Discussion
Respiratory viral infections in immunosuppressed patients usually
present a more severe clinical evolution, longer viral excretion,
several pulmonary complications, and a higher mortality
rate11. In the specific case of HCoV, a study
published by Ogimi et al12 observed an association
between the immunocompromised state and an increased risk of serious
virus-related lower respiratory tract disease. During the period of data
collection for this report, Spain was the second most affected country
by the SARS-CoV-2 pandemic. In our country, around 1,300 children and
adolescents are diagnosed with cancer every day (155.5 new cases
annually per million children aged 0-14 years, similarly to other
European countries)13. This report includes almost all
Spanish centers with Pediatric hemato-oncology (PHO) units, providing a
significative representation of the current situation in the country
from the beginning of the pandemic. Thereafter, including only cancer
diagnosis we observed a COVID-19 infection rate of approximately 2.5 %
among this patient population over the first 3 months of the pandemic.
As expected, most of the reported patients (68%) were from the States
of Madrid and Catalonia, the two most affected areas in Spain by
SARS-CoV-214. Fifteen of the patients included in the
present study were previously reported in the Madrid cohort recently
published by de Rojas et al15. Initial experiences
from Italy (Lombardy)16, China
(Wuhan)17,18 and Europe suggest a low number and
severity of COVID-19 cases in pediatric patients with oncologic,
hematologic, or post allo-SCT diseases6. However, a
recently published study in France, observed a higher incidence of
critical patients, as 5 out of the 33 included patients were admitted to
the PICU19. In addition, as the pandemic develops, and
with a higher availability for viral testing, our study shows that we
may expect an increasing number of reported cases in the literature. Our
series represents a good initial “snapshot” of the Spanish number of
cases and severity in the midst of the peak of SARS-CoV-2 cases within
the country.
Data from China’s nationwide case series of 2135 pediatric patients with
COVID-19 observed that more than 90% of all patients had asymptomatic,
mild, or moderate cases3. In our series, most of the
cases remained asymptomatic (25%) or with mild symptoms (51.1%).
However, severe and critical cases comprised 23.4%, higher than the
3-10.6% described in the previously healthy Chinese pediatric
population (according to age range)3. Most of our
patients who presented lower respiratory tract symptoms developed
dyspnea and/or hypoxemia, were managed successfully in the ward with
good clinical outcome. The proportion of infected children requiring
intensive care management was 8.5%, a higher percentage compared to
that observed in the general pediatric population20.
Of note, all four patients were either receiving intensive chemotherapy
or severely immunosuppressed post allo-SCT. Noteworthy, laboratory
abnormalities accompanying more severe forms of infection and admission
to the PICU identified as surrogate markers low total lymphocyte count
and high ferritin levels at onset of symptoms. One of the deaths in the
post allo-SCT subgroup was probably related to an uncontrolled systemic
inflammatory response that closely resembled that of secondary
hemophagocytic lymphohistiocytosis (sHLH) or macrophage activation
syndrome (MAS), as it has been described in other severe COVID-19
patients21. SARS-CoV-2 infection seems to trigger a
cytokine storm and hyper-activation of the immune response, with
consequent multiple organ damage. In this cohort of patients, no
diagnosis of Kawasaki disease or toxic syndrome were observed as
described elsewhere22.
Regarding therapy, hydroxychloroquine and antivirals
(lopinavir/ritonavir, remdesivir, and oseltamivir) were used mainly in
early stages23. In those with a more aggressive
disease and/or hyperinflammation component, immunomodulatory treatments
similar to those used in the cytokine release syndrome associated with
CART therapy (i.e . tocilizumab, siltuximab, anakinra,
corticosteroids) were administered24. Clear
recommendations of anti-viral therapy, immunomodulation, and of an
effective vaccine are not available yet, but hopefully they will be
stablished soon after the ongoing basic and clinical trials
progress25. According to our data, most patients will
have a good outcome with supportive care. However, it may be postulated
that patients receiving intensive chemotherapy, severely
immunosuppressed, or GVHD may be at a higher risk of morbidity and even
mortality secondary to COVID-19.
There is also the concern that during this pandemic, children with
cancer may have an incremented risk of presenting a poor prognosis for
their disease, due to late diagnosis and not appropriate treatment26-27. In this respect,
half
of the patients included in our cohort had interrupted their anticancer
directed treatment for a number of days due to the concomitant
infection. Larger series of cases and longer follow up information will
be needed to understand its real impact. However, it is not infrequent
that chemotherapy regimens have to be stopped during opportunistic
infections in patients undergoing immunosuppression. Recent guidelines
published from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St
Jude Global for children with cancer recommend that the standards of
care for the diagnosis, treatment and supportive care should not be
compromised or electively modified during the pandemic, if at all
possible28. In this line and based on our experience,
we recommend individualized multidisciplinary discussions whenever a
COVID-19 case is identified. A number of variables including the
underlying condition, stage of disease, prognosis and clinical infection
related impact should be taking into consideration for interrupting or
delaying anti-cancer therapy.
Limitations of this report include the small sample size, which limits
the extrapolation of results to the general hemato-oncological pediatric
population. Moreover, the data was collected both retrospectively and
prospectively. Thus, it may be a limitation when reporting disease
evolution and other time-dependent factors. Finally, as the present
study is multicentric and data was collected from different hospitals
around the country, a potential interindividual variability may exist
when reporting the different clinical scenarios. However, since most of
the physicians of the Spanish Units of PHO took part in this initiative,
we believe our report represents an accurate infection prevalence among
children diagnosed with cancer and chronic hematological disorders in
our country.
This is one of the largest series of COVID-19 in pediatric cases with
solid and hematological malignancies, benign hematologic conditions, and
post allo-SCT reported during the present pandemic. Recent publications
based on a low number of cases seem to suggest that immunosuppressed
pediatric patients do not present an increased risk of developing severe
SARS-CoV-2 infection616 Our results show that the
clinical course of most patients is overall good. However, severe forms
of infection can be seen in highly immunosuppressed patients or in those
with chronic co-morbidities such as GVHD, or patients receiving CART
cell therapy. International collaborative groups’ series cases will
surely be published soon in order to better establish the real impact of
this infection in our vulnerable pediatric population.