Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread around the world causing 410,465 cases and 18,295 deaths as of March 24, 2020. Spain is one of the most affected countries by the SARS-CoV-2 pandemic, with 39,673 cases and 2696 deaths to date.1 Only 1 death has occurred in our country in pediatric population (none below 10 years of age), which correlates with published data of China and Italy.2 Risk factors for poor outcome, including age, male sex and comorbidities (heart disease, chronic lung disease, renal injury, diabetes or obesity) have been reported. Infection seems to have a better outcome in children. However, we all are particularly concerned about immunocompromised children, especially pediatric patients with hematologic and oncologic disorders on chemotherapy getting infected.
We would like to share our experience with 2 cases in the Castilla la Mancha region in Spain.
A 13-year-old female diagnosed with metastatic Ewing sarcoma in January 2020, receiving treatment according to the Euro Ewing 2012 protocol was admitted because of febrile neutropenia (maximum temperature 38.2°C) after the fifth cycle of chemotherapy (vincristine, doxorubicin, cyclophosphamide), without other symptoms except a sore throat.
Body mass index 19.5 kg/m2, 40th percentile. Temperature 38.3°C, blood pressure 92/63 mm Hg, respiratory rate 14 bpm, heart rate 120 bpm, Sat 99%. She was well appearing and only showed grade II oral mucositis. SARS-CoV-2 PCR (SARS-CoV-2 REALTIME PCR KIT, Vircell S.L., Spain) was performed on nasopharyngeal swab, resulting positive. Biochemistry and blood count are detailed in Figure 1. A chest radiograph was performed according to our SARS-CoV-2 hospital protocol, and it was unremarkable.
Treatment with meropenem (60 mg/kg/d) and teicoplanin (10 mg/kg/d) was started according to local guidelines for febrile neutropenia. As SARS-CoV-2 infection was diagnosed, and considering a hypothetically higher risk because of immune suppression, lopinavir/ritonavir (400/100 mg orally, twice a day) was started at admission, according to recommendations of the Spanish Paediatric Infectious Diseases Society.3 She developed watery diarrhea which started after the first dose of lopinavir/ritonavir, and persistent neutropenia (longer than in previous cycles) despite granulocyte colony-stimulating factor administration (started after the last chemotherapy cycle), and we were not comfortable delaying the next cycle. Therefore lopinavir/ritonavir was switched to hydroxychloroquine (200 mg orally, twice a day first day and 100 mg twice a day for 4 days) 48 hours later.
She became afebrile in the first 12 hours after admission, without development of new respiratory or gastrointestinal symptoms. Diarrhea resolved 24 hours after lopinavir/ritonavir cessation. Neutrophil recovery is shown in Figure 1. Two SARS-CoV-2 polymerase chain reaction (PCR) tests have been negative, the first of them 1 week after admission.
A 2-year-old male diagnosed with Wilms tumor (stage III, intermediate risk) diagnosed in December 2019, receiving treatment according to the Umbrella Protocol International Society of Paediatric Oncology 2016. Nephrectomy and partial thrombectomy were performed in January 2020. He developed postsurgical chylothorax and was admitted because of fever in a non-neutropenic patient, being diagnosed with bacteremia by Staphylococcus epidermidis, treated with intravenous vancomycin (50 mg/kg/d) for 14 days. He became afebrile after 2 days, but his fever returned 7 days later, during the fifth week of postsurgery chemotherapy (vincristine and actinomycin-D) without any other symptoms except diarrhea.
Body mass index 11.7 kg/m2, <1st percentile. Temperature 38°C, blood pressure 99/60 mm Hg, respiratory rate 24 bpm, heart rate 100 bpm, Sat 98% with no remarkable findings. D-dimer, lactate dehydrogenase were normal. He was not neutropenic, but lymphopenia was noticed in his blood count (Fig. 1). Chest radiograph was normal.
Blood and stool cultures, together with a nasopharyngeal swab for SARS-CoV-2 PCR were performed and empirical cefepime (50 mg/kg/q. twice a day) was started.
After the SARS-CoV-2 PCR returned positive, hydroxychloroquine (6.5 mg/kg/d) was started. Lopinavir/ritonavir was considered following Spanish Paediatric Infectious Diseases Society recommendations.3 We favored hydroxychloroquine over lopinavir/ritonavir to avoid the potential drug interaction with vincristine (administered 24 hours before) that may lead to increased vincristine toxicity.
