SARS-CoV-2 in pediatric cancer: a systematic review

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan challenges pediatric oncologists in an unexpected way. We provide a comprehensive overview, which systematically summarizes and grades evidence (QoE) on SARS-CoV-2 infections in pediatric cancer patients at 1.5 years of pandemic. A systematic literature search in PubMed combined with an additional exploratory literature review in other international databases was conducted to identify studies on children (aged < 18 years) with a malignant disease and COVID-19 infections. In total, 45 reports on 1003 pediatric cancer patients with SARS-CoV-2 infections were identified out of 1397 reports analyzed. The clinical course of COVID-19 was reported mild or moderate in 358 patients (41.7%), whereas 11.1% of patients showed severe COVID-19. In 12.7% of patients, chemotherapy was postponed, whereas 19% of patients with different underlying malignancies received chemotherapy during SARS-CoV-2 infection. Twenty-five patients with SARS-CoV-2 infections died, potentially related to COVID-19. Conclusion: Despite a favorable COVID-19 outcome in most pediatric cancer patients, the morbidity is reported higher than in children without comorbidities. However, no severe COVID-19 complications were associated to the continuation of chemotherapy in some cohort studies and reports on two patients. Therefore, the risk of cancer progress or relapse due to interruption of chemotherapy has carefully to be weighed against the risk of severe COVID-19 disease with potentially fatal outcome. What is Known: • Most of pediatric patients with malignant diseases show an asymptomatic, mild or moderate clinical course of SARS-CoV-2 infection. • Current need for a basis for decision-making, whether to stop or interrupt cancer treatment in a patient infected with SARS-CoV-2, and when to continue chemotherapy. What is New: • Review results comprising over 1000 pediatric COVID-19 cancer patients confirm mild courses of SARS-CoV-2 infection in most patients but also show the attributable mortality is at least 10 times higher compared to reports on hospitalized children without comorbidities. • Review identifies that chemotherapy was continued despite SARS-CoV-2 positivity in 18% of patients with individual chemotherapy modification according to the clinical course of SARS-CoV-2 infection and existing comorbidities. On this basis, no severe COVID-19 complications were associated to the continuation of chemotherapy in several cohort studies and two case reports. Supplementary information The online version contains supplementary material available at 10.1007/s00431-021-04338-y.


Introduction
Pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has considerably affected pediatric oncology services worldwide. Multiple SARS-CoV-2-related effects on both population and individual patient levels have emerged. For example, delayed hospital admissions or the reduced availability of chemotherapeutic drugs have led to substantial disruptions of cancer diagnosis and management [1][2][3]. In addition, it remained unclear, which cancer patients were at high risk for a severe clinical course, whether to stop or interrupt cancer treatment in a patient infected with SARS-CoV-2, and when to continue therapy, all questions which might have an important impact on overall outcome.
The aim of this systematic review was to update the available information on SARS-CoV-2 infections in pediatric cancer patients and to grade existing evidence as defined by the European Society of Clinical Microbiology and Infectious Diseases (ECCMID) [28] to optimize the rational management for this vulnerable group of patients.
All manuscripts published after the onset of SARS-CoV-2 pandemic (December 2019) were included. Search results were narrowed by the following filters (primary review inclusion criteria): species = human and language = english. Studies were included if patients were pediatric patients as defined by age up to 18 years. References were included in the analysis if SARS-CoV-2-positive patients had an underlying malignant disease and had received or were receiving immunosuppressive therapy. Detections of SARS-CoV-2 by rtPCR or Rapid Antigen Detection Test (RADT) were accepted. Two reviewers (SaS and NT) independently evaluated the titles and abstracts of publications identified by the search strategy, and all potentially relevant publications were retrieved in full text. The final decision to include studies into the systematic review was consented by all authors. According to the Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) [27], we added the quality of evidence (QoE) following the grading system proposed by the European Society of Clinical Microbiology and Infectious Diseases (ECC-MID) [28]. We additionally added codes for QoE level III to provide most comprehensive grading information. The codes for QoE level III were defined as follows: RA opinions of respected authorities, EC consensus of expert committees, CE based on clinical experiences of experts, CS based on descriptive case studies and CR based on case reports.

Procedure of data analysis
After matching the review search inclusion criteria, the eligibility of all retrieved studies and reports was assessed on full text manuscripts. During this process, 45 publications were evaluated via modified consort criteria for transparent reporting. From all manuscripts meeting the eligibility criteria, data were obtained and integrated into evidence tables (Table 1 and Online Resource 1). The clinical courses of SARS-CoV-2 infections of all pediatric cancer patients were classified according to Dong et al. [32].

