Analysis of the current Covid-19 infection and vaccination status in patients with neurofibromatosis type 1

Background To investigate the common symptoms after Covid-19 infection, characteristics of adverse events after vaccination, changes in clinical manifestations related to Neurofibromatosis type 1 (NF1), as well as the current vaccination status and factors related to vaccine hesitation among NF1 patients, in order to provide a basis for scientific protection and vaccine acceptance in NF1 individuals in the new phase of pandemic management. Methods From December 29, 2022, to January 10, 2023, we conducted a self-assessment questionnaire survey among diagnosed NF1 patients. General data were provided including sex, age, main clinical presentations, and current treatment. This study mainly focused on the infection and vaccination status of Covid-19 among these patients with NF1. The data were statistically analyzed using SPSS26.0 software. Results Of the 250 questionnaires distributed, 226 were valid. Among the 164 patients (72.6%) with Covid-19 infection, the most common infection symptoms and incidence of patients were not significantly different from those in the normal population (P>0.05), but the incidence of symptoms such as nasal congestion, headache, myalgia, sore throat, abdominal pain, diarrhea, and eye discomfort was higher than that in the normal population (P<0.05), and no severe infection was observed; 186 patients (82.3%) had completed the Covid-19 vaccination, and more than half of those who were not vaccinated had no plans for vaccination. Among the vaccinated patients, there was no significant difference in the incidence of adverse events, such as fever, pain, redness, and swelling at the injection site after vaccination, compared to the normal population (P>0.05), but the incidence of fatigue and headache was higher in NF1 patients (P<0.001). Most patients with NF1 believe that there is no significant progressive change in NF1-related clinical manifestations after Covid-19 infection and vaccination. Conclusion Currently, some NF1 patients appear to be worried about the evolution of their disease after Covid-19 infection in the face of large fluctuations in the pandemic situation, and some patients hesitate to receive the vaccine due to their special disease condition. Thus, clinical trials should be conducted to develop a refined pandemic response and vaccination program for this special group.


Introduction
As the Covid-19 pandemic caused by the novel coronavirus SARS-CoV-2 officially entered a phase of loose control, the peak of infection in the population emerged. During this period, vaccination against Covid-19 became one of the most effective measures for the general public to strengthen baseline immunity, prevent severe infections, and establish an immune barrier among the population. Oncology patients are a susceptible group to SARS-CoV-2, with a significantly higher rate of severe illness and death in case of infection. 1 The recently published "Chinese expert Consensus on Issues related to the Protection, Treatment, and Management of Patients with Solid Tumors during COVID-19 (2022 Edition)" states that Covid-19 vaccination is equally safe and effective in patients with solid tumors. After comprehensive evaluation of the patient's physical condition and immune function, the consensus suggests that patients should be encouraged to actively receive the Covid-19 vaccine at the recommended dosage. 2 Neurofibromatosis type 1 (NF1) is a relatively rare autosomal dominant disorder caused by mutations in the NF1 gene, with an incidence of approximately 1/3 000 in the population. 3 The typical clinical symptoms include axillary and inguinal freckles, caf e-au-lait macules, and multiple neurofibromas, with cutaneous and plexiform neurofibromas being the most common and characteristic. 4,5 For patients with NF1, it is difficult to determine whether Covid-19 infection and vaccination will aggravate their disease progression. The major concern regarding disease status and lack of authoritative studies for support have caused severe anxiety and "vaccine hesitation" in some patients.
This study aims to evaluate the characteristics of the main symptoms and changes in the clinical manifestations of NF1 patients after Covid-19 infection, as well as the incidence of adverse events and the evolution of disease progression after vaccination. We conducted a questionnaire evaluation of 226 NF1 patients to investigate the current stage of Covid-19 infection and symptoms, the vaccination rate, post-vaccination reactions, and the main considerations of non-vaccinated patients. The results of this study help alleviate the confusion of NF1 individuals facing the dramatically changing status of pandemic control and provide a reference basis for the rational vaccination of NF1 patients against Covid-19.

Patients
From December 29, 2022, to January 10, 2023, we included patients with NF1 who were diagnosed by genetic testing and volunteered to participate in the study, excluding those who were unable to read, understand, or complete the questionnaire independently. The risk of this study was relatively low because no identifiable personal information of the patients was collected.

Investigation content
General data included sex, age, main clinical manifestations, and current treatment of NF1 patients. The study mainly included the severity of symptoms compared to the general population and the impact on clinical manifestations in patients with NF1 following Covid-19 infection or vaccination.

Investigation methods
A questionnaire was administered for this study. The purpose, method, and significance of the study are explained in the text and reference standards for completing the questionnaire are provided in the form of notes. A total of 250 questionnaires were distributed, and 226 valid questionnaires were completed, with a valid rate of 90.40%.

