https://orcid.org/0000-0002-3962-3526
ABSTRACT
Background
There is a high incidence and mortality rate in children with hematologic tumors (CHT), who are more prone to various infectious diseases. This study aims to clarify the real-world National Immunization Program (NIP) vaccination status of CHT before and after chemotherapy.
Methods
Medical records, NIP vaccination data, and the Adverse Event Following Immunization (AEFI) of CHT who were admitted to the Children’s Hospital, Zhejiang University School of Medicine, from 1 January 2011 to 1 December 2021 were completely collected.
Results
A total of 2,874 CHT were included, and 1975 (68.7%) had vaccination records. Among the enrolled patients, the vaccination rate of all NIP vaccines was lower than 90% before diagnosis. Only 24.29% of CHT (410/1688) resumed vaccination after chemotherapy, and 69.02% (283/410) resumed vaccination more than 12 months after chemotherapy. No uncommon or serious side effects were reported.
Conclusion
The vaccination rate of CHT after chemotherapy was lower than that before the disease was diagnosed. It is necessary to provide more evidence-based support and formulate specific regimens to perfect the vaccination procedure after chemotherapy so as to improve the quality of life of CHT.
1. Introduction
Malignancies refer to a group of conditions that can pose serious threats to children and affect their quality of life. These diseases are characterized by multiple categories, enormous treatment difficulties, long treatment cycles, high medical expenses, and low reimbursement rates. Therefore, they have brought huge economic burdens to patients’ families and countries. Hematologic tumors are the most prevalent malignant tumors worldwide, with at least 30,000 to 40,000 new cases every year. Under the influence of heredity and social environment, tumor-induced death has become the second cause of child death (second only to accidental death) [Citation1,Citation2]. Hence, it has become a major public health problem that cannot be ignored. A baseline model estimated 360,114 total childhood cancers occurring worldwide in 2015, 54% in Asia and 28% in Africa [Citation3]. Five-year net survival rate of children and adolescents diagnosed with cancer is approximately 80% in many high-income countries [Citation4]. According to the data of the National Cancer Center from 2000 to 2010, the incidence and mortality of cancers among Chinese children reached 8.71/105 and 3.63/105 [Citation5]. The average annual registration rate of patients (0–14 years old) who were newly diagnosed with leukemia in China reached 42.9/1,000,000 from 2016 to 2018 [Citation6].
Meanwhile, the long-term quality of life of cancer patients has gradually become a major concern [Citation7]. Since tumors and relevant treatment will damage the immune function of children, the incidence of infectious diseases caused by various pathogens reaches 60% [Citation8]. Children with infectious diseases may even become an infectious source, which would endanger the health of other individuals. Compared with healthy individuals, the condition of cancer patients may get worse after infection, accompanied by a higher risk of other serious or fatal complications [Citation9,Citation10]. Although antibiotics have been widely used in clinical practice to reduce the bacterial infection burden, there is a lack of consensus about their preventive application [Citation11].
For CHT, vaccination is still the most economical and effective means to prevent infectious diseases [Citation12–14]. As stated in the National Immunization Program (NIP) initiated by the Chinese government in recent years, patients with immunodeficiency or receiving immunosuppressive treatment can be vaccinated with inactivated vaccines but are not recommended to receive live-attenuated vaccines [Citation15], for the immune function of children with cancers is impaired due to chemotherapy. However, there is still a lack of evidence-based support related to the real-world vaccination status, as well as the safety and efficacy of vaccination among these patients. These insufficiencies can lead to hesitation in vaccination among medical staff and parents of children with cancer. On account of potential safety hazards and responsibility assumption, it is common to delay vaccination for children with cancers [Citation16–18]. Currently, an immunization procedure for children with CHT in China has not been proposed. Hence, there are many challenges for this immunization program, and it is necessary to pay more attention to improving the vaccination rate among these vulnerable population. This study aims to clarify the real-world vaccination status of CHT before and after chemotherapy. The findings of this study are expected to provide foundations for the implementation of vaccination policies or health education among CHT.
