Eosinophilic myocarditis I42.3

The first description of eosinophilic myocarditis dates from 1898 from an autopsy observation by Freund. In addition to extensive thrombosis in both ventricles, abundant eosinophilic granulocytes were found (Hort 2000).

Wilhelm Löffler (1887 - 1972) first described a disease caused by eosinophilic infiltration in myocardial tissue in 1935. A correlation between eosinophils and heart disease is extremely rare (Zhong 2021). His description was of endocarditis pathologically characterized by eosinophilic infiltration of endocardial cells with formation of myocardial fibrosis (Zhong 2021). The clinical picture was named after him as "Löffler endocarditis" (Zhong 2021).

Eosinophilic myocarditis (EM) is an acute life-threatening (Brambatti 2017) inflammatory form of cardiomyopathy characterized by eosinophilic infiltration of myocardial tissue (Zhong 2021).

EM represents the most important manifestation of the hypereosinophilic syndrome (Kasper 2015). It is one of the non-infectious forms of myocarditis (Herold 2022).

EM progresses in different stages:

- 1st stage:

Eosinophilic infiltration of the heart with subsequent myocardial necrosis.

- 2nd stage:

The so-called thrombotic stage. Elevated levels of circulating thrombin are found here. The eosinophil cationic proteins combine with the anionic thrombomodulin in this process.

- Stage 3:

In the 3rd and final stage, fibrotic scarring is found (Kutschynka 2016).

In Western countries, hypereosinophilic syndrome is usually idiopathic. In Mediterranean countries and Africa, on the other hand, it is more likely to be a consequence of a previous infection (Kasper 2015).

EM represents a rarely occurring form of myocarditis (Brambatti 2917). However, the exact incidence rate is difficult to determine due to the clinical limitations of endomyocardial biopsy (Zhong 2021).

In a study by Brambatti (2017) that included 179 patients with histologically confirmed EM, the mean age was 41 years, gender preference was not evident, and comorbidities were present in 168 of the 179 patients.

Autopsies of young people who died of sudden cardiac death showed myocarditis in 2%-42%, in children with dilated cardiomyopathy it was 46% , in adults with non-ischemic dilated cardiomyopathy 9%-16% (Zhong 2021).

The etiology of EM is heterogeneous (Kutschynka 2016).

Three main groups can be found that can cause EM:

• 1. infection (most common cause)
• 2. autoimmunity
• 3. cardiotoxic substances (Zhong 2021)

To 1. infection such as:

• Coxsackie- B- infection (Zhong 2021)
• Parasitic infections with e.g.
  • Toxocara canis and cati (dog and cat roundworms, respectively) (Zhong 2021)
  • Toxoplasma gondii
  • Echinococcus spp.
  • Trichinella spiralis (Kutschynka 2016)

To 2. autoimmune diseases such as:

• Allergic granulomatosis with polyangiitis (formerly called Churg-Strauss syndrome) (Kasper 2015).

To 3. cardiotoxic substances such as:

• chronically taken antibiotics (most frequent cause) especially sulfonamides, penicillin, tetracycline, streptomycin (Roskamm 1999)
• Thiazides
• Anticonvulsants
• Indometacin
• Methyldopa (Kasper 201%)
• amphotericin B
• Antipsychotics such as clozapine
• Angiotensin converting enzyme inhibitors (ACE inhibitors), e.g. captopril, enalapril
• Inotropics such as digoxin, dobutamine (Kutschynka 2016)
• In the context of malignant diseases (Kasper 2015) such as lung carcinoma, gastrointestinal tumors, urogenital tumors, T-cell and Hodgkin's lymphomas, leukemia , etc. (Kutschynka 2016).

There is now evidence that certain gene products such as an absent interferon gamma (IFNγ) as well as IL-17A play a role (Zhong 2021).

In EM, direct damage by eosinophils may occur, releasing toxic substances and activating endogenous coagulation. There is also likely to be activation of the autoimmune system (Zhong 2021).

However, the severity of cardiac injury does not correlate with the level of eosinophils in peripheral blood (Zhong 2021).

As a result of EM, myocardial edema, hyperemia, capillary leakage, fibrous scarring, and cell necrosis may occur (Zhong 2021).

The clinical picture ranges from asymptomatic cases to life-threatening conditions with cardiogenic shock or sudden cardiac death (Kutschynka 2016).

