Received: 17 August 2022 Revised: 20 September 2022 Accepted: 19 October 2022 DOI: 10.1002/jimd.12572 ORIGINAL ARTICLE Impact of the SARS-CoV-2 pandemic on the health of individuals with intoxication-type metabolic diseases—Data from the E-IMD consortium Ulrike Mütze 1 | Florian Gleich 1 | Ivo Baric 2 | Mathias Baumgartner 3 | Alberto Burlina 4 | Kimberly A. Chapman 5 | Yin-Hsiu Chien 6 | Elisenda Cortès-Saladelafont 7 | Corinne De Laet 8 | Dries Dobbelaere 9 | Francois Eysken 10 | Matthias Gautschi 11 | Rene Santer 12 | Johannes Häberle 3 | Clara Joaquín 13 | Daniela Karall 14 | Martin Lindner 15 | Allan M. Lund 16 | Chris Mühlhausen 17 | Elaine Murphy 18 | Dominique Roland 19 | Angeles Ruiz Gomez 20 | Anastasia Skouma 21 | Sarah C. Grünert 22 | Margreet Wagenmakers 23 | Sven F. Garbade 1 | Stefan Kölker 1 | Nikolas Boy 1 Correspondence Nikolas Boy, Centre for Child and Abstract Adolescent Medicine, Department of The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within General Paediatrics, Division of inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication- Neuropaediatrics and Metabolic Medicine, University Hospital Heidelberg, Im type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) Neuenheimer Feld 430, D-69120 show risk for infection-induced morbidity and mortality. This study (observa- Heidelberg, Germany. tion period February 2020 to December 2021) evaluates impact on medical Email: nikolas.boy@med.uni- heidelberg.de health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Funding information European Commission Registry and Network for intoxication type metabolic diseases Consortium (E- IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 Communicating Editor: Olaf Bodamer adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%–50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not For affiliation refer to page 10 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. J Inherit Metab Dis. 2022;1–12. wileyonlinelibrary.com/journal/jimd 1 2 MÜTZE ET AL. reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hos- pitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complica- tions have not been observed. KEYWORDS coronavirus, COVID-19, E-IMD, IMD, intoxication-type inherited metabolic diseases, pandemic, SARS-CoV-2, survey 1 | INTRODUCTION (UCD), are characterized by accumulation of small metabo- lites, such as ammonium, organic acids and corresponding Severe acute respiratory syndrome coronavirus type CoA esters, causing endogenous intoxication through 2 (SARS-CoV-2) was isolated first in January 2020 and impairment of energy metabolism and ureagenesis.17 Acute declared as pandemic by the WHO in March 2020.1 More metabolic decompensations, occurring in all age groups, are than 565 million patients were infected worldwide up to life-threatening and precipitated by catabolic episodes such July 2022, (https://covid19.who.int; accessed on July as infections.18,19 International patient registries, such as 25, 2022). European Registry and Network for intoxication type meta- SARS-CoV-2 is a single-stranded RNA virus.2 The clini- bolic diseases (E-IMD), have been established to investigate cal spectrum of SARS-CoV-2 infections varies from asymp- long-term disease course and impact of treatment.18–20 tomatic to severe respiratory infections (“COVID-19”) and Systematic analyses of SARS-CoV-2 infections in indi- lethal courses. Frequent symptoms include fever, coughing, viduals with intoxication-type IMDs do not exist and it is and respiratory distress, but also fatigue, anosmia, muscle unclear, whether SARS-CoV-2 infections in these patients pain, headache, weight loss, vomiting, or diarrhea.3 Com- are associated with increased risk for metabolic decom- pared to adults, symptoms in children are less severe.4 Gen- pensation or long-term complications. This study aims at eral hospitalization rate for all patients are 7.3%, but differs evaluating the impact of the COVID-19 pandemic on between adults >60 years (21.9%), newborns and infants medical health care in pediatric and adult patients with (8.8%), and children and adolescents (0.7%–1.3%). Intensive intoxication-type IMD and to characterize the disease care unit (ICU) treatment was required in 1%–5% of children course and outcome of SARS-CoV-2 infections using an and 7%–10% of adults.5,6 However, children and adolescents international survey. with chronic medical conditions more frequently require inpatient and ICU treatment.7,8 COVID-19-associated com- plications in this age group comprise myocarditis9 and pedi- 2 | POPULATION AND METHODS atric inflammatory multisystem syndrome (PIMS).10 Postacute entities comprise “subacute” (4–12 weeks) and 2.1 | The European Registry and “chronic” COVID-19 (>3 months) with variable multisystem Network for