Cohort analysis of SARS-CoV-2-infected patients
The results of the systematic and non-systematic searches and the decisions concerning the inclusion and exclusion of the retrieved articles are described in Fig. 1. A total of 45 original articles and ten reviews were retrieved from 1397 articles analyzed. The original studies include 1 survey, 10 case series, 19 case reports, 3 prospective cohort studies, 7 retrospective cohort studies, 4 multicentric studies, and 1 cross-sectional cohort study. The dates of online publications ranged between April 2020 and October 2021.
Data from pediatric cancer patients of 5 continents (Europe, North America, South America, Asia, Africa) were assessed comprising 39 cohorts of children below 18 years of age and 6 cohorts of children and adults. In these studies, the number of all SARS-CoV-2 patients reported varied between a case report on one patient and 179 patients described in a multicentric cohort study (QoE between III CR and II T , median: 24 patients per study). The reason for SARS-CoV-2 testing was only sporadically reported. In 33 studies, SARS-CoV-2 infections were identified by nasopharyngeal swabs (73.3%), in one study by throat swabs (4.4%), and ten studies did not comment on the material for SARS-CoV-2-detection (22.2%). SARS-CoV-2-positive results were obtained by rtPCR in 41 studies (91.1%). In all studies no SARS-CoV-2 variants were reported. Twenty one of 45 publications reported on inpatients with SARS-CoV-2 infection (46.7%) as well as one publication reported on outpatients (2.2%). In 23 studies, patients received inpatient and outpatient medical care during SARS-CoV-2 infection (51.1%). An overview on the study results of 15 studies on pediatric COVID cancer patients is presented in Table 1.

Analysis of individual SARS-CoV-2 patients
In total, 79 patients with SARS-CoV-2 infection were retrieved from all reviewed studies, including studies with QoE II U , II T , II CR , and III CS . Of these 79 patients, 45 were male (57.1%), 17 female (33.0%), and the gender of 8 patients (10.1%) was not reported. The median age was 8 years and varied between 6 months and 17 years.

Types of underlying malignancy
The most common malignant disease reported was acute lymphoblastic leukemia (ALL) in 40 patients (50.1%), followed by AML in eight patients (10.1%). Four patients each (5.1%) had malignant teratoid rhabdoid tumor, Wilms' tumor, hepatoblastoma or lymphoma. Three patients each (3.8%) had osteosarcoma or neuroblastoma. Two patients were reported with melanoma (2.5%) and two patients with myelodysplastic syndrome (2.5%). One patient had a CNS glioma (1.3%), and one patient had a mixed germ cell tumor (1.3%). Four patients acquired the SARS-CoV-2 infection 3 to 5 months after hematopoietic stem cell transplantation (5.1%). Three of these patients suffered from graft-versushost disease (one male and two female patients, all with grade III) [21][22][23].

Data on chemotherapy
During the time of SARS-CoV-2 infection onset, 55 patients received first-line intensive chemotherapy or were on oral maintenance therapy (69.6%), 15 patients were in remission (18.9%), 8 patients had progressive disease and received various individual rescue treatment regimens (10.8%), and one patient had refractory malignant diseases and was on palliative oral chemotherapy (1.5%).
In 2 patients without therapy modification, no SARS-CoV-2 related complications were observed. In the other 14 patients the detailed clinical courses were not described. In 51 patients (64.6%), no data concerning treatment modification were available. The clinical courses of both SARS-CoV-2-positive patients without chemotherapy modification were as follows: in a 17-year-old girl the SARS-CoV-2 PCR was positive at day 0 after HSCT in cause of AML subtype 5, treated by Mye child high-risk protocol [21]. She only had mild rhinitis and showed no other viral reactivation. She developed a GVHD grade III (cutaneous and digestive) treated with corticosteroids. After 3 months her bone marrow showed a complete donor chimerism. After the positive SARS-CoV-2 PCR result, her treatment with prednisolone (0.4 mg/kg/day), cyclosporine (4 mg/kg/ day), and ACE inhibitors (0.12 mg/kg/day) was not postponed. She received intravenous immunoglobulins and her preventive antiinfectious treatment was regularly continued with sulfamethoxazole-trimethoprime, posaconazole, phenoxymethylpenicillin, and valacyclovir. The chest CT revealed scattered ground-glass opacities on day 7. She remained SARS-CoV-2-PCR-positive on days 21 and 42. Anti-SARS-CoV-2-IgM antibodies could be detected on day 14 and remained positive on day 56. Anti-SARS-CoV-2-IgG antibodies were positive on day 56. All in all, it was reported as a mild course of infection. The other patient was a 5-year-old boy with precursor B cell ALL with standard risk [42]. He presented with fever and petechiae. Clinical neck swelling associated with swollen lip and tongue as well as with inspiratory stridor while oxygen saturation was normal. His chest ray showed peribronchial sickening. His TWCC was 6.76 × 10 9 /l. He was treated with remdesivir for 5 days in parallel to the start of ALL induction therapy. He was monitored by daily blood tests. On day 3 an increased ALT was recognized, which peaked at 408 U/l on day 5. In summary, a mild course was reported, and he could be discharged home on day 8. At the end of induction therapy, bone marrow showed a morphological remission with undetectable minimal residual disease. SARS-CoV-2-PCR also remained negative.