Statistical methods
SPSS software (version 26.0) was used for the statistical analysis. For comparison of the count data involved in this study, the chi-square test was used, and all statistical tests were performed using a two-sided test, with P<0.05 indicating statistically significant differences.

Characteristics of Covid-19 infection and symptoms in NF1 patients
Of the 226 NF1 patients included in this study, 164 (72.6%) were infected with Covid-19 at the time of the study, 160 of whom were infected after the pandemic was open for management (Table 1). In a previously published study, Guan et al. 6 analyzed data related to various symptoms presented on admission and during hospitalization in Chinese patients with Covid-19 infection from December 2019 to January 2020. The researchers discovered that the most common symptoms in the population were fever and cough, which is consistent with our findings. Further, we performed a statistical analysis of the incidence of common symptoms after Covid-19 infection in NF1 patients compared to the incidence of infection among the general population, and the results suggested that there was no significant difference between the two groups in the incidence of fever and cough (P¼0.120; P¼0.059). However, in the NF1 patients group, the occurrence rates of other symptoms, such as nasal congestion, headache, myalgia, sore throat, abdominal pain, diarrhea, and eye discomfort, were significantly higher than those in the normal population. In contrast, dyspnea was more common after infection in the general population (P<0.5). See Table 2.

Changes in clinical manifestations of NF1 patients after Covid-19 infection
We collected data on the surface area and color of the axillary or inguinal freckles and caf e-au-lait macules, the number of cutaneous neurofibromas, progression of plexiform neurofibromas, and trend of malignant transformation in NF1 patients before and after Covid-19 infection. We found that most NF1 patients had no significant changes in their clinical manifestations, only a small number of patients felt that their disease presentation improved or worsened further, and more of these patients thought that their disease progressed faster after infection. However, these results were unable to exclude the influence of other factors such as baseline conditions and drug treatment. See Fig. 1.

Covid-19 vaccination in NF1 patients and evaluation of adverse events
Among the 226 patients, 186 were vaccinated, and the vaccination rate reached 82.3%. Of these, 101 patients (44.7%) had received the third booster dose, 72 (31.9%) and 13 (5.7%) had received the second and first doses, respectively, and the remaining 40 patients (17.7%) had not received the Covid-19 vaccine. Of all the NF1 patients who had not received the vaccine, 24 (60%) had no vaccination plan, the most important reason being concerns about the adverse effects of vaccination on tumor progression, followed by other underlying diseases or contraindications to vaccination, and the belief that vaccination was not useful or had unacceptable side effects. See Table 3.
Compared to the data on systemic and local adverse events of Covid-19 vaccination derived from a meta-analysis published in 2022, our findings showed that there was no significant difference in local reactions, such as injection site pain, redness, swelling, and hard nodules, after vaccination between NF1 patients and the normal population (P>0.5). 7 Compared with the normal population, there was no statistically significant difference in the incidence of fever after vaccination in NF1 patients (P>0.5). However, NF1 patients had a higher incidence of fatigue and headache after vaccination than normal controls (P<0.001), and no serious adverse effects were observed in the 226 patients included in the study. See Table 4.

Changes in clinical manifestations of NF1 patients after Covid-19 vaccination
For NF1 patients who had received the Covid-19 vaccine, we collected data on the changes in clinical manifestations related to NF1 after vaccination, including axillary or inguinal freckles, caf e-au-lait macules, and the progression of tumors. The results showed that most patients were not affected by vaccination, but some patients thought their disease conditions changed after vaccination, including 25 patients (19.2%) with pre-existing cutaneous neurofibromas who thought the number of tumors or their volume increased, and 12 patients (5.6%) that thought their caf e-au-lait macules increased in size or number after vaccination. Three patients (3.2%) with preexisting plexiform neurofibromas thought that the tumor had shrunk in size or slowed in growth, and four patients (4.3%) thought that the tumor had increased in size or accelerated in growth (Fig. 2). Some patients were not evaluated for changes in their disease because they did not undergo outpatient follow-up after vaccination. At the same time, changes in the patient's condition need to exclude factors other than Covid-19 vaccination, including the influence of psychological factors, basic condition, medications, or external factors.

