The COVID-19 pandemic, caused by the SARS-CoV-2, emerged in the fall of 2019 in Wuhan, China, and rapidly spread throughout the world. In March 2020, the World Health Organization (WHO) declared the outbreak to be a pandemic, and as of August 30, 2023, the WHO has reported >770 million confirmed cases and >6.9 million confirmed deaths attributable to the disease [1,2]. More than 103 million cases and 1.1 million deaths from COVID-19 have occurred in the United States [1,3], with devastating consequences for the health system [4,5] and the well-being of the entire population [6].

The Journal of Medical Internet Research and affiliated JMIR publications, including JMIR Public Health and Surveillance, have extensively documented the global impact of the COVID-19 pandemic; a total of 99 articles have reported the results of web-based surveys and analyses of internet browsing patterns and social media postings (search terms “Rare disease” and “COVID-19,” run on July 7, 2023). For example, during the early months of the pandemic, an artificial intelligence–based analysis of >902,000 tweets was used to identify sentiments regarding COVID-19 in the United States [7], and large-scale web-based surveys were conducted in China [8,9], South Korea [10], Russia [11], and Spain [12]. Several surveys have documented a negative impact on anxiety and depression, self-reported well-being, and quality of life in the general population [11-16] and in vulnerable groups such as pregnant women [17-19], university students [20-22], older people [23,24], and health care workers [25,26].

Despite the extensive JMIR literature on the impact of the pandemic, only a single study described the experience of people living with rare diseases (RDs), which documented the impact of the pandemic on conversation patterns in the Reddit platform (subreddit r/CysticFibrosis) [27]. Indeed, the literature on the impact of the pandemic on people living with RDs is sparse even 3 years into the pandemic. A PubMed search (search terms “Rare disease” and “COVID-19,” run on July 6, 2023) identified 148 potential matches, but review of the abstracts indicated that most publications were case reports, discussion papers, or other reports that do not entail data collection from people living with RDs: only 25 articles reported results of cross-sectional surveys or longitudinal studies of patients with RD or their caregivers [28-52]. Large studies (≥50 participants) in Asia [29,37,40], Europe and the United Kingdom [30,33,36,41,49,51], the United States [45,52], and Brazil [43] reported variable impact of the pandemic, including increased risk of acquiring COVID-19 [33,37,39], increased COVID-19–related mortality [33,37], increased anxiety and depression and other psychological problems [29,30,36,41,51,52], low quality of life [41,51], difficulties with access to care [36,40,43,45,52], and difficulties complying with public health recommendations such as masking [49].

According to US laws, an RD is defined as a condition affecting <200,000 individuals at a given time [53,54]. The Genetic and Rare Disease information system of the National Center for Advancing Translational Sciences lists >10,000 RDs [55,56]. Although each condition is rare, the aggregate prevalence may amount to 30 million [55]. RDs are often difficult to diagnose [57,58], most often lack specific treatments [59], and place a significant burden on families and society [60]. Some people with RDs have primary respiratory manifestations [61], immunocompromised states [62], and chronic comorbidities including intellectual disabilities [63]. People with RDs report a lower quality of life than the general population [64]; they are vulnerable and dependent on the health care system [65].

The Rare Diseases Clinical Research Network (RDCRN) is funded by 10 of the National Institutes of Health (NIH) to promote progress in the diagnosis and treatment of RDs. The RDCRN comprises 20 Rare Disease Clinical Research Consortia and a Data Management and Coordinating Center, >200 research sites worldwide, and many patient advocacy groups that ensure that patients’ voices are heard. The RDCRN has been active for 2 decades, and >40,000 people have participated in its studies [66].

The RDCRN was strategically well placed to study the impact of the pandemic among people living with RDs in the United States. We designed a cross-sectional survey to describe the characteristics of the COVID-19 infection in this population, to determine whether patient subgroups were affected more frequently or experienced increased severity, to determine whether the pandemic changed RD symptom and treatment patterns, and to understand the broader impact of the pandemic on people living with an RD and their families.

