Baseline characteristics, disease severity, and outcomes of enrolled patients (N = 97)

Abbreviations: COVID-19, coronavirus 2019; IQR, interquartile range; SD, standard deviation.

The disease severity by type of cancer in the COVID-19 children is depicted in [Fig. 2]. Seventeen patients (54.8%) had hematological malignancies (HM; acute myeloid leukemia = 1, B-cell acute lymphoblastic leukemia = 11, T-cell acute lymphoblastic leukemia = 1, Hodgkin Lymphoma = 3, non-Hodgkin Lymphoma = 1), whereas 14 patients (45.1%) were diagnosed to have solid tumors (retinoblastoma = 3, Ewing sarcoma = 4, choroid plexus tumor = 1, hepatoblastoma = 1, juvenile ossifying fibroma = 1, Wilms tumor = 1, teratoma = 1, posterior fossa mass = 1, neuroblastoma = 1).

Pediatric COVID-19 symptoms and symptom complex at presentation

Abbreviations: COVID-19, coronavirus disease 2019; GI, gastrointestinal.

Laboratory Investigations

Group A had significantly a greater number of patients who had leukopenia (p = 0.003), neutropenia (p = 0.003), and lymphopenia (p = 0.005). There was no significant difference between the rest of the checked laboratory parameters between the two groups ([Table 3]).

Laboratory investigations of pediatric COVID-19 patients at presentation

Radiological Investigations

Among group A, chest X-ray was done for 21 patients out of which 5 showed infiltrates and 1 showed hilar lymphadenopathy. Among group B, a chest X-ray was done for 23 patients, in which 8 showed infiltrates, 3 exhibited hilar lymphadenopathy, and 1 showed pleural effusion.

Oxygen Requirement

Only two patients (6.45%) in group A required oxygen (nasal prongs = 2), while eight patients (12.1%) required oxygen in group B (ventilator support = 1, high-flow nasal cannula = 1, nasal prongs = 2, simple mask = 3, oxygen hood =1; p = 0.49).

Mean Duration of Hospital Stay

The mean duration of hospital stay among group A was 11.6 ± 6.8 days as compared to 9.6 ± 5.4 days among group B (p = 0.33).

Outcome

The case fatality rate among cancer patients was 3.2% as compared to 1.5% in noncancer patients. However, there was no difference in mortality rate as both the groups had one death each. In both groups, the death was attributed to severe COVID-19 infection. There was no death due to progression of cancer or complications of chemotherapy, during the period of study. Among group A, the expired patient was a 12-month-old female child who was diagnosed to have sacrococcygeal teratoma with hepatic metastasis with severe COVID-19 pneumonia. While in group B, the expired patient was a 9-year-old male child with tubercular meningitis stage-3 and multiorgan dysfunction.

Risk Factors

Risk factors for moderate-to-severe COVID-19 disease among cancer patients are detailed in [Table 4]. Poor nutritional status, higher cancer stage, and presence of coinfections seemed to be associated with moderate-to-severe COVID-19. However, these results were statistically not significant.

Risk factors for moderate-to-severe COVID-19 disease in cancer patients

Abbreviation: COVID-19, coronavirus disease 2019.

Discussion

To our knowledge, this is one of the few studies to directly compare the clinical, biochemical, radiological, and outcome profiles of COVID-19 infection in children with and without cancer.

In our study, we found that 15% of the hospitalized pediatric patients with COVID-19 had cancer as a comorbidity. A previously published meta-analysis showed the worldwide prevalence of COVID-19 in adult patients with cancer to be around 4.6%.[8] Other studies have variably reported the prevalence of COVID-19 in patients with cancer to be between 2.6 and 11%.[8] [9] Studies done in children hospitalized with COVID-19 in India have reported cancer as a comorbidity in as many as 7-15%.[1] [10] The reasons for a high proportion of cancer as comorbidity in children with COVID-19 may be manifold. Due to the nature of their disease and related therapy, children with cancer are at high risk of developing viral infections.[11] Likewise, it is logical to expect higher infectivity of COVID-19 in children with cancer. At our center, we found an even higher proportion of children having cancer as comorbidity. Additional factors that may have contributed to this include a referral bias as our hospital is one of the few public sector hospitals in the area dealing with pediatric cancer patients. Moreover, our hospital was designated as an exclusive COVID-19 treating center during the pandemic; thus, all children with COVID-19 with any comorbidity were referred to us. Another reason for the difference in this prevalence may be the difference in admission criteria for COVID-19 children in various centers.

