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.