We designed a cross-sectional survey to describe the characteristics of the COVID-19 infection in the population with RD. People who lived in the United States, had an RD, and were aged <90 years (including children of any age) were eligible for the survey. There were no explicit exclusion criteria beyond failure to meet the eligibility criteria. The survey was advertised through the internet, social media, an NIH press release, and outreach by patient advocacy groups. Interested individuals were asked to access a dedicated web page and complete a REDCap (Research Electronic Data Capture; Vanderbilt University [67]) survey instrument on the web (Multimedia Appendix 1).

The data collection instrument was designed ad hoc by the authors in spring 2020, with contributions from all the principal investigators of the RDCRN consortia (included as a group author as “The Principal Investigators of the Rare Diseases Clinical Research Network - Cycle 4” refer to the collaborators list), based on their expert knowledge of RDs. The instrument comprises 8 sections:

All these sections include a checklist of symptoms compatible with COVID-19; ask whether the pandemic interfered with access to medical care, RD treatment, and special food related to RD management; whether stay-at-home orders affected their mood or behavior; and whether the respondent or family members had to seek professional help to cope with stress and anxiety. A final question asks if the target respondent died during the interval leading to the survey. In addition to the abovementioned common questions, section 7 asks additional questions about the course of the COVID-19 infection, the need for hospitalization and special treatment (assisted ventilation), the duration of the illness, and whether the respondent received investigational drugs to treat COVID-19.

We aimed at enrolling 5000 participants based on a precision analysis, rather than a power analysis, because the survey was not designed to test specific hypotheses. At the time of planning the survey, the WHO estimates suggested that the prevalence of COVID-19 infection may be between 1% and 2%. Thus, if the patients with RD experienced the same risk as the general population, the target sample size would provide information on approximately 50-100 COVID-19 cases. As the 95% CI of 50 observed events was 37-66 based on the Poisson distribution, our estimate of the overall prevalence of COVID-19 infection among respondents would be very precise. The precision of survey measures of more common characteristics and experiences among respondents (eg, changes in access to treatment) would be much higher. Furthermore, given a sample size of 50 cases, the 95% CI of a simple mean would be between +0.25 and –0.25 SD units from the mean, affording adequate precision of measures such as the average duration of hospitalization, and estimates of rates for any categorization of the case group into 5-10 subgroups would also yield adequate precision in describing the variation in risk across population subgroups.

As the survey was conducted on the web, the REDCap survey instrument verified the eligibility of a prospective participant, provided an explanation of the objectives and process of data collection, verified consent, and gathered the required information. First, the instrument assessed the eligibility of the intended participant (ie, the person was living with an RD, was living in the United States, and was aged <90 years), automatically terminating data collection from ineligible individuals; ascertained whether the intended participant or a surrogate would be completing the survey; and ascertained whether the potential participant had participated in the RDCRN research. Next, it provided a comprehensive explanation of the study objectives and process and asked whether (1) the participant agreed to respond to the survey, provide contact information, and allow future contact for follow-up interviews and opportunities to participate in RD research; (2) if agreeing to (1), the participant further agreed to allow linkage of the survey results with data about the same individual provided as part of the RDCRN studies; or (3) the participant agreed to respond to the survey without any identifiers (1-time, anonymous response). The explanatory language clarified that no adverse events were expected except for a possible breach of confidentiality for participants who agreed to provide identifiable information and that the study team intended to minimize the risk of a confidentiality breach by keeping identifiers and survey responses in separate files and by presenting the study results in a format that would not allow the reidentification of individual patients with RD. No compensation was offered for participating in this study. The institutional review board (IRB) at Cincinnati Children’s Hospital Medical Center reviewed and approved the research protocol, all recruitment materials, and the survey instrument, including the language explaining the survey and asking for consent. The IRB granted a waiver of documentation of informed consent (IRB ID 2020-0299).

In this report, we aimed to address the following outstanding questions in the field:

We used simple descriptive statistics (frequencies and percentages for count variables and means, medians, and ranges for continuous variables) and provided 95% CIs as a measure of the precision of the estimates for survey results. Statistical hypothesis testing was used for select analyses.

