis of the aorta is present in the majority of cases [19,24].
Steroids are the first line therapy for IgG4-RD, but long term they may induce aortic wall remodelling and luminal dilation:
Research has found perivascular masses shrink by over 30% in patients receiving glucocorticoid therapy [2]. According to current guidelines, inflammatory aortic aneurysms should be treated with glucocorticoid therapy immediately due to the risk of enlargement and dissection [2].
However, it should be noted that luminal dilation may progress or occur even while the patient is receiving medical treatment due to steroid-induced aortic wall remodeling [2,[20], [21], [22]].
As a relapse-remitting course is quite common in IgG4-RD, it is not uncommon for progression of disease despite corticosteroid treatment as in our patient [18]. When our patient returned two years later with the onset of chest pain, repeated CTA once again suggested IgG4-RA. The patient was successfully managed with prednisone treatment and rheumatology follow up.
This was from 2021, after the rollout of the experimental gene agents, and a reason for writing this review. Almost all death certificates probably misdiagnose it, let alone fail to mention the underlying cause:
This immune-mediated entity is known to simulate other acute aortic syndromes on clinical and radiologic presentation, including aortic dissection, atherosclerotic aneurysm and other inflammatory conditions.
Thoracic and abdominal vessel involvement in IgG4-RA have been scarcely described in the literature; however, its recognition is of utmost importance to guide appropriate treatment and to avoid potentially life-threatening complications such as aortic dissection and aneurysm formation.
Case 2
“Coronary artery involvement in a patient with IgG4-related disease”23 (2023), by Mohammadzadeh et al.
The previous case report noted that the typical onset of IgG4-RD is in later life, at around 58 ± 11 years. Our second case report shows that youth is not necessarily protective against the group of diseases. The authors note that coronary artery involvement is “rarely seen in IgG4-RD patients; thereby, we aim to outline the noninvasive imaging findings of this rare case.”
The imaging used was cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA); the female patient was only 15.
She presented with dyspepsia, chronic fatigue, activity intolerance, and poor left ventricular (LV) function.
This time they were able to diagnose IgG4-RD via histopathological assessment - an orbital biopsy. This is usually conducted to help diagnose inflammatory or cancer-like diseases of the eye socket (e.g. lymphoproliferative disease).
“Fine needle aspiration biopsy (FNAB) is a technique used for diagnosing orbital lesions. This outpatient procedure allows for retrieval of a cytological specimen through a well-controlled and minimally invasive surgical technique.”24
Five years before referral she had a history of left eye swelling (proptosis, or a bulging eye) with inflammatory redness (erythema). The biopsy revealed significant fibrosis, collagen formation and chronic CD138 inflammatory cell infiltration. Over 40% of plasma cells were IgG4+, reaching their diagnostic threshold for chronic sclerosing IgG4-RD.
CMR revealed cardiac impairment in the form of a severely reduced left ventricular ejection fraction (LVEF), and impaired contractions (akinesia) of the basal to mid-lateral, anterior, and septal walls.
LVEF measures the fraction of chamber volume ejected when the heart contracts (systole, or stroke volume) in relation to the volume of blood at the end of diastole (end-diastolic volume, or relaxation of heart muscle and chamber filling). In this case, it was only 27%.
From StatPearls: “Left Ventricular Ejection Fraction”25:
LVEF (%) among the male population:
52% to 72% normal range
41% to 51 mildly abnormal
30% to 40% moderately abnormal
Less than 30% severely abnormal
LVEF (%) among the female population:
54% to 74% normal range
41% to 53 mildly abnormal
30% to 40% moderately abnormal
Less than 30% severely abnormal
[SV: Stroke volume, EDV: End-diastolic volume]
The simplest classification as per the American College of Cardiology (ACC) that is used clinically as follows:
Hyperdynamic = LVEF greater than 70%
Normal = LVEF 50% to 70% (midpoint 60%)
Mild dysfunction = LVEF 40% to 49% (midpoint 45%)
Moderate dysfunction = LVEF 30% to 39% (midpoint 35%)
CMR also revealed inflammation and signs of tissue death (necrosis, or infarction) in the basal to apical lateral and mid inferoseptal walls.
Meanwhile, CCTA revealed stenosis in branches of the left main artery (LM); left anterior descending artery (LAD); and right coronary artery (RCA); aortitis; and aortic wall thickening.
Key takes:
Cardiovascular system involvement is less common in these patients and is often revealed as an incidental finding on extensive diagnostic imaging [3].
It rarely affects small arteries, like the coronary arteries. Coronary artery involvement can manifest as obstructive intraductal lesions, pseudotumors, or lymphoplasmacytic arteritis, predisposing to lethal complications like acute coronary syndrome (ACS) or sudden cardiac death. [2,4]
CMR findings before treatment. These highlight wall thickening:
From: “Fig. 1. Representative images of CMR on admission before proper treatment. (a) STIR T2 increased signal intensity in the basal to apical lateral wall (red arrow) in 4 chambers view, (b) STIR T2 increased signal intensity in the basal to apical lateral wall (red arrow) in short axis view, (c) subendocardial enhancement in the basal to the apical lateral and mid inferoseptal wall (yellow arrow) in 4 chambers view, (d) subendocardial enhancement in the basal to the apical lateral and mid inferoseptal wall (yellow arrow) in short axis view (e) thickening of the aortic wall (blue arrow) in axial view.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440403/
CCTA findings before treatment. These highlight vessel narrowing (stenosis) & aortic wall thickening:
From: “Fig. 2. Representative images of CCTA findings before proper treatment. (a) Distal LM stenosis (green arrow) in axial view, (b) proximal RCA stenosis (yellow arrow) in axial view, (c) proximal LAD stenosis (red arrow) in coronal view, (d) circumferential thickening of the aorta (blue arrow) in axial view.” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440403/
They administered anti-inflammatories including 100mg of aspirin/day; a statin (rosuvastatin); an anti-hypertensive (bisoprolol fumarate); a steroid (prednisolone); an anti-rejection drug (CellCept); and an anti-TNFα / anti-autoimmunity drug (Adalimumab).