2. Materials and methods
2.1. Study design
We conducted a retrospective study on CHT who were admitted to the Children’s Hospital, Zhejiang University School of Medicine, from 1 January 2011 to 1 December 2021.
2.2. Participants
A total of 2,874 CHT were included in this study. Criteria for enrolment included patients aged 0–15 years who were diagnosed with malignant hematologic tumors by specialists in hematology and patients who had received treatment for hematologic tumors. The exclusion criteria included patients complicated with malignant tumors in other systems and patients aged over 16 years at their initial diagnosis.
Based on the ages at initial diagnosis, the enrolled patients were divided into the<4-year-old group, 4–7-year-old group, and≥8-year-old group.
2.3. Data collection
Medical records of these CHT were collected from the Tumor Reporting System of the hospital, including their name, age, gender, registered permanent residence, admission date, admission number, disease diagnosis, and treatment history. Immunization records of the target population were extracted from the Zhejiang Provincial Immunization Information System, and the data of Adverse Events Following Immunization (AEFI) were collected from the Chinese national adverse event following immunization information system.
A total of 31,310 hospitalization records of CHT were collected from the tumor reporting database. Since the same patient may have multiple hospitalization records, the matching duplicate checking was conducted based on the name, birthday, and admission number.
In this study, the clinical data, NIP vaccination status, and AEFI of CHT were analyzed. Based on the name and birthday, the patients’ information was matched and retrieved from the Tumor Reporting System and the Immunization Information System. A total of 8 kinds of NIP vaccines (22 doses) for each CHT were collected, including Bacillus Calmette-Guerin (BCG) vaccine, Hepatitis B vaccine1–3 (HepB1–3), Polio vaccine1–4 (PV1–4), Diphtheria and tetanus toxoids and acellular pertussis vaccine1–4 (DTaP1–4), Diphtheria tetanus toxoids (DT) vaccine, Vaccine contains measles1–2 (MCV1–2), Meningococcal meningitis-A vaccine1–2 (MPV-A1–2), Meningococcal meningitis-AC vaccine1–2 (MPV-AC1–2), Japanese encephalitis vaccine1–2 (JE1–2), and Hepatitis A (HepA) vaccine. The vaccination rates for each type of vaccine were calculated.
2.4. Evaluation index and judgment standard
In this study, the total number of patients who received inactive Hepatitis A (HepA-I) or live-attenuated Hepatitis A (HepA-L) was counted into that of patients who received HepA. The total number of patients who received inactive Japanese encephalitis vaccine (JE-I) or live-attenuated Japanese encephalitis vaccine (JE-L) was counted into that of patients who received JE. The total number of patients who received inactivated polio vaccine (IPV) or oral live-attenuated polio vaccine (OPV) was counted into that of patients who received PV. The number of patients who received such non-NIP vaccines as HepA, HepB, DTaP-IPV-Hemophilus influenzae type B (DTaP-IPV-Hib), DTaP-Hib, and MPV-AC-Hib was counted into that of patients who received their analogs in the corresponding NIP vaccines, respectively.
The full-dose vaccination rate (%) = the number of individuals who had received a specific vaccine in full doses/the number of individuals who should receive this vaccine in full doses × 100%.
The vaccination rate of a specific vaccine (%) = the number of individuals who had received the vaccine/the number of individuals who should receive this vaccine × 100%.
The vaccination rate of a specific vaccine after treatment (%) = (the total number of individuals who had received the vaccine before and after treatment – the number of deaths in this population during treatment)/(the number of individuals who should receive this vaccine – the number of deaths in this population during treatment) * 100%.
The comparison of coverage of the vaccines is population based. Since 2007, the vaccination rate of all kinds of NIP vaccines for general population in China has been set at 90%, and the published AEFI data of the general population were 25.60–38.94/100,000 doses [Citation19].
2.5. Statistical analysis
In this study, SPSS 23.0 was used for statistical analysis. A descriptive statistical analysis was performed on the basic vaccination rate of CHT. The χ2 test was adopted to perform a comparative analysis of (1) the overall NIP vaccination status between different age groups; (2) the NIP vaccination status of CHT before and after treatment; and (3) the NIP vaccination resuming status between different age groups and different time intervals after treatment. P < 0.05 indicated that the difference was statistically significant.