To identify participants who acquired COVID-19, we used the answer to the simple survey question, “Did you acquire COVID-19?” which allowed the answers yes, no, or do not know (Multimedia Appendix 1, survey item 5.1). The 3-category answer was a pragmatic approach to identifying cases of infection because at the time we conducted the survey, access to laboratory tests remained limited.

We estimated the denominator at risk of infection considering each respondent at risk every day from the beginning of the pandemic to the day they reported acquiring COVID-19 (the outcome event) or the day they filled out the survey, whichever was earlier, as is done in retrospective cohort studies. We computed exact 95% CIs for the number of cases and the corresponding incidence rate under the assumption that the number of cases follows the Poisson distribution. We compared the monthly number of self-reported COVID-19 cases with the number expected based on data reported by the New York Times [68], computed by multiplying the national monthly infection rate by the number of respondents who were at risk of acquiring a COVID-19 infection during that month. The cases reported in the New York Times database are a mix of laboratory-confirmed cases and cases meeting the state-determined diagnostic criteria. We present the observed and expected cases in a graph and test the null hypothesis that the number of observed cases equals the expected value using an exact Poisson distribution method.

For all respondents before the beginning of the pandemic (Multimedia Appendix 1, survey instrument item 4.9) and in separate sections for the respondents who answered yes, no, or do not know to the question “Did you acquire COVID-19?” (Multimedia Appendix 1, survey instrument items 6.1, 7.3, and 8.3), the instrument asked the question, “Did you have symptoms related to COVID-19? (answer options: Yes/No),” offering a checklist of 20 symptoms (new or increased cough, fever >38.0 °C, new or increased shortness of breath, sore throat, stuffy nose, runny nose, chest pain, sneezing, wheezing, headache, muscle aches, loss of taste, loss of smell, conjunctivitis or pink eye, confusion, seizures, weakness, and other).

For 65 RD-related symptoms grouped into 18 categories, the instrument asked the questions “Please check if you had any of the following symptoms before the COVID-19 pandemic began in the USA. Think about your symptoms in January-February 2020. Check all that apply” (answer options: yes or no) and “Did anything change after the beginning of the pandemic (March 2020)?” (If the previous answer was “No,” answer options: yes or no; if the previous answer was “Yes,” answer options: symptom absent, less severe, same severity, or more severe; Multimedia Appendix 1, survey instrument item 4.6).

For 91 medications and treatments grouped into 15 categories, the instrument asked the questions “Please check if you used any of the treatments before the COVID-19 pandemic began in the USA. Think about the medications you took or treatments you routinely received in January-February 2020. Check all that apply” (answer options: yes or no) and “Did anything change after the beginning of the pandemic (March 2020)?” (If the previous answer was “No,” answer options: yes or no; if the previous answer was “Yes,” answer options: treatment not used, lower dosage, same dosage, or higher dosage; Multimedia Appendix 1, survey instrument item 4.7).

We computed odds ratios (ORs) and their 95% CIs to illustrate the strength of the association between self-reported infection and specific COVID-19–related symptoms as well as the number of symptoms.

To assess changes in the prevalence or intensity of a specific COVID-19 symptom, we compared the number of patients who reported the symptom appearing during the pandemic (ie, the symptom was absent before the beginning of the pandemic but was present afterward) with the number of patients who reported the symptom disappearing (ie, the symptom was present before the beginning of the pandemic but was not present afterward) and used an exact binomial test of the null hypothesis that the 2 counts were equal (ie, the parameter of the binomial distribution was 0.5).

To assess changes in the prevalence and intensity of a specific RD symptom, we compared the number of patients who reported the symptom appearing or increasing in intensity during the pandemic with the number of patients who reported the symptom disappearing or decreasing in intensity and used the exact binomial test of the null hypothesis that the 2 counts were equal. We used the same logic and statistical test to assess the changes in the prevalence of the use or dosage of a specific medication. We used heat maps to summarize the changes in COVID-19–associated symptoms, RD symptoms, and RD treatment before and after the beginning of the pandemic.