Overall, the median age, gender, and distribution of disease severity of the enrolled cohort were similar to the previously published literature.[3] However, children with cancer were significantly underweight as compared to children without cancer that may be due to their underlying disease or therapy-related anorexia leading to malnutrition.

In this study, a greater proportion of admitted pediatric cancer patients with COVID-19 had HM (54.8%) as comorbidity as compared to solid tumors (45.1%). This result corroborates with the data reported in the global registry which showed that among pediatric patients with COVID-19, 67.1% had HM, while only 32.9% had solid tumors.[12] It has been reported that patients with HM have a more severe course of COVID-19 as compared to solid tumors and consequently a higher hospitalization rate.[13] Patients with HM have been shown to have delayed seroconversion, prolonged viral shedding, higher viral load, and immune disturbance following COVID-19 infection compared to patients with solid tumors.[14] [15] Furthermore, patients of COVID-19 with HM have been shown to have remarkably lower percentages of monocytes, double-positive T cells, natural killer cells, and B-cells.[16] [17] These patients also have impaired CD4 T-cell and B-cell reaction to SARS-CoV-2 and lower levels of anti-COVID-19 antibodies in comparison to patients suffering from solid cancer.[18] All these factors are likely to contribute to higher hospitalization rates of children with COVID-19 with HM compared to those with solid tumors.

In terms of severity, most of the patients in both groups were either asymptomatic or had a mild disease that is consistent with data from other studies and larger Registries.[3] [12] Higher proportion of patients without cancer had severe disease (12.1%) as compared to patients with cancer (6.2%). However, this difference was statistically nonsignificant. More severe disease in noncancer patients may be explained by the pathophysiology of COVID-19 that involves the host's immune response to the viral antigen leading to cytokine-induced tissue damage.[19] Most of the cancer patients are immunosuppressed, rendering them incapable of mounting an adequate immunological response to infection and hence making them less likely to manifest symptoms.

In both groups, fever, cough, and fatigue were common symptoms among patients. However, noncancer group had significantly a greater number of patients who presented with fever and GI tract manifestations. It has been shown that SARS-CoV2 enters host cells via the angiotensin-converting enzyme receptor 2 and transmembrane protease serine 2 that are found in the type II alveolar cells of the lung, in enterocytes of colon and ileum, and in the glandular cells of the stomach, duodenum, and rectal epithelium.[20] Thereafter, COVID-19 invaded cells release many chemokines and inflammatory mediators causing a cytokine storm and aggregation of immune system cells in the GI tract.[21] Patients with cancer often have chemotherapy-induced mucositis.[22] This may interfere with the entry of the virus into the GI tract. Also as previously stated, patients with cancer are unable to mount a cytokine storm in response to COVID-19 due to their weakened immune responses. These two factors may be responsible for a low prevalence of GI manifestations in children with cancer.

In our study, 47.8% of children with cancer had lymphopenia and 39.1% had neutropenia. This is comparable to the global data which shows that 41.3% of pediatric cancer patients had lymphopenia and 32.3% had neutropenia.[12] In terms of laboratory parameters, COVID-19-infected children with cancer had significantly more leukopenia (p = 0.003), neutropenia (p = 0.003), and lymphopenia (p = 0.005). It has already been shown in previous studies that the most common hematological manifestation of COVID-19 among children is leucopenia.[23] Pediatric cancer patients with COVID-19 may be prone to develop severe leukopenia due to their underlying immunosuppressed state, chemotherapy, and also due to the additive effect of COVID-19.

Both groups received similar treatment as per the prevailing Indian Council of Medical Research protocol. There was no difference with respect to oxygen requirement and outcome. Mean period of hospital stay among cancer patients was higher (11.6 ± 6.8 days) as compared to noncancer patients (9.6 ± 5.4 days), although this difference was statistically non-significant. A higher mean duration of hospital stay among cancer patients reflects increased morbidity in them. As demonstrated in previously published literature, patients with cancer have delayed seroconversion, prolonged viral shedding, and a higher viral load following COVID-19 infection.[14] Since our discharge criteria included RTPCR negativity, hence patients with cancer had a longer mean duration of hospital stay as they took a longer time to become RTPCR negative.