2.6. Ethical considerations
This program was approved by the ethics committee of Hangzhou Center for Disease Control and Prevention (the relevant judgment’s reference number: 2021–18) and the ethics committee of Children’s Hospital Zhejiang University School of Medicine (the relevant judgment’s reference number: 2022-IRB-028).
3. Results
3.1. Demographic characteristics ()
A total of 2,874 CHT were enrolled in this study, including 1,669 males (58.07%) and 1,205 females (41.93%). The average age of these patients was 10.91 ± 5.343 years old. Six hundred and eighty-eight patients (23.9%) were under the age of 7, 1,156 (40.2%) between the age of 7 and 12, and 1,030 (35.9%) were over the age of 13 (including 13). Seven hundred and seventy-five patients were registered permanent residence in Hangzhou (27.0%), 1,598 with registered permanent residence in other cities of Zhejiang Province (55.6%), and the other 501 were with registered permanent residence in other provinces (17.4%). In terms of vaccination status, 1975 people (68.7%) were registered, while the rest were not registered (899, 31.3%). After chemotherapy, 1,688 patients (85.5%) registered, 170 (8.6%) lost to follow-up, and 117 patients (5.9%) died.
Table 1. Sample characteristics (N = 2874).
3.2. The vaccination status of NIP vaccines in CHT before chemotherapy ()
The NIP vaccination status of 1975 CHT who had vaccination records was analyzed. The results showed that the vaccination rate of these patients was lower than 90% before the initial diagnosis. HepB1 had the highest first-dose vaccination rate (89.42%), while MPV-AC1 had the lowest first-dose vaccination rate (62.77%). HepB had the highest full-dose vaccination rate (86.03%), while MPV-AC had the lowest full-dose vaccination rate (34.22%).
Table 2. Vaccination status of NIP vaccines in children with hematologic tumors before chemotherapy (N = 1975).
3.3. Comparison of the NIP vaccination status of CHT before chemotherapy between different age groups
The analysis based on the ages at their initial diagnosis revealed that there were significant differences in the vaccination rates of 8 kinds of NIP vaccines (22 doses in total) among the three groups (P < 0.001). With an increase in their age at their initial diagnosis, the vaccination rate of BCG, HepB, PV1–3, DTaP1–3, and MPV-A1–2 decreased, while that of DT and MPV-AC2 increased. Other vaccines had the highest vaccination rate in patients between the age of 4 and 7 ().
Table 3. Comparison of the vaccination rates of NIP vaccines in children at different diagnosed ages (N = 1975).
3.4. Comparison of the vaccination resuming status of CHT between different age groups and different time intervals after chemotherapy ()
The vaccination status of these CHT after chemotherapy indicated that 24.29% of patients (410/1688) resumed vaccination. Further analysis results suggested that most CHT resumed vaccination more than 12 months after chemotherapy (283/410, 69.02%), and about one-quarter of them resumed vaccination within 6 months after chemotherapy (104/410, 25.37%). Most of these children who resumed vaccination more than 12 months after chemotherapy were 7–12 years old, accounting for 55.83%; most of those children who resumed vaccination within 6 months after chemotherapy were under 7 years old, accounting for 54.81%.
Table 4. Comparison of the time of re-immunization in different age groups after chemotherapy (N = 1688).
3.5. Comparison of the NIP vaccination status of CHT before and after chemotherapy ()
A total of 1,755 doses of NIP vaccines were given to 410 CHT who resumed vaccination after chemotherapy. Except for BCG, PV3, and MPV-A2, the vaccination rates of other NIP vaccines increased to varying degrees, among which the vaccination rate of HepB1, PV1, and MCV1 was more than 95% and that of HepB2, PV2, DTaP1, and JEV1 was more than 90%. MPV-A+C2 had the lowest vaccination rate (only 40.72%). Post-immunization vaccinations for CHT were catch up of previously missed vaccinations.