intoxication type metabolic involvement primarily described in adults, while prevalence diseases in children is thought to be low.11,12 For individuals with inherited metabolic diseases E-IMD, initiated in 2011 as an EU-funded activity (IMDs), previous studies reported on significant impact (CHAFEA agreement no. December 1, 2010), manages a of the COVID-19 pandemic on medical health care in web-based patient registry20 (https://www.eimd-registry.org/; Europe13 and other continents.14 Disease courses of German Clinical Trials register: DRKS00013085) gathering SARS-CoV-2 infections in patients with IMDs in general, comprehensive clinical data on individuals with several OA, however, were mostly mild.15,16 that is, methylmalonic aciduria (MMA; OMIN #251000), Within IMDs, the subgroup of intoxication-type IMDs, propionic aciduria (OMIN #606054), isovaleric aciduria such as organic acidurias (OA) and urea cycle disorders (OMIN #243500), and glutaric aciduria type 1 (OMIN MÜTZE ET AL. 3 F I G U R E 1 E-IMD study centers participating the SARS-CoV-2 survey. Twenty-two E-IMD study centers (red dots in 14 countries on two continents [dark blue]) of all current E-IMD centers (n = 44 in 20 countries [dark and light blue]) participated in the survey. #231670), as well as UCDs, that is, N-acetylglutamate assistance to participating clinical centers in study man- synthase (OMIN #237310), carbamylphosphate synthetase agement and record keeping. 1 (OMIN #237300), ornithine transcarbamylase (OTC; OMIN #311250), argininosuccinate synthetase (OMIN #215700), argininosuccinate lyase (OMIN #207900), arginase 2.3 | Ethical and legal aspects 1 (OMIN #207800) deficiency and hyperornithinemia–hyper- ammonemia–homocitrullinuria syndrome (OMIN #238970). E-IMD was first approved by the local ethics committee E-IMD is implemented as an observational, noninterven- of Heidelberg Medical Faculty (application no. S- tional, multicenter registry study with participation of 525/2010), followed by approvals of the respective ethics 44 international healthcare providers in 20 countries committees of further associated and collaborating part- (Figure 1; June 2022). ners contributing to the registry. 2.2 | Survey organization 2.4 | Statistical analysis The online questionnaire (Table S1) was developed All data were extracted from the questionnaires and ana- using LimeSurvey (https://www.limesurvey.org/de). It lyzed using Microsoft Excel and R language21 for statisti- consisted of 17 main questions on (1) general informa- cal computing. For comparative analyses of OA and UCD tions on the participating metabolic center (e.g., number pediatric and adult groups, we used χ 2 test and Pearson and diagnoses of IMD patients, adaptions in medical residuals to interpret differences in observed and care during the pandemic), (2) management and care of expected frequencies. patients with IMDs and SARS-CoV-2 infection (e.g., out- or inpatient care, requirement of ICU treatment), and (3) outcome and mortality. The survey covered a 3 | RESULTS 22 months observation period (February 1, 2020– December 1, 2021), was distributed to all 44 E-IMD Fifty percent (n = 22/44) of E-IMD study centers responded study centers, followed by two reminders, and was (Supporting Information Material S1). The participating E- closed for data entryon December 31, 2021. The princi- IMD centers in 14 countries from three continents (Figure 1) ple investigator at the coordinating study center at the manage a total of 792 patients (n = 479 pediatric; n = 313 University Children's Hospital Heidelberg, Germany, adult) with intoxication-type IMDs (n = 454 OA; n = 338 was responsible for administrative management and UCD; Figure 2). All participating centers managed both communication with the local investigators, providing pediatric as well as adult patients. 4 MÜTZE ET AL. F I G U R E 2 Total patients (adult and pediatric) with intoxication-type IMDs followed by contributing E-IMD study centers. Seven hundred ninety- two patients (N = 478 pediatric; N = 314 adult) with (IMDs) N = 454 organic acidurias (OA; yellow-orange); N = 338 urea cycle disorders (UCD; green blue) are followed-up at the participating centers. All centers cared pediatric as well as adult patients. 