The case fatality rate among cancer patients was 3.2% as compared to 1.5% in noncancer patients. The mortality rate among pediatric cancer patients in this study is similar to that reported in the Global Registry of COVID-19 in childhood cancer (3.62%). Similar to our study, a greater mortality risk in pediatric cancer patients has also been reported in a systematic review.[24] However, most studies have not reported COVID-19 as an exclusive cause of death in cancer patients. An increased risk of mortality among cancer patients may be attributable to the fragile health status of the individuals due to underlying disease, the type and stage of cancer, ongoing immunosuppressive therapy, and poor nutrition.[25]

We also tried to explore the risk factors for moderate-to-severe COVID-19 among cancer patients in terms of cancer type, staging/risk stratification, intensity of chemotherapy, neutropenia, nutritional status, and presence of coinfections. In our study, chemotherapy was continued for all cancer patients except two patients among which one was under palliation and another was a sick newly diagnosed cancer patient. There was no significant difference observed in terms of severity or outcome based on recent chemotherapy use. Similar to our study, recent chemotherapy was not associated with worse clinical outcomes in many other studies including adult cancer patients with COVID-19.[13] [26] Contrary to our results, few studies from adult cancer patients who had COVID-19 show that recent chemotherapy was associated with poor clinical outcome.[27] This may be due to the older age group of the enrolled cohort and a higher incidence of other comorbidities such as hypertension and type 2 diabetes in adult patients. However, it is well known that interruptions or delays in starting therapy lead to relapses and an increase in cancer-related mortality among pediatric oncology patients.[28] Also due to a low mortality rate among children with COVID-19, it has been suggested to continue cancer-related therapy in them.[3]

Our results show that among cancer patients with moderate-to-severe COVID-19 disease, a higher proportion of children was less than 2 years of age, was underweight, was in the advanced stage of their cancer, and had the presence of co-infections. Similar to our results, a previously published meta-analysis revealed that infants were at higher risk for severe COVID-19 and at higher risk for admission to critical care units.[29] It has been suggested in previous studies that COVID-19-induced cytokine storm can exacerbate malnutrition by causing muscle protein breakdown and albumin consumption. Malnutrition has also been considered as a risk factor for severe COVID-19 in children.[30] Another risk factor for severe COVID-19 is the presence of a coinfection. Children with coinfections often have a higher need for supportive therapy and have a higher duration of hospital stay.[31] However, these risk factors were not found to be statistically significant. Further large-scale studies are required to investigate these risk factors.

However, ours is one of the few studies to directly compare clinical characteristics and outcomes of pediatric COVID-19-infected patients with and without cancer while exploring risk factors for severe COVID-19 disease among pediatric cancer patients. It has certain limitations as well like small sample size and inability to follow up patients who were discharged. Another limitation is that the following data represents the inpatient population only and misses out on the disease characteristics of outpatient population.

Conclusion

Cancer is a significant comorbidity among pediatric patients with COVID-19. Most children with cancer have asymptomatic to mild symptoms of COVID-19. However, their case fatality rate is higher than in children without cancer. Fever and GI tract manifestations were found to be significantly less common among pediatric cancer patients. Among COVID-19 infected children with cancer, younger age, under-nutrition, advanced stage of cancer, and presence of coinfections predispose to the development of severe COVID-19. It may be reasonable to continue chemotherapy in COVID-19 infected children with cancer except those with identified risk factors for severe disease.

Conflict of Interest

None declared.

Acknowledgements

The authors are indebted to the patients, their families and staff involved in their care.

Authors' Contributions

P.K.S. conceptualized, drafted, and critically appraised the manuscript.

V.K. helped in data collection, reviewed literature, and drafted the manuscript. A.G. conceptualized, reviewed literature, and critically appraised the manuscript.

M.D., P.M., and Divyanshi helped in data collection and review of literature.

Funding

None.

Ethical Approval

Ethical approval was taken from the Institute Ethics Committee prior to commencement of this work.

Patient Consent

None declared.