The most common symptoms are:

- dyspnea (in 59.4%)

- peripheral eosinophilia (in 75.9 %)

- Fever 26.7% (Brambatti 2017).

- palpitations

- cardiogenic shock possible in severe cases

Overall, a rather nonspecific clinical picture with predominantly thoracic pain and tightness is usually found (Zhong 2021).

The diagnosis of the rarely occurring EM is still a challenge today (Kandolf 2011).

Guidelines for the diagnosis of EM are:

• 1. changes such as:
  • Symptoms such as thoracic pain, dyspnea and palpitations.
  • Laboratory chemical changes such as:
    • CK- MB- elevation
    • Eosinophilia > 500 µl
    • Troponin T elevation
  • Changes in the ECG
  • sonographically detectable transient hypertrophy or asynergia of wall motion in the left ventricle
• 2. anamnestic information:
  • presence of allergic diseases such as bronchial asthma, rhinitis allergica or urticaria (found in approx. 33 %)
  • before the onset of EM occurrence of a common cold (found in about 66%)
• 3. endomyocardial biopsy:

Although endomyocardial biopsy is the gold standard of myocarditis (Zhong 2021), it has very limited sensitivity (when 10 biopsies were taken, only 37% of those with the disease were positive, as the changes are usually only focally present [Pinger 2019]). Schwimmbeck (2015), referring to the American Heart Association (AHA) guidelines, considers myocardial biopsy to be indicated in existing dilated heart failure in which an allergic reaction or hypereosinophilia is suspected (recommendation class IIa, level of evidence C).

Echocardiography

- Edema of the ventricular wall

- Pericardial effusion (found in 32-57% of patients with EM [Zhong 2021])

- Thrombus (found in 13.7% [Brambatti 2017])

Coronary angiography

EM cannot be diagnosed by coronary angiography, but this examination is often required for differential exclusion because of ST-segment changes, troponin elevation, and thoracic pain (Zhong 2021).In the study by Brambatti (2017), coronary artery disease was found angiographically in 0.9%.

Cardiac magnetic resonance imaging (CMR).

CMR currently represents the gold standard of non-invasive examinations (Kutschynka 2016). Therefore, to standardize the examination methods and to compare myocardial changes, the so-called Lake- Louise criteria were first established in 2009. In December 2018, a revision of these criteria took place. Thereby, Late Ga dolinium Enhancement was left as a single factor (see also w. u. [Maintz 2019]).

Lake- Louis- criteria:

Cardio- MRI can detect in case of myocarditis :

- 1. edema:

Inflamed areas show hyperintensity (edema) in the fat-saturated T2- weighting; a ratio > 1.9 is considered pathological and represents an indication of myocardial edema (Niebauer 2015).

- 2. early gadolinium enhancement:

Hyperemia occurs when a capillary leak exists (Pinger 2019). In T1- weighting after contrast administration, the uptake of contrast in the inflammatory areas is measured and related to the contrast uptake of skeletal muscle. The normal ratio is < 2.5; early gadolinium enhancement with ratios above 4.0 or an absolute increase of > 45% are indicative of myocarditis(Herold 2018).

- 3. late gadolinium enhancement:

Late gadolinium enhancement indicates irreversible cellular damage (Pinger 2019). The inflammatory altered areas of the myocardium take up contrast in the Delayed- Enhancement sequences (also called Late Gadolinium Enhancement), which occurs subepicardially in the acute phase of myocarditis, especially in the inferior lateral wall portions of the left ventricle.

In myocardial infarction , on the other hand - in contrast to myocarditis - the accumulation of contrast agent is typically subendocardial and can be assigned to a supply area of the coronary arteries (Puls 2010).

Provided the Lake- Louis criteria are met, sensitivity of 67% and specificity of 91% are shown for CMR (Schuler 2017). Typical changes in the presence of EM are:

- Restriction of left ventricular ejection fraction between 25 50 % (Brambatti 2017).

- myocardial edema on T2-weighted imaging.

- fibrous scars

- myocardial necrosis

- pericardial effusion (Zhong 2021)

ECG:

The ECG may show the following changes:

- Changes in the ST-T pathway

- AV block

- ventricular arrhythmia

- thigh block (Zhong 2021).

In a study by Brambatti (2017), 9.4% of patients showed a normal ECG.

