ABSTRACT
We present the case of a 3-year-old female with cyclic neutropenia and
history of febrile seizures who died acutely from coronavirus disease
2019 (COVID-19). While most children with COVID-19 infection are
asymptomatic or have mild symptoms, there may be increased risk of
severe disease in immunocompromised children. To the best of our
knowledge, this is the first reported case of a COVID-19-related death
in a pediatric patient with cyclic neutropenia.
INTRODUCTION
Cyclic neutropenia is a rare hematologic condition defined by
intermittent and severe neutropenia [absolute neutrophil count (ANC)
<0.50 x 103/µL] that occurs in a
predictable pattern, often every 21 days. The decline in ANC is
frequently accompanied by classic symptoms of fevers, mouth ulcerations
and recurrent bacterial infections. Fevers and infections in this
population require prompt attention and treatment with antibiotic
therapy and often granulocyte colony-stimulating factor
(G-CSF).1,2 Cyclic neutropenia is inherited in an
autosomal dominant fashion secondary to pathologic variants of the ELANE
gene. ELANE encodes neutrophil elastase, an enzyme that is required for
neutrophil function. In the case of cyclic neutropenia, the abnormal
enzyme is not packaged correctly and damages neutrophils during their
development, leading to a shortened neutrophil
lifespan.2
There is still much to learn about COVID-19 in children as well as which
children are at risk for severe disease. The incidence of COVID-19 in
children is less than that of adults, however, with improved screening
capabilities and testing availability, we are seeing a significant
increase in pediatric cases. Even with this increase, severe disease
appears to be more prevalent in adults than children.3Most children with COVID-19 have mild symptoms including fever, cough,
rhinorrhea, sore throat, diarrhea and/or vomiting which can be managed
supportively. Severe consequences of this disease may include
thromboses, respiratory failure and Multisystem Inflammatory Syndrome in
Children (MIS-C), which may lead to pediatric intensive
care.4,5 Neurologic symptoms have also been published
in pediatric case reports of new onset febrile or afebrile seizures or
status epilepticus in the setting of COVID-19.6,7
The mechanism of an apparent innate protection against infection in
children is not yet fully understood. Overall, children tend to have
fewer co-morbidities and less cumulative environmental toxic exposures
compared to adults, as well as more active immune
systems.8 For example, it is known that as we age, our
innate and adaptive immune responses dampen via thymic
atrophy9, and that low CD4+ T-cells have been
associated with increased severity of disease from COVID-19 infection in
adult populations.10 Therefore, it stands to reason
that children with diminished immune capabilities (whether adaptive or
innate responses) could potentially be at risk for severe disease and
worse outcomes from COVID-19 as well. Below we present the first
reported COVID-19-related death in a pediatric patient with cyclic
neutropenia, demonstrating a potential vulnerable population in the
current pandemic.
CASE DESCRIPTION
We present a 3-year-old twin female who was undergoing initial work-up
for presumed cyclic neutropenia that died acutely and whose post-mortem
examination was significant for COVID-19 infection and pneumonitis. The
patient’s father had a confirmed diagnosis of cyclic neutropenia and
patient herself had history of recurrent ear infections, oral ulcers,
febrile seizures, and documented low ANC on several occasions. She had
been referred to a hematologist for diagnostic workup and treatment of
cyclic neutropenia just two weeks prior to her untimely death.
On the day of presentation, patient had sustained a febrile seizure at
home and was brought to her local emergency department (ED). Upon
arrival, she was post-ictal, febrile and tachycardic with an oxygen
saturation of 90% on room air. Full laboratory work-up is shown in
table 1, however significant findings include leukopenia (2.97
x103/µL) and associated neutropenia (ANC 0.19
x103/µL). Electrolytes were notable for
hypoalbuminemia (3.3 gm/dL), hypochloremia (91 mEq/L) and hyponatremia
(126 mEq/L). Inflammatory markers were significant for elevated
C-reactive protein (34.7 mg/dL), procalcitonin (97.26 ng/mL) and lactic
acid (10.1 mmol/L). COVID-19 PCR was positive from a nasopharyngeal swab
upon arrival. CT head showed no abnormal findings and chest X-ray showed
clear lung fields, normal pulmonary vasculature and normal heart size.
Approximately 3 hours after arrival to the ED, the child had significant
and rapid clinical deterioration. Her respirations became agonal and she
developed bradycardia evolving into asystole. The patient received
multiple rounds of cardiopulmonary resuscitation. Return of spontaneous
circulation was not achieved, and time of death was called an hour after
her initial code event.
An autopsy performed by the state medical examiner revealed multiple
important findings. The lungs had significant pneumonitis consistent
with viral toxicities as well as diffuse alveolar damage with hyaline
membranes noted. There was acute inflammation noted in the
gastrointestinal tract located at the terminal ileum and cecum. Central
nervous system (CNS) evaluation did not show any overt findings of
encephalitis or meningitis but noted scattered immature neuronal
clusters in the amygdala and a single cluster of left hippocampal
heterotopic granule cells. Microbiology evaluation revealed postmortem
bacterial colonization/contaminants that were not contributory to death.
Viral panel was negative except for a positive COVID-19 antigen test.
The cause of death in this patient with cyclic neutropenia was
determined to be “complications of novel COVID-19 infection.”
On subsequent follow-up, the patient’s twin sister and 9-year-old sister
were both confirmed to have a heterozygous ELANE mutation, which causes
cyclic neutropenia and is consistent with their father’s diagnosis.
DISCUSSION
As the COVID-19 pandemic evolves, new complications and treatments of
the infection are continually emerging, as well as realizations of risk
factors for severe disease. While a vast majority of children can be
managed with conservative measures and isolation, there are potentially
vulnerable populations of children who may exhibit severe manifestations
of this disease.
We know children with cyclic neutropenia are at an innately higher risk
for recurrent bacterial infections, though neutrophils may also play a
prominent role in viral infections. Neutrophils have been implicated in
antiviral immunity through cytokine release, reactive oxygen species and
through creation of neutrophil extracellular traps.11Therefore, those who are severely neutropenic may be at an increased
risk of severe viral illness as well.
Current literature reviewing histopathology and gross autopsy findings
in those who have died from COVID-19 is still evolving, however some
patterns in pulmonary findings are emerging. One cohort study showed the
most common pulmonary finding included significant pulmonary congestion
and hyaline membrane formation with diffuse alveolar damage, similar to
our presented patient.12 CNS findings related to
COVID-19 appear to be widely variable at the time of this writing, and
the literature likewise does not appear to have a common
gastrointestinal finding at autopsy related to this disease.
While the exact significance of the contribution of neutropenia to the
terminal disease process in our case is uncertain, her underlying
condition rendered her a high risk for viral respiratory infections in
general. It is of upmost importance for children with neutropenia to be
evaluated by a medical professional immediately at first sign of
illness, with attention paid to COVID-19 as a potential etiology.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
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