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To the Editor:
The recently emerged SARS-CoV-2 virus causes pneumonia and, in severe
cases, acute respiratory distress syndrome (ARDS) in adults, but its
clinical picture can be markedly different in children, most of whom
undergo only a mild or even asymptomatic course of the
disease1–3. In some cases, however, profound systemic
inflammatory response is triggered, sharing few similarities with the
more commonly seen self-limited respiratory infection.
Here we report a case of an 8-year-old girl who manifested with fever
(>40°C), headache, abdominal pain and vomiting, but no
signs of respiratory involvement with only mildly elevated C-reactive
protein (CRP, 27 mg/l, Fig 1A). Over the next 2 days she developed
diffuse itchy maculo-papular rash (Fig 1B) and watery diarrhea with CRP
of 139 mg/l. At this point, SARS-CoV-2 nasopharyngeal swab polymerase
chain reaction (PCR) was negative. The girl was started on
amoxicillin/clavulanic acid. However, her condition deteriorated with
ongoing high-grade fever, diarrhea and headache necessitating hospital
admission on day 5 from symptom onset. She was febrile and dehydrated
with severe abdominal pain, diarrhea and positive meningeal signs. She
had high inflammatory parameters (CRP 267 mg/l, procalcitonin 70 μg/l),
elevated D-dimers and urea, creatinine, liver enzymes, troponin and
proNT-BNP. Stool PCR showed only weak positivity for rotavirus and
astrovirus, chest X-ray was largely normal (Fig 1C), spinal tap
suggested mild serous meningoencephalitis. At this point, the
nasopharyngeal swab PCR was still negative, however, anti-SARS-CoV-2 IgG
antibodies were positive, with negative IgM. Due to recurrent episodes
of hypotension and other signs of septic shock the patient was started
on intravenous ceftriaxone and transferred to an intensive care unit.
Abdominal ultrasound suggestive of paralytic ileus with appendicitis and
overall worsening of clinical status resulted in an empirical exchange
of ceftriaxone for piperacillin, tazobactam and metronidazole and
abdominal surgery on day 6 of the disease, which revealed serous
peritonitis but no appendicitis or other pathology. Subsequent serology
showed positive IgA against Yersinia enterocolica, but negative
rectal swab culture.
After extubation and discontinuation of analgosedation on day 7, the
patient’s consciousness deteriorated towards Glasgow coma scale (GCS) of
7-8 on day 8, despite normal central nervous system magnetic resonance
imaging (MRI) and lack of topical neurological symptoms. Here the
patient developed dry cough for the first time. Even though all tests
including the cerebro-spinal fluid, blood culture, urine, stool and
broncho-alveolar lavage were negative for any microbial pathogens, with
the sole exception of nasopharyngeal swab PCR positivity for SARS-CoV-2,
her CRP and procalcitonin remained very high (199 mg/l and 28,4 μg/l
respectively). The persistent elevation of inflammatory markers along
with very high soluble IL-2 receptor (6326 IU/ml), ferritin (577 μg/l)
and history of juvenile idiopathic arthritis (oligoarticular subtype,
currently inactive without therapy) lead to suspicion of viral-induced
macrophage activation syndrome (MAS) / secondary hemophagocytic
lymphohistiocytosis (HLH), which however was not abundant in bone marrow
aspirate and the patient did not fulfill diagnostic criteria for
MAS/HLH4. Heart ultrasonography was repeatedly normal,
making the diagnosis of Kawasaki disease unlikely. The patient was
administered intravenous methylprednisolone (2mg/kg/day in 3 doses), one
dose of 400 mg/kg intravenous immunoglobulins, prophylactic nadroparin
and the piperacillin and tazobactam were discontinued due to apparent
lack of effect in favour of ceftriaxone. This therapy lead to gradual
improvement of clinical symptoms with full recovery of her consciousness
by day 11. Her inflammatory markers, cardiac enzymes, liver and renal
functions normalized apart from the mild hepatopathy most likely related
to the combined antibiotic therapy. The patient was finally discharged
from the hospital in good health on the 15th day after
onset of symptoms.
