Clinical Characterization of Patients with Rare Diseases Who Had Covid-19 or Covid-19 Like SymptomsAbstract
COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, first identified in China, which later gave rise to a global pandemic. Little is known about the impact of COVID-19 on patients with rare diseases. More than 8,000 rare diseases have been identified, which makes this quite a significant contingent of patients. This study aims to characterize SARS-CoV-2 infection in unvaccinated patients with rare diseases. Data were collected by means of a specific form distributed to medical teams involved in the care of rare diseases and disseminated to communities of patients with rare diseases via social networks in Brazil and Argentina. COVID-19 infection was characterized in 75 patients (82.7% with confirmatory tests), both pediatric and adult (age 6 months to 64 years), representing 40 different genetic and non-genetic rare diseases. Inborn errors of metabolism (IEM) accounted for most genetic cases. Fifty-nine patients (78.7%) required medical care, of which 17 (22.6%) required hospitalization. Three patients (4%) died due to complications from COVID-19 (Glycogenosis type II, 50 years old; Mitochondrial Myopathy, 11 years and Trisomy 18, 0.5 years). Extreme patient ages and diseases characterized by muscle involvement were associated with worse COVID-19 outcomes.
Keywords:
COVID-19; Rare diseases; Genetic diseases; Inborn errors of metabolism
Introduction
Coronavirus disease 19 COVID-19, a disease caused by infection with the SARS-CoV-2 virus, was first reported in Wuhan, China, in December 2019 and was declared a global pandemic by the World Health Organization (WHO) in March 2020. The first case of COVID-19 in Brazil was reported on February 26, 2020, and measures to contain the spread of the virus were subsequently implemented.
Brazil has been one of the countries most severely affected by COVID-19, with approximately 37.5 million cases and more than 702,000 deaths reported by May 2023 [1]. Worldwide, at least 766 million people have been infected and 6.9 million have died [2]. February 2021 saw a marked increase in cases and deaths, largely due to emergence of the so-called P.1 variant of SARS-CoV-2, which was first recognized through genomic surveillance in the Brazilian city of Manaus in the preceding month [3]. In August 2021, cases rose again due to the new Delta variant, which originated in India and had high transmissibility [4]. In November 2021, yet another new variant, Omicron, led to a further increase in cases. First detected in South Africa, Omicron was defined by the World Health Organization as a variant of concern (VoC) due to its unparalleled transmission rate [5-7].The COVID-19 pandemic resulted in widespread reorganization of health systems to prioritize fighting the virus. Social distancing measures interfered with existing treatment flows, which may have had negative effects on the most vulnerable groups, such as the rare disease community [8].
According to the Brazilian Ministry of Health, diseases are considered rare when they affect ≤ 65 people per 100,000 population [9]. Although each rare disease, taken separately, affects only a limited number of people, their collective epidemiological impact is significant, considering that there are up to 8,000 such diseases worldwide [10]; together, these conditions affect up to 8% of the world's population, according to WHO data. Approximately 80% of rare diseases are caused by genetic factors, with the rest being of environmental, infectious, or autoimmune etiology [11].
During the COVID-19 pandemic, the need to provide high-level care for many COVID-19 patients affected resource procurement and limited routine care for all other illnesses. The impact of this health emergency has been particularly relevant for those with rare diseases [12]. Concern about the effect of the pandemic on the rare disease community were expressed in a statement made by EURORDIS-Rare Diseases Europe on March 31, 2020, in Paris, which raised alarm about discrimination in European critical care guidelines during the pandemic [13]. Rare diseases may represent a special risk group for serious complications of SARS-CoV-2 infection or for disease decompensation due to infection. Within this context, this article aims to evaluate the determinants and impact of COVID-19 in a sample of Brazilian patients with rare diseases prior to availability of the COVID-19 vaccine.
Methodology
This observational, cross-sectional, population-based study with a convenience sampling strategy was approved by the Hospital de Clínicas de Porto Alegre Research Ethics Committee (CAAE 04030512.9.0000.5327). All participants gave informed consent prior to inclusion.