A follow-up CMR showed that LV systolic function had improved significantly to 37% (moderate dysfunction), and all the inflammation had gone. However, cardiac fibrosis isn’t easily reversed and there was still evidence of chronic subendocardial infarction in the basal to apical lateral walls. Aorta wall thickness had returned to normal:
From: “Fig. 3. Representative images of the follow-up CMR after proper treatment. (a, b) STIR T2 no edema detected, (c, d) reduced subendocardial late gadolinium enhancement in the basal to the apical anterolateral and inferolateral wall (yellow arrows), (e) aorta with normal thickness after proper therapy (blue arrow).” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440403/
Aortitis or pericardial involvement is the most common cardiovascular presentation. In contrast, coronary artery involvement is rarely identified and difficult to diagnose, which includes various types such as obstructive lesions, periarterial thickening, aneurysms, dissections, and pseudotumor formation that can be completely asymptomatic or lead to lead to myocardial ischemia, aneurysmal rupture, heart blocks, and sudden cardiac death[2,[4], [5], [6], [7], [8].
LAD: left anterior descending artery.
LM: left main coronary artery.
RCA: right coronary artery.
In our case, stenosis was detected in the Ostial branches of LM and RCA and the long segmental branch of LAD.
Distinguishing between IgG4-related disease and atherosclerosis using imaging can be challenging, but certain imaging features may help differentiate the 2 conditions. In IgG4-related disease, coronary CT angiography often reveals diffuse or segmental thickening of the coronary artery walls, affecting the entire circumference.
Conversely, CT angiography in atherosclerosis typically demonstrates focal plaques within the coronary arteries, resulting in stenosis or narrowing of the vessel lumen.
The tip of the iceberg?
Coronary artery disease due to IgG4-RD is an underreported manifestation due to clinical misattribution to atherosclerotic coronary artery disease, especially in middle age men.
Misdiagnosis could prove fatal due to graft failure and impaired healing.
“Dehiscence is a partial or total separation of previously approximated wound edges, due to a failure of proper wound healing.”26
“An anastomosis is a surgical connection between two structures.”27
“Percutaneous coronary intervention (PCI) is a non-surgical, invasive procedure with a goal to relieve the narrowing or occlusion of the coronary artery and improve blood supply to the ischemic tissue. This is usually achieved by different methods, the most common being ballooning the narrow segment or deploying a stent to keep the artery open.”28
This misdiagnosis could lead to an attempt at coronary revascularization, which can cause tissue dehiscence and anastomosis failure in the setting of percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) whether the underlying inflammatory condition is not controlled [4].
IgG4-RD diagnosis is complex and requires specific clinical, serological, radiological, and pathological findings defined as the comprehensive diagnostic criteria by Umehara et al. [11]. Serological findings demonstrate raised serum IgG4 concentration.
Regardless, approximately 30% of patients demonstrate normal or mildly raised IgG4 serum levels, and this elevation is more common in patients with pancreatic disorder.
Besides, elevated igG4 concentration is not specific for IgG4-RD and is also associated with other diseases like ANCA-associated vasculitis, lymphoma, pancreatic adenocarcinoma, and asthma.
Glucocorticoids are considered first-line-therapy that is also used for remission maintenance though the majority of patients experience disease relapse during or after glucocorticoid tapers. Therefore, B cell-depleting therapy such as rituximab or adalimumab may also be required [2], [3], [4].
Conclusion
IgG4-RD is an uncommon cause of coronary artery disease but can lead to life-threatening complications including myocardial infarction. Regarding the importance of early treatment, clinicians should be aware of cardiac complications in these patients. Besides, IgG4-RD should be a concern in young patients in cases of myocardial ischemia.
Case 3
“A ruptured abdominal aortic aneurysm was just the tip of the iceberg – A rare case of IgG4-related disease and multiple giant aneurysms”29 (2023), by Jin & Frahm-Jensen.
This case report of IgG4-RD involves a 65-year-old male patient who presented with concurrent giant inflammatory aneurysms, which included a ruptured abdominal aortic aneurysm (AAA). As a result of this, he was admitted with very low blood pressure (“profound hypotension”) of 55/35mmHg, with a heart rate of 86bpm, severe onset left groin pain, and a Glasgow Coma Scale of 14 (“mild head injury”).
He was pale and sweating profusely (diaphoretic), with a tender abdomen and “a palpable large pulsatile mass” (- of, or marked by pulsation). They urgently conducted a computed tomography (CT) aortogram, which revealed a 12x11cm ruptured AAA with bleeding into the retroperitoneal space, posterior to the peritoneal cavity (left retroperitoneal haematoma).
But that wasn’t all. There was also a 5.5x4cm right common iliac artery aneurysm (CIAA); a 7.5x7cm right coronary artery aneurysm (CAA); and a 3cm lesion on the pancreas. Type 1 autoimmune pancreatitis (AIP) is a pathology associated with IgG4-RD. It can resemble pancreatic cancer.30
From: “Fig. 1. Axial (A-C) and coronal (D-F) images from the initial computed tomographyaortogram showing the ruptured 12×11 cm infrarenal abdominal aortic aneurysm (cross) with left retroperitoneal haematoma; as well as a 5.5×4 cm right common iliac artery aneurysm (arrow heads), a 7.5×7 cm right coronary artery aneurysm (diamond), and a 3 cm ill-defined obliterative lesion on the body of pancreas (arrow).” Source: https://www.sciencedirect.com/science/article/pii/S2772687823000697
They performed an emergency open repair of the ruptured AAA to stop the bleeding, using a 16mm Dacron tube graft. They decided not to operate on the right CIAA, due to circulatory imbalances to the vital organs (haemodynamic instability). No macroscopic aortitis or retroperitoneal fibrosis was found during the surgery, which lasted 2.5 hours. Recovery was complicated by bowel dysmotility (ileus), and hospital-acquired pneumonia, both of which were treated successfully.
