Keywords
ROHHAD - COVID-19 - inflammatory syndrome
Introduction
The rates of hospitalization and mortality of severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2) infection across the globe are increasing. There is a modicum of literature
that describes the management of coronavirus disease 2019 (COVID-19) in pediatric
patients. Features such as elevated serum ferritin and bilateral abnormalities on
chest computed tomography (CT) are commonly described in adult literature but poorly
described in pediatric literature.[1] We describe a case of a 10-year-old boy with ROHHAD (rapid-onset obesity with hypothalamic
dysregulation, hypoventilation, and autonomic dysregulation) presenting with COVID-19
and highlight his initial presentation, clinical course, challenges with his comorbidities,
and management strategies leading to a successful hospital discharge.
Case
A 10-year-old boy with ROHHAD (rare disorder of abnormalities associated with the
autonomic nervous system, endocrine system, and respiratory control), morbid obesity
(weight: 95 kg, body mass index: 45.2), severe obstructive sleep apnea requiring nocturnal
continuous positive airway pressure, and intellectual delay, presented with 1 day
of abdominal pain and nonbilious, blood-tinged vomiting.[2] On presentation to the emergency department, he was found to be afebrile, tachycardic
(heart rate 113 beats per minute), hypoxic (oxygen saturation 50%), and in respiratory
distress. Initially, oxygen saturations improved with nasal cannula. CT of the chest
demonstrated a pericardial effusion measuring 1.8 cm in thickness, bilateral pulmonary
ground glass infiltrates, pulmonary congestion, and hepatosplenomegaly ([Fig. 1]). Initial laboratories revealed leukopenia and an elevated N-terminal probrain natriuretic
peptide of 1,038 pg/L. He was suspected to have acute congestive heart failure and
was transferred to our children's hospital for further management.
Fig. 1 Computed tomography of the chest demonstrating ground glass opacities, pericardial
effusion.
The patient was initially admitted to the pediatric step-down intensive care unit
in a negative pressure room, pending COVID-19 testing. Approximately 4 hours after
arrival, the patient was escalated to high-flow nasal cannula (HFNC) and transferred
to the pediatric intensive care unit for worsen respiratory distress. He was febrile
up to 104.2°F. Chest X-ray (CXR) was concerning for alveolar and interstitial pulmonary
edema at the lung bases ([Fig. 2]). Intravenous furosemide was administered for radiographic and clinical evidence
of pulmonary edema. Dexmedetomidine drip was started for agitation and vasopressor
support for hypotension. His respiratory viral panel resulted negative, while his
COVID-19 testing (DiaSorin nasopharyngeal swab polymerase chain reaction test) resulted
positive.
Fig. 2 Chest X-ray demonstrating alveolar and interstitial pulmonary edemas.
He was intubated due to progressive hypoxic respiratory failure with rapid sequence
intubation using ketamine, succinylcholine, and direct laryngoscopy. Full personal
protective equipment (including an intubation hood) was used with minimal essential
personnel present. Endotracheal, blood, and urine cultures were sent, and broad-spectrum
antibiotics were started for persistent fever and leukopenia. Infectious disease recommended
starting hydroxychloroquine as well as remdesivir, which was requested from Gilead
pharmaceuticals for compassionate use. Heparin drip was initiated for a presumed hypercoagulable
state associated with COVID-19. A milrinone infusion was also started for afterload
reduction in the setting of acute congestive heart failure. Initial laboratories were
concerning for transaminitis and elevated inflammatory markers. His initial laboratories
on admission are listed in [Table 1]. Echocardiogram showed a small globally distributed pericardial effusion with normal
biventricular function, no evidence of elevated pulmonary artery pressure, and an
ejection fraction of 63%.