We observed a spike in markers of inflammation around day 8, coincident
with the worsening of patient’s symptoms. Of particular interest in the
context of COVID-19 was the elevation of CRP and PCT, but relatively
“low” levels of serum IL-6 (cytokine associated with severe course of
the disease and higher mortality in adults5) – the
patient reached IL-6 of 215 pg/ml (normal range 0-6 pg/ml) at the time
of worst clinical symptoms. For comparison, adult patients admitted to
our hospital with severe course of COVID-19 who required mechanical
ventilation frequently reached IL-6 levels in the thousands. Soluble
IL-2 receptor which is produced by activated mononuclear
cells6 was very high, while both monocytes and
lymphocytes were normal on day 8 and increased only slightly between
days 10 and 15 (Fig 2A). On the other hand, neutrophils and eosinophils
peaked on day 8 and decreased sharply thereafter. While the elevation of
neutrophils and lymphopenia are both well-established as negative
prognostic markers of COVID-19 in adults7, the role of
eosinophils remains more elusive, with some reports suggesting they are
decreased in severe cases8. Aside from the waxing and
waning of leukocyte subpopulations, the pivotal role of innate immunity
in defense against SARS-CoV-2 is further supported by the depletion and
gradual recovery of complement (C3 and C4 proteins) during the disease
(Fig 2B).
We additionally show stark changes in
neutrophil phenotype during the course of the disease (Fig 2C). The
expression of HLA-DR, previously described to be decreased in
COVID-199, was low on day 8 and gradually recovered to
normal levels. CD10, a marker of neutrophil maturation associated with
immunosuppressive function10, was markedly decreased
during the worst clinical symptoms, suggesting efflux of young, active
neutrophils from the bone marrow, but together with the inhibitory
molecule PD-1L and CD15, a marker of activation in mature neutrophils,
reached supra-normal expression during recovery as these cells matured.
The adhesion molecule CD62L was low during the time of most fulminant
infection, but its expression recovered and was even elevated on day 19
at recovery. Together, these data suggest full activation and engagement
of neutrophils during the disease with compensatory contraction of the
response and contra-regulation of neutrophil phenotype during recovery.
In summary, our patient developed systemic inflammatory response to
SARS-CoV-2 infection in absence of other infectious pathogens, which had
some but not all hallmarks of secondary MAS/HLH and which quickly
deteriorated and then resolved with corticosteroids, preventive
anticoagulation and supportive therapy only. This case report
illustrates the variability of clinical presentation of SARS-CoV-2
infection in children, which should be suspected in case of unexplained
inflammatory symptoms even in the absence of signs of respiratory
infection. Immunosuppressive therapy may be helpful for these patients.
Adam Klocperk1, M.D., Ph.D., Zuzana
Paračková1, MSc., Jitka Dissou2,
M.D., Hana Malcová3, M.D., Ph.D., Petr
Pavlíček4, M.D., Tomáš Vymazal4,
M.D., As. Prof., Pavla Doležalová5, M.D., Prof., Anna
Šedivá1, M.D., Prof.
1Department of Immunology, 2ndFaculty of Medicine, Charles University in Prague and University
Hospital in Motol, Prague, Czech Republic
2Emergency Department for Children, University
Hospital in Motol, Prague, Czech Republic
3Department of Children and Adult Rheumatology,
University Hospital in Motol , Prague, Czech Republic
4Department of Anesthesiology and Intensive Care
Medicine, 2nd Faculty of Medicine, Charles University in Prague and
University Hospital in Motol, Prague, Czech Republic
5Centre for Paediatric Rheumatology and
Autoinflammatory Diseases, Department of Paediatrics and Adolescent
Medicine, General University Hospital in Prague and
1st Faculty of Medicine, Charles University in Prague,
Prague, Czech Republic