Challenges of following patients with inherited metabolic diseases during the COVID-19 outbreak. A cross-sectional online survey study

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Ece Oge Enver, Duhan Hopurcuoglu, Seffa Ahmadzada, Tanyel Zubarioglu,

Ay

şe Cigdem Aktuglu Zeybek and Ertugrul Kiykim*

Challenges of following patients with inherited

metabolic diseases during the COVID-19 outbreak.

A cross-sectional online survey study

https://doi.org/10.1515/jpem-2020-0441

Received July 23, 2020; accepted October 12, 2020; published online November 12, 2020

Abstract

Objectives: There has been a recent worldwide outbreak of coronavirus disease (COVID-19). Most of the health system capacity has been directed to COVID-19 patients, and routine outpatient clinics have been suspended. Chronic disease patients, such as inherited metabolic disorders (IMD), have had trouble accessing healthcare services. Methods: An online cross-sectional survey was conducted among patients with IMDs who were present for a follow-up at our clinic to address their problems during pandemic period. Our clinic’s Instagram and Facebook accounts were used to invite the participants. Three reminders were given between May 1, 2020, and May 30, 2020. Survey questions were analyzed using descriptive statics.

Results: A total of 213 patients completed our survey. Incomplete surveys were excluded, and 175 questionnaires were evaluated. Most of patients had a special diet, and 51% of them had some difficulty with their diet. The reported rate of using a special treatment was 38%, and most of these patients (91%) had no problem receiving these special therapies during this time. Parents who were wearing masks while caring for their child were very few (17%), but a vast majority of parents (73.7%) had high handwashing rates. None of the patients had a SARS-COV2 infection until this paper was written.

Conclusion: This is the first study that aims to determine the problems faced by patients with IMD during the

COVİD-19 period. Considering that the pandemic will not immediately pass, recognizing the problems faced by pa-tients with chronic diseases and developing solutions would help these patients avoid long-term damage.

Keywords: COVID-19; inherited metabolic disorders; online survey; SARS-COV2.

Introduction

There has been a recent worldwide coronavirus disease (COVID-19) outbreak of a new form of coronavirus, SARS-COV-2. The pandemic started in Wuhan in China’s Hubei province in December 2019 and subsequently spread all over the world. Up until July 1, 2020, according to the World Health Organization’s (WHO) COVID-19 database, there have been 6,799,713 confirmed cases and 397,388 deaths (WHO 2020). Since respiratory droplets are spreading very quickly with close contact, each country has started to take preventive measures and has tried to prevent an uncontrolled spread of the disease among the people and a collapse of its healthcare system [1]. After the ﬁrst case in Turkey was seen on March 11, 2020, some un-precedented steps were taken in Istanbul and other prov-inces of Turkey to regulate COVID-19 transmission, including limiting domestic travel, stopping all interna-tional ﬂights, closing most commercial activities and businesses and public places, and implementing a curfew on weekends. Practicing social distancing and wearing a mask in public were made mandatory. Most of the hospitals were designated as pandemic hospitals, and most of the inpatient capacity was reserved for patients with COVID-19. Routine outpatient clinics with chronic diseases, such as inherited metabolic diseases (IMD), were suspended in this period.

Though metabolic diseases are rare, they collectively form a large group, and Turkey is one of the few countries that has a high prevalence of IMDs. For example, while the global prevalence of phenylketonuria (PKU) is 1/12,000, in Turkey it is 1/4200 [2]. Similarly, biotinidase deﬁciency (BD) has a frequency of 1/400,000–600,000 births in the

*Corresponding author: Ertugrul Kiykim, MD, Cerrahpasa Medical Faculty, Division of Nutrition and Metabolism, Department of Pediatrics, Istanbul University-Cerrahpaşa, Kocamustafapasa Fatih, 34098, Istanbul, Turkey, Phone:_{+90 507 2598474,}

E-mail: ertugrulkiykim@hotmail.com

Ece Oge Enver, Duhan Hopurcuoglu, Seffa Ahmadzada, Tanyel Zubarioglu and Ay_{şe Cigdem Aktuglu Zeybek, Cerrahpasa Medical} Faculty, Division of Nutrition and Metabolism, Department of Pediatrics, Istanbul University-Cerrahpa_{şa, Istanbul, Turkey}

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world according to previous studies, but in some countries prevalence may be higher due to high rates of consan-guinity [3]. Based on the data published by the Turkish Ministry of Health, BD incidence in Turkey is 1/11,000 in newborn screening (Turkish Ministry of Health, 2018).

