Endocarditis, eosinopholia, etiology, pathogenesis, symptoms, treatment, follow up, prognosis

1. LOEFFLER ENDOCARDITIS
Prof Ariyanto Harsono MD PhD SpA(K)

2. Background
Loeffler endocarditis and endomyocardial
fibrosis are restrictive
cardiomyopathies, defined as diseases of the
heart muscle that result in impaired
ventricular filling with normal or decreased
diastolic volume of either or both ventricles.
Systolic function and wall thickness may
remain normal, especially early in the
disease, as reported by Richardson and
associates. Both conditions are associated
with eosinophilia.

3. Etiology
The associations among eosinophilia, active
carditis, and multiorgan involvement were
first described by Loeffler in 1936. Pathologic
specimens in Loeffler endocarditis show
eosinophilic myocarditis, a tendency toward
endomyocardial fibrosis and clinical
manifestations of thromboembolism, and
acute heart failure.

4. Eosinophilic states that may occur in association
with Loeffler endocarditis include
hypereosinophilic syndrome, eosinophilic
leukemia, carcinoma, lymphoma, drug
reactions or parasites, as reported in multiple
case series.

5. Although eosinophilic endocardial disease has been well
described, myocardial and vascular damage due to
eosinophilic infiltration and degranulation is rarely
diagnosed during life, as reported by Oakley et al and
others. Herzog et al and Tonnesen et al have proposed
that the reason for this situation may be the rapidly
fatal evolution of most cases of eosinophilic arteritis
and myocarditis. These conditions are usually
diagnosed based on postmortem examination and
nonspecificity of clinical manifestations, as reported by
Kim et al, Isaka et al, and Seshadri et al.

6. Pathophysiologically, the fibrotic stage of
Loeffler endocarditis is very similar to the
disease entity described as endomyocardial
fibrosis, which is indolent in comparison to
Loeffler endocarditis. The tropical form of
endomyocardial fibrosis is associated with
eosinophilia, a common finding in Loeffler
endocarditis.

7. Pathophysiology
Endomyocardial damage in Loeffler endocarditis is
well known and described in a study by Solley
and associates. Myocardial involvement is less
well known and has been considered a
manifestation of an acute necrotic stage of
eosinophilic endomyocardial disease, as reported
by Olsen and colleagues. More recently, cases of
isolated eosinophilic myocarditis have been
reported without signs of endomyocardial
involvement, with or without vasculitis.

8. Additionally, idiopathic eosinophilic endomyocarditis, in the
absence of peripheral eosinophilia, has been reported by
Priglinger et al.
Morphologic abnormalities of eosinophils have been noted in
patients with Loeffler endocarditis, suggesting that these
eosinophils were mature or stimulated. The
intracytoplasmic granular content of activated eosinophils
is thought to be responsible for the toxic damage to the
heart, as reported by Tai and associates. Spry et al reported
eosinophilic degranulation of basic proteins causing
myocardial damage in tissue cultures in vitro. Gliech et al
reported a dose-dependent cytotoxic effect of the
eosinophilic granular proteins, inhibiting multiple enzyme
systems.

9. The cationic eosinophilic proteins bind to the
anionic endothelial protein, thrombomodulin.
This complex impairs anticoagulant
activities, leading to enhanced endocardial
thrombus formation, as reported by Slungaard
and colleagues.

10. Toxins released by the eosinophils include
eosinophil-derived neurotoxin, cationic
protein, major basic protein, reactive oxygen
species, and arachidonic acid derivatives. As
described by Cunningham et al, these toxins
may cause endothelial and myocyte
damage, resulting in thrombosis, fibrosis, and
infarction.

11. The intensity and timing of the active carditis is
related closely to the severity of the circulating
eosinophilia. Some have suggested
that, particularly in the tropics, patients who
present with later fibrotic stages of
endomyocardial disease may have had either
transient earlier bouts of moderate eosinophilia
with spontaneous resolution, or only moderate
levels of eosinophilia leading to a low-grade
endomyocarditis with gradual progressive
fibrosis, as reported by Olsen et al.