Study design and participants
For inclusion in the study, patients had to have 1) a rare disease; AND 2) COVID-19 (confirmed in testing or clinical symptoms of the disease: such as loss of smell or taste, fever, cough, myalgia); AND 3), no immunization against COVID-19 nor participation in a clinical trial/study protocol for a drug to treat COVID-19; AND 4) to have completed a specific questionnaire developed by the research team. Individuals diagnosed with COVID-19 based on clinical manifestations alone were not excluded, as tests were not always available for confirmation.
A flowchart which summarizes the study is shown in Figure 1. The survey was widely disseminated among medical teams involved in the care of rare diseases and on social media in Brazil and Latin America, both in Portuguese and Spanish, between April 2020 and July 2021. The questionnaire (obtainable from the authors upon request) consists of 21 items divided into 3 groups of interest: (1) general information (sex, age, weight, place of birth, follow-up center); (2) information about the rare disease (diagnosed disease, date of diagnosis, high-risk conditions or comorbidities); and (3) information about COVID-19 (date of symptom onset, symptoms, other suspected cases in the family, confirmatory testing, prescribed medications, care received, information on hospitalization, etc.).
Definitions and variables of interest
Rare diseases were classified as per the Brazilian Policy on Rare Diseases. According to this Policy, rare genetic diseases can be categorized into (1) congenital anomalies, (2) intellectual disabilities, or (3) inborn errors of metabolism (IEM), while non-genetic diseases can be of (1) infectious, (2) inflammatory, or (3) autoimmune etiology [14,15].
Decompensation was defined as any change in the underlying condition which occurred during SARS-CoV-2 infection and could lead to patient deterioration.
Data on obesity were based solely on responses to the questionnaire, i.e., on reported weight only; height data were not collected and were thus not available for BMI calculation. In pediatric patients, weight-for-age z-scores and percentile tables were used [16]. In adult participants, for the purposes of this study alone considering the limited available data, we defined obesity as weight >90 kg for females and >100 kg for males, following the guidance of a dietitian on our medical team.
Data extraction and statistical analysis
Data were tabulated in Microsoft Excel (Microsoft, Redmond, WA, USA). Survey data was gathered by question/category and responses compared using proportions/percentages calculated from the rate of each possible response for each survey question. Descriptive statistical analyses were performed in SPSS 22.0 (IBM, Armonk, NY, USA)
Results
A total of 81 questionnaires were completed, of which 75 (92.5%) were included in this study. Six questionnaires (7.4%) were excluded: 2 of patients who did not have a rare disease and 4 of patients without an established diagnosis of a specific rare disease. The questionnaires were administered between April 2020 and June 2021 (April-August 2020= 9 patients; September 2020-January 2021= 35 patients; February-June 2021= 37 patients). In 35 cases (47%), the questionnaire was administered by the patient’s attending physician (in person during a medical appointment or by telephone), while in in 40 (53%) cases it was completed by the patients or their caregivers via (1) e-mailed forms, which were completed and returned as photos or scans; (2) online forms accessed through an e-mailed link; or (3) by telephone interview with a member of the research team.
Of the 75 participants, 48 (64%) were female, with a mean (SD) age of 26.7 (17.7) years (range, 6 months-64 years). Among them, 23 were aged 0-12 years; 12 were aged 13-21 years; and 40 were over age 21.
Most participants were from the Brazilian South, study headquarters location (n= 33, 44.0%) and Southeast (n= 22, 29.3%), although the other regions of Brazil were also represented: Northeast (n= 10, 13.3%), North (n=5, 6.7%), and Midwest (n= 4, 5.3%). One (1.3%) participant from Argentina was included.
Confirmatory COVID-19 tests were performed for 62 (82.7%) patients. Among the 13 cases without a confirmatory test, all (100%) presented classic symptoms of the disease-loss of smell (anosmia/hyposmia) and taste (dysgeusia/ageusia), fever, cough, headache, and myalgia. Among these, 84.6% came from households with members who had themselves undergone confirmatory testing and found to be positive for SARS-CoV-2.