Discussion
To the best of our knowledge, this review comprises the largest cohort reported on pediatric cancer patients with COVID-19 summarizing evidence of 45 articles after systematic literature search and comprehensive analysis of in total 1397 articles at the time of 1.5 years of SARS-CoV-2 pandemic. In comparison to previous reviews, this review focuses unambiguously on pediatric cancer patients and provides quality of evidence levels (QoE) assigned to every study included in the review. The QoE definitions were used as proposed by the European Society of Clinical Microbiology and Infectious Diseases [28] and supported for adult cancer patients by the Guideline by the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO) [27]. With respect for this grading system and the intention for its best possible use, we added extra codes for QoE level III, which we also suggest using in future for providing most comprehensive grading information for recommendations.
Our meta-analysis revealed that out of 1003 reported pediatric cancer patients with SARS-CoV-2 infection, 23.9% of patients were asymptomatic and the clinical courses of COVID-19 were mild or moderate in 41.7%. In 11.1% of patients the clinical courses of COVID-19 were severe, and 25 patients (2.5%) eventually died related to COVID-19. These results point towards a more favorable situation in pediatric cancer patients compared to adults with malignant disease (QoE II T ) [43], most probably due to a lesser prevalence of other underling conditions and comorbidities, and due to the higher risk of an adverse outcome of SARS-CoV-2 infection in patients over 65 years (QoE II T ) [44]. However, these data do not rely on prospective cohort studies in which all pediatric cancer patients are regularly screened for SARS-CoV-2. Therefore, there is no tentative denominator to comment on COVID-19 related hospitalization rates, morbidity and mortality (QoE III EC ) [48], and the true incidence of SARS-CoV-2 detection and COVID-19 in pediatric cancer patients remains unknown. Of note, despite a mild course of SARS-CoV-2 infection was reported in most of the cancer patients (QoE II T [40], QoE II T [41], QoE II T [46], QoE II T [47]), the attributable mortality of 6.7% is at least 10 times higher compared to reports on hospitalized children without comorbidities (QoE II T ) [44]. However, most studies (QoE III CR [10], QoE II T [23], QoE III CR [34], QoE III CR [35], QoE III CR [18], QoE II U [38], QoE II U [39], QoE II T [40], QoE II U [49]) did not clearly differentiate between deaths related to COVID-19 and death due to cancer progression. Only two studies explicitly report on one patient out of 54 as well as on four patients out of five with COVID-19-related deaths, respectively (QoE II U [48], QoE II T [41]). One multicenter cohort study reported on an increased mortality of pediatric patients who had completed cancer treatment or had undergone HSCT compared with patients on active treatment (QoE II T ) [41]. An Algerian study reported on a very high case fatality rate of 28% and pointed out that differences in the use of critical care resources could have influenced the outcome of cancer patients with SARS-CoV-2 infections, which potentially increases the vulnerability of cancer patients in limited resource settings (QoE III CS ) [36]. In many of the reviewed studies, the reason for SARS-CoV-2 testing was not mentioned. One large cohort study (QoE II U ) [50] and one case series (QoE III CS ) [20] recommend routine PCR-based SARS-CoV-2 screening in immunocompromised children to guide management and the ongoing risk of transmissions. Especially when the incidence of newly diagnosed SARS-CoV-2 infections is high in the attending region, an admission screening is performed in most pediatric cancer centers (QoE II T ) [51]. This approach seems reasonable and may explain the detection of SARS-CoV-2 in asymptomatic patients. In line, our meta-analysis on individual patients revealed 27.8% asymptomatic SARS-CoV-2-positive cancer patients in comparison to 70.9% cancer patients showing clinical symptoms at the time of SARS-CoV-2 positivity (QoE II U , II T , III CS , II CR ). If clinical symptoms (such as fever or gastrointestinal symptoms) are attributes of SARS-CoV-2 infection or common side effects in pediatric cancer patients receiving chemotherapy may be difficult to differentiate.
Regarding SARS-CoV-2 infection route, it was reported that most SARS-CoV-2 infections in children derive from a close adult contact (e.g., family or household member; QoE III CR [5], QoE III CR [6], QoE III CS [20], QoE III CR [21], QoE II U [30]). In the reviewed dataset, 16 patients (20.3%) acquired the infection from family members, whereas in 86.4% of all patients the origin of SARS-CoV-2 infection was not reported. However, these data underline the importance to provide the whole family with detailed information on preventive strategies (QoE II U ) and the need for SARS-CoV-2 vaccination of all close contact adults (including all healthcare workers) and adolescents (QoE II T ). Many studies recommended strict adherence to effective hygiene measures (such as hand hygiene, social distance in public places, wearing masks correctly) and ward management for risk reduction of SARS-CoV-2 transmission (QoE II U [30,50]).