The instrument asked the question, “Do you have other diseases or complications related to the rare disease? Check all that apply,” offering a list of 26 comorbidity categories (Multimedia Appendix 1, survey instrument item 4.8).

We computed ORs and their 95% CIs to illustrate the strength of the association between self-reported infection and specific comorbidities, reporting the exact P value for the test of the null hypothesis of no association (ie, OR=1). We regarded a finding as statistically significant if the statistical testing of a specified null hypothesis yielded a P value <.05.

This study reports results from the largest survey assessing the impact of the COVID-19 pandemic on people living with RDs; >3000 individuals representing a wide range of RDs participated in the study. Women, adults, and White non-Hispanic individuals were overrepresented. Recruitment and data collection procedures may have discouraged the participation of minority groups, although the causes of their underrepresentation are probably broader. For instance, the racial and ethnic profile of the respondents living with myasthenia gravis was similar to that of the participants of a national registry [31], but it is possible that the registry also underrepresented minority groups. Similarly, in the National Amyotrophic Lateral Sclerosis Registry, of the estimated 25,000 prevalent cases in 2017, 64.97% (16,127/24,821) were White, 5.92% (1469/24,821) were Black. [70]. In 2012 pediatric Medicaid records, 59.38% (2872/4836) of the patients with eosinophilic esophagitis were White and 15.47% (748/4836) were Black, whereas race was missing for 11.81% (571/4836) of the patients [71]. Our survey was widely advertised and relied on outreach by patient advocacy groups. Participation of >1300 respondents with an RD not studied by the RDCRN suggests that our outreach was effective in the RD community.

Underrepresentation of minority groups may be related to the globally recognized barriers to access to RD diagnosis, specialized care and social support [72,73], and other determinants of lack of participation in research [74,75]. Spurred by these findings, the RDCRN has established a cross-consortia Diversity Committee to identify actions to support and expand the participation and engagement of research participants, family members, advocates, and research staff from underrepresented or marginalized communities.

COVID-19 infection was reported by a few respondents (71/3413, 2.08%), but the number was larger than expected. The excess cases were concentrated in the first months of the pandemic and at the end of the data collection period. Thus, individuals who experienced COVID-19 early may have been more motivated to participate in the study. Likewise, survey advertisements in late 2020 could have motivated the participation of patients with an RD who were experiencing the next surge in the epidemic in the United States. Although selection is possible, the number of self-reported infections must underestimate the incidence of COVID-19 in the RD community, as underscored by the large proportion (566/3413, 16.58%) of those who did not know if they acquired the infection. This group reported COVID-19–related symptoms far more frequently than those who did not acquire COVID-19. Given the lack of access to testing early during the pandemic, many individuals with mild COVID-19 infection may have never been diagnosed. An NIH serosurvey of a sample of the US population estimated that 5 undiagnosed SARS-CoV-2 infections occurred for every COVID-19 case, and that approximately 17 million undiagnosed infections occurred in the United States by mid-July 2020 [76]. These findings have been confirmed in independent assessments [77,78]. Thus, despite the uncertainty about the true number of cases, our results indicate that COVID-19 has had a large impact on the RD community.

Self-reported COVID-19 was not associated with specific RD conditions, but RD comorbidities were associated with increased odds of acquiring COVID-19. Respondents who acquired the infection described a mild disease, with few requiring hospitalization or critical care and only 1 death reported. A mild course of COVID-19 infections has been reported among patients with hereditary hemorrhagic telangiectasia in Italy [50], rare endocrine diseases in a European registry study [38], lysosomal storage diseases in London [79], and Gaucher disease in New York [42]; in a large group of patients with RD in Brazil [43]; and among people with myasthenia gravis in a subanalysis of this survey [52]. These reassuring findings are in contrast with higher COVID-19–related mortality among patients with RD in Hong Kong hospitals compared with in-patients from the general population [37] and people with neurological and neurodevelopmental diseases in a Genomics England cohort study [33]. We observed that the frequency and severity of RD-related symptoms worsened during the pandemic among those who reported acquiring COVID-19 or did not know compared with those who were uninfected, indicating that COVID-19 complicated the underlying RD.