Forty different rare diseases were represented in the sample; n= 36 (90%) were genetic (including 57% IEM) and 4 (10%) were non-genetic. The diseases were classified into 6 different ICD-10 groups and 34 ICD-10 codes. The groups, in descending order of prevalence, were: group E, endocrine, nutritional, and metabolic diseases (17 diseases, 60%); group G, diseases of the nervous system (15%); group D, blood cell formation disorders and immune dysfunctions (10%); group Q, congenital malformations, deformations, and chromosomal anomalies (10%); group K, oral problems and digestive disorders (2.5%); and group L, diseases of the skin and subcutaneous tissue (2.5%)[17-19]. (Table 1).
High-risk conditions for COVID-19
A total of 23 high-risk conditions or comorbidities were reported by the participants, with n=56 (74.7%) having at least 1 such condition. The most frequent comorbidities were lung disease (n=25, 44.6%), obesity (n=14, 25%), hypertension (n=12, 21.4%), and heart disease (n=7, 12.5%) (Figure 2).
Risk factors associated with severe COVID-19 as reported by participants (n = 56/75). Each number represents the number of patents who reported the risk factor. *Obese or overweight adults; children classified according to z-score and percentile analysis.
Obesity was reported by only 5 patients (10.2%), and since weight - but not height - data were collected, the BMI could not be calculated. However, a total of 14 (18.6%) participants may have been overweight or obese according to our definition (Table 2).
COVID-19 symptoms
Of the 75 participants, 69 (92%) had COVID-19-related symptoms and 6 (8%) were asymptomatic. A total of 21 different symptoms were reported, the most frequent being loss of smell (anosmia/hyposmia) (n=35, 50.7%), rhinorrhea, and loss of taste (ageusia) (n=32, 46.4% each) (Figure 3).
Symptoms associated with COVID-19 as reported by participants (n = 69/75). Each number represents the number of patents who reported the symptom.
Medical attention and hospitalization
Fifty-nine (85.5%) of the 69 participants who had symptoms of COVID-19 received medical attention while infected: 47.4% in hospitals, 23.7% through teleconsultations, 13.5% at primary health care units, 11.9% at urgent care facilities or freestanding emergency rooms, 8.5% at doctor’s offices, and 5.0% through house calls or home visits. Of these, 17 (24.6%) patients required hospitalization, 9 (13%) in intensive care units (ICU), and 3 (4.3%) died as of COVID-19 complications.
Of the 17 patients who required hospitalization, 4 (28.5%) had obesity as a pre-existing clinical condition (3 adult participants with obesity reported on the questionnaire and 1 pediatric patient with a weight-for-age z-score and percentile consistent with obesity); one of these patients required ICU admission (a 63-year-old male with glycogen storage disease type II weighing 134 kg) (Table 2).
Among hospitalized patients, 8 (47%) were pediatric (ranging in age from 6 months to 21 years); of these, 4 (23.5%) required ICU admission and 2 (11.7%) died. Among the adult population (n=40), 11 were hospitalized, 5 required ICU admission, and 1 (5.8%) died (a 50-year-old with glycogen storage disease type II) (Table 3 and 4).
The frequency of ICU admission was 11.4% in the pediatric group (n=4/35) and 12.5% in the adult population (n=5/40). The mortality rate was 5.7% among pediatric patients (n=2/35) and 2.5% in the adult population (n=1/40).
Of the 13 patients with rare diseases characterized by muscle involvement (mitochondrial myopathy, n=11; glycogen storage disease type II, n=2), 30.8% were hospitalized (n=4/13), all ultimately requiring ICU admission. The mortality rate for this group was 15.4% (n=2/13).
Decompensation of underlying diseases due to COVID-19
Decompensation of the underlying disease was reported by 19 (25.3%) of the 75 participants. Of these 19 patients, 11 (57.8%) required hospitalization, 6 (31.6%) were admitted to ICU, and 3 (15.7%) died. (Table 5)
Discussion
Many studies have been published on the effects of COVID-19 and a large amount of data has been collected on the clinical course of the disease in adult and pediatric patients [18-26]. However, little is known about the effects of COVID-19 on rare diseases. The present study describes how the course of SARS-CoV-2 infection affected a sample of patients with such diseases. Other research has found that most people living with a rare disease experienced disruptions in their health care during the pandemic [1], which has increased their vulnerability.