3.1 | Impact of the SARS-CoV-2 3.2 | Incidence, disease course, and pandemic on management and medical management of SARS-CoV-2 infections in health care of patients with intoxication- intoxication-type IMDs type IMDs Within the observation period of 22 months 59 of During the observation period (February 1, 2020– 792 individuals (OA: n = 36 [13 pediatric; 23 adult]; December 1, 2021), 41% (n = 8/22) of the participating UCD: n = 23 [17 pediatric, 6 adult]), that is, 7.4% of all E-IMD study centers provided less regular outpatient intoxication-type IMD patients managed at the study cen- visits for patients with intoxication-type IMDs (mean ters, were reported to suffer from a SARS-CoV-2 infec- reduction rate visits of 40%, range 10%–50% [n = 5]). tion. Infection rates with respect to age and diagnosis Almost all centers (95%; 21/22) were increasingly con- group were analyzed and revealed significant differences tacted throughout the pandemic by the patients and (χ 2 = 36.096, df = 4; p < 0.0001). According to Pearson families with intoxication-type IMD managed at the residuals, noninfected pediatric UCD patients were center asking for COVID-19-specific advices, including underrepresented compared to noninfected adult UCD general information, additional risks, recommenda- patients and, vice versa, noninfected adult OA patients tions for prevention, school attendance/home office, or were underrepresented compared to noninfected pediat- indication for vaccination. The vast majority of partici- ric OA patients (Figure S1). Infection rate was higher in pating centers (86%; 19/22) compensated the increased adult OA (n = 23) compared to pediatric OA patients consultation requests by phone/video consultations. (n = 13), but expected frequencies did not differ between COVID-19-specific recommendations, that is, in addi- pediatric UCD (n = 17) and adult UCD patients (n = 6). tion to the general recommendations for managing While 49 of 59 (83%) of infected individuals were trea- potential metabolic risk situations for intoxication- ted at home showing no or only mild clinical symptoms, type IMDs such as febrile infections (e.g., specific let- 17% of the SARS-CoV-2-positive individuals with ter, webinars, tele care, information) were provided to intoxication-type IMD (n = 10 [7 pediatric, 3 adults]; the patients by 32% (7/22) of the study centers. Note- n = 6 OA [4 pediatric; 2 adult]; and n = 4 UCD [3 pediat- worthy, only 33% of centers (7/21) reported reimburse- ric, 1 adult]) had to be admitted to a hospital (Figure 3). ment for their additional COVID-19-associated Hospitalization rate did not differ between age (pediatric/ services, while significant problems with medical sup- adult) and diagnosis groups (OA/UCD; χ 2 = 0.08, df = 1; ply (medication, prescriptions, dietary products) were p = 0.778). Indications for hospitalizations and clinical reported to be rare during the study period (5%; 1/22). characteristics of hospitalized patients are summarized in This included shortage of hydroxocobalamin in the Table 1. Median (range) age at admission of pediatric United States. patients was 10 (3–17), and 31 (22–32) years for adult MÜTZE ET AL. 5 F I G U R E 3 Clinical course and management of intoxication-type IMD patients with SARS-CoV-2-infection. The vast majority of SARS-CoV- 2-positive patients (49/59; 83%) was managed at home showing no or only mild clinical symptoms. Ten patients (17%; seven pediatric, three adults; n = 6 OA [4 pediatric patients; 2 adults] and n = 4 UCD [3 pediatric, 1 adult]) were hospitalized. Clinical characteristics of admitted patients is shown in Table 1. patients. Of the 10 patients, 9 were admitted with acute missense variant in SPINK1, a genetic risk factor for manifestation of SARS-CoV-2 infection. Four (two pediat- chronic pancreatitis. The patient experienced repetitive ric, two adult) of five admitted MMA patients earlier episodes of acute pancreatitis and febrile infections fre- underwent liver and/or kidney transplantation, of which quently resulting in metabolic decompensation requiring three of four patients (p3, p8, p9) were admitted due to hospitalization. She developed chronic kidney disease acute symptoms, while one pediatric MMA patient (CKD) III–IV and is currently under peritoneal dialysis. (p2) due to deteriorated chronic MMA-complications, However, SARS-CoV-2-positive obstructive bronchitis did possibly triggered by immunosuppression. All 10 admitted not result in metabolic decompensation or signs of pan- patients were treated on normal wards for a median creatitis. After treatment with IV fluids (preventive), met- (range) length of seven (1–25) days. ICU treatment, inva- abolic emergency treatment, and noninvasive oxygen sive ventilation or extracorporeal membrane oxygenation administration, she fully recovered and received com- were not required in any patient. One adult OTC patient bined liver/kidney transplantation 3 months later. (p10) with pneumonia and secondary pulmonary embo- P2: A 9-year old individual with homozygous mut0 lism, and one pediatric MMA patient (p1) with obstruc- MMA, who underwent liver transplantation 1 year before tive bronchitis received ventilation assistance with she suffered from CKD. SARS-CoV-2 infection started oxygen (Table 1). Of the 10 admitted patients, 2 received with loss of