Table 1
Initial serum laboratory values on admission to the pediatric ICU
|
WBC
|
12.9 bil/L
|
|
HGB
|
9.2 g/dL
|
|
HCT
|
29.6%
|
|
Platelets
|
145 bil/L
|
|
PT
|
17.9 s
|
|
INR
|
1.5 n/a
|
|
PTT
|
49.8 s
|
|
ESR
|
36 mm/h
|
|
Na
|
141 mMol/L
|
|
K
|
3.7 mMol/L
|
|
Cl
|
102 mMol/L
|
|
CO2
|
27 mMol/L
|
|
Anion gap
|
12 n/a
|
|
BUN
|
17 mg/dL
|
|
Creatinine
|
1.1 mg/dL
|
|
Albumin
|
4.2 g/dL
|
|
AST
|
151 U/L
|
|
ALT
|
56 U/L
|
|
Alk phos
|
55 U/L
|
|
T. bilirubin
|
0.6 mg/dL
|
|
LD
|
429U/L
|
|
CRP
|
11.5 mg/dL
|
|
Ferritin
|
295 ng/mL
|
|
Lactate
|
3.8 mMol/L
|
|
Pro-BNP
|
3,347 pg/mL
|
|
Troponin-T
|
0.02 ng/mL
|
|
IL-6
|
91.9 pg/mL
|
|
Procalcitonin
|
10.13 µg/L
|
Abbreviations: ALT, alanine aminotransferase; Alk phos, alkaline phosphatase; AST,
aspartate aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; HCT, hematocrit; HGB, hemoglobin; ICU, intensive care
unit; IL, interleukin; INR, international normalized ratio; LD, lactate dehydrogenase;
PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell.
On day 2 of admission, the patient developed blood-tinged oral, nasal, and respiratory
secretions; therefore, the heparin was held. Patient was continued on hydroxychloroquine.
On day 3, he was no longer febrile. Subcutaneous enoxaparin was started due to concern
for hypercoagulability with persistently elevated D-dimers. Remdesivir was initiated
(dose: 200 mg first day, followed by 100 mg daily for 9 additional days) and hydroxychloroquine
was discontinued. On day 4, the patient began to have transient episodes of hypoxia
and hypercarbia with no change in CXR. Inhaled nitric oxide (iNO) was initiated for
persistent hypoxemia and suspected elevated pulmonary vascular resistance. On day
5 of admission, the patient's sodium level rose to 162 mMol/L. Urine was dilute (specific
gravity 1.002) and serum osmolality was elevated (344 mOsm/kg). Free water flushes
were initiated. Due to declining PaO2/FiO2 (P/F) ratio (221 to 138), the patient was prone, resulting in rapid significant improvement
in P/F ratio to 428.
On day 6, the patient's sodium remained elevated at 167 mMol/L despite free water
flushes. The patient's hypotension improved and epinephrine was titrated off. He was
weaned off iNO with improving oxygenation and enteral feeds were initiated. Patient
returned to supine position after intermittent proning. The next 2 days saw further
increases in sodium levels (peak at 170 mMol/L) and D-amino D-arginine vasopressin
(DDAVP) was started for suspected diabetes insipidus, resulting in normalization of
sodium levels over the next 7 days.
On day 9, the patient's hemodynamics were very difficult to control. His P/F ratios
worsened, and proning and iNO were reinitiated, showing improvement in P/F (240 to
316).
On day 15 of admission, the patient's fevers returned (102.1°F) secondary to methicillin-sensitive
Staphylococcus aureus pneumonia, requiring antibiotics. Over the next 3 days, the patient tolerated ventilator
weaning trials and was successfully extubated to HFNC by day 19 of admission. He was
subsequently weaned to room air, transitioned to enteral medications, and discharged
from the hospital after a 23-day hospital stay ([Fig. 3]).
Fig. 3 Trends and treatments throughout hospital course. All dates that have no lab value
correspond to the sample not being drawn that day at the clinician's direction. CRP,
C-reactive protein; DDAVP, D-amino D-arginine vasopressin; HFNC, high-flow nasal cannula;
iNO, inhaled nitric oxide; IV, intravenous.