“Further investigations were completed following the emergency operation to unearth the immensity of this clinical iceberg.”
They also found:
An 8x6.5cm right coronary artery aneurysm (CAA), via a CT coronary angiogram.
Another aneurysm, this time on the cardiac left anterior descending artery (LAD), via a CT study.
Occlusion of the right coronary artery, distal to (furthest from) the CAA, revealed by catheter coronary angiogram.
70% stenoses (narrowing) of the proximal LAD and left circumflex arteries.
The right CAA was revealed by transthoracic echocardiogram to be compressing the right atrium, and obstructing right ventricular outflow to the lungs.
No signs of a tumor or malignancy in the pancreas via MRI, but his serum IgG4 level of 2.36 g/L (reference: 0.04 – 0.86 g/L) strongly indicated IgG4-RD.
From: “Fig. 2. An axial image (A) from the computed tomography (CT) coronary angiogram showing the right coronary artery aneurysm (diamond), measuring 8×6.5 cm on this study, compressing onto the right atrium and obstructing the right ventricular outflow tract. There was another 7 mm aneurysm (arrowheads) in the mid left anterior descending artery, as shown on the 3D reconstructed image (B) from the same CT study.” Source: https://www.sciencedirect.com/science/article/pii/S2772687823000697
From: “Fig. 3. Axial images from the magnetic resonance imaging of the pancreas showing the 3 cm ill-defined lesion, that was isointense on T1-FL2D (A) and hypointense on T2-FIRM (B), in the proximal body with obliteration of the adjacent ducts and atrophy of the distal body.” Source: https://www.sciencedirect.com/science/article/pii/S2772687823000697
He was discharged 19 days after the initial presentation, but returned a month later to repair the right common iliac artery aneurysm (CIAA) that was too dangerous to operate on earlier. They used a 23 mm Gore Excluderendoprosthesis and a Cookiliac branch device (IBD):
They avoided using stents in case he developed further aneurysms or needed further surgery.
He was really going through the mill. Another month later he returned for an elective open repair of the right CAA and triple coronary artery bypass grafts (CABG).
Histopathology of the right CAA tissue confirmed the diagnosis of IgG4-RD, with dense perivascular infiltrates of plasma cells enriched for the IgG4+ isotype:
From: “Fig. 5. Histopathology images of the excised tissue from the right coronary artery aneurysm showing dense perivascular infiltrates of plasma cells (A) that are enriched for the IgG4+ isotype (B).” Source: https://www.sciencedirect.com/science/article/pii/S2772687823000697
Key takes:
NB. Data from 2021 onwards will probably show an incidence rate much greater than 1 per 600,000.
IgG4-RD is a rare immune-mediated fibroinflammatory disorder that was formally recognised in 2003.5, 6, 7, 8 Its estimated prevalence is 1 case per 600,000 population and estimated incidence is 0.28 to 1.08 case per 100,000 population-years.8,9
“Tip of the iceberg” in incidence numbers as well as presentation, with symptomatic cases building steadily. This is a recurrent theme. The pathology predicts a similar steady escalation in cancer cases, cardiovascular disease, neurological disorders, and autoimmune disorders:
Clinically, IgG4-RD is insidiously progressive – it often manifests as pseudotumours.6, 7, 8, 9. Multi-organ involvement is seen in 60 to 90 % of the cases; and almost any organ can be affected.
IgG4 plasma cells are only elevated in 2/3rds of IgG4-RD cases, so tissue samples (histopathology) are the gold standard for diagnosis:
The four key features of IgG4-RD on histopathology are dense polyclonal lymphoplasmacytic infiltrates with mainly IgG4+ plasma cells; storiform fibrosis; obliterative phlebitis; and tissue eosinophilia.6,8,9
Our case of IgG4-RD was uncommon with the concurrence of aortoiliac and coronary aneurysms as well as a pancreatic lesion. Matsuyama and colleagues reported a 74-year-old man with IgG4-RD whose right CAA had grown markedly from 2×2 cm to 8.5×6.5 cm a decade after corticosteroid treatment and open AAA repair.10
Due to the urgency to conduct emergency surgery, they couldn’t confirm a diagnosis of IgG4-RD via histopathology. But this precluded the early use of steroids, as a mistake could have proved fatal:
Unfortunately, immunomodulatory therapy for IgG4-RD could not be initiated without a tissue diagnosis due to the controversial possibility of corticosteroids causing accelerated aneurysmal degeneration and increased rupture risk.11, 12, 13
They also needed to rule out pancreatic cancer:
A multidisciplinary consensus thus supported the sequence of firstly excluding pancreatic malignancy, followed by endovascular repair of the CIAA and then open repair of the CAA with tissue sampling. Once the diagnosis of IgG4-RD was substantiated on histopathology, he was commenced on immunomodulatory therapy. This had a favourable clinical response as supported by the normalisation of serum IgG4 level.
There is no cure, and steroids can only slow it down:
He will continue to have regular surveillance for IgG4-RD activity and aneurysm progression in the upcoming years.10,14
This is theory - does it translate into practice?