Eosinophilia: Peripheral eosinophilia was found in 75.9% of patients (Brambatti 2017).

However, the circulating number of peripheral eosinophils does not reach the extremely high levels seen in hypersensitivity myocarditis (Kasper 2015).

• Creatinine kinase elevated
• ECP(eosinophil cationic protein) increase in serum (Zhong 2021).
• Troponin level increase at 95.7 % (Brambatti 2017).
• CRP increase at 79.5

Bioptically, there is an infiltration of:

- lymphocytes

- mononuclear cells with a high proportion of eosinophils (Kasper 2015)

- Myocarditis of other genesis

- Myocardial infarction:

In myocardial infarction, the accumulation of contrast agent on cardio- CT is typically found subendocardially and can be assigned to a coronary artery supply area [Puls 2010]).

• Dilated cardiomyopathy:

This is found in approximately 30% of biopsy-confirmed myocarditis cases (Zhong 2021).

• Cerebral infarction (also described as an initial symptom [Bahlmann 2017]).
• Löffler endocarditis (Hort 2000).

Therapy consists primarily of symptomatic and immunosuppressive treatment (Zhong 2021). In the acute phase of the disease, a strict restriction of physical activities applies. Following EM, the patient should generally avoid sports activities for at least 6 months (Kutschynka 2016).

Symptomatic therapy of heart failure:

• Angiotensin converting enzyme inhibitors (ACE inhibitors)
• Angiotensin receptor blockers
• Aldosterone receptor antagonists
• Pericardial drainage
• Mechanically adjuvant therapy in case of failure of conventional treatment in the form of:
  • extracorporeal membrane oxygenation
  • intra-aortic balloon counterpulsation
  • VAD = ventricular assist device (Zhong 2021)
• Glucocorticoids: Glucocorticoids should be used early because they can prevent the intermediate stage with thrombotic necrosis and fibrosis (Zhong 2021). Dosage recommendation: e.g. methylprednisolone 1 mg / kg bw / d for 2 weeks, then weekly reduction of the dose by 10 mg every 4 weeks. The maintenance dose of 10 mg / d should be maintained until the end of treatment, which is reached after 6 months. Subsequently, discontinue methylprednisolone gradually (Kühl 2012).
• Gastric protection: Pantoprazole and calcium can be used as gastric protection. Dosage recommendation (pantoprazole 20 mg / d); calcium substitution1 x 1 g / d (Kühl 2012).
• Cytostatic drugs: There are now reports that good results can be achieved by cyclophosphamide or methotrexate without additional glucocorticoids (Zhong 2021).
• Immunosuppressive therapy: In eosinophilic myocarditis, there is an indication for treatment with immunosuppressants. In this regard, it is recommended to contact centers that have treatment protocols available (Herold 2022). Kühl (2012) recommends, for example, azathioprine at a dosage between 50 - 150 mg / d for 6 months.
• IL- 5- monoclonal antibodies: If therapy with immunosuppressants and high-dose prednisone does not lead to improvement, treatment with IL- 5- monoclonal antibodies such as mepolizumab is recommended. This often significantly improves cardiac function and reduces pericardial effusion (Zhong 2021).

Parasite infestation: Albendazole is recommended for parasite infestation (Zhong 2021). Dosage recommendation: 15 mg / kg bw / d (Speer 2019).

Churg- Strauss syndrome (CSS): Patients with CSS should be treated primarily with a glucocorticoid. Dosage recommendation: prednisone or equivalents 1 mg / kg bw / d. As soon as a clinical response is achieved, which is usually only the case after several weeks, the steroids can be slowly phased out. If the clinical picture is more advanced, a combination with immunosuppressants is recommended (Kutschynka 2016).

Note: The ECP level is used to check the effectiveness of a therapy. This rises again, for example, after reduction of the corticosteroid (Zhong 2021).

Specific data on the prognosis of EM are not available. According to Zhong (2021), mortality during hospitalization is about 10% and about 30% in the first 3 years thereafter. He considers regular myocardial biopsy after discharge to be necessary.

Brambatti, in his study published in 2017, describes a mortality rate of 22.3% during the inpatient stay. Cardiac arrest occurred in 27.2% of his patients.

Kühl (2012) speaks of an extremely poor prognosis with 4-year survival rates of <20%.

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