12. Clinical Manifestations
The initial clinical presentation and stages of
eosinophilic endomyocardial disease are as
follows:
Necrotic stage (early stage)
[21]
– Hypereosinophilia with systemic illness (20-30%)
•
•
•
•
•
Fever
Sweating
Chest pain (as described by Bestetti et al )
Lymphadenopathy
Splenomegaly
[22]

13. – Acute carditis (20-50%)
•
•
•
•
•
•
•
•
Anorexia
Weight loss
Cough
Pulmonary infiltrates
Skin and retinal lesion
Atrioventricular valve (AV) valve regurgitation
Biventricular failure
Polymorphic ventricular tachycardia
[23]

14. Thrombotic stage
– Thrombotic emboli (10-20%)
• Cerebral, splenic, renal, and coronary infarction
• Splinter hemorrhages
Fibrotic stage (late stage)
– Restrictive myopathy (10%)
• AV valvular regurgitation
• Right and left heart failure

15. The image shows dense fibrosis of ventricle in a
postmortem dissected heart.

16. History
Patients with Loeffler endocarditis may present
with weight loss, fever, cough, rash, and
symptoms related to congestive heart failure.
Initial cardiac involvement has been reported
in about 20-50% of cases; however, cardiac
involvement rarely presents with chest
pain, as reported by Bestetti et al.

17. Physical
Signs of biventricular failure (eg, pedal edema, elevated jugulovenous
pressure, pulmonary edema, third heart sound [S3] gallop) are commonly seen
once congestive heart failure develops.
Cardiomegaly may be present without overt signs of congestive heart failure.
Murmur of mitral regurgitation may be present, as reported by multiple
authors, including Weller et al.
Systemic embolism is frequent and may lead to neurologic and renal dysfunction.
The Kussmaul sign may be present.
S3 gallop may be present, but rarely fourth heart sound (S4).
Restrictive cardiomyopathy, such as Loeffler endocarditis, is sometimes difficult to
differentiate from constrictive pericarditis. Physical signs in constrictive
pericarditis that may help differentiate the 2 conditions include a nonpalpable
apex (usually), presence of pericardial knock, and usually absent regurgitation
murmurs.

18. Published case reports highlight presentations with unusual
ECG changes mimicking posterior myocardial infarction as
described by Maruyoshi et al, acute myocardial infarction
as described by Mor et al , and aortic valve regurgitation
secondary to valve fibrosis and fibrotic vegetations on the
aortic valve as described by Gudmundsson et al.
Recently, a presentation with inflow and outflow tract
obstruction of the left ventricle with a large organized
thrombus on the mitral valve apparatus was described.[28]
Occlusion and obstruction of the aortic bifurcation has been
reported (Leriche syndrome).

19. Differential Diagnoses
Cardiac Catheterization(Left Heart)
• Cardiac Neoplasms, Primary
• Cardiomyopathy, Hypertrophic
• Cardiomyopathy, Restrictive

20. Laboratory Studies
CBC counts should be performed to look for the
presence of eosinophils. Peripheral
eosinophilia should not be considered
mandatory for the diagnosis of Loeffler
endocarditis, as described by Priglinger et al.
Cytogenetics, fluorescent in situ hybridization
(FISH), and molecular analysis show the
presence of the FIP1L1-PDGFRA fusion gene as
demonstrated by Cools et al and Rotoli et al.