In a cohort of 11,613 pediatric patients hospitalized throughout Brazil, Oliveira et al [19]. found that 23.8% were admitted to ICUs, of whom 7.5% died, and highlighted the negative effect of any preexisting medical condition on mortality. The frequency of pediatric patients admitted to intensive care in our sample (23.5%) and in the Oliveira et al. study was higher than that reported in the United Kingdom (18%) [20], in a multicenter European study (13%) [21], and in the United States (10%) [22]. Mortality in our sample (11.7%) was also higher than in Oliveira et al [19]. and other pediatric studies [23,24], suggesting a greater risk of death among patients with rare diseases. Previous studies have shown a pattern of lower COVID-19 severity in children than adults, with only a small proportion of pediatric patients requiring intensive care [24-27]. A recent study from Turkey with a cohort of 223 patients with IEM, the majority (n=131) being children, demonstrated an increased risk of more severe COVID-19 in children with complex molecule degradation disorders [28]. In our sample, we had 2 pediatric patients representing this group (mucopolysaccharidosis I and glycogen storage disease type Ib), both hospitalized. However, we also observed severe disease in pediatric patients with other categories of IEMs, such as mitochondrial respiratory chain diseases, fatty acid oxidation defects, and organic acid oxidation disorders. Of the pediatric patients who required hospitalization (n= 8/17), 7 had IEMs (2 with mitochondrial myopathy and 1 each with methylmalonic aciduria, LCHAD deficiency, glycogen storage disorder type Ib, porphyria variegata, and mucopolysaccharidosis I); there was 1 death within this group (an 11-year-old girl with mitochondrial myopathy).
Although pre-existing medical conditions have been strongly associated with poor prognosis in adults with COVID-19 [29], pediatric evidence is limited by a lack of data. Our study demonstrates that pre-existing comorbidities-in this case, rare diseases-may indeed be associated with an increased risk of worse outcomes and death.
Regarding overweight or obesity, our sample had 23.5% of hospitalized patients with this pre-existing condition. Studies of the general population have observed that 40% of hospitalized COVID-19 patients are overweight or obese [30]. Another study found a higher prevalence of obesity among younger patients (18-49 years), reaching up to 59% in this age group [31]. Although we did not observe significantly worse outcomes among obese patients in our sample, there is evidence that it plays an important role in COVID-19 severity [32] and should therefore always be considered a risk factor, both in the general population and in the rare disease community.
A large part of our sample had IEMs, and we observed a trend toward decompensation in these patients compared to those with other rare diseases. A study by the Istanbul University Cerrahpaşa School of Medicine on patients with IEMs and COVID-19 also suggested that they should be considered vulnerable to SARS-CoV-2 infection and have a high risk of acute metabolic decompensation, which can lead to fatal complications [33].
In the general population, clinical conditions associated with worsening COVID-19 are: cardiovascular and neurological disorders, chronic lung conditions, severe asthma, diabetes, liver disease, kidney disease, obesity and immunocompromise. [26, 29] In our sample, in addition to the comorbidities already well determined in the literature, a trend toward worse outcomes was also seen in patients with muscle involvement, such as mitochondrial myopathy and glycogen storage disorder type II, with an increased frequency of deaths in this group (15.4%). Muscle impairment has been noted to pose an increased risk in COVID-19 infection [34,35]. This highlights the importance of continued patient-centered care for individuals with these conditions during resource-constrained times, such as the COVID-19 pandemic [36].
Conclusions
Despite the high morbidity and mortality of COVID-19 in patients with chronic diseases, most of the cohort included in this study did not have severe clinical manifestations or decompensation of their underlying diseases. Nevertheless, we did observe trends toward worse outcomes with extremes of age (greatest risk in pediatric patients and those > 50 years of age) and muscle involvement. We believe that patients with rare diseases should be considered vulnerable to COVID-19, and appropriate follow-up should be arranged to ensure that this community is prioritized for vaccination in any similar situations in future.