Discussion
To our knowledge, this is the first described case of COVID-19 infection in a patient
with ROHHAD. These children are seemingly normal before developing hyperphagia and
subsequent rapid-onset weight gain early in childhood. Over time, these patients may
develop endocrine abnormalities resulting in sodium and water imbalances, and elevated
prolactin and cortisol levels. The rapid weight gain is believed to contribute to
the onset of obstructive sleep apnea and alveolar hypoventilation. Autonomic findings
may manifest, including altered pupillary responses, changes in intestinal motility,
temperature dysregulation, and bradycardia. At this time, no specific cause for ROHHAD
has been found.[3]
[4]
At the time of this patient's hospital discharge, the World Health Organization reported
more than 3.5 million global cases of COVID-19 with more than 200,000 deaths, including
75 pediatric deaths.[5] Even as the number of cases grows, there is only a modicum of infectious, epidemiologic,
and clinical data available to assist in the treatment of COVID-19-positive pediatric
patients. To date, the most common presentation of the acute pediatric COVID-19 patient
ranges from completely asymptomatic to symptoms of an acute upper respiratory tract
infection to gastrointestinal symptoms with progression to respiratory failure, coagulopathy,
acute renal injury, and shock in severe cases.[6]
There were several challenges in this patient's management throughout his hospitalization,
such as abnormal ventilation and oxygenation, labile hemodynamics, and hypernatremia.
Upon intubation, several modes of ventilation were attempted, but we settled on airway
pressure release ventilation as an effective mode for alveolar recruitment, especially
with his heavy body habitus, short status, and propensity for hypoventilation.[7] Proning and iNO also proved to be effective adjuncts for improving oxygenation.[8] Prone positioning has been used in the management of hospitalized COVID-19 patients,
has decreased mortality in adults with severe lung disease, and is currently being
studied in pediatric trials.[9]
[10]
The patient's hemodynamics were also difficult to control, likely due to a combination
of reasons, such as his underlying propensity for autonomic dysregulation. This was
evidenced later in the patient's ICU course by the presence of bradycardia while off
dexmedetomidine, and persistent constipation.
The patient's sodium was difficult to control despite adequate free water administration,
possibly secondary to hypothalamic dysfunction as part of the patient's underlying
genetic abnormality. The hypothalamus is responsible for the formation of arginine
vasopressin in the posterior pituitary which functions to regulate extracellular fluid
volume. The administration of DDAVP provided a significant improvement in the patient's
hypernatremia and suggests a diagnosis of diabetes insipidus.
Laboratory tests, including but not limited to the D-dimer and serum ferritin, were
trended throughout the patient's care as clinically indicated to monitor for the laboratory
findings of COVID-19 sequelae that has been seen in the adult population. D-dimer,
fibrinogen, and prothrombin time/partial thromboplastin time testing were utilized
to monitor the development of thrombosis despite anticoagulation therapy. Serum ferritin,
C-reactive protein, procalcitonin, and lactate dehydrogenase testing were utilized
to evaluate the development of rheumatologic and systemic inflammatory manifestations
such as cytokine storm, and to detect possible superimposed bacterial infection.
Hospital protocol upon admission required the utilization of the COVID-19 DiaSorin
(RNA) test with an approximate turnaround time of 2 hours. During the patient's ICU
encounter, both nasopharyngeal and sputum samples were obtained and sent weekly to
Mayo Clinic (RNA). Only the nasopharyngeal swabs returned with a positive result.
Serologies returned positive for both immunoglobulin (Ig)G and IgM antibodies.
After the patient's initial COVID-19 RNA test returned positive, hydroxychloroquine
and zinc supplementation were initiated based on preliminary reports available at
the time suggesting viral load reduction in COVID-19 patients.[11] However, recent literature suggests no benefit with hydroxychloroquine administration
and it is unclear if our patient improved after its use.[12] Remdesivir, an adenosine analog that inhibits viral replication with included antiviral
activity against SARS-CoV-2, was administered under compassionate use, also with an
unclear role in this patient's improvement.[13] Preliminary evidence from a case series involving adult patients suggests clinical
improvement but there has not been a randomized controlled trial to this date.[14]
Conclusion
We report a case of severe pediatric SARS-CoV-2 in the United States in a patient
with a complex genetic condition. Our patient's course was complicated by respiratory
failure, hemodynamic instability, endocrine abnormalities, and autonomic dysregulation.
This case report may serve as a reference for other critical care clinicians tasked
with caring for complex pediatric patients who are infected with COVID-19. It is imperative
for further literature to better describe the clinical presentation, course, and treatment
of COVID-19 in the pediatric population.