Indeed, there are case reports for both types of mRNA gene tech: Pfizer’s “BNT162b2” and ModeRNA’s “mRNA-1273”. IgG4 response is more associated with Moderna. It is thought the higher dose that Moderna used (100 vs 30µg) may explain the differences:
Compared to BNT162b2, the mRNA-1273 vaccine had a greater capability for inducing a prolonged IgG4 response. The amount and duration of the spike protein produced are presumably affected by the higher mRNA concentrations in the mRNA-1273 vaccine (100 µg) compared to the BNT162b2 vaccine (30 µg). Intriguingly, among the mRNA vaccines, the mRNA-1273 vaccine generated increased anti-S1 serum IgG4 concentrations in COVID-19-uninfected individuals with previously unknown repercussions on pathogen defense. Until day 270, uninfected people who received the adenovirus-based vaccine did not exhibit this long-lasting IgG4 response [31].
From: “IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein“ (2023), by Uversky et al.
Of course, it is routine for all such case reports to be “rare” or “very rare”, even if this is greatly detached from reality. For instance “very rare and mild” myocarditis. We now know that around 3% of recipients suffer from a measurable degree of heart damage and of these around a third have signs of permanent fibrosis and scarring, with an expectation of reduced life expectancy.
The first case was published this year and reports how a 62-year-old woman presented with a 5-day history of fever and fatigue. This developed the day after she had her third dose of Moderna mRNA-1273.
In the light of the above case reports, without knowing her immunoglobulin subclasses and monitoring over a longer period of several years it may be premature to label it as “transient aortitis”:
Key takes from “Transient Aortitis after COVID-19 mRNA Vaccination”31 (2024) by Nihioka & Okumura:
All her bloods were markedly elevated, indicating inflammation and possible blood clotting disorders too (which is now a well-established and sometimes fatal adverse effect).
The normal neutrophil count for a healthy adult is between 2,500 and 7,000 per μL, but infections can cause this to increase.32 Hers was at 11,300 /μL.
The same applies to the inflammatory marker CRP, of around 0.8-1.0 mg/dL (or 8-10 mg/L) or lower. It should be less than 0.3 mg.dL in most healthy adults.33 Hers was at 16.0 mg/dL.
Erythrocyte sedimentation rate (ESR) also gives an indication of systemic inflammation or cell damage. For females older than 50 the normal rate is ≤30 mm/hr.34 The patient’s was recorded at 118 mm/h.
The patient did not report any other symptoms. Physical examination revealed unremarkable findings, except for a low-grade fever. Laboratory tests showed a white blood cell (WBC) count of 11,300 /μL (neutrophils: 71.8%), C-reactive protein (CRP) level of 16.0 mg/dL, and erythrocyte sedimentation rate of 118 mm/h.
Basic autoimmune markers were negative, and there was no bacterial infection:
The test results for antinuclear antibody, myeloperoxidase-anti-neutrophil cytoplasmic antibodies (ANCA), proteinase-3-ANCA, and rheumatoid factor were negative. Blood culture did not contain any bacteria.
Aortic wall thickening was detected:
Contrast-enhanced computed tomography (CECT) revealed wall thickening of the ascending aorta and aortic arch with fat stranding (Figure 1). Ultrasonography did not reveal any abnormal findings in the temporal, subclavian, or carotid arteries. We tentatively diagnosed her with aortitis.
Acetaminophen = paracetamol. Immunosuppressive.35 Depletes a key antioxidant called glutathione36, which helps protect DNA from cancer-causing damage37, amongst many other things.
They wouldn’t ever consider Ivermectin or even NAC. Root cause analysis? I don’t think so.
Again, it’s perhaps early days to draw firm conclusions:
We prescribed acetaminophen and followed-up the patient at our outpatient department without any specific intervention. Three days later, her fever relieved, and 4 more days later, her fatigue disappeared, and WBC count and CRP level returned to normal levels. CECT at one month after her first presentation revealed diminishment of wall thickening of the aorta. Her symptoms have not recurred for more than one year.
We made a diagnosis of COVID-19 vaccine-associated large-vessel vasculitis in the aorta. The patient’s Naranjo adverse drug reaction probability scale registered at 6 points, which indicated a probable relationship between her symptoms and adverse drug reactions to COVID-19 vaccine.1
From: “Figure 1. Contrast-enhanced computed tomography reveals thickening of the wall of the ascending aorta and aortic arch with fat stranding (red arrows).” Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082765/
I already received a comment where someone’s sister sustained aortitis and needed surgery after being vaxxed. I was even polling at the time. But, by all means, comment below if you have personal experience.
So much for being “rare”. It is much more likely a case of aortitis not being reported, or being misdiagnosed:
Vasculitis after COVID-19 vaccination has often manifested as cutaneous small-vessel vasculitis or glomerulonephritis,2 while aortitis is rare. Only four cases of aortitis following vaccination have been reported.3–6 The patients ranged in age from 52 to 81 years. Three patients had received BNT162b2 vaccine, and one patient had received ChAadOx1 nCoV-19 vaccine.
Our patient may be the first to demonstrate aortitis after the administration of Moderna COVID-19 vaccine (mRNA-1273). The differential diagnosis of aortitis includes bacterial aortitis, syphilitic mesoarteritis, Takayasu arteritis, giant cell arteritis, IgG4-related diseases, and Behçet’s disease.
Other conditions, including recurrence of malignancy and bacterial infections such as pyelonephritis and spondylitis, can present with similar symptoms to aortitis. Judging from this patient’s clinical course, these diagnoses were less likely in our case.
It was after her third booster, and we know IgG4 may be elevated after just your second. IgG4-RA could easily be a pathology that becomes much more prevalent in the population with time. This is partly because autoimmune conditions may take several years to develop (eg lupus), and due to repeated IgG4 back-boosting with each breakthrough infection. This is a major concern for both myself and my colleagues.
And there is no rule that says you cannot have both atherosclerosis AND IgG4-RA. In this study, there was an atherosclerotic plaque with IgG4 plasma cell infiltration in a carotid artery.