Acknowledgments
The authors would like to thank all the participants, especially Maria Regina Araújo, who tirelessly searched for patients willing to collaborate in the study, posting information on her personal social media accounts and in rare-disease community groups. We would also like to thank the rare-disease family groups for sharing our study on their social networks.
References
-
1. Ministry of Health - Brazil. Panel Coronavirus Brazil COVID-19. https://covid.saude.gov.br/. 2022 Accessed: March 24, 2023.
» https://covid.saude.gov.br/. 2022 -
2. World Health Organization. Coronavirus (COVID-19) Dashboard. https://covid19.who.int/. 2022 Accessed: March 24, 2023.
» https://covid19.who.int/. 2022 -
3. Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 2021;372(6544):815-821. doi:10.1126/science.abh2644.
» https://doi.org/10.1126/science.abh2644 -
4. Silva JP, de Lima AB, Alvim LB, et al. Delta Variant of SARS-CoV-2 Replacement in Brazil: A National Epidemiologic Surveillance Program. Vírus 2022;14:847. doi:10.3390/v14050847.
» https://doi.org/10.3390/v14050847 -
5. Kannan S, Shaik Syed Ali P, Sheeza A. Omicron (B.1.1.529) - variant of concern - molecular profile and epidemiology: A mini review. Eur Rev Med Pharmacol Sci 2021;24:8019-8022. doi:10.26355/eurrev_202112_27653.
» https://doi.org/10.26355/eurrev_202112_27653. -
6. Sao Paulo’s State Government. São Paulo confirms the first two cases of the Ômicron variant in Brazil. https://www.saopaulo.sp.gov.br/noticias-coronavirus/sp-confirma-os-dois-primeiros-casos-da-variante-omicron-no-brasil/ 2021. Accessed: November 22, 2022.
» https://www.saopaulo.sp.gov.br/noticias-coronavirus/sp-confirma-os-dois-primeiros-casos-da-variante-omicron-no-brasil/ -
7. Butantan Institute. Six facts about omicron, the most transmissible variant of Covid-19. https://butantan.gov.br/noticias/seis-fatos-sobre-a-omicron-a-variante-mais-transmissivel-da-covid-19/ 2021. Accessed: November 22, 2022.
» https://butantan.gov.br/noticias/seis-fatos-sobre-a-omicron-a-variante-mais-transmissivel-da-covid-19/ -
8. Schwartz IVD, Randon DN, Monsores N, et al. SARS-CoV-2 pandemic in the Brazilian community of rare diseases: A patient reported survey. Am J Med Genet Part C 2021;187:301-311. doi:10.1002/ajmg.c.31883.
» https://doi.org/10.1002/ajmg.c.31883 -
9. Martelli DRB, Martelli Júnior H. Undiagnosed and rare diseases: Current challenges, perspectives and contribution of oral cavity examination. Oral Surg Oral Med Oral Pathol Oral Radiol 2020;130(2):227-228. doi:10.1016/j.oooo.2020.04.011.
» https://doi.org/10.1016/j.oooo.2020.04.011. -
10. Martelli-Júnior H, Machado RA, Miranda Filho AEF, et al. Rare Diseases and COVID-19: How are the patients? Pesqui Bras Odontopediatria Clín Integr 2021;21:e0172. doi:10.1590/pboci.2021.044.
» https://doi.org/10.1590/pboci.2021.044. -
11. Ramalle-Gómara E, Ruiz E, Quiñones C, Andrés S, Iruzubieta J, Gil-de-Gómez J. Opinion on rare diseases. J Eval Clin Pract 2015;21:198-201. doi:10.1111/jep.12281.
» https://doi.org/10.1111/jep.12281. -
12. Talarico R, Aguilera S, Alexander T, et al. The impact of COVID-19 on rare and complex connective tissue diseases: The experience of ERN ReCONNET. Nat Rev Rheumatol 2021;17:177-184. doi:10.1038/s41584-020-00565-z.
