(Chest. 2000;117:905-907.)
© 2000
American College of Chest Physicians
Giant Cell Myocarditis Responding to Immunosuppressive Therapy*
Andrea Frustaci, MD, FCCP;
Cristina Chimenti, MD;
Maurizio Pieroni, MD and
Nicola Gentiloni, MD
*
From the Departments of Cardiology (Drs. Frustaci, Chimenti, and Pieroni) and Internal Medicine (Dr. Gentiloni), Catholic University, Rome, Italy.
Correspondence to: Andrea Frustaci, MD, FCCP, Cardiology Institute, Catholic University, Largo Gemelli, 800168 Roma, Italy
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Abstract
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An unusual case of giant cell myocarditis presenting with
cardiogenic shock that dramatically responded to conventional dose of
steroids and azathioprine is reported. Cardiac recovery was rapid,
complete (left ventricular ejection fraction rose to 55% from
10%), and was accompanied by the disappearance of the inflammatory
infiltrates including giant cells in the control endomyocardial biopsy.
Maintenance of the recovery at 16 months of follow-up on a low dose of
azathioprine suggests that giant cell myocarditis might be a
heterogeneous disease having either a negative untreatable trend
necessitating cardiac transplantation, or a curable substrate
responding to immunosuppressive drugs.
Key Words: giant cell myocarditis • heart failure • immunosuppressive therapy
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Introduction
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Giant
cell myocarditis is a progressive disease of unknown cause that has
been reported in subjects aged 6 months to 70 years. This entity has a
grim prognosis, as conventional immunosuppressive therapy is usually
ineffective and affected patients die in a short time unless a heart
transplant is rapidly done. Causes of death include progressive heart
failure and sudden death.1
The authors report the unusual
case of a young patient presenting with cardiogenic shock due to giant
cell myocarditis that responded dramatically to a combination of
steroids and azathioprine maintaining a complete recovery for a long
period.
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Case Report
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A 23-year-old girl was admitted because of rapidly worsening
shortness of breath. Two months before, she had a flu-like syndrome. On
admission, she was stable. Tachycardia was present (heart rate, 130
beats/min) with a gallop rhythm; BP was 130/80 mm Hg. The ECG showed
low voltages, left anterior bundle branch block, and diffuse ST-T wave
abnormalities. Chest radiograph was normal. Routine laboratory tests
including glucose, creatinine, BUN, serum electrolytes, and urinalysis
were within normal limits. Erythrocyte sedimentation rate was 108 mm/h
at the first hour. C-reactive protein was 187.5 mg/L (normal
value, < 5 mg/L). Blood cell count revealed a leukocytosis
(13.4 x 109) with 80% neutrophils. The
echocardiogram showed normal cardiac dimensions and mild reduction of
left ventricular [LV] contractility (ejection fraction [EF] of
45%). Three days later, the patient had a clinical
deterioration with worsening of dyspnea and severe hypotension (BP,
70/40 mm Hg). A new echocardiogram revealed LV dilatation of 61 mm,
with marked impairment of LV contractility (EF, 10%). The patient
underwent an invasive cardiac study including cardiac catheterization,
LV (Fig 1
, left) and coronary angiography, and LV endomyocardial
biopsy with extraction of three good-sized tissue samples that were
processed for histology following standard techniques and stains
(hematoxylin-eosin, Miller’s elastic Van Gieson, and Masson’s
trichrome). Coronary angiography was normal, LV end-diastolic pressure
was elevated (25 mm Hg), and LV function was extremely compromised. The
histology showed in all samples the presence of extensive inflammatory
infiltrates mainly represented by lymphocytes, histiocytes,
eosinophils, and multinucleated giant cells in close apposition to
injured myocytes (Fig 2
, top). No epithelioid histiocytes or distinct granulomas
were observed on several sections so that sarcoid and granulomatous
myocarditis were ruled out, while a diagnosis of giant cell myocarditis
was established. At immunohistochemistry, giant cells stained for the
macrophage marker CD68 but not for the muscle markers actin and desmin,
suggesting the macrophage origin of giant cells. Serologic tests for
cardiotropic viruses (echovirus, Coxsackievirus B, cytomegalovirus,
adenovirus, influenza, and parainfluenza viruses) were negative.
Antinuclear, anti-DNA, anticardiolipin, antineutrophil cytoplasmic
antibody, anti-extractable nuclear antigens antibodies, circulating
immune complexes, C3c, and C4 were within the normal range. Patient
serum was also tested for cardiac autoantibodies by standard indirect
immunofluorescence as previously described,2
showing a
strong positivity with diffuse cytoplasmic immunofluorescence staining
of myocytes (antibodies titer, 1/40). The patient received IV
prednisolone, 7 mg/kg for 3 days, followed by prednisone, 1.5 mg/kg/d
orally for 2 weeks tapered to 1 mg/kg/d for 4 weeks. On day 7 after the
beginning of therapy, the patient had a visible improvement of
symptoms, with reduction of heart rate to 70 beats/min and
disappearance of gallop rhythm. The echocardiogram showed an increase
of LV function (left ventricular ejection fraction [LVEF], 30%).
