To the Editor: Since December 2019, the coronavirus pandemic has been the deadliest disaster with over 6.5 million people confirmed to have died in less than 3 years.[1] The coronavirus disease 2019 (COVID-19) has created the biggest global crisis in generations. Children are less likely to develop severe illness than adults, but children with cancer are more likely to develop a serious clinical course and even die after the infection.[2,3] Since early 2022, the Omicron variant has become the main variant of SARS-CoV-2 across the globe. In the first three years of the pandemic when China has taken very strict infection control measures, the number of reported cases of COVID-19 infection in China was low and children with cancer were rarely affected by the COVID-19 infection. Since early December 2022, China has changed the infection control policy for COVID-19 and allowed more flexible approaches to patients infected with COVID-19. The number of infected cases increased rapidly in the subsequent two months and reached the peak of more than 40 million per week in mid-December 2022.[4] Although vaccination rate against COVID-19 was high in China in general, the Omicron variant has very high infection rate and vaccination may only protect patients from serious illnesses.
As most of the children with cancer had not been infected with COVID-19 in the past few years, they did not acquire the immunity against SARS-CoV-2. The vaccination rate in children with cancer was also low. Acute lymphoblastic leukemia (ALL), the most common malignancy in children, requires intensive chemotherapy for 2.0–2.5 years and in some also allogeneic hematopoietic cell transplantation, which causes severe immunosuppression. The data of COVID-19 infection among children with ALL in China are scarce, and the impact of the infection at various treatment phases is unknown. This study aims at evaluating the prevalence of COVID-19 infection and its clinical course among children treated in two consecutive China Children Cancer Group (CCCG) ALL clinical trials for newly diagnosed ALL, CCCG-ALL 2015 and CCCG-ALL 2020 studies, and those for relapsed disease on the CCCG relapsed ALL 2017 study.
A survey through the internet network was sent to all participating centers of the CCCG ALL studies (See supplementary materials, http://links.lww.com/CM9/C52 for the full coauthors list).[5] The centers would report on COVID-19 positive cases to the Data Centre at Shanghai Children’s Medical Centre (SCMC). The data were collected by healthcare workers of study centers and retrieved electronically using the online survey software Wenjuanxing (www.wjx.cn, Changsha Ranxing Information Technology Co., Ltd., China). The eligibility of the cases include the following: (1) the cases of ALL diagnosed and managed at the CCCG ALL study centers, (2) the cases receiving chemotherapy on one of the three clinical trials or within one year after completion of chemotherapy, hematopoietic stem cell transplant (HSCT), or chimeric antigen receptor T-cell (CAR-T) therapy, and (3) the cases who were confirmed to have COVID-19 infection either by reverse transcription-polymerase chain reaction (RT-PCR) or rapid antigen test (RAT) for SARS-CoV-2 in a clinical specimen, either nasal swab or pharyngeal swab. The study period was confined to December 1, 2022 to January 31, 2023, the peak period of the COVID-19 pandemic in China.
The primary objective of this study was to evaluate the prevalence of severe COVID-19 infection (i.e., oxygen requirement, hospital or intensive care unit [ICU] admission, ventilator support, and mortality). The secondary objectives were: (1) to assess the demographic data of the patients with COVID-19 infection; (2) to evaluate the impact of prior vaccination; and (3) to evaluate the impact of the intensity of treatment on the severity of COVID-19 infection.
Ethical approval was obtained at SCMC for conducting the survey study of COVID-19 infection with waive of consent. All the patients had previously signed consent for the CCCG ALL studies.
Categorical variables are presented with frequencies and percentages, and continuous variables with median and range. Univariable analysis of risk factors for oxygen requirement and hospital admission from community was performed with logistic regression model. Associations between two categorical variables (treatment status and lymphocytes count) were tested by the Fisher’s test. Statistical tests were two-sided and P values <0.05 were considered nominally significant. All statistical computing was done by the statistical software R, v.4.1.3. (R Project for Statistical Computing [https://www.r-project.org/]).