It’s also a depressing example of life-changing surgery due to misdiagnosis:
… A 67-year-old man had a history of autoimmune pancreatitis, pericarditis, asthma, and peripheral eosinophilia of undetermined etiology. He had undergone a modified Whipple procedure for the erroneous diagnosis of pancreatic cancer before the correct diagnosis of lymphoplasmacytic sclerosing pancreatitis (now termed type 1 [IgG4-related] autoimmune pancreatitis) was established. He had become an insulin-requiring diabetic as a complication of this procedure.
… Six months after the second rituximab course, the patient presented with recurrent episodes of right-sided amaurosis fugax. A magnetic resonance angiography (MRA) revealed moderate to severe stenosis of the right common carotid artery (Fig. (Fig.1).1). A carotid endarterectomy was undertaken without event, following which the amaurosis fugax resolved. Pathological examination of the carotid artery revealed a complex atherosclerotic plaque with a focal lymphoplasmacytic infiltrate and occasional eosinophils.More than 50% of the plasma cells within the lesion stained for IgG4 (Fig. (Fig.2)2) compatible with focal involvement by IgG4-RD.
From: “Figure 1. Magnetic resonance angiography with moderate to severe stenosis of the right common carotid artery.”
From: “Figure 2. IgG4-related disease in a carotid artery atherosclerotic plaque. (A) Depicted is a low power (20× magnification) histologic image showing the carotid endarterectomy specimen from Case 2 with regions of dense inflammatory cell infiltration in the periphery (arrowheads). (B) At higher power (400× magnification) in these regions, there is a lymphoplasmacytic infiltrate with occasional eosinophils. By immunohistochemistry for IgG (C) and IgG4 (D), the majority of the IgG+ plasma cells expressed IgG4 (both 400× magnification).”
From: “Large vessel involvement by IgG4-related disease“ (2016), by Perugino et al.
According to the totally unconflicted and not Pharma-owned American Heart Association, and others, “Post-vaccine myocarditis in young people is rare and usually mild”.38 So that’s good to know then.
We know from the follow-up to case studies that IgG4-related aortitis is “insidiously progressive”. This is typical for autoimmune-type disorders as the immunogens are always present (our tissues) or re-acquired (through infections or exposure to allergens).
Although you can suppress our immune responses using drugs or monoclonal antibodies you can never practically totally suppress it through drugs, apart from in extreme circumstances, such as briefly for procedures including bone marrow transplants.
The consequence of this with IgG4-RA is that although corticosteroids may significantly reduce inflammation and the risk of aortic dissection they can only slow, but not necessarily halt progression of the disease.
The pathology of acute myocarditis overlaps with the vasculopathy of aortitis, including plasma cell infiltration, endothelial damage, hypertrophy and the risk of fibrosis.
Despite the oft-repeated “rare and mild” mantra by Pharma shills, an analysis from 2021 by Ozierański et al. of patients hospitalised with myocarditis ranging from mild to severe found that, apart from with 81+ females, there was no improvement in survival probabilities or relative survival rates with time.39 In other words, you cannot recover from it with time, some degree of damage is permanent and impairs lifespan.
The older you are, the worse the prognosis.
One caveat is that this data is mainly virally induced, not through LNP-Spike-mRNA platforms, although the authors question why more cases are being reported? There is a link between flu vaccination and cardiomyopathy/chest pain (~3% of vaccines), and our health is the sum of its parts.
Your aortitis prognosis is influenced by the totality of exposure to different vaccines, drugs, epigenetics (lifestyle), infections, and your genetic profile.
Myocarditis hospitalisation rates by age and sex:
From: “Figure 1. Age and gender distribution of all patients hospitalized for myocarditis in Poland in years 2011–2019. Red—females; blue—males.” Source: https://www.mdpi.com/2077-0383/10/20/4672
An upward trend, and this was before the rollout of products many times more cardiotoxic:
The inpatient database in the United States presented an increasing incidence of hospitalizations due to myocarditis in the years 2007–2014, both in men and women [5].
The Global Burden of Disease 2016 Study (GBD2016) showed a 9% increase in all-age deaths due to myocarditis over a ten year period [6]. GBD2016 also highlighted that observed levels of years of life lost due to cardiomyopathy and myocarditis were much higher than expected, particularly in Eastern and Central Europe [6].
The recently published GBD 2019 showed that disability-adjusted life years and deaths due to cardiomyopathy and myocarditis have significantly increased over the past 30 years [7].
The presented data indicate a pressing need for actual populational data on myocarditis.
Therefore, a nationwide MYO-PL (the occurrence, trends, management and outcomes of patients with myocarditis in Poland) database combining information on all patients with myocarditis was created. In the current study, we aimed to evaluate the incidence, clinical characteristics and outcomes of patients with a hospital-based diagnosis of myocarditis in the last ten years in Poland.
From: “Figure 2. Age-standardized hospitalization rates for myocarditis of males and females by the number of residents in Poland in the years 2011–2019.” Source: https://www.mdpi.com/2077-0383/10/20/4672
Most of the clinical characteristics differed between patients aged ≤20 and >20 years. Chronic diseases, except for a history of asthma, were more common in the older group. Diagnoses of otolaryngologic and ophthalmic or digestive infectious disease in the prior 6 months were observed more frequently in the younger group.
Patients aged ≤20 years were more likely to suffer from bradycardia or tachycardia/palpitations, while atrial fibrillation and ventricular tachycardia were more common in those aged >20 years.
… approximately 2% of patients required hospitalization in an intensive (cardiac) care unit—more likely for patients ≤20 years than for the older group. Reported use of diagnostic procedures, particularly CMR and endomyocardial biopsy, was very low.
Observed and relative survival rates in relation to sex and age are shown in Table 3 (five-year follow up) and Figure 3 (ten-year follow up). Relative survival was associated with age and sex and was higher in younger male age groups than in younger female age groups, while the rate was better in females than in males in older patients. A decline with age and follow-up time in both observed and relative survival rates was observed. Relative survival was substantially less affected by the patient’s age than observed survival.