taste and chronic diarrhea. Subsequently, she total parenteral feeding. Thirty percent (p2, p4, p5) of lost 10 kg (20%) of her body weight. Admission to hospi- admitted patients showed mild to moderate laboratory tal followed an epileptic seizure, probably caused by cal- signs of metabolic decompensation effectively managed cineurin induced neurotoxicity with high tacrolimus by metabolic emergency treatment which was (preven- levels induced by a decline of kidney function due to tively) administered to all but two (p8, p9) admitted dehydration. Tacrolimus was discontinued and switched patients. In contrast, only six (12%) of infected individ- to everolimus. A mild metabolic decompensation uals (three pediatric OA, two adult OA, one adult UCD) (Table 1) was treated with carglumic acid, IV fluids, IV managed at home received metabolic emergency scavengers, and total parenteral feeding. She did not fully treatment. recover and still shows mild neurological deficits. P5: 3.5-year-old boy with genetically confirmed early- onset OTC deficiency who suffered from a severe neonatal 3.3 | Selected case descriptions of hyperammonemic crisis at Day 3 (NH3 5200 μM) followed hospitalized patients by repetitive (>15) metabolic decompensations precipitated by febrile infections since then. SARS-CoV-2 infection P1: A 4-year-old girl with late-onset mut /mut0 MMA, started with mild coughing, repetitive vomiting, lethargy diagnosed symptomatically at age 11 months after severe and reduced general state of health. Laboratory work-up metabolic decompensation (pH 6.9; NH3 178 μM). showed moderate hyperammonemia (NH3 251 μM), ele- Genetic evaluation revealed an additional heterozygous vated plasma glutamine concentration (1440 μM), and 6 TABLE 1 Clinical characteristics of admitted patients with intoxication-type IMDs and SARS-CoV-2 infection Metabolic Metabolic Age Age at Length of Reason for Invasive Metabolic emergency Pat# diagnosis admission stay (days) admission Fever Treatment Oxygen ventilation decompensation treatment Full recovery 1 MMA 4 years 4 Obstructive bronchitis No IV fluid Yes No No Yes (preventive) Yes 2 MMA with liver 9 years 25 Weight loss 20%, No IV fluids, IV No No Mild Yes No (mild transplantation feeding disorder, scavengers, neurologic at age 7 years seizure (tacrolimus- carglumic acid, total symptoms) (2019) induced?) parenteral feeding 3 MMA with 14 years 13 Hoarseness, fever Yes Observation reduction No No No No Yes kidney-liver of transplantation immunosuppression at age 13 years 4 PA 17 yearrs 5 Vomiting, reduced oral Yes IV fluids, carnitine, No No Yes (NH3 143 μM), Yes Yes intake metronidazole, elevated lactate caglumic acid 4.1 mmol/L, ketone 4+ 5 OTC def 3 years 4 Fever, vomiting, No IV fluid, IV No No Yes (NH3 251 μM) Yes Yes lethargy scavengers + IV scavenger bolus 6 CPS1 def 10 years 8 Feeding problems No IV fluid No No No Yes (preventive) Yes 7 Arginase def 16 years 1 Preventively No IV fluid, IV scavengers No No No Yes (preventive) Yes 8 MMA with liver 22 years 6 Vomiting, diarrhea, Yes IV fluids, total No No No No Yes transplantation reduced oral intake parenteral feeding at age 19 years (2018) 9 MMA with 31 years 8 Mild respirator Yes IV fluids No No No No Yes kidney-liver symptom, reduced transplantation oral intake at age 28 years (2018) 10 OTC def 32 years 6+4 Pneumonia, Yes IV fluid, remdesevir, Yes No No Yes (preventive) Yes pulmonary dexamethasone, embolism amoxiclav, toculizumab, enoxaparin N per item or median (range) All N = 6 OA 15 (3–32) 7 (1–25) n.a. N = 5 yes n.a. N = 2 yes N = 10 no N = 3 yes N = 7 yes N = 9 yes N = 4 UCD N = 5 no N = 8 no N = 7 no N = 3 no N = 1 no Abbreviations: CPS1, carbamoyl-phosphate synthetase 1; def, deficiency; IV, intravenous; MMA, methylmalonic aciduria; n.a., not applicable; OA, organic acidurias; OTC, ornithine transcarbamylase; PA, propionic MÜTZE ET AL. aciduria; UCD, urea cycle defects. MÜTZE ET AL. 7 moderate signs of hepatopathy (GOT 196 U/L [N 43], GPT COVID-19-related complications such as subacute (4– 415 U/L [N 50]). Metabolic emergency treatment was started 12 weeks after infection) or postacute (beyond 12 weeks as sodium benzoate including additional bolus, followed by after the infection) manifestations (PIMS, chronic pulmo- IV fluids with glucose, L-arginine and accompanied by die- nary symptoms, subacute or chronic long COVID syn- tary emergency regimen. Glycerol phenylbutyrate was con- drome) were reported for the observed period. tinued via gastrostomy tube. After 3 days, he showed full clinical recovery and normalization of laboratory parameters. P10: 32-year-old female patient with late onset female 4 | DISCUSSION OTC deficiency. SARS-CoV-2 infection started with shortness of breath and mild hypoxia (oxygen saturation The main findings of this