Patients with IMDs have specific clinical routines and need frequent blood controls and dietary changes. A high level of care and attention to the needs of these patients should be sustained, particularly in emergencies, such as acute metabolic decompensation or COVID-19 infection. Since our hospital became identified as a pandemic hos-pital and regular elective outpatient clinics were dis-continued, also most patients have been afraid to come to the hospital. As such, we had to develop new strategies for patient follow-up. The current shift in the paradigm of patient care and the thread of a new infectious disease are challenging for IMD patients, their families, and their doctors. Nevertheless, this situation is very new for every chronic disease patient, and the potential challenges they will face are uncertain. We conducted a survey study to address these challenges and patients’ and parents’ awareness to avoid these infectious diseases.

Methods

An online cross-sectional survey was distributed to IMD patients who had a follow-up in our clinic. Our clinic_{’s Instagram and} Facebook accounts were used to invite the participants to respond to our survey. In addition, patients who had shared their e-mail addresses for communication purposes had been used to increase the response rate. Patients’ data were collected anonymously, and their responses were not used outside of this research, which was disclosed to the participants at the beginning of the questionnaire. Three reminders were given between May 1, 2020, and May 30, 2020. Only surveys with complete data were included for the final analysis.

The survey was designed and distributed using the Google Form (Google, Inc., Mountain View, CA, USA), and data were collected and exported to Microsoft Excel 2016 (Microsoft® Corp., Redmond, WA, USA). The questionnaire addressed the following areas: demographics; medical history, including their current diet; routine follow-up times; and challenges during the COVID-19 period. The survey is included in Supplement 1. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Istanbul University_{–Cerrahpasa Ethics Committee.}

Survey questions were analyzed using descriptive statics. Patients were divided into two groups as frequent comers (FC) and occasional comers (OC) according to the frequency of clinical visits. Pearson Chi-square test was used to examine the relationship of these groups and preventive measures such as frequency of washing hands in one day and wearing masks during childcare and using additional dietary supplements. Statistical analyzes were performed with IBM SPSS Statistics for Windows (version 21.0: IBM Corporation).

Results

A total of 213 patients completed our survey. Patients with incomplete information and who did not have follow-ups at our clinic were excluded, and in the end 175 question-naires were evaluated. The distribution of patients’ diagnoses is given in Figure 1. Of the respondents, 86 (49%) were female and 89 (51%) were male, and their mean age was 87 months (±85 months). Of the ground, 117 (67%) lived in Istanbul, 4 (2%) in Ankara, and 3 (1.75%) in Izmir, while the remaining participants lived in other cities of Turkey. Two patients were living in Azerbaijan. Regarding frequency of follow-up, 35 (20%) of the respondents came to the clinic every 15 days, 41 (23%) once a month, 57 (32.5%) once every three months, 31 (18%) once every six months, and 11 (6%) once a year. Thirty-seven percent of the PKU patients, who normally have a frequent need for blood sampling, came to follow-ups every 15 days. The proportion of patients who had difﬁculty performing routine blood controls was 61.7%. This rate was 56% in hyperphenylalaninemia and PKU patients.

The vast majority of patients had a special diet (113; 64%). Once asked about their compliance, most of them said they had no difficulty in following their diet (n=54, 47.7%) whereas 35 (31%) patients sometimes and 24 (21%) patients always had issues with their diets. The majority of patients (74%) who were applying a diet did not have a problem about reaching their special formulas and low-protein dietary products. The reported rate of using a special treatment such as biotin, sapropterin, enzyme replacement therapy, or ammonia scavenger drugs was 38%, and most of these patients (91%) had no problem

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receiving special therapies during this time. There was a large portion of participants (72%) living in crowded houses with more than four people, and 74% of them had ﬁnancial problems. Most of the respondents (77.7%) had to work out of the house. Only a small group (16.5%) used extra vitamin or immune-boost supplements to try to pre-vent contracting a SARS-COV-2 infection.

During the time of