Keywords
eosinophilic endomyocarditis - myocarditis - erythema toxicum - cardiac arrest - hypereosinophilic
syndrome
Eosinophilic endomyocarditis (EEM) is histologically diagnosed by eosinophilic infiltration
of the endocardium and subendocardial myocardium. It is rare but can be seen in all
ages[1]; infant cases are extremely rare.[2] EEM is frequently associated with hypereosinophilic syndromes, such as leukemia,
allergic disorders, and Loeffler endocarditis, and can present with peripheral eosinophilia.[3]
[4] There is one published neonatal case of EEM: a 26-day-old infant presented with
poor feeding and cardiopulmonary arrest without other organ involvement on postmortem
exam.[2]
Case
Baby B was born to a 30-year-old married primigravida mother with normal routine prenatal
laboratories. Mother reported asthma, allergies, anxiety, constipation, esophageal
stricture, and gastroesophageal reflux. Family history was negative for heart disease.
Pregnancy was complicated by fetal bradycardia, heart rates under 120 bpm at 334/7 weeks, but with normal fetal movement and unremarkable antenatal ultrasounds, including
four-chamber heart view at 20 weeks' gestation. Due to low baseline fetal heart rate,
serial fetal growth studies, nonstress tests, and biophysical profiles were performed.
These were found to be reassuring.
Presentation to obstetric triage at 391/7 weeks' gestation was due to recent history of vomiting and diarrhea, since resolved.
However, induction of labor was performed for nonreactive nonstress test and fetal
heart rate of 105. Oxytocin administration and artificial rupture of membranes occurred
at 6 hours before delivery with no fluid return, but with meconium present and one
loose nuchal cord at delivery. APGAR scores were 9 and 9 and heart rate was greater
than 100. Birth weight was 2,892 g (15.9th World Health Organization [WHO] percentile),
length was 49.5 cm (42.1st WHO percentile), and head circumference was 34 cm (34.5th
WHO percentile). The placenta was visually normal with three-vessel umbilical cord.
In the postnatal course, mild jaundice developed by 8 hours of age, with normal voiding,
stooling, and vigor at breastfeeding. A rash with erythematous macules and patches
with central yellow papules was clinically diagnosed as erythema toxicum. Recorded
heart rate was between 108 and 168 per minute and respiratory rate between 38 and
62 per minute. Remainder of vital signs and exam findings were normal. The filter
paper newborn screen test later resulted as normal. Congenital heart disease screening
initially showed low preductal pulse oximetry at 94% at 25 hours but was normal (100%)
at 35 hours of age. Total bilirubin was 9.0 mg/dL at 36 hours of age, below phototherapy
treatment guidelines. The infant failed bilaterally on hearing screening and outpatient
exam was scheduled. The rash was fading by discharge, at approximately 41 hours of
age, weighing 2,806 g (3% weight loss since birth) in good condition. Follow-up bilirubin
level and weight check were planned for 1 to 2 days after discharge.
One day after discharge, at a local clinic, mother reported concern for cold skin.
Respiratory distress with stridor of unknown duration was appreciated with respiratory
failure. The pediatrician began mouth-to-mouth resuscitation. Emergency Medical Service
was called. The infant developed pulseless cardiac arrest and underwent unsuccessful
cardiopulmonary resuscitation including failed intubation, compressions, medication
administration, and fluid resuscitation. Although intubation was attempted multiple
times, this was unsuccessful due to swollen epiglottis. Bag-mask ventilation continued,
with poor air exchange appreciated. One hour after presentation, the infant was pronounced
dead.
Pathology
Postmortem examination demonstrated a normally developed male with anatomic parameters
appropriate for gestational age, without rash. External exam findings were consistent
with resuscitation. Internal examination showed a moderate amount of straw-colored
pleural, pericardial, and peritoneal fluid. Epiglottic swelling was not confirmed,
nor was mucus plugging of the airways present. Multifocal gastrointestinal hemorrhage
and acute bilateral renal papillary necrosis were identified interpreted as manifestations
of cardiac failure. Postmortem comprehensive toxicologic screening of venous blood
was negative. Nasopharyngeal and colorectal swabs were negative for adenovirus, cytomegalovirus,
enteroviruses, herpes simplex virus, and varicella-zoster virus. Nasopharyngeal swabs
were also negative for influenza A and B; parainfluenza 1,2,3; and respiratory syncytial
virus. The heart and lungs weighed 90.25 g (expected weight 85.25 g). Microscopic
heart sections were notable for an eosinophilic inflammatory infiltrate involving
the endocardial aspect of the myocardium, focally associated with acute extravasation
of blood and early subendocardial myocyte necrosis ([Fig. 1]). Microscopic studies were otherwise normal. No vascular inflammation, thrombosis,
microorganisms, or viral inclusions were present. The lungs revealed diffuse congestion
and perimortem hemorrhages. The liver and spleen demonstrated mildly increased eosinophils;
however, no intravascular eosinophilic infiltrates were found in any other tissues
examined.
