A 9 year old girl presents with body swelling, shortness of breath

and backache

Patient presentation
History
Differential Diagnosis
Examination
Investigations
Special investigations
Discussion
Treatment
Case Final outcome
Case Evaluation - Questions & answers

Patient presentation

A 9 year old girl presents with a one month history of generalised body swelling associated with
shortness of breath and backache.

Acknowledgement
This case study was kindly provided by Dr Bhadrish J Mistry, Paediatrician, Department of Paediatrics,
Chris Hani Baragwanath Hospital and the University of Witwatersrand.

Partnership

We have partnered with The International Union of Basic and Clinical Pharmacology (IUPHAR) to bring
you in-depth information about drugs and pharmacology with links to the Guide to
ImmunoPharmacology.

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History

Two and a half weeks previously the patient had been admitted to her local hospital for a similar
episode.

No other illnesses or admissions were noted.

Differential Diagnosis

Nephrotic Syndrome
Liver disease
Cardiac Failure
Protein Losing Enteropathy
Malnutrition

Examination

On Admission- 20 February
She was found to have multiple naevi on her trunk, neck and face. Mostly small, dark brown,
polygonal, irregularly shaped macules, 2-5 mm in diameter except for one large naevus on the right
temple which was 3 cm in diameter.

Clinically she was in congestive cardiac failure which was complicated by:

2 large left ventricular thrombi (seen on echo, see investigations)

Renal and liver dysfunction secondary to poor perfusion and congestion

Investigations

Normal
Examination Value
Limits

On Admission 41703 41723 41752

41690

(4-12
WBC 12.7
x109/L)

(12.1-15.2
HB 14.6
g/L)

HCT 0.43 (.31-.42)

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 Normal
Examination Value
Limits

(140-450
Platelets 138
x109/L)

(80-100
MCV 94
fl)

CRP 8.1999999999999993 (<1mg/l)

(135-147
NA 126 129 136 137
mmol/L)

(3.5-5.1
K 5.9 6 4.3 4.2
mmol/L)

(95-107
CL 89 92 99 100
mmol/L)

(22-33
CO2 10 30 25 26
mmol/L)

(2.5-6.7
UREA 20.9 11.7 8.8000000000000007 6.6
mmol/L)

(70-150
CREAT 74 51 37 42
µmol/L)

(3-17
TBIL 91 16
µmol/L)

(0-6
INDIR BIL 58 6
µmol/L)

TPROT 48 60 (60-80g/L)

ALB 30 35 (35-50g/L)

(30-150
ALP 208 78
U/L)

(11-51
GGT 269 551
U/L)

ALT 468 17 (5-35 U/L)

AST 1287 28 (5-35 U/L)

25-195
CK 9663
iu/L

CKMB 616 < 12 IU/L

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 Normal
Examination Value
Limits

<0.01
Troponin T 0.16
µg/l

ANA negative

C3 <0.165 Treatment Treatment 1.24 1.18 (0.5-1.53)

C4 <0.057 0.191 0.27800000000000002 0.251 (0.2-1)

with with IV

Coxsackie

Immunoglobulin Methylprednisone

Viral Titres-

IgG

B1 <10 <10

B2 40 160

B3 10 <10

B4 >640 320

B5 320 80

B6 <10 <10

Special investigations

Echocardiography
Showed dilated cardiomyopathy with a shortening fraction of 9% (SF 28-44%) with pulmonary
hypertension and 2 large left ventricular thrombi.

ECG

R axis deviation
P pulmonale
Small wide QRS complexes

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Chest X-Ray

Cardiomegaly

Skin Biopsy
Skin biopsy of a naevus was reported as an intradermal congenital melanocytic naevus

Discussion

Based on the echo and blood results the cause is now considered to be:

viral myocarditis, or
LEOPARD syndrome, a complex dysmorphogenetic disorder of variable penetrance and
expressivity. The acronym LEOPARD is used to describe the main features of the disorder:

Lentigines (multiple)

Electrocardiographic conduction abnormalities

Ocular hypertelorism

Pulmonary stenosis

Abnormalities of genitalia
Retardation of growth
Deafness

The discussion for this case study will focus on the immunological process of viral myocarditis.

Myocarditis is an inflammatory disorder of the myocardium with necrosis of the cardiomyocytes and
associated inflammatory infiltrate. It is usually caused by viruses which have tropism for
myocardiocytes such as adenovirus and coxsackie B viruses. These viruses are therefore frequently
associated with viral myocarditis. (see investigations)

Myocarditis generally results in a decrease in myocardial function, with accompanying cardiac

enlargement and an increase in the end-diastolic volume due to increased preload. Normally, the
heart compensates for dilation with an increase in contractility (Starling law), but because of
inflammation and muscle damage, the heart is unable to respond to the increase in volume.

Dilated cardiomyopathy (DCM), is idiopathic in most cases and is a primary myocardial disorder
characterised by cardiac enlargement and impaired systolic function of one or both ventricles.
Despite conventional therapies for DCM the prognosis remains poor. There is increasing evidence that

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suggests that myocarditis and dilated cardiomyopathy are closely linked. Autoimmunity is one of the
main mechanisms in the pathogenesis that links myocarditis to DCM.

Autoimmune myocarditis is thus thought to be precipitated by an initial infection with a pathogen,

such as a virus, that expresses surface B-cell epitopes which are highly similar to host epitopes found
on the cell surface of cardiomyocytes. This is known as molecular mimicry.