21. Imaging Study
ECG, echocardiography, Doppler studies using echocardiogram, cardiac
catheterization, endomyocardial biopsy, and CT scan or MRI of the chest may all
be useful in diagnosis, as for cardiomyopathy of any cause.
The echocardiographic hallmark of Loeffler endocarditis includes a restrictive
pattern of filling with relatively preserved left ventricular systolic function, as
reported by Parillo et al.
Localized thickening of the basal posterior wall of the left ventricular free wall and
restricted motion of the posterior leaflet of the mitral valve are seen, as reported by
Spyrou et al and Child et al.
Apical thrombus in the left ventricle also has been reported. Also, presentation with
restriction of the mitral apparatus with a large thrombus has been reported.
Regurgitant AV valve lesions are often present.
Recurrent thrombosis of the prosthetic mitral valve in the setting of rising eosinophilia is
reported by Watanabe et al.
Three echocardiographic features of amyloidosis, another cause of restrictive
cardiomyopathy, include thickened interatrial septum; thickening of the cardiac
valves; and granular, sparkling texture of the myocardium. All may be present in
amyloidosis but not in Loeffler endocarditis.
[28]

22. Echocardiographic Doppler findings are of restrictive cardiomyopathy, including
decreased right ventricular and left ventricular velocities with inspiration and
inspiratory augmentation of hepatic-vein diastolic flow reversal.
Cardiac catheterization reveals markedly elevated ventricular filling pressures
and the presence of mitral or tricuspid regurgitation.
On left ventriculography, a characteristic feature is preserved left ventricular
systolic function with obliteration of the left ventricular apex, as reported by
Weller and associates.
The hemodynamic picture on cardiac pressure tracings reveals a restrictive
picture due to dense endocardial scarring and a reduction in left ventricular
cavity caused by an organized thrombus, as reported by Weller et al and
Parillo et al. The hemodynamic picture may include elevation of left
ventricular end diastolic pressure, often greater than 5 mm Hg over right
ventricular end diastolic pressure; however the pressures may be identical at
times.
Cardiac MRI findings of endomyocardial fibrosis include right ventricular diastolic
dysfunction, mild systolic dysfunction, and extensive subendocardial delayed
contrast enhancement.

23. Other Tests
ECG shows nonspecific ST-segment and T-wave
abnormalities as reported by Spyrou et al and
Arnold et al.
Arrhythmia, especially atrial fibrillation, and
conduction system defects, particularly rightbundle branch block, may be present, as reported
by Fawzy et al. For related information, see
Medscape's Atrial Fibrillation and Cardiac Rhythm
Management Resource Centers.
Nonspecific findings may include pseudo infarction
patterns of left-axis deviation.

24. Procedures
Percutaneous endomyocardial biopsy often
confirms diagnosis. As endomyocardial
involvement may be patchy, a false-negative
biopsy result also is possible, as reported by
Felice and colleagues.

25. Histologic Findings
Histologic specimens of the myocardial biopsy
reveal thick and deep layers of loosely
arranged collagen tissue, which, although
localized primarily to the endocardium, may
have strands extending into the underlying
myocardium. Although peripheral eosinophilia
is characteristic of Loeffler
endocarditis, eosinophilic infiltration of the
tissues and arteries is less common, possibly
because of the infrequency of biopsy.

26. Medical Care
Symptomatic relief is achieved by routine cardiac therapy, including
diuretics, digitalis, afterload reduction, and anticoagulation, as indicated
by Weller et al and Parillo et al.
Treatment with low-dose imatinib causing rapid regression of both
eosinophilic proliferation and endomyocardiopathy is described by Cools
et al, Vandenberghe et al, and Rotoli et al.
Early phases of the disease have been treated with immune suppressant and
cytotoxic medications with varying degrees of success.
Corticosteroids appear to be beneficial in acute myocarditis, as reported by
Uetsuka et al, among others. Together with cytotoxic drugs, including
hydroxyurea, corticosteroids may prolong survival substantially, as
reported by Weller et al, Parillo et al, and Arnold et al.
Interferon therapy also has been reported by Butterfield et al as having some
success.