After 6 weeks of therapy, the ECG showed an increase of voltages with
disappearance of conduction and repolarization abnormalities, the
echocardiogram revealed a reduction of LV dimension (LV dilatation, 56
mm), and a marked improvement of LV contractility (LVEF, 55%). A new
cardiac catheterization including LV angiography and endomyocardial
biopsy was performed. LV end-diastolic pressure (10 mm Hg) and LV
function (Fig 1
, right) normalized, and biopsy showed a
healed myocarditis with the disappearance of inflammatory infiltrates,
including giant cells, and focal replacement fibrosis (Fig 2
,
bottom). On the basis of hemodynamic and histologic
findings, prednisone was reduced to 0.33 mg/kg/d and azathioprine, 2
mg/kg/d, was included in the treatment. After 6 months, steroids were
tapered and withdrawn. Azathioprine from the sixth month was reduced to
1 mg/kg/d. At 16 months of follow-up, the patient is receiving
maintenance low doses of azathioprine, and is still asymptomatic with
normal cardiac volumes and function.
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Figure 1. Contrast LV angiography on right anterior oblique
view showing increased LV dimension and severe impairment of LV
systolic function (left) with complete recovery
(right) after 6 weeks of steroid therapy (EF from 10 to
55%).
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Figure 2. Top: LV endomyocardial biopsy
showing extensive inflammatory infiltrates represented by lymphocytes,
histiocytes, eosinophils, and multinuclear giant cells often in close
apposition to injured myocytes. No epithelioid histiocytes and distinct
granulomas were present (hematoxylin-eosin, original x 250).
Bottom: Control LV biopsy revealing healed myocarditis
with interstitial and focal replacement fibrosis. Giant cells and
myocyte necrosis are no longer visible (Masson Trichrome,
original x 160).
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Discussion
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Giant cell myocarditis is a rare disorder presenting with
progressive heart failure or in up to 50% of cases with sudden cardiac
death.1
It is usually an untreatable disease, and affected
patients are rapidly forwarded to cardiac transplantation as soon the
diagnosis is established through endomyocardial biopsy. Unfortunately,
the disease recurs in the transplanted heart in as many as 24% of
cases,3
although it may respond to augmentation of
immunosuppression, suggesting an autoimmune pathogenetic mechanism.
Successful treatment of severe heart failure due to giant cell
myocarditis has been rarely reported,4
5
while no
histologic study after clinical recovery has ever been obtained in the
responders. Indeed, histologic confirmation of myocarditis being healed
is crucial to tapering of the immunosuppression dose, lessening the
risk of inflammatory recurrences.
In this report, the authors describe a dramatic recovery of cardiac
volume and function (LVEF, 55% from 10%) in a young patient with
cardiogenic shock and giant cell myocarditis who was treated by a
conventional immunosuppressive treatment. In particular, steroids and
azathioprine were administered at the usual dose while cyclosporine, an
additional component of the immunosuppressive regimen normally unable
to control the disease, was not included in the
treatment.3
Moreover, patient recovery was accompanied by
the disappearance of inflammatory infiltrates including giant cells at
a repeated cardiac biopsy, and finally a full cardiac recovery was
maintained on a low dose of azathioprine at 16 months of follow-up.
These observations suggest giant cell myocarditis might be a
heterogeneous disease having either a curable or an untreatable
substrate. It can be argued that a sarcoid or a granulomatous
myocarditis (such as Wegener’s disease or Churg-Strauss syndrome,
commonly more susceptible to immunosuppression than giant cell
myocarditis)6
7
might have been missed. However no
systemic manifestation, such as vasculitis, renal and lung disease, nor
hematologic (ie, eosinophilia for Churg-Strauss) nor
immunologic (ie, antineutrophil cytoplasmic antibody for
Wegener’s disease) abnormalities, usually associated with these
entities, were documented in our patient. Finally neither epithelioid
histiocytes nor distinct granulomatous lesions were observed on several
histologic sections of three cardiac biopsies.
On the other hand, additional reports4
5
of giant cell
myocarditis responding to immunosuppression are currently available.
In conclusion, conventional doses of steroids and azathioprine may
relieve in some cases the severe cardiac compromise of a giant cell
myocarditis, avoiding the need for a heart transplantation.
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Footnotes
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Abbreviations: EF = ejection fraction; LV = left
ventricular; LVEF = left ventricular ejection fraction
Received for publication May 10, 1999.
Accepted for publication September 21, 1999.
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References
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-
Davies, MJ, Pomerance, A, Teare, RD (1975) Idiopathic giant cell myocarditis-a distinctive clinico-pathological entity. Br Heart J 37,192-195[Abstract/Free Full Text]
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Frustaci, A, Chimenti, C, Maseri, A (1999) Global bi-ventricular dysfunction in patients with symptomatic coronary artery disease may be caused by myocarditis. Circulation 99,1295-1299[Abstract/Free Full Text]
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Cooper LT JR, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis: natural history and treatment: multicenter Giant-Cell Myocarditis Study Group Investigators. N Engl J Med 1997; 336:1860–1866
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Desjardins, V, Pelletier, G, Leung, TK, et al (1992) Succesful treatment of severe heart failure caused by idiophatic giant cell myocarditis. Can J Cardiol 8,788-792[ISI][Medline]
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Ren, H, Poston, RS, Jr, Hruban, RH, et al (1993) Long survival with giant cell myocarditis. Mod Pathol 6,402-407[ISI][Medline]
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Litovsky, SH, Burke, AP, Virmani, R (1996) Giant cell myocarditis: an entity distinct from sarcoidosis characterized by cytotoxic T cells and histiocytic giant cells. Mod Pathol 9,1126-1134[ISI][Medline]
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Frustaci, A, Gentiloni, N, Chimenti, C, et al (1998) Necrotizing myocardial vasculitis in Churg-Strauss syndrome: clinico-histologic evaluation of steroids and immunosuppressive therapy. Chest 114,1484-1489[Abstract/Free Full Text]
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Abstract
Introduction