From: “Figure 3. Observed (a,b) and relative (c,d) ten-year survival rates of patients hospitalized for myocarditis in relation to sex and age.” Source: https://www.mdpi.com/2077-0383/10/20/4672
They daren’t use the V-word here:
Previous studies demonstrated that the incidence of myocarditis was even higher than in our database (1.8–18 per 100,000) [12,13]. There are still no reliable explanations for the increasing incidence of myocarditis.
Perhaps it is associated with greater accessibility, mainly to non-invasive tests, such as echocardiography and CMR, or greater awareness of myocarditis. On the other hand, the increased incidence might be related to the greater number of infectious, non-infectious and immune-mediated factors causing myocarditis. To address this question, etiological and pathological analyses should be performed in adequately designed clinical trials.
There is nothing “mild” about this, and misclassification of cause-of-death hides the true incidence. We see it in VAERS too. Why would that be?
Myocarditis has been shown in post-mortem studies to be a major cause (up to 42% of cases) of sudden and unexpected death in children and young adults [14,15].
In contrast, a recently published study on autopsies reported that 6% of 14,294 sudden deaths were assigned as being caused by myocarditis [16]. These differences are likely explained by the heterogenicity of the study populations and differences in sudden death, as well as myocarditis definitions and classifications.
In patients with biopsy-proven myocarditis in long-term observation (the median follow up of 4.7 years), all-cause mortality was 19.2%, while sudden death occurred in 9.9% of cases [19].
Worse outcomes were reported in patients with symptomatic heart failure, reduced LVEF, presence of late contrast enhancement in CMR, malignant ventricular arrhythmias and/or confirmed viral infection in endomyocardial biopsy [20].
In our study, patients with myocarditis had worse survival rates in all age groups than their counterparts in the general population.
Our study included a broad spectrum of clinical presentations of myocarditis; therefore, the presented survival rate comprised an average of patients with mild to severe clinical status.
The older the age group, the worse the prognosis in comparison to the sex-age-matched general population, although the relative five year survival rate differed in terms of age and sex: In younger age groups, it was better in male patients, while in older age groups female patients had higher survival rates than male patients.
IgG4-related myocarditis
I’m not sure if the case report from 2023 by Woo et al. is reassuring or not, as many pathologies formerly described as “rare” turned out to be much less “rare” after 2021. Either way, these authors describe IgG4-RD with myocarditis as “extremely rare”, but it does happen.
“Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates”.
“Eosinophil.” Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436., CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=56845138
“Eosinophil under a microscope from a blood smear. (400x)” By Bobjgalindo - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=7761793
Key takes from “Immunoglobulin G4-Related Myocarditis with Eosinophilic Infiltration: A Case Report“40 (2023):
A 52-year-old male with dyspnea and chest discomfort underwent cardiac MRI that revealed edema and nodular, patchy, mesocardial and subendoardial delayed enhancement of left ventricle, suggesting myocarditis.
Laboratory findings revealed elevated serum IgG4 and eosinophilia. Cardiac biopsy confirmed eosinophilic myocarditis with IgG4-positive cells.
However, IgG4-RD involving the myocardium is rare. Radiological findings of IgG4-RD involving the myocardium are not well known (3). In this report, we present an unusual case of IgG4-RD manifesting as eosinophilic myocarditis.
He had a lot of inflammatory markers; heart damage indications; liver damage indications; and difficulty breathing:
Elevated creatine kinase is a marker for skeletal or cardiac muscle damage.
Creatine kinase MB isoenzyme is found almost exclusively in the myocardium.
Terminal–pro B-type natriuretic peptide is a marker for heart failure.
Eosinophils are associated with myocarditis, as well as IgG4-RD:
A 52-year-old male with a history of asthma presented with aggravated dyspnea, generalized edema, and wheezing sounds for a few days prior to hospitalization.
Laboratory findings revealed elevated C-reactive protein level of 3.0 mg/dL (normal: 0–0.6 mg/dL), creatine kinase level of 991 U/L (normal: 45–44 U/L), creatine kinase MB isoenzyme of 159.7 ng/mL (normal: 0.6–6.3 ng/mL), N-terminal–pro B-type natriuretic peptidelevel of 20813 pg/mL (normal: 2.3–7.5 pg/mL), liver enzymes, including alanine transaminase of 157 U/L (normal: 13–33 U/L) and alkaline phosphatase of 51 U/L (normal: 8–42 U/L), and white blood cell count of 31000/µL (normal: 3800–10000/µL) with eosinophilia (eosinophil percentage: 39.1%; normal: 0%–10%).
A. Circumferential subendocardial and patchy mesocardial, subepicardial high signal intensity areas (arrows) at middle LV on the short tau inversion recovery T2 weighted SA image, suggest inflammation and edema.
B, C. Diffuse circumferential delayed subendocardial enhancement foci (arrows) at the basal anterior and nearly the whole middle to apical wall of the LV with spring apex are observed on 2D PSIR late enhancement of four- and two-chamber images.
D. Patchy, nodular, and curvilinear delayed enhancement foci (arrows) at the mesocardial and subendocardial mid-septal, anterior, and lateral walls of the LV on the 2D PSIR late-enhancement SA image.
E. Photomicrographs showing the infiltration of lymphocytes, histiocytes, and eosinophils (hematoxylin and eosin stain, × 200).
F. Immunohistochemical staining of IgG4 shows more than 80 IgG4-positive cells/high-power field (× 400).
Ig = immunoglobulin, LV = left ventricular, PSIR = phase sensitive inversion recovery, SA = short axis
Approximately three weeks after discharge, the patient visited the emergency center again for chest pain.
Repeated TTE revealed aggravation of diastolic dysfunction compared to previous TTE findings.