27. Surgical Cares
Once fibrosis ensues, surgical therapy may have a positive impact on
palliation of symptoms.
Dubost et al performed the first endocardiectomy in endomyocardial fibrosis,
which consists of decorticating the fibrosed endocardium in a manner
similar to resection of constricting densely fibrotic pericardium.
In 150 published cases of surgical therapy of endomyocardial fibrosis and
eosinophilic myocarditis, an operative mortality rate of 15-29% is
reported, with AV block requiring a permanent pacemaker as a common
complication.
Endocardiectomy is directed toward the predominant location of the
restrictive process.
The mitral and tricuspid valves may be subject to replacement or repair,
depending on the involvement of the subchordal apparatus.

28. Early surgery is assisted by the fact that fibrous septa may not
have extended into the adjacent myocardium.
When the restrictive process is advanced, in individuals with
congestive heart failure refractory to medical therapy, the
only potential approach is endocardiectomy.
The extent to which fibrosis recurs postoperatively is not
known.
In 2006, Tanaka et al reported endomyocardial resection as
well as mitral valve replacement in a patient with severe
restrictive myocardial disease and mitral leaflets
involvement; however, the patient died 3 months later of
cerebral infarction. Jategaonkar et al reported a similar
patient with a 4-year survival until last follow up.

29. Further Inpatient Care
Further inpatient care includes serial CBC
counts.

30. Further Outpatient Care
Outpatient follow-up includes close follow-up
observation for recurrence of symptoms of
heart failure. Serial echocardiograms to
evaluate ejection fraction are also helpful for
titration of medications.

31. Prognosis
The overall prognosis of patients with Loeffler
endocarditis is poor and depends on the location
of involvement in the heart.
Disease is usually slow in onset, with progression to
increasing degrees of right and left heart failure.
Sudden death and syncope are not as common as in
other causes of restrictive cardiomyopathy.

32. Medication Summary
Symptomatic relief is achieved by routine cardiac therapy
including diuretics, digitalis, afterload reduction, and
anticoagulation.
Early phases of the disease have been treated, with
varying degrees of success, with immune
suppressants, including steroids and interferon
therapy, and cytotoxic medications, particularly
hydroxyurea.
Corticosteroids appear to be beneficial in acute
myocarditis, together with cytotoxic drugs, including
hydroxyurea, and may prolong survival substantially.
Interferon therapy has also been reported as having
some success.

33. Tyrosine kinase inhibitors
These agents inhibit tyrosine kinase, which, in
turn, inhibit activation of intracellular
pathways that can promote deregulated cell
proliferation.

34. Imatinib (Gleevec)
Small molecule that selectively inhibits the
tyrosine kinase activity of c-kit, bcr-abl, and
PDGFR.

35. Antineoplastic agents, antimetabolite
These agents inhibit cell growth and proliferation
Hydroxyurea (Hydrea)/Hydroxycarbamide
Inhibitor of deoxynucleotide synthesis and DOC for
inducing hematologic remission in CML. Less
leukemogenic than alkylating agents such as
busulfan, melphalan, or chlorambucil.
Myelosuppressive effects last a few days to a week
and are easier to control than those of alkylating
agents. Hydroxyurea can be given as a single daily
dose or divided bid or tid at higher dose ranges.

36. Corticosteroids
These agents have anti-inflammatory properties and
cause profound and varied metabolic effects.
Corticosteroids modify the body's immune response to
diverse stimuli
Methylprednisolone (Adlone, Solu-Medrol, DepoMedrol, Medrol)
Immune-modifying agents that can be used, with varying
degrees of success, in early stage of Loeffler
endocarditis. Monitoring of liver function tests and
eosinophil count may help to observe long-term
response.

37. Diuretics
These agents provide relief of congestive heart failure sym
Bumetanide (Bumex)
Increases excretion of water by interfering with chloride-binding cotransport
system, which, in turn, inhibits sodium and chloride reabsorption in
ascending loop of Henle. Does not appear to act in distal renal tubule.
Furosemide (Lasix)
Increases excretion of water by interfering with chloride-binding cotransport
system, which, in turn, inhibits sodium and chloride reabsorption in the
ascending loop of Henle and distal renal tubule. Dose must be
individualized to patient. Depending on response, administer at
increments of 20-40 mg, no sooner than 6-8 h after previous dose, until
desired diuresis occurs. When treating infants, titrate with 1-mg/kg/dose
increments until satisfactory effect achieved.