Table 5. Comparison of vaccination rates of NIP vaccines before and after chemotherapy in children with hematologic tumors (N = 1688).
3.6. Safety of vaccination
The number of AEFIs and the distribution of associated clinical diagnoses were analyzed based on the AEFI case report database. There were five AEFI cases (5/25863, 19.33/100,000 doses) among 1,975 CHT included in this study. This result was similar with the reported incidence of AEFI in healthy children in recent years (25.60–38.94/100,000 doses) [Citation19]. Among these five pediatric patients with AEFI, four females and one male were all under 2 years old. Among them, one patient received BCG, one received IPV, two received DTaP, and one received DTaP-IPV-Hib. Specifically, four patients presented with general reactions (fever, redness, and induration), and one patient presented with abnormal reactions. The AEFI of these five patients was resolved after subsequent treatment. Moreover, complications, severe AEFI, and community AEFI did not occur among these patients.
4. Discussion
In this study, we found that there was a low vaccination rate among CHT before diagnosis and after chemotherapy. Male patients accounted for a large proportion, and most of these patients were under 4 years old, with acute lymphoblastic leukemia ranking first. Besides, the gender, age, and disease classification of these CHT were basically consistent with the research results at home and abroad [Citation20,Citation21].
Before diagnosis, the vaccination rate of CHT vaccine was not high, which did not meet the requirements of our country [Citation22]. Besides, the vaccination rate of booster immunization (multiple vaccinations) of all vaccines was lower than that of basic immunization (primary vaccinations), which was consistent with the findings of CAO related to the vaccination rate of Chinese children in 2012 [Citation23]. Importantly, the vaccination rate of these patients >7 years old was lower than 80%.
The possible reasons were that: (a) national vaccination requirements in China before 2006 were low; (b) many vaccines were not included in our National Immunization Program in early years; (c) vaccination records were handwritten and lacked a unified electronic information management system before 2006, which may lead to the loss of some information [Citation24]. For the reasons mentioned above, patients who were born before 2006 had a lower vaccination rate. From the geographical distribution of these patients, it was found that nearly three-quarters of them had registered permanent residence outside the city or province, and they were classified into the migrant population. Compared with the resident population, the high mobility of migrant children may block vaccination management. The complete vaccination data cannot be obtained in time during the collection across regions, and the vaccination data of some migrant children may not be transferred to immigrant places, which would also increase the difficulty of follow-up. As per some studies related to the NIP vaccination of migrant children, the parents of migrant children had a low education level and insufficient awareness of the significance of vaccination [Citation25]. Meanwhile, the medical staff in some vaccination institutions may have insufficient initiative and fail to perform vaccination screening on time. These factors may exert significant impacts on the vaccination rate of these children.
In this study, about one-quarter of CHT resumed vaccination after chemotherapy, and most of them initiated to resume vaccination more than 1 year after chemotherapy. CHT required different immune reconstruction intervals because of different chemotherapy regimens. In general, the immune function would begin to recover 1 month after chemotherapy. It would take at least 6 months to stimulate sufficient immune responses to the vaccine, and the immune function can be completely recovered after 12–24 months [Citation26]. Accordingly, in 2013, the Infectious Disease Society of America put forward guidelines for children with tumors, suggesting that inactivated vaccines could be vaccinated 3 months after chemotherapy, and live-attenuated vaccines resumed 12 months later [Citation27]. In China, these children were suggested to be vaccinated with inactivated vaccines 6 months after chemotherapy [Citation28,Citation29]. In our study, however, the majority of patients resumed vaccination 1 year after chemotherapy, which was later than the recommended time. This may be caused by the following two reasons. First, parents of CHT may worry about the risks brought by vaccination and give up the vaccination program. Second, many vaccination institutions were excessively strict with the contraindications of vaccination for these patients. Thus, there were many marks with ‘contraindications’ or ‘refusals’ in vaccination records. Medical staff and parents worried about the safety and effectiveness of vaccines, which induced the delay, rejection, or omission of vaccination. As a result, these CHT accompanied by lower immunity would be exposed to high risks to suffer from infectious diseases [Citation30].