Viral myocarditis, is first detected by the innate immune response involving phagocytes macrophages
and dendritic cells) that engulf virus and viral antigens released from infected cells. Viral peptide
antigens are processed by dendritic cells and are bound to HLA class I and II receptors for
presentation to CD4+ and CD8+ T cells in regional lymph nodes.

Dendritic cells present peptide antigens bound to surface HLA class II receptors to naive CD4+ helper
T lymphocytes in the T cell zone of lymph nodes. CD4+ T cells expressing T cell receptors recognise
antigen and become activated and proliferate into effector and memory CD4+ T cell populations.

Dendritic cells also present peptide antigens bound to surface HLA class I receptors to naive CD8+
cytotoxic T lymphocytes in the lymph nodes. These CD8+ T cells then receive activation signals from
CD4+ helper T lymphocytes and become primed for cell-killing. Once activated they differentiate into
effector or memory CD8+ T cells with effector cells able to kill host cells bearing viral peptide
antigens.

In viral myocarditis the cardiomyocytes which are infected with virus express surface HLA class I
receptors with bound viral peptide antigens. Effector CD8+ cytotoxic T lymphocytes that express T
cell receptors able to recognise viral peptide antigens actively kill infected cells.

Virus-specific antibodies are synthesised by plasma B cells following priming and activation of virus-
specific B lymphocytes.

The CD4+ helper T lymphocytes which recognise antigen bound to HLA class II receptors on B cells
become activated and in turn activate primed B cells to differentiate into effector plasma B cells that
secrete antibodies and memory B cells. Naive B cells initially synthesise IgM while re-stimulated
memory B cells are able to isotype-switch depending on the type of activation signals obtained from
CD4+ helper T cells.

Virus-specific antibodies function to neutralise and opsonise free virus particles. Virus and viral
antigens opsonised with antibodies also form immune complexes which can be detected and
destroyed by phagocytes expressing Fc receptors. Furthermore the classical complement cascade
can augment this response by opsonising virus and viral antigens with C3b complement.

Autoimmune disease as a consequence of viral myocarditis is thought to be mediated by virus-

specific antibodies previously synthesised that cross-react with a surface protein expressed on

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cardiomyocytes (molecular mimicry). Antibodies of the IgM and IgG class can activate the classical
complement cascade which leads to lysis of healthy cells. Triggering the classical complement
pathway (link to complement classical pathway drawings) also results in consumption of C3 and C4
(see investigations). Natural killer cells and phagocytes bearing Fc receptors may also play a role in
the destruction of antibody-bound host cells.

Destruction of healthy cardiomyocytes results in the release of large quantities of intracellular

antigens that are engulfed by macrophages. Macrophages present self-peptides to CD4+ T helper
cells which results in a breakdown in tolerance of auto-antigens leading to the generation of
autoreactive CD4+ helper T cells. These CD4+ helper T cells that can provide activation signals to
autoreactive B cells. In this way secondary antibodies directed against intracellular host antigens
derived from the heart can develop. These antibodies include anti-nucleic acid, anti-myosin and anti-
actin which are detectable in severe autoimmune myocarditis.

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Treatment

IV Immunoglobulin was given after the first C3 and C4 result was measured. Subsequent
C3 and C4 results were normal.
Methylprednisone was given after one month because there was deterioration in the cardiac
function of this patient and worsening ascites and respiratory distress. Shortly after
treatment a rise in coxsackie B2 titre was seen, which was thought to be due to
immunosuppression.

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Final outcome

Patient developed a possible gastritis or peptic ulcer disease and was commenced on
omeprazole.
She later developed hypovolaemic or cardiogenic shock and was transfused with packed
red cells and treated with inotropes.
This was followed by a gradual resolution of renal & liver dysfunction.
The two left ventricular thrombi were resolved with warfarin.
Cardiac function improved from SF 9% to SF 19%.

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Evaluation – Questions & answers

What is the diagnosis?

Viral myocarditis, an inflammatory disorder of the myocardium with necrosis of the cardiomyocytes
and associated inflammatory infiltrate.

What is the cause of viral myocarditis?

Most typically caused by adenovirus and coxsackie viral infections which have tropism for
myocardiocytes.

What is autoimmune myocarditis?

Autoimmune myocarditis is thought to be precipitated by an initial infection with a pathogen, such as

a virus, that expresses surface B-cell epitopes highly similar to host epitopes found on the cell surface
of cardiomyocytes.

What is molecular mimicry?

Infection with certain pathogens is particularly associated with autoimmune sequelae. Some
pathogens express protein or carbohydrate antigens that resemble host molecules. The induction of
antibodies and T cells that react against the pathogen but also cross react with self antigens is

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molecular mimicry.

How is viral infection in the heart first detected?

Viral infection in the heart is first detected by the innate immune response involving phagocytes
(macrophages and dendritic cells) that engulf the virus and viral antigens released from infected cells.
Viral peptide antigens are processed by dendritic cells and bound to HLA class I and II receptors for
presentation to CD8+ and CD4+ T cells in regional lymph nodes.

What is the process for antibody secretion?

CD4+ helper T lymphocytes that recognise antigen bound to surface HLA class II receptors on B cells
become activated and in turn provide activation signals to primed B cells to differentiate into effector
plasma B cells which secrete antibodies and memory B cells.

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