However, akinesia of the LV wall with mild LV dysfunction (ejection fraction = 50%) was similar to that observed in the previous TTE. Laboratory findings revealed eosinophilia (eosinophil percentage: 18%, white blood cell count: 11100/µL) and elevated IgG4 level of 5590 mg/L (normal 30–2010 mg/L).
Pathologically, infiltration of lymphocytes, histiocytes, and eosinophils in the myocardium was observed, suggestive of eosinophilic myocarditis (Fig. 1E, F).
Immunohistochemical analysis revealed IgG4-positive cells (up to 80 cells per high-power field) and an IgG4/IgG ratio > 40%. The patient met the diagnostic criteria for IgG4-RD, including organ dysfunction, elevated serum IgG4 concentration, and IgG4-positive plasma cell organ infiltration.
The final diagnosis was definite IgG4-RD. Three days after the cardiac biopsy, the patient was discharged.
With the benefit of hindsight…
However, the patient was transferred to the emergency center for cardiac arrest the following day.
After successful resuscitation with extracorporeal membrane oxygenation and targeted temperature management, the patient regained consciousness within four days.
They started him on high-dose steroids, followed by a maintenance dose:
The patient was treated with a high dose of methylprednisolone (1000 mg/d) for three days followed by gradual tapering to oral methylprednisolone (30 mg/d).
After about three weeks the IgG4 count had come down to high-end normal, from 5590 mg/L, (“ml/L” is a typo!):
Approximately three weeks after the cardiac arrest event, the patient’s serum IgG4 level (1960 ml/L) and the percentage of eosinophil (eosinophil percentage: 0.8%, white blood cell count: 18830/µL) were normalized. After discharge, the rheumatologist gradually tapered the oral methylprednisolone dose to 5 mg/d. Oral methylprednisolone treatment was continued for IgG4-RD.
It’s quite severe if untreated, with apical clot formation in your left ventricle:
From: “Figure 2. (A) Apical four chamber view showing a layered, mural thrombus causing the apex to appear foreshortened. (B) A schematic drawing identifies more detailed anatomy.” Source: https://heart.bmj.com/content/80/suppl_1/S6
Eosinophilic myocarditis is a rare type of myocarditis that is caused by eosinophilic infiltration. This condition is often associated with peripheral eosinophilia. Eosinophilic myocarditis can progress rapidly, leading to fatalities.
Cardiac MRI is a useful noninvasive imaging modality for evaluating eosinophilic myocarditis (4).
Typically, cardiac injuries due to eosinophilia occur in three successive phases.
In the early phase, eosinophils infiltrate the endocardium and subendocardial interstitium. These inflammatory changes can be detected on cardiac MRI as intensely delayed subendocardial enhancement.
As eosinophilic activation continues, the endomyocardial surface is damaged and apical thrombi are formed (5). Normal myocardium, thickened enhanced endomyocardium, and overlying thrombus make a “double V” sign at the ventricular apex, which can help us diagnose eosinophilic myocarditis more easily (6).
During the fibrotic stage, irreversible damage to the endomyocardium develops into restrictive cardiomyopathy. It also involves the atrioventricular valves (7).
Based on laboratory findings, peripheral eosinophilia led us to prioritize eosinophilic myocarditis. Additional evaluation was performed to determine the cause of the eosinophilia, and elevated IgG4 levels were observed.
Pathological examination confirmed eosinophilic myocarditis, IgG4-positive plasma cells, and an elevated IgG4/IgG ratio. Therefore, IgG4-RD-associated eosinophilic infiltration with radiological findings of eosinophilic myocarditis was considered.
These percentages aren’t that low, so it is something to be aware of:
However, IgG4-RD involving the myocardium and manifesting as myocarditis is extremely rare (3). Based on previous studies, approximately 11%–38% of IgG4-RD cases are associated with eosinophilia. Patients with IgG4-RD with eosinophilia have a higher disease burden than those without eosinophilia (1).
Treatments and prognosis:
Glucocorticoid therapy is the first-line treatment for IgG4-RD. Patients with IgG4-RD usually respond well to corticosteroid therapy, particularly during the early stages. The treatment may be maintained for 2–4 weeks. Subsequently, the steroid dose should be tapered within two months. Rituximab can also be administered to patients with life-threatening conditions.
The prognosis of IgG4-RD varies depending on the organ involved and combined complications. IgG4-related aortic aneurysm and IgG4-RD involving the coronary arteries significantly affect morbidity and mortality (2).
Conclusion
The conclusions from the last case report highlight why we need to increase awareness of the health risks caused by mRNA GeneTech-induced IgG4 class switching.
I was going to conclude this review with a section on the signalling pathways involved, and must give a hat tip to Annelise Bocquet for mentioning peroxisome proliferator-activated receptors (PPARs) due to their involvement with aortic dissection.
But as is typical with BioChem, a deep dive into anything can quickly become much more complex - like zooming in on a fractal.
It doesn’t help that the IgG4-RA research hasn’t been done yet, or it’s well hidden! This must therefore be carried over into Part II.
As this Substack’s number of posts has grown to 157 since 2021 I investigated the best ways to make older posts more accessible. Even as author, I was struggling to find reviews from just a few months ago.
One way would be to add an index page, but then you must keep referring to that.
The other way is to add sections to the home page site, and thats the route I have taken. I may tweak these with time or add to them.
By default, all new subscribers or followers will have access to them all, and I have almost no paywalled content. (The one that is concerns a defunct Viber account).
A great advantage of this approach is that you can unsubscribe from sections you have little interest in. For example, if you don’t want notifications about “Therapeutics/Allopathics” you can do this.
DoorlessCarp’s Scientific Literature Reviews is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.
DoorlessCarp’s Scientific Literature Reviews is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.