He did not develop further complications except for 1 isolated episode of fever (38°C) 4 days after hydroxychloroquine was started. Blood and stool cultures were all negative. We stopped antibiotics (after 7 days) and hydroxychloroquine (7 days) after the patient remained afebrile for 72 hours and was discharged without symptoms. Chemotherapy has been postponed until 2 negative SARS-CoV-2 PCRs were obtained, the first of them 13 days after admission.
In this report, we describe 2 pediatric cancer patients from the same area in Spain with acute infection by SARS-CoV-2.
The coronavirus (CoVs) are a large family of single-stranded RNA viruses that can be isolated in different animal species, especially bats or other mammalian hosts, which can cross species barriers and cause morbidity in humans, ranging from a common cold to acute respiratory distress syndrome or sepsis.4
It has been described that pediatric patients seem to have a milder disease than adults during the SARS-CoV-2 outbreak in China, with an infection rate of 12.3% among children with known contact and only 1 death reported.5 This correlates well with the SARS-associated CoV outbreak in 2002, with very few cases reported in childhood who also developed milder disease, especially in children <12 years of age.6 However, there is a lack of knowledge and high concern about higher risk in immunocompromised patients, including pediatric cancer patients treated with chemotherapy.
In fact, there is a report of one 8-year-old child with acute lymphoblastic leukemia on maintenance therapy, who developed severe COVID-19 with bilateral pneumonia requiring ventilation and admission to pediatric intensive care unit,7 which contrasts with the mild course of both patients reported here.
Anticancer therapy in children causes impairment of cell-mediated and humoral immunity, as well as neutrophil count and function. Respiratory viral infections cause morbidity and even mortality in patients treated with chemotherapy, particularly among hematopoietic stem cell transplant recipients.8
However, it has been proposed that CoVs, as well as other zoonoses, may implicate dysregulated and excessive innate immune response as drivers for tissue damage during infection. If so, immunocompromised patients could be hypothetically protected because of a weaker immune response against infection. In Italy, where SARS-CoV-2 infection is endemic as in Spain, only 3 immunocompromised children with SARS-CoV-2 infection have been reported so far; none of them developed clinical pulmonary disease.9
Many antiviral and immunologic drugs have been proposed for the treatment of SARS-CoV-2 infection; none of them has proven its efficacy yet, but several clinical trials are ongoing.10
We would like to underline the intestinal symptoms in both patients; we associated diarrhea with lopinavir/ritonavir in the first patient, but as the second one also developed diarrhea at diagnosis, this sign could be attributed directly to SARS-CoV-2, as it has been described in early reports from Wuhan.11,12
In our 2 patients, SARS-CoV-2 infection presented as mild disease, even in the first patient who had severe immunosuppression at the moment of infection.
Pediatric cancer patients may have milder disease than adults with malignancies, but larger studies are needed to confirm this conclusion.
1. Worldometer. COVID-19 coronavirus pandemic. Available at: https://www.worldometers.info/coronavirus/
. Accessed March 24, 2020
2. Centro de cooordinación de alertas y emergencias sanitarias. Actualización n° 54. Enfermedad por el coronavirus (COVID-19). Ministerio de Sanidad, Gobierno de España. Available at: https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/documentos/Actualizacion_54_COVID-19.pdf
. Accessed March 24, 2020
4. Hsu LY, Chia PY, Lim JF. The novel coronavirus (SARS-CoV-2
) epidemic. Ann Acad Med Singapore. 2020; 49:105–107
5. Lu X, Zhang L, Du H, et al. SARS-CoV-2
infection in children. . N Engl J Med
. 2020; 382:1663–1665
6. Stockman LJ, Massoudi MS, Helfand R, et al. Severe acute respiratory syndrome in children. Pediatr Infect Dis J. 2007; 26:68–74
7. Sun D, Li H, Lu X-X, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center’s observational study. World J Pediatr. 2020; 16:251–259
8. Kaltsas A, Sepkowitz K. Community acquired respiratory and gastrointestinal viral infections: challenges in the immunocompromised host. Curr Opin Infect Dis. 2012; 25:423–430
9. D’Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transplant. 2020; 26:832–834
10. Wang L-S, Wang Y-R, Ye D-W, et al. A review of the 2019 novel coronavirus (COVID-19) based on current evidence. Int J Antimicrob Agents. 2020; 55:105948
11. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395:507–513
12. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323:1061–1069