Between December 1, 2022 and January 31, 2023, there were 675 COVID-19 positive cases reported by 19 centers [Supplementary Table 1, http://links.lww.com/CM9/C52]. The median age was 5.1 years (range 0.5–17.1 years). Of these, 427 patients (63.3%) were boys and 248 were girls (36.7%). Among this cohort, 511 patients (75.7%) were staying in community for at least 7 days before diagnosis of COVID-19 infection, and 149 children (22.1%) had returned to school. The other patients within 7 days of diagnosis of COVID-19 infection were staying in hospital mainly for the chemotherapy treatment. Over 97% of the family members were also infected with COVID-19 during the same period. Before the COVID-19 infection, 184 patients (27.3%) had received at least two doses of COVID-19 vaccine. At the diagnosis of COVID-19 infection, most patients were still on chemotherapy and only 94 patients (13.9%) had completed chemotherapy within one year. COVID-19 infection caused treatment delay in 209 patients (36%). The median time of treatment delay was 8 days (range 11–60 days). Twenty-four patients received allogeneic transplantation or CAR-T therapy.
Among the 675 patients, the most common symptoms were fever (78.8%), cough (57.2%), fatigue (29.5%), and sore throat (26.4%) [Table 1]. Diarrhea was observed in only 8.9% and dyspnea in 1.3% of the patients. There were 140 (20.7%) patients with minimal or no symptoms who did not require any treatment. Only 39 (5.8%) patients had radiological findings of pneumonia by chest X-ray or CT scan. Before the onset of COVID-19 infection, 77 (11.8%) patients had neutrophil count below 0.5 × 109/L and 32 (5.3%) had lymphocyte below 0.3 × 109/L. Symptomatic treatment was provided for most patients and included antipyretics (71.4%), antibiotics (12.4%) for concurrent fever, and neutropenia and granulocyte colony stimulating factor (4.7%) for neutropenia. Specific anti-viral agent, paxlovid, was only given to 7 (1.0%) patients.
Table 1.
Symptoms, care, test, and treatment for COVID-19 infection in ALL patients (N = 675).
| Characteristics | N | Percentage (%) |
|---|---|---|
| Symptoms | ||
| No symptoms | 40 | 5.9 |
| Fever | 532 | 78.8 |
| Cough | 386 | 57.2 |
| Fatigue | 199 | 29.5 |
| Sore throat | 178 | 26.4 |
| Headache | 124 | 18.4 |
| Myalgia | 119 | 17.6 |
| Dizziness | 100 | 14.8 |
| Chills | 90 | 13.3 |
| Vomit | 68 | 10.1 |
| Nausea | 65 | 9.6 |
| Ageusia | 64 | 9.6 |
| Diarrhea | 60 | 8.9 |
| Anosmia | 39 | 5.8 |
| Chest pain | 11 | 1.6 |
| Dyspnea | 9 | 1.3 |
| Treatment | ||
| No treatment | 140 | 20.7 |
| Antipyretics | 482 | 71.4 |
| Paxlovid | 7 | 1.0 |
| Granulocyte colony-stimulating factor | 32 | 4.7 |
| Antibiotics | 84 | 12.4 |
| Oral | 40 | 5.9 |
| Intravenous | 44 | 6.5 |
| Intravenous immunoglobulin | 19 | 2.8 |
| Corticosteroids | 5 | 0.7 |
| Oxygen support | 11 | 1.6 |
| Ventilator support | 4 | 0.6 |
| Place of care | ||
| Hospital admission from community | 35 | 6.8 |
| Pediatric ICU treatment required | 5 | 0.7 |
| Laboratory tests* | ||
| Lymphocytes count | ||
| <0.3 × 109/L | 32 | 5.3 |
| ≥0.3 × 109/L | 570 | 94.7 |
| Neutrophil count | ||
| <0.5 × 109/L | 77 | 11.8 |
| ≥0.5 × 109/L | 578 | 88.2 |
| Radiological imaging* | ||
| Pneumonia changes | 39 | 5.8 |
ALL: Acute lymphoblastic leukemia; COVID-19: Coronavirus disease 2019; ICU: Intensive care unit. *Data are not available in all patients.
