COVID-19 in childhood cancer patients: What are the risk factors?

A large international database study has shown that children and adolescents with cancer have an elevated risk of severe or critical disease if infected with COVID-19. Furthermore, about half the patients receiving cancer therapy experienced modifications to their treatment regimens. 

“The results clearly and definitively show that children with cancer fare worse with COVID-19 than children without cancer,” said corresponding author Dr Sheena Mukkada from the St Jude Departments of Global Pediatric Medicine and Infectious Diseases, St Jude Children’s Research Hospital, Memphis, Tennessee, US.

“We have shown that although infection outcomes are generally favourable, severe disease can occur, particularly in patients receiving intensive chemotherapy, and patients with lymphopenia and neutropenia,” said Mukkada and co-authors.

Data was compiled from the ongoing St Jude Global and International Society of Paediatric Oncology Global Registry of COVID-19 in Childhood Cancer (GRCCC) between April 15, 2020 and February 1, 2021. The study included 1,500 children and adolescents aged <19 years (median age 8 years) from 45 countries with a current or previous diagnosis of cancer or had received haematopoietic stem-cell transplantation (HSCT) and had laboratory-confirmed SARS-CoV-2 infection. About half the population (54.9 percent) were aged 1–9 years and 40.5 percent were female. The most common cancer type was acute lymphoblastic leukaemia or acute lymphoblastic lymphoma (ALL; 49.1 percent). Only 5.4 percent had received HSCT. Most patients (54.9 percent) were from World Bank upper-middle-income countries.

Thirty-day follow-up data was available for 1,319 patients, of whom 67.4 percent were hospitalized and 17.5 percent required admission or transfer to increased level of care. About 29 percent of patients received treatment for COVID-19, primarily azithromycin and steroids (71.2 and 51.0 percent, respectively). Thirty-five percent of patients were asymptomatic.

About 20 percent of patients (n=259) developed severe or critical infection and 50 deaths (3.8 percent) were attributed to COVID-19. Of the 1,092 patients who were on active cancer treatment, 55.8 percent underwent treatment modification, with chemotherapy withheld in 44.6 percent. [Lancet Oncol 2021;doi:10.1016/S1470-2045(21)00454-X]

Factors associated with severe or critical illness* included age (odds ratio [OR], 1.6, 95 percent confidence interval [CI], 1.1–2.2; p=0.013 for 15–18 years), lymphopenia (absolute lymphocyte count ≤300 cells/mm³; OR, 2.5, 95 percent CI, 1.8–3.4; p<0.0001), neutropenia (absolute neutrophil count ≤500 cells/mm³; OR, 1.8, 95 percent CI, 1.3–2.4; p=0.0001), and receipt of intensive treatment (OR, 1.8, 95 percent CI, 1.3–2.3; p=0.0005).

Children from low-income or lower-middle-income countries were also more likely to have severe or critical illness compared with those from high-income countries (OR, 5.8, 95 percent CI, 3.8–8.8; p<0.0001), with the risk elevated, but to a lesser degree, among children in countries with upper-middle-income status (OR, 1.6, 95 percent CI, 1.2–2.2; p=0.0024).

Patients residing in upper-middle-income countries were less likely to have cancer treatment modification** (OR, 0.5, 95 percent CI, 0.3–0.7; p=0.0004), as were those with a primary diagnosis of haematological cancer aside from ALL (OR, 0.5, 95 percent CI, 0.3–0.8; p=0.0088). Conversely, presence of ≥1 COVID-19 symptom at presentation (OR, 1.8, 95 percent CI, 1.3–2.4; p=0.0002) and ≥1 comorbidity (OR, 1.6, 95 percent CI, 1.1–2.3; p=0.020) were associated with an increased likelihood of treatment modification.

 

Children at lower risk than adults, but risk remains

While mortality rates in children with cancer and COVID-19 were lower than that of adults with these concomitant conditions, the rates were still fourfold that of the general paediatric population, the authors said.

“The results are reassuring that many children can continue their cancer treatment safely, but they also highlight important clinical features that may predict a more severe clinical course and the need for greater vigilance for some patients,” commented co-author Professor Kathy Pritchard-Jones from UCL Great Ormond Street Institute of Child Health, London, UK.

Reasons for the association between lower income status and illness severity could be “differences in supportive care infrastructure and delays in presentation,” the authors said. “In addition, healthcare system disruptions that affect all aspects of care delivery might be more pronounced in low-income and lower-middle-income countries.”

 

Results influence treatment strategies

According to the authors, the association between lymphopenia and neutropenia with severe or critical illness in this population may warrant certain treatment modifications.

“[This finding] suggests that it might be prudent to delay myelosuppressive and lymphocyte-depleting therapy during active infection if this is feasible in patients with other risk factors for severe disease,” they said.

Additionally, while about 20 percent of patients developed severe or critical illness, most patients did not require advanced support.

“These findings suggest that, in most cases, cancer-directed therapy can proceed and no antiviral therapy for SARS-CoV-2 is required for COVID-19 disease resolution,” the authors said.

“[P]atients receiving or anticipated to receive intensive cancer-directed therapies should be prioritized for early access to vaccination, when appropriate, and for other supportive care interventions when resources are limited,” they added.

“[In addition,] the large proportion of asymptomatic patients underscores the need for aggressive infection control measures as these patients can pose infection risks to other patients and healthcare providers.”

“This global collaboration helps clinicians make evidence-based decisions about prevention and treatment, which, unfortunately, remain relevant as the pandemic continues,” highlighted Mukkada.

 

Limitations require addressing in future research

The use of a hospital-based registry prevents the results from being applicable in a population-level setting. Additionally, the inclusion of only confirmed SARS-CoV-2 cases may have resulted in under-representation of countries with limited access to testing. The lack of data on race or ethnicity prevented determination of association between these factors and illness severity.

The causes of cancer treatment modification, and its subsequent effect on survival outcomes, could not be determined in this study which presents an avenue for future research, noted the authors.

They also pointed out that these results were compiled before the COVID-19 vaccine was available to older children in certain countries and prior to the circulation of the more recent variants (eg, delta).