Besides the complex issues of infection prevention in pediatric oncology units, several reports on different treatment options against COVID-19 exist in pediatric cancer patients [24-26, 36, 45, 49, 53]. Whereas early studies reported on hydroxychloroquine administration (QoE III CS [36], QoE II U [49], QoE III CS [53]), no case-control study revealed a relevant benefit of hydroxychloroquine in pediatric cancer patients. Two studies reported on reconvalescent plasma to treat patients with severe COVID-19 (QoE III CR [22], QoE III CR [54]). However, the Guideline by the Infectious Diseases Working Party limit their recommendation on the effect of reconvalescent plasma (QoE III CR ) [27,56]. Systemic steroids, which are an integral component of most leukemia protocols, were reported to be beneficial in three symptomatic SARS-CoV-2-positive patients (QoE III CR ) [54,55]. However, without a comparable (at least propensity-matched) control group, this effect may also be difficult to illuminate.
Early reports did not often comment on whether treatments directed against COVID-19 had any positive impact on the course of the disease. However, two studies recommended antiviral treatment that could be beneficial in managing severe courses of SARSCoV-2 infection to shorten the time of recovery and allowing earlier administration of chemotherapy (QoE I U [39], QoE III CR [42]).
The decision whether and how to proceed with anticancer treatment remains a major challenge for the attending pediatric oncologists facing patients with a positive SARS-CoV-2 test result. In these patients, the risk of cancer progress or relapse due to interruption of chemotherapy has to be weighed against the risk of severe COVID-19 disease with potentially fatal outcome. The fact that chemotherapy was continued in 14 of 79 patients of our meta-analysis despite SARS-CoV-2 positivity clearly demonstrates the conflict of different aims. Several studies (QoE II T [23], QoE II U [49]) recommend a multidisciplinary decision approach on treatment postponement, modification, or continuation in these situations. To overcome an individualized interdisciplinary clinical and ethical decision process, the characterization of prognostic factors for severe COVID-19 disease courses is recommended in two studies (QoE II T [41], QoE III CR [55,56]). Unfortunately, blood parameters are only reported sporadically and often lack temporal relation to SARS-CoV-2 infection, which significantly limits further analysis of prognostic factors. In contrast to studies, in which the majority of anticancer treatment was postponed (QoE III CS [15], QoE II T [23], QoE II T [50]), some reports recommend individual chemotherapy modification according to the clinical course of SARS-CoV-2 infection and existing comorbidities (QoE I U [39], QoE II T [41], QoE II U [49]).
In conclusion, our data indicate that SARS-CoV-2 infection in pediatric cancer patients results in a severe clinical course in the minority of patients (QoE II T [41], QoE II T [46]). As most children are infected by a close adult contact (QoE III CR [5], QoE III CR [6], QoE III CS [20], QoE III CR [21], QoE II U [38]), vaccination of adults could be an important strategy (QoE II T [52]). Continuation of chemotherapy in individual pediatric cancer patients with SARS-CoV-2 infection seems possible (QoE II T [23], QoE II T [47]), but more data is needed before solid recommendations can be made. More information on pediatric cancer patients with SARS-CoV-2 infection in prospective national and international data registries would be helpful as well as an international guideline on the management on pediatric patients with SARS-CoV-2 infections.
Authors' contributions All authors planned the study and consented the search criteria. SaS and NT performed the systematic literature search and constituted the summary of findings tables. TL and AS supplied further articles from their reference manager. All authors contributed to the article and approved the submitted version.
Funding Open Access funding enabled and organized by Projekt DEAL.

Availability of data and material
The Supplementary material of this review is available in Online Resource 1. All data are available from the corresponding author upon reasonable request.
Code availability Not applicable.

Declarations
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Consent to participate Not applicable.
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Conflict of interest The authors declare no competing interests.
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