Among the 511 patients who stayed at the community, 35 (6.8%) patients required hospital admission for the management of COVID-19 infection. Of the 11 patients who required oxygen supplement during hospitalization, 5 required intensive care and 4 of them needed ventilatory support. Of the five patients who required intensive care, two patients were at the induction phase, one at the re-induction phase, and one at the maintenance phase during second remission. These four patients recovered from COVID-19 infection and were discharged from the ICU after 1–11 days. The only patient with relapsed and refractory ALL after CAR-T therapy and allogeneic transplantation died of COVID infection.
Risk factors predicting for oxygen requirement included T cell ALL (odds ratio [OR], 5.4; 95% confidence interval [CI], 1.4–18.2; P = 0.009), treatment during remission induction (OR, 9.4; 95% CI, 2.0–48.9; P = 0.004), and neutrophil count <0.5 × 109/L (OR, 4.5; 95% CI, 1.1–15.2; P = 0.02) [Supplementary Table 2, http://links.lww.com/CM9/C52]. Patients with intermediate or high-risk ALL (OR, 4.1; 95% CI, 1.0–27.1; P = 0.07) and those with lymphocyte count <0.3 × 109/L (OR, 4.2; 95% CI, 0.6–17.0; P = 0.08) also tended to require oxygen supplement. Risk factors for the requirement of hospitalization included the presence of pneumonia (OR, 25.0; 95% CI, 10.1–63.3; P <0.001) and being on therapy for ALL (P = 0.005). While 33 of 412 patients receiving active treatment for ALL were hospitalized for COVID-19 infection, no hospitalization was happened in the 75 patients who had completed treatment [Supplementary Table 3, http://links.lww.com/CM9/C52]. Notably, COVID-19 vaccination had an impact on neither oxygen requirement nor hospitalization.
In the early period of COVID-19 pandemic, the mortality from COVID-19 infection was high, especially for patients with immunosuppression.[6] Favorable outcomes of SARS-CoV-2 infection were reported in pediatric hematology patients during the second and third pandemic waves in Italy between April 2020 and May 2021.[7] Of the 153 infected patients, 100 were asymptomatic and 41 had a mild clinical course; moderate, severe, and critical courses were reported in only 2, 5, and 5 cases, respectively.[7] In a retrospective report of 201 hospitalized non-tumor children with SARS-CoV-2 infection in China, 83% of them displayed symptoms that were generally mild.[8] Likewise, this wave of Omicron infection caused mild illness in our study of children with ALL even though the majority of them were still receiving chemotherapy. Among the 675 children with ALL, only one with refractory disease who had received very intensive treatment including CAR-T cells and allogeneic transplantation died of COVID-19 infection. Severe infection requiring oxygen supplement is uncommon (1.6%), and ICU admission or ventilator support only happened in five patients.
In our study, low neutrophil count was associated with severe illness requiring oxygen supplement but not hospital admission. The value of vaccination to prevent infection of COVID-19 in children on chemotherapy, especially for those after transplantation, remains uncertain. Among our COVID-19 confirmed cases, 27.3% of them had received at least two doses of COVID-19 vaccine. Our study did not have the power to analyze the protective effect of COVID-19 vaccination in children treated with chemotherapy, nor the efficacy to prevent serious illness or mortality. However, we would still advocate the children on immunosuppressive treatments to receive the vaccination, similar to the seasonal influenza vaccination.
In conclusion, this wave of Omicron infection caused mild illness in children even when they were receiving chemotherapy for ALL. Most of the patients did not require specific anti-viral treatment and recovered. The only mortality was observed in a child with uncontrolled leukemia after intensive treatments. Suspension of chemotherapy may not be necessary in most patients or should be limited to minimal duration. This study provided data to support clinicians in reassuring parents and patients on the mild nature of Omicron infection.
Funding
The operation of Data Center was supported by the VIVA China Children’s Cancer Foundation, and the American Lebanese and Syrian Associated Charities (to C.-H.P. and C.C.).
Conflicts of interest
None.
Footnotes
How to cite this article: Cai JY, Li CK; on behalf of the CCCG ALL Study Group. COVID-19 infection in children with acute lymphoblastic leukemia in China: Mild clinical course after Omicron infection. Chin Med J 2024;137:2008–2010. doi: 10.1097/CM9.0000000000003183
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