» https://doi.org/10.1038/s41584-020-00565-z -
13. EURORDIS - Rare Diseases Europe. Rare disease community raises alert over discrimination in critical care guidelines during COVID-19 pandemic. https://download2.eurordis.org/pressreleases/EURORDISstatement_COVID19Triage.pdf 2020. Accessed: November 22, 2022.
» https://download2.eurordis.org/pressreleases/EURORDISstatement_COVID19Triage.pdf -
14. Ministry of Science and Technology - Brazil. National Council for Scientific and Technological Development. Call CNPq/MS/SCTIE/DECIT Nº 25/2019 - Survey on the profile of Rare Diseases in Brazil. http://memoria2.cnpq.br/web/guest/chamadas-publicas?p_p_id=resultadosportlet_WAR_resultadoscnpqportlet_INSTANCE_0ZaM&filtro=encerradas&detalha=chamadaDivulgada&idDivulgacao=9142
» http://memoria2.cnpq.br/web/guest/chamadas-publicas?p_p_id=resultadosportlet_WAR_resultadoscnpqportlet_INSTANCE_0ZaM&filtro=encerradas&detalha=chamadaDivulgada&idDivulgacao=9142 -
15. Ministry of Health - Brazil. Ordinance Nº 199, of January 30, 2014. Establishes the national policy for comprehensive care for people with Rare Diseases, approves the guidelines for comprehensive care for people with rare diseases within the scope of the Unified Health System (SUS) and establishes financial incentives for costing. https://bvsms.saude.gov.br/bvs/saudelegis/gm/2014/prt0199_30_01_2014.html 2014. Accessed: November 22, 2022.
» https://bvsms.saude.gov.br/bvs/saudelegis/gm/2014/prt0199_30_01_2014.html -
16. Brazilian Society of Pediatrics. Growth charts. https://www.sbp.com.br/departamentos-cientificos/endocrinologia/graficos-de-crescimento/ 2022. Accessed: November 22, 2022.
» https://www.sbp.com.br/departamentos-cientificos/endocrinologia/graficos-de-crescimento/ -
17. Portal to Rare Diseases and orphan drugs - Portugal. International Classification of Diseases - ICD. https://www.orpha.net/consor/cgi-bin/index.php?lng=PT 2022. Accessed: November 15, 2022.
» https://www.orpha.net/consor/cgi-bin/index.php?lng=PT -
18. Chowdhury SF, Sium SMA, Anwar S. Research and Management of Rare Diseases in the COVID-19 Pandemic Era: Challenges and Countermeasures. Front Public Health 2021;15(9):640282. doi:10.3389/fpubh.2021.640282.
» https://doi.org/10.3389/fpubh.2021.640282 -
19. Oliveira E A, Colosimo E A, Simões e Silva AC, et al. Clinical characteristics and risk factors for death among hospitalized children and adolescents with COVID-19 in Brazil: An analysis of a nationwide database. Lancet 2021;5(8):559-568. doi:10.1016/S2352-4642(21)00134-6.
» https://doi.org/10.1016/S2352-4642(21)00134-6 -
20. Swann OV, Holden KA, Turtle L, et al. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: Prospective multicentre observational cohort study. BMJ 2020;370:m3249. doi:10.1136/bmj.m3249.
» https://doi.org/10.1136/bmj.m3249 -
21. Götzinger F, Santiago-García B, Noguera-Julián A, et al. COVID-19 Study Group. COVID-19 in children and adolescents in Europe: A multinational, multicentre cohort study. Lancet 2020;4(9):653-661. doi:10.1016/S2352-4642(20)30177-2.
» https://doi.org/10.1016/S2352-4642(20)30177-2. -
22. Bialek S, Gierke R, Hughes M, McNamara LA, Pilishvili T, Skoff T. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States (EUA). MMWR Morb Mortal Wkly Rep 2020;69(14):422-426. doi:10.15585/mmwr.mm6914e4.
» https://doi.org/10.15585/mmwr.mm6914e4 -
23. Castagnoli R, Votto M, Licari A, et al. Severe Acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents: A systematic review. JAMA Pediatr 2020;174(9):882-889. doi:10.1001/jamapediatrics.2020.1467.
» https://doi.org/10.1001/jamapediatrics.2020.1467. -
24. Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York. JAMA Pediatr 2020;174(10):e202430. doi:10.1001/jamapediatrics.2020.2430.
» https://doi.org/10.1001/jamapediatrics.2020.2430. -
25. Liguoro I, Pilotto C, Bonanni M, et al. SARS-COV-2 infection in children and newborns: A systematic review. Eur J Pediatr 2020;179(7):1029-1046. doi:10.1007/s00431-020-03684-7.
» https://doi.org/10.1007/s00431-020-03684-7 -
26. Aparicio C, Willis ZI, Nakamura MM, et al. Risk factors for pediatric critical Covid-19: A systematic review and meta-analysis. J Pediatric Infect Dis Soc 2024;13(7):352-362. doi:10.1093/jpids/piae052.
» https://doi.org/10.1093/jpids/piae052 -
27. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics 2020;145(6):e20200702. doi:10.1542/peds.2020-0702.
» https://doi.org/10.1542/peds.2020-0702 -
28. Kahraman AB, Yıldız Y, Çıkı K, Erdal I, Akar HT, Dursun A, Tokatlı A, Sivri S. COVID-19 in inherited metabolic disorders: Clinical features and risk factors for disease severity. Mol Genet Metab 2023;139(2):107607. doi:10.1016/j.ymgme.2023.107607.
» https://doi.org/10.1016/j.ymgme.2023.107607 -
29. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-436. doi:10.1038/s41586-020-2521-4.
» https://doi.org/10.1038/s41586-020-2521-4 -
30. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: Prospective cohort study. BMJ 2020;369:m1966. doi:10.1136/bmj.m1966.
» https://doi.org/10.1136/bmj.m1966. -
31. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed Coronavirus disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep 2020;69(15):458-464. doi:10.15585/mmwr.mm6915e3.
» https://doi.org/10.15585/mmwr.mm6915e3 -
32 . Petrova D, Salamanca-Fernández E, Rodríguez BM, Navarro PP, Jiménez Moleón JJ, Sánchez MJ. La obesidad como factor de riesgo en personas con COVID-19: Posibles mecanismos e implicaciones. Aten Primaria 2020;52(7):496-500. doi:10.1016/j.aprim.2020.05.003.
» https://doi.org/10.1016/j.aprim.2020.05.003. -
33. Zubarioglu T, Hopurcuoglu D, Ahmadzada S, et al. Inborn errors of metabolism and coronavirus disease 2019: Evaluation of the metabolic outcome. Ped Int 2022;64:e14938. doi:10.1111/ped.14938.
» https://doi.org/10.1111/ped.14938. -
34. Silva RD, Souza MRF, Oliveira ASB, Iório MCM. Mitochondrial myopathy and sensorineural hearing loss: Case study. Codas 2021;33(4):e20200021. doi:10.1590/2317-1782/20202020021.
» https://doi.org/10.1590/2317-1782/20202020021. -
35. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet 2008;372(9646):1342-1353. doi:10.1016/S0140-6736(08)61555-X.
» https://doi.org/10.1016/S0140-6736(08)61555-X. -
36. Theunissen MTM, Elsen RM, House TL, Crittenden B, Doorn PA, et al. The impact of COVID-19 infection, the pandemic and its associated control measures on patients with Pompe disease. J Neurol 2024;271(1):32-45. doi:10.1007/s00415-023-11999-2.
» https://doi.org/10.1007/s00415-023-11999-2.
-
Funding
This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Financiamento e Incentivo à Pesquisa (FIPE) - Hospital de Clínicas de Porto Alegre.
-
Limitations of the Study
The difficulty in retrieving information about patients who died from COVID-19 should be considered a limitation of the study, biasing toward inclusion of cases with milder symptoms. A high degree of representativeness from the southern region and patients with IEM should also be considered a bias, since the authors work with this community of patients at the study site
*Other reportedsymptoms: fever < 38°C, otitis, diaphoresis, conjunctivitis, loss of concentration, memory loss, skin lesions, cardiac arrhythmia, acute respiratory distress syndrome, and bone pain.