38. Cardiac Glycoside
These agents are used for treatment of systolic
dysfunction in congestive heart failure.
Digoxin (Lanoxin)
Cardiac glycoside with direct inotropic effects in addition
to indirect effects on cardiovascular system. Acts
directly on cardiac muscle, increasing myocardial
systolic contractions. Indirect actions result in
increased carotid sinus nerve activity and enhanced
sympathetic withdrawal for any given increase in mean
arterial pressure.

39. Angiotensin-converting enzyme inhibitors
These agents are used to treat congestive heart
failure and reduce afterload.
Enalapril (Vasotec)
Competitive inhibitor of ACE. Reduces
angiotensin II levels, decreasing aldosterone
secretion.

40. Anti-interleukin-5 monoclonal antibodies
These agents inhibit the production, activation, and maturation of
eosinophils.
Mepolizumab
Received orphan drug status for first-line treatment in patients with
hypereosinophilic syndrome in the US and the EU in 2004. Interleukin-5
stimulates the production, activation, and maturation of eosinophils. Since
mepolizumab inhibits interleukin-5 and has a long terminal halflife, treatment with mepolizumab causes a sustained reduction in the
numbers of circulating eosinophils. Thus, mepolizumab may be a useful
therapeutic agent for the treatment of conditions characterized by
increased levels of eosinophils.
A phase III, compassionate use trial of mepolizumab (NCT00244686) in
patients with hypereosinophilic syndrome was ongoing in October 2007 in
the US. Patients who have significant clinical disease but are unresponsive
to traditional treatment and those who have demonstrated clinical benefit
from previous anti-IL-5 treatment are eligible to take part in the trial.

41. Mepolizumab is also in phase I/II clinical development for the treatment of
eosinophilic esophagitis.
A phase I/II trial (NCT00358449) began in August 2006 in the US, Australia, the
UK, and Canada, and will enroll approximately 72 pediatric patients with
eosinophilic esophagitis. The randomized, parallel-group clinical trial will evaluate
the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous
mepolizumab for 12 weeks. In September 2006, GSK completed enrollment in a
phase I/II study of mepolizumab for the treatment of eosinophilic esophagitis in 10
adult patients in Switzerland (NCT00274703). The randomized, doubleblind, placebo-controlled study will evaluate the
pharmacokinetics, pharmacodynamics, safety, and tolerability of IV mepolizumab.
A phase I/II trial of mepolizumab in 4 patients with eosinophilic esophagitis conducted
by Cincinnati Children's Hospital found the monoclonal antibody was safe and
effective. Brigham and Women's Hospital, in association with GSK, is conducting a
phase I/II trial of mepolizumab, in the US, in patients with Churg-Strauss Syndrome
(CSS). The trial, which started in September 2007, will evaluate the potential of
mepolizumab to reduce the need for corticosteroid therapy in patients with CSS
(NCT00527566). CSS, otherwise known as allergic granulomatosis, is defined by
patients with asthma, eosinophilia, and vasculitis.

42. Interferons
These agents are naturally produced proteins with antiviral, antitumor, and
immunomodulatory actions. Alpha, beta, and gamma interferons may be given
topically, systemically, and intralesionally.
Interferon alfa-2b (Intron A)
Protein product manufactured by recombinant DNA technology. Mechanism of
antitumor activity not clearly understood; however, direct antiproliferative effects
against malignant cells and modulation of host immune response may play
important roles. Butterfield et al reported use of interferon alpha in treatment of
HES with some success.
Interferon alfa 2a (Roferon A)
Protein product manufactured by recombinant DNA technology. Mechanism of
antitumor activity not clearly understood; however, direct antiproliferative effects
against malignant cells and modulation of host immune response may play
important roles. Butterfield et al reported use of interferon alpha in treatment of
HES with some success.

43. Thank You
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