We found a greater use of selected medications among those who acquired COVID-19, little change among those who did not know, and decrease in use and dosage of many medications among those who did not acquire COVID-19. We did not expect the uninfected respondents to report reduced medication use. The need for some medications may have normally decreased between the winter before the beginning of the pandemic and the early summer when most surveys were completed. Seasonal variation exists in the use of antibiotics and prescription drugs for asthma, cystic fibrosis, and other respiratory illnesses [80-83] but not for other medications evaluated in the survey. It is possible that the pandemic decreased access to care and reduced medication use among those who were not in immediate need, whereas respondents with confirmed or possible COVID-19 infection continued to use their medications. This interpretation is not fully supported by the survey responses, which suggest that the pandemic interfered with access to regular health care, treatment for the RD, and hospitalization less frequently with respondents who did not acquire COVID-19. Several studies involving patients with RD have reported reduced access to care [36,40,43,45,52], and of patient organizations [84-88] and providers [79,89-93] have reported increased difficulties in delivering care and services, negatively affecting patients with RD. However, some reports indicate that the rise in telehealth services has had a positive impact in the RD community [43,47,90]. Access to prescription medications for asthma and chronic obstructive pulmonary disease in Great Britain initially briefly increased and then declined to below prepandemic levels during 2020 [94].

We found that the pandemic caused greater mood changes, anxiety, and stress in both respondents and their family members to an extent that required medical attention. These effects were experienced by a significant proportion of all respondents.

This study had certain limitations. First, we could not determine whether respondents were representative of the RD population. However, this concern is mitigated by the representative geographic distribution and the large number of diagnoses reported by the respondents: 48.17% (1644/3413) reported a diagnosis that was not studied by the RDCRN, suggesting that the outreach effort was effective in the RD community at large. Demographics and self-reported outcomes did not vary considerably across RDs, suggesting that the same selection forces affected all respondents.

Second, the information collected pertains mostly to adult, White non-Hispanic people with RDs. Thus, we could not examine racial or ethnic disparities in the impact of the COVID-19 pandemic.

Third, the main motivation for conducting this survey was that most studies examining the impact of COVID-19 would focus on the general population and not on people living with an RD. We did not have access to a suitable comparison group; therefore, this report is based only on internal comparisons. Finally, data collection was based on self-reports, and we did not have external information to validate our observations. Our inference is based on internal comparisons, the validity of which relies on the assumption that between-group differences are unbiased.

Despite these limitations, this survey had substantial strengths. This is the largest survey conducted to learn about the experience of people living with RDs during the COVID-19 pandemic. The large number of respondents allowed a precise assessment of the prevalence and changes in symptoms and medications used during the early phase of the pandemic and robust internal comparisons among respondents who reported acquiring COVID-19 or were uncertain but had symptoms (ie, may have had an infection without a clinical or laboratory diagnosis). The survey provided a necessary assessment of the impact of the pandemic on the families of people living with RDs. Most participants stated their willingness to participate in follow-up surveys and future research. Thus, this survey provides a basis for evaluating the longitudinal impact of the pandemic on respondents and their families.

In conclusion, the incidence of self-reported COVID-19 infection in this survey of people living with RDs was higher than expected based on population rates, and many respondents were unsure if they had acquired the infection. COVID-19–related symptoms were strongly associated with self-reported infection and with unknown infection status. Although the clinical severity of the infection was not high, self-reported COVID-19 was moderately associated with RD comorbidities and was strongly associated with increased prevalence and severity of RD-related symptoms as well as greater use and dosage of certain medications. The pandemic negatively affected access to health care, RD treatment, and hospitalization; it caused mood changes and greater anxiety for respondents and their family members, requiring medical attention for some. These effects were experienced not only by those who acquired the infection but also by those who did not acquire COVID-19 during the early months of the pandemic or were unsure about it. Continued surveillance of this population is needed to inform interventions to mitigate the impact of COVID-19 and better prepare people with RDs, the health care system, and society for a future pandemic.