The resuming vaccination status of CHT was also analyzed based on their ages at their initial diagnosis. It was found that patients over 7 years old had the highest resuming vaccination rate. This may be explained that the completion of NIP vaccination was one of the admission conditions for registration in primary schools in China. Therefore, parents of CHT with stable conditions at their school age (over 6 years old) were more willing to accept the vaccination. This contributed to a higher resuming vaccination rate among this age group.
Reconstruction of the immune system, especially humoral immunity, after chemotherapy in CHT is of great significance for maintaining disease remission and preventing disease recurrence and also plays an important role in immune surveillance. Compared with healthy contemporaries, the immune function of cancer patients is seriously impaired, which would induce poor or no response of the immune system to vaccines, thus leading to failure of vaccination and potential risk of spreading infections. However, there is no consensus on the specific vaccination procedures for CHT after chemotherapy. As can be seen from the follow-up data in this study, the vaccination rate of the first-dose vaccination and the second-dose booster vaccination for children who had resumed vaccination increased to varying degrees. However, there was no significant increase in the full-dose vaccination rate, which still did not reach the national standard of 90%. This indicated that the medical staff in vaccination institutions tended to perform vaccination according to the supplementary vaccination process after chemotherapy, and they did not implement the re-vaccination regimen due to chemotherapy. Moreover, immunosuppressive therapy can also decrease neutropenia counting and reduce serum antibody titer in CHT, which would result in a low immune level for a long term after chemotherapy [Citation31,Citation32]. According to some clinical practice guidelines in the US [Citation27], live-attenuated vaccines should be given at least 4 weeks before initiating immunosuppressive therapy. Additionally, some vaccines, such as pneumonia vaccine and influenza vaccine, shall be strengthened before chemotherapy for CHT. These regimens can improve the resistance of these patients during and after chemotherapy. However, there is no prospective and large-sample study on the effectiveness of vaccination before and after chemotherapy and the maintenance time of protective antibodies at home and abroad. Therefore, more evidence-based support should be provided for the scientific and reasonable arrangements of vaccination programs among CHT.
In this study, there was a low incidence of AEFI in CHT after chemotherapy, which was equivalent to that in healthy contemporaries in recent years. These adverse reactions mainly occurred in children under 2 years old, who mainly presented with general reactions, and the outcome was favorable. In this study, most patients resumed vaccination 1 year after treatment. This indicated that favorable vaccination safety can be achieved among CHT during the gradual recovery of immune functions after treatment, especially for the vaccination of inactivated vaccines.
The main strength of our study was that it was the first large sample study regarding the real-world vaccination status of children with hematologic tumors before and after chemotherapy in China. However, it was limited just because the study is based on a real-world retrospective study without a control group, so there is a lack of comparative results of vaccination rates and AEFI between children with CHT and healthy children.
5. Conclusion
CHT have a lower vaccination rate after chemotherapy than that before the disease was diagnosed. The relatively low vaccination rate in CHT would increase the risk to suffer from vaccine-controllable infectious diseases. To provide CHT with more comprehensive vaccine protection, it is required to increase the timely vaccination rate among these patients. Furthermore, it is necessary to provide more evidence-based support and formulate specific regimens to perfect the vaccination procedure after chemotherapy, so as to improve the quality of life of CHT.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Authors’ contributions
The contributions of the authors are as follows: Formal analysis, Yuyang Xu and Chai Ji; Investigation, Heping Shen, and Minyan Li; Methodology, Yuyang Xu and Yan Liu; Project administration, Yan Liu; Software, Yuyang Xu; Validation, Xuechao Zhang; Writing – original draft, Chai Ji and Yuyang Xu; Writing – review & editing, Chai Ji and Yuyang Xu.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Ethical approval
The procedures and protocols of this study were approved by the Ethics Committee of the Children’s Hospital Zhejiang University School of Medicine. The Informed Consent was waived by the Ethics Committee of the Children’s Hospital Zhejiang University School of Medicine (2018-IRB-105)
Additional information
Funding
References
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