Fig. 1 Endomyocardial surface of the heart showing eosinophil infiltration, magnified ×400.
Discussion
This healthy-appearing male infant developed symptomatic heart failure and cardiopulmonary
arrest within 24 hours of hospital discharge. His rapid deterioration and postmortem
diagnosis of EEM prompted review of his case for clues to explain his unexpected unfortunate
outcome and illuminate warning signs. The prenatal history and persistent low heart
rate with otherwise normal exam did not raise specific clinical concerns for heart
failure after birth. The infant's erythema toxicum rash (known to be eosinophil mediated)[5]
[6] was more prominently distributed and arose earlier than seen routinely, but was
otherwise consistent with this common benign newborn rash, and resolved by time of
death. There were no other signs of extracardiac hypereosinophilia. Given what is
known about EEM, there were no clear risk factors or warning signs, although his bradycardia,
initial low oxygen saturations on congenital heart screen, early and prominent erythema
toxicum rash, and failed hearing screen were notable. There are case reports of eosinophilic
granulomas forming in the middle ear of patients with idiopathic hypereosinophilic
syndromes, which is one plausible explanation of the failed hearing screen.[7]
[8] In addition, mother's history of esophageal stricture and reflux are interesting
to note, as these clinical findings can often overlap with findings of eosinophilic
esophagitis. The infant's mother has not been evaluated for hypereosinophilic syndromes
and there has not been any testing for the 4q12 deletion, a known genetic cause of
hypereosinophilic syndromes.
The pathogenesis of EEM involves three stages beginning with (1) an intense myocarditis
and acute eosinophilic inflammatory infiltrate followed by (2) myocyte necrosis developing
approximately 5.5 weeks after onset of symptom, and eventually (3) fibrosis in the
final stage of the disease.[9] The “intense” myocarditis during the first stage refers to the presence of inflammatory
cells (eosinophils) in the patient's cardiac histology. The necrotic second stage
of the disease is associated with high mortality due to cardiac deterioration. Over
several months, thrombotic material may form at the damaged endocardium as the inflammation
abates. Cardiac remodeling and fibrosis occur in the third and final stages, which
may progress to a dilated and even a restrictive cardiomyopathy in cases with extensive
endomyocardial fibrosis. Although typically associated with hypereosinophilia, rare
cases of EEM have been reported without it.[2]
[3]
[10] Loeffler syndrome, one variation of restrictive EEM, could present similarly to
this infant; however, the infant was still in the acute stage and had not yet developed
fibrosis or restrictive physiology associated with Löeffler syndrome. Based on the
histologic findings and natural history of the disease, this infant appears to have
experienced acute cardiac failure in the early stage of the disease process due to
the intensity of the eosinophilic infiltration and degranulation with early subendocardial
myocyte necrosis, before extensive myocyte necrosis could take place.
This case appears to be the youngest patient ever reported with EEM. Lie and Hunt
report an adult case of eosinophilic endomyocarditis which was associated with conduction
abnormalities; this patient died of myocardial infarction and cardiogenic shock. Unexpectedly
on autopsy, EEM was discovered.[11] The only other neonatal case of EEM in the literature is a 26-day-old infant with
a brief history of poor feeding leading to cardiorespiratory arrest. The finding of
only an eosinophilic infiltrate in the myocardium on postmortem makes it similar to
our case.[2] Perhaps the fetal bradycardia and nonreactivity were subtle clues pointing toward
poor cardiovascular adaptation to EEM, but given the paucity of neonatal cases, and
unclear natural history of neonatal EEM, the jury is still out.