Buhre JS, Pongracz T, Künsting I, et al. mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine.Front Immunol. 2022;13:1020844. doi:10.3389/fimmu.2022.1020844
Kiszel P, Sík P, Miklós J, et al. Class switch towards spike protein-specific IgG4 antibodies after SARS-CoV-2 mRNA vaccination depends on prior infection history.Sci Rep. 2023;13(1):13166. doi:10.1038/s41598-023-40103-x
Emmenegger M, Fiedler S, Brugger SD, et al. Both COVID-19 infection and vaccination induce high-affinity cross-clade responses to SARS-CoV-2 variants.iScience. 2022;25(8). doi:10.1016/j.isci.2022.104766
Selva KJ, Ramanathan P, Haycroft ER, et al. Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections.JCI Insight. 2023;8(18). doi:10.1172/jci.insight.172470
Valk AM, Keijser JBD, Dam KPJ van, et al. Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination. Published online October 2, 2023:2023.09.29.23296354. doi:10.1101/2023.09.29.23296354
Hartley GE, Fryer HA, Gill PA, et al. Third dose COVID-19 mRNA vaccine enhances IgG4 isotype switching and recognition of Omicron subvariants by memory B cells after mRNA but not adenovirus priming. Published online September 19, 2023:2023.09.15.557929. doi:10.1101/2023.09.15.557929
Farkash I, Feferman T, Cohen-Saban N, et al. Anti-SARS-CoV-2 antibodies elicited by COVID-19 mRNA vaccine exhibit a unique glycosylation pattern.Cell Reports. 2021;37(11):110114. doi:10.1016/j.celrep.2021.110114
Sheehan J, Ardizzone CM, Khanna M, Trauth AJ, Hagensee ME, Ramsay AJ. Dynamics of Serum-Neutralizing Antibody Responses in Vaccinees through Multiple Doses of the BNT162b2 Vaccine.Vaccines. 2023;11(11):1720. doi:10.3390/vaccines11111720
Akhtar M, Islam MdR, Khaton F, et al. Appearance of tolerance-induction and non-inflammatory SARS-CoV-2 spike-specific IgG4 antibodies after COVID-19 booster vaccinations.Frontiers in Immunology. 2023;14. Accessed January 3, 2024. https://www.frontiersin.org/articles/10.3389/fimmu.2023.1309997
Espino AM, Armina-Rodriguez A, Alvarez L, et al. The Anti-SARS-CoV-2 IgG1 and IgG3 Antibody Isotypes with Limited Neutralizing Capacity against Omicron Elicited in a Latin Population Switch toward IgG4 after Multiple Doses with the mRNA Pfizer-BioNTech Vaccine. Published online January 10, 2024. doi:10.20944/preprints202401.0815.v1
Kalkeri R, Zhu M, Cloney-Clark S, et al. Altered IgG4 antibody response to repeated mRNA versus recombinant protein SARS-CoV-2 vaccines.Journal of Infection. 2024;88(3). doi:10.1016/j.jinf.2024.106119
Valluri A, Sitta J, Howard CM. Multifocal IgG4-related aortitis and periaortitis simulating aortic dissection.Radiol Case Rep. 2021;16(8):2274-2279. doi:10.1016/j.radcr.2021.05.030
Mohammadzadeh A, Houshmand G, Pouraliakbar H, et al. Coronary artery involvement in a patient with IgG4-related disease.Radiol Case Rep. 2023;18(10):3699-3703. doi:10.1016/j.radcr.2023.07.062
Kosaraju A, Goyal A, Grigorova Y, Makaryus AN. Left Ventricular Ejection Fraction. In: StatPearls. StatPearls Publishing; 2024. Accessed June 12, 2024. http://www.ncbi.nlm.nih.gov/books/NBK459131/
Jin L, Frahm-Jensen G. A ruptured abdominal aortic aneurysm was just the tip of the iceberg – A rare case of IgG4-related disease and multiple giant aneurysms.Annals of Vascular Surgery - Brief Reports and Innovations. 2023;3(4):100227. doi:10.1016/j.avsurg.2023.100227
Koufoglou E, Kourlaba G, Michos A. Effect of prophylactic administration of antipyretics on the immune response to pneumococcal conjugate vaccines in children: a systematic review.Pneumonia (Nathan). 2021;13(1):7. doi:10.1186/s41479-021-00085-8
Slattery JT, Wilson JM, Kalhorn TF, Nelson SD. Dose-dependent pharmacokinetics of acetaminophen: Evidence of glutathione depletion in humans.Clinical Pharmacology & Therapeutics. 1987;41(4):413-418. doi:10.1038/clpt.1987.50
Sáez GT, Valls V, Muñiz P, et al. The role of glutathione in protection against DNA damage induced by rifamycin SV and copper(II) ions.Free Radic Res Commun. 1993;19(2):81-92. doi:10.3109/10715769309056502
Ozierański K, Tymińska A, Kruk M, et al. Occurrence, Trends, Management and Outcomes of Patients Hospitalized with Clinically Suspected Myocarditis—Ten-Year Perspectives from the MYO-PL Nationwide Database.Journal of Clinical Medicine. 2021;10(20):4672. doi:10.3390/jcm10204672
Immunoglobulin G4-Related Myocarditis with Eosinophilic Infiltration: A Case Report. J Korean Soc Radiol. 2023;84(3):686-691. doi:10.3348/jksr.2022.0058
Great research, many thanks for your dedication. I’ve always thought a “vaccine” that turns our human cells into viral antigens, would not be good for the host, completely messing up our complement system, as described.
Excellent as always. It’s difficult to find the time to read many of your articles due to length but I’m always rewarded for having made the effort. You are a gift to the SS community
Great research, many thanks for your dedication. I’ve always thought a “vaccine” that turns our human cells into viral antigens, would not be good for the host, completely messing up our complement system, as described.
Excellent as always. It’s difficult to find the time to read many of your articles due to length but I’m always rewarded for having made the effort. You are a gift to the SS community