Discussion
Since the optimal management of the Covid-19 pandemic, the daily lives of the general public have been gradually restored, albeit with a rapid spread of the virus among the population and a very high rate of infection. During this period, vaccination plays a vital role in preventing severe infections by activating the body's innate and adaptive immune   systems. However, in challenging situations, patients with tumors, as a population susceptible to SARS-CoV-2, often have serious concerns about whether Covid-19 infection will adversely affect tumor progression, whether tumor patients should be vaccinated against Covid-19 just like individuals without tumors, the benefit-to-risk ratio of vaccination for tumor patients, and whether changes in the body's immune status caused by vaccination will further aggravate problem. A review article published in 2021 summarized 21 studies focusing on the efficacy and safety of vaccination in patients with tumors; a total of 5 012 patients were included. This provides scientific evidence to support the vaccination of tumor patients. 8 As a rare genetic disease with tumor susceptibility, NF1 is currently underrecognized and underappreciated, and a systematic treatment and management system has not been established nationwide, resulting in the poor survival of NF1 patients. Compared to common solid tumors, this group of patients is often excluded from evaluations of the efficacy of drugs and vaccines, resulting in a lack of evidence for Covid-19 protection recommendations and vaccination for NF1 patients. At the same time, previous studies have shown that serum levels of inflammatory cytokines, such as IFN-γ, TNF-α, and IL-6, are significantly elevated in NF1 patients than in the healthy population, and suggested that a strong inflammatory response may be a factor promoting neurofibroma progression. 9,10 Immune hyperreactivity in NF1 patients makes it difficult to explain whether further activation could cause accelerated progression of the disease and raises questions about the availability and dose of the Covid-19 vaccine in some NF1 patients. According to the literature, the willingness of our population to receive the Covid-19 vaccine is 91.3%, 11 and the percentage of patients in our study who received one or more doses of the vaccine was 82.3%, which is lower than that of the general population. More than half of all NF1 patients who had not been vaccinated until now indicated that they had no vaccination plans, the most important reason being concerns about the adverse effects of vaccination on tumors. This suggests that vaccine hesitancy still exists among NF1 individuals, which can harm both themselves and the establishment of population immunity. A recently published paper based on the National COVID Cohort Collaborative electronic health record data showed that severe outcomes of Covid-19 infection were not greater in the NF1 cohort than in other disease cohorts. 12 However, there is still a lack of validated research data to support the vaccination of NF1 patients, which leaves patients' concerns unaddressed. Based on our analysis of the common symptoms and changes in the condition of NF1 patients after Covid-19 infection and vaccination, we found that the most common symptoms of NF1 patients after infection were fever and cough, which were consistent with the general population and did not differ significantly in incidence. There were also differences in the incidence of symptoms such as nasal congestion, headache, sore throat, and dyspnea. Importantly, no patients with severe infection took partin our study. No serious adverse reactions were observed in patients with NF1 who had received the Covid-19 vaccine so far. Most patients reported no significant changes in the main clinical manifestations of NF1 after infection or vaccination. The findings derived from our study were consistent with those of previous studies focusing on other tumors, in which the safety and efficacy of the Covid-19 vaccine were almost equal in oncology patients and the general population. 8 The limitations of this study are that our findings rely mainly on information from patients' self-assessed data in questionnaires as well as the small sample size. Patients are in a special period, and psychological concerns about their disease status may cause some patients to overevaluate the degree of disease progression. However, the small sample size may lead to a lack of representation in the statistical results of the incidence of Covid-19 symptoms and the incidence of adverse reactions to vaccination in the NF1 patient population. However, the results of this study provide a more comprehensive picture of the severity of Covid-19 infection, the extent of adverse reactions to vaccination, and the effects of infection and vaccination on disease progression in NF1 patients, which, to a certain extent, fills the cognitive gap in this field. Currently, relevant clinical scientific data have been used to evaluate the effectiveness and safety of vaccination in patients with solid tumors, and guidance and optimization protocols have been given to explore the vaccination of tumor patients. [13][14][15][16] It is hoped that the relevant authorities can fully take into account the actual situation of the pandemic, pay attention to the needs of NF1 patients, encourage the development of large-scale clinical studies to properly guide NF1 patients to receive vaccination according to uniform regulations, and be able to receive regular follow-up to assess adverse events and changes in their condition to reduce the psychological and physical burden of the complex pandemic situation on NF1 patients.

Conclusion
At the turning point of pandemic control, NF1 patients as a rare genetic disease population with tumor susceptibility, are often excluded from epidemic protection and vaccination-related studies, resulting in a continued lack of scientific guidance. This study aimed to fill this gap by investigating the current status of new coronary infections and vaccinations in NF1 patients, as well as the impact of Covid-19 infection and vaccination on NF1-related clinical manifestations.

Ethics approval and consent to participate
The study was approved by the Ethics Committee of Shanghai Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine (approval no: SH9H-2023-T25-1). All participants provided written informed consent prior to study enrolment.

Consent for publication
All patients gave written informed consent to publish the data contained within this study.