study on SARS-CoV-2 infections 90%) 2 weeks postpartum. Ammonium level was only in individuals with intoxication-type IMD in a 22 months mildly elevated (67 μM), but she showed neutropenia period from 2020 to 2021 are that (1) the pandemic signifi- and lymphopenia. She was treated with oxygen, anti- cantly affects but not endangers medical care of patients, COVID-19 remdesivir, dexamethasone, and antibiotics (2) increased request of medical services is effectively alle- due to pulmonary bacterial superinfection. Thorax CT viated by remote techniques, (3) disease course is mostly scan showed marked multifocal consolidation and mild and managed without hospitalization, (4) metabolic ground glass with parenchymal involvement of 30% (pre- decompensations in hospitalized patients are rare and, if dominantly the right lower lobe). Brain CT was normal. present, mild to moderate (5) hospitalization rate is higher She received metabolic emergency treatment and IV than in the general population but comparable to other medication. She was discharged after 6 days, but re- reported chronic medical conditions, (6) mortality rate is admitted 1 day later with fever, secondary deterioration not increased, and (7) overall prognosis of patients is and hypoxia (oxygen saturation 86%). D-Dimer concentra- promising without increased incidence of IMD-specific or tion was raised (11 770 μg/L, N 0-550) and thorax CT COVID-19-related complications. scan confirmed pulmonary embolism with low volume thromboembolic clot in the distal arteries leading to the right lower lobe. The 4C Mortality Score and 4C Deterio- 4.1 | Challenge of medical health care ration score (ISARIC 4C), used for hospitalized COVID- for individuals with intoxication-type 19 patients, was assessed as 4–8 (intermediate risk, 9.9% IMDs during the pandemic inpatient mortality). Treatment consisted of oxygen, toci- lizumab, and therapeutic enoxaparin followed by apixa- Studies on the impact of COVID-19 on medical health ban for 3 months. She recovered completely. Causal care of patients suffering from IMD are scarce and espe- embolic factors (e.g., postpartum period and/or SARS- cially systematic analyses for individuals with CoV-2 infection) could not be clearly identified. intoxication-type IMDs do not exist. Previously published data for the beginning of the pandemic analyzed patient satisfaction and management in IMDs. In the beginning 3.4 | Outcome of SARS-CoV-2 infections of the pandemic (March–May 2020), a significant disrup- in intoxication-type IMDs tion of care of 50–100% was reported for Europe13 and of 60%–80% in 16 centers in Asia, Africa, and Europe.14 Reg- Survival rate during the observation period for the ular follow-up appointments in these studies were can- reported SARS-CoV-2 infections in patients with intoxica- celed (55%) or missed frequently (75%–100%) during this tion type IMDs was 100%. All patients (100%) managed at period13 and the median worldwide reduction rate of home or the outpatient department and the vast majority medical services was reported to be 60%–80%.14 In com- of hospitalized individuals (90%) with intoxication-type parison, the lower rate of 41% of centers reducing medi- IMD and SARS-CoV-2 infection showed full recovery. cal services for intoxication type IMDs in our study may One hospitalized pediatric MMA patient (p2) developed highlight improved compensating strategies of metabolic persistent mild neurological deficits following the acute healthcare providers to reduce the rate of missed follow- treatment phase. Of note, this patient was admitted due up investigations for this vulnerable patient group. to chronic MMA complications and earlier underwent In contrast to other studies reporting on problems with liver transplantation. Outcome in the other three admit- treatment administration in IMD patients22 or treatment ted MMA patients with immunosuppression due to trans- discontinuation in up to 65%,13 however, the rate of relevant plantations was favorable all showing full recovery. No problems with medical supply for intoxication-type IMDs deterioration or new onset of intoxication-type IMD- was comparably low in this study, demonstrating effective specific disease manifestations was reported. No case of compensation mechanisms developed by healthcare 8 MÜTZE ET AL. providers and pharmacological companies enabling continu- 37.5% of individuals showing mild symptoms. Comple- ous treatment for patients with intoxication-type IMD. Of mentary, our study confirms that, similarly to the general note, most patients themselves (n = 175) stated in an online population, the clinical course of SARS-CoV-2-infections survey not to have faced significant problems in receiving is mostly asymptomatic or mild also for individuals with special therapies (91%) but suffered from the consequences intoxication-type IMDs who, in more than 80% of indi- of quarantine (e.g., crowded apartments, isolation23). viduals, could be managed at home and did not require Telemedicine has experienced a strong upward trend hospitalization. since the beginning of the pandemic and people have Overall hospitalization rate for patients with SARS- become familiar with the technology.24 Many centers CoV-2-infections in Germany was reported to be 7.3%, started telemedicine appointments and used videoconfer- but differ between adults >60 years (21.9%), newborns ences as a replacement for face-to-face meetings.13,25 and infants (8.8%), and children and adolescents (0.7%– Rates of satisfaction among patients proved to be high, 1.3%).28 The hospitalization rate of 17% found in our with lack of laboratory tests26 and medication being study are therefore higher than in the general population, reported by patient organizations13 as the main disadvan- and is comparable to another report on SARS-CoV- tages. Rate of telemedicine used for IMD patients (90%) 2-positive patients with diabetes.15 For IMDs, one survey- was reported to be higher compared to the general rare based multicenter study found severe symptoms and hos- disease community in Europe and United States.13 Our pitalization rates in 1%–25% of IMD patients reported by study confirms the high compensation rate of increas- less than 10% of survey respondents,15 while one single ingly requested medical services using remote techniques center study reported on 1 of 19 hospitalized patient.16 (83% of centers) and highlights that these relevant and Further data for hospitalization rates for patients with new digital tools for reducing physical and geographical IMDs or intoxication-type IMDs are not available. barriers have been successfully established in health care ICU treatment of SARS-CoV-2 infections are required for IMD patients by metabolic centers worldwide. in 1%–5% of pediatric and 7%–10% of adults.5,6,29 How- The low overall incidence of 7.4% positive SARS-CoV-2 ever, children and adolescents with chronic diseases are infections in our study cohort may be hampered by the admitted to hospital and treated on ICU more frequently. fact that the observation period did not cover very recent Risk factors for severe disease course in children com- viral variants such as Omicron showing a much higher prise age <1 month, male sex, asthma, obesity, diabetes infection rate.27 Of note, another study16 also found an mellitus, immunosuppression or trisomy 21.7,8 Of note, infection rate of 7% in 272 patients covering an observa- our study demonstrates that intoxication-type IMDs are tion period of 12 months (March 2020–2021). Further- not a risk factor for ICU treatment in adult or pediatric more, as SARS-CoV-2 infections showed asymptomatic to patients. mild diseases courses in children, also underreporting has to be considered. 4.3 | Inpatient management and risk for metabolic decompensations 4.2 | The disease course of SARS-CoV-2 infections is mostly mild in intoxication- Compared to patients with other IMDs, patients with type IMDs intoxication-type IMDs have an additional risk for life- threatening acute metabolic decompensations during cat- In general, pediatric patients with SARS-CoV-2 infections abolic episodes such as intercurrent infections, that may are more frequently asymptomatic compared to adults require metabolic emergency treatment, hospitalization, and show milder symptoms.4 One single center study or even ICU admission with potentially hemofiltration. reported that disease severity of SARS-CoV-2 infections These episodes are associated with increased morbidity in 272 patients with different IMDs was comparable to and mortality.30–33 For UCD patients for instance, a the reference population in pediatric and adult patients.16 recent study found a mean frequency of 0.6–1.7 hyperam- Another study reported on 44 IMD patients with mostly monemic events per years requiring hospitalization, mild symptoms.22 A pan-European survey by the depending on disease severity.34 It was hypothesized that European Reference Network for hereditary metabolic in case of SARS-CoV-2 infection the risk for metabolic diseases (MetabERN; https://metab.ern-net.eu) among decompensation may even be higher and the disease healthcare providers following about 26 000 metabolic course may show gradual worsening, or even progressive patients15 reported 452 (213 pediatric) cases of COVID-19 neurological deterioration.13,25 However, a systematic in the first year of the pandemic with the majority of evaluation whether intoxication type IMDs are at adult and pediatric patients being asymptomatic and increased risk for life threatening metabolic MÜTZE ET AL. 9 decompensation triggered by SARS-CoV-2 was not per- should be classified as a high priority group for receiving formed so far. Although our study cohort is too small to the COVID-19 vaccination. assess the general risk for metabolic decompensation and Furthermore, we observed full recovery in 100% of further data for comparison rates of emergency visits do outpatients and 9 out of 10 admitted infected individuals not exist, our findings of only 30% mild to moderate met- including four admitted MMA patients treated with immu- abolic decompensations in 10 admitted patients without nosuppression following transplantation, while only one any further complications, ICU treatment, invasive venti- female MMA patient with immunosuppression suffered lation, or extracorporeal membrane oxygenation demon- from chronic mild neurological deficits after discharge. No strates that SARS-CoV-2-related decompensations in cases of acute COVID-19-related complications like myocar- intoxication-type IMDs do not seem to be aggravated ditis or PIMS have been detected. This observation also compared to other intercurrent infections or conditions confirms that chronic COVID-19-related complications likely to induce catabolism (such as febrile reactions to comprising “subacute” (4–12 weeks) and “postacute” vaccinations) and are generally well manageable. In line COVID-19 (>3 months) are not increased in our cohort of with this, one recent review found no increased risk for pediatric or adult patients with intoxication-type IMD. metabolic decompensation in OA or UCD following vac- cinations.35 Of note, several patients in our study admit- ted to hospital without metabolic decompensation 4.5 | Limitations received preventive metabolic emergency treatment. However, more studies are necessary to evaluate the risk First, the amount of collected data is relatively small and for metabolic decompensation in patients with only involves half of the E-IMD study centers. Second, intoxication-type IMDs in case of SARS-CoV-2 infections. the questionnaire was only directed at healthcare profes- Anosmia and gastrointestinal dysfunction like nau- sionals and not to patients, since the main study focus sea, vomiting, and diarrhea that affect both, food intake was to evaluate the impact on disease course and treat- and absorption frequently accompanied COVID-19. ment decisions and the resulting effect on health out- About 15% of hospitalized patients with COVID-19 are come. As a consequence, data do not reflect the patient reported to need parenteral nutritional support, in partic- perspective. Third, assessment of hospitalization and ular those with the severe conditions, high inflamma- severe cases may be hampered by the fact that the age some profile, or ICU treatment.36 but also patients with group with the most severe courses in the general popula- intoxication-type IMDs treated on normal wards as our tion, i.e. individuals aged 60 years and older and suffering data show (2 of 10 admitted patients). To recover, high from various comorbidities, is underrepresented in our protein content diet for about 8 weeks following dis- cohort of individuals with intoxication-type IMDs. charge from hospital, is recommended for SARS-CoV- Fourth, impact of vaccinations, becoming broadly acces- 2-infected patients with chronic endocrinological disor- sible at the end of the observation period and to a vari- ders.37 Certainly, this is not practicable in patients with able degree in each country, was beyond the scope of this intoxication-type IMDs treated since high protein intake study, and, therfore, could not be evaluated. Fifth, SARS- in this disease group can precipitate life-threatening met- CoV-2-associated long-term complications might be abolic decompensations. underreported since data entry was closed shortly after the end of the observation period. 4.4 | Outcome and mortality 5 | CONCLUSION Mortality in SARS-CoV-2 has been reported to be 0.08% in children.5 Most centers in one survey-based study did In conclusion, this study demonstrates a significant impact not report on death among their patients (85% adults to of the COVID-19 pandemic on medical health care of indi- 97% pediatric),15 but in contrast, several lethal courses in viduals with intoxication-type IMDs worldwide with dif- pediatric and adult patients with IMDs have been pub- ferent medical services being increasingly requested by lished.15,22 In our study, survival rate was 100%, showing patients and families, while medical supply and manage- that SARS-CoV-2-infection does not seem to be associ- ment was not endangered. Notably, the clinical course of ated with increased mortality in intoxication-type IMDs. SARS-CoV-2-infections in this subgroup is predominantly Although the vaccination status was not covered in our mild and mostly managed in the outpatient clinic. Rates of questionnaire, these data are insufficient to decide metabolic decompensations for admitted patients, mostly whether or not individuals with intoxication-type IMD receiving preventively metabolic emergency treatment, 10 MÜTZE ET AL. 21 was not increased and the overall prognosis for the vast Institouto Ygeias Tou Paidiou, Institute of Child majority of affected individuals is promising. Health, Athens, Greece 22 Department of General Pediatrics, Adolescent Medicine A FF IL I AT I O N S and Neonatology, Medical Centre, University of Freiburg, 1 Centre for Child and Adolescent Medicine, Division of Faculty of Medicine, Freiburg, Germany Neuropaediatrics and Metabolic Medicine, Department 23 Erasmus Medical Center, Rotterdam, The Netherlands of General Paediatrics, University Hospital Heidelberg, Heidelberg, Germany ACKNOWLEDGMENTS 2 University of Zagreb, School of Medicine and The authors thank all E-IMD (European Registry and Department of Pediatrics, University Hospital Center Network for intoxication type metabolic diseases) sites that Zagreb, Zagreb, Croatia contributed to the data used in this publication, as well as 3 University Children's Hospital and Children's Research the E-IMD registry for the support during the study period. Center, University of Zurich, Zurich, Switzerland Furthermore, we are indebted to all E-IMD individuals 4 Division of Inherited Metabolic Disease, University and their families for their trust, patience and participation Hospital Padova, Padova, Italy in longitudinal registry studies for many years. The E-IMD 5 Children's National Medical Center, Washington, patient registry has received funding by the European DC, USA Union (E-IMD; EAHC no 2010 1201; coordinator: Stefan 6 Department of Medical Genetics and Pediatrics, Kölker), in the framework of the Health Program. After National Taiwan University Hospital, Taipei, Taiwan the end of the EU funding period the E-IMD patient regis- 7 University Hospital Germans Trias i Pujol, Department try has been sustained by funding from the Kindness-for- of Paediatrics, Unit of Inherited Metabolic Diseases and Kids Foundation (Munich, Germany), the Kettering Fund, Neuropediatrics, Universitat Autònoma de Barcelona, and Dietmar Hopp Foundation. Open Access funding Badalona, Spain enabled and organized by Projekt DEAL. 8 Hôpital Universitaire des Enfants Reine Fabiola- Université Libre de Bruxelles, Brussels, Belgium CONFLICT OF INTEREST 9 Medical Reference Center for Inherited Metabolic Rene Santer, Chris Mühlhausen, Elisenda Cortès-Saladela- Diseases, Jeanne de Flandre University Hospital and font, and Sarah C. Grünert, gave presentations during meet- RADEME Research Team for Rare Metabolic and ings organized by a pharmaceutical company. Mathias Developmental Diseases, CHRU Lille, Lille, France Baumgartner received research grants by a pharmaceutical 10 Department of Pediatric Inherited Metabolic Diseases, company. Kimberly A. Chapman reports unpaid advocacy University Hospital of Antwerp UZA, Antwerp, Belgium for two metabolic associations. Matthias Gautschi was con- 11 Department of Paediatrics, Division of Paediatric sultant for a pharmaceutical company. Ivo Baric received Endocrinology, Diabetology and Metabolism, Inselspital, support for attended meetings. Other authors declare no University Hospital Bern, Bern, Switzerland conflict of interest. 12 University Children's Hospital, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany DA TA AVAI LA BI LI TY S T ATE ME NT 13 Endocrinology and Nutrition Department, Hospital The datasets of this study are not publicly available due to Universitari Germans Trias i Pujol, Badalona, Spain existing data protection laws. Data ownership is incum- 14 Clinic for Pediatrics, Medical University of Innsbruck, bent upon the members of the E-IMD consortium making Innsbruck, Austria data available for specific research purposes upon request. 15 Goethe University Frankfurt/Main, Uni.-Children's Hospital, Frankfurt/Main, Germany ET HI CS S TA TE MEN T 16 Centre Inherited Metabolic Diseases, Departments of The Institutional Ethics Committee of the coordinating cen- Paediatrics and Clinical Genetics, Copenhagen ter and all contributing study sites approved the study University Hospital, Copenhagen, Denmark (University Hospital Heidelberg, application no. S-525/2010). 17 Universitätsmedizin Göttingen, Georg-August- Universität, Göttingen, Germany ORCID 18 National Hospital for Neurology and Neurosurgery, Nikolas Boy https://orcid.org/0000-0001-7665-6602 Charles Dent Metabolic Unit, London, UK 19 Institute of Pathology and Human Genetics (IPG), RE FER EN CES Charlerois, Belgium 1. Lu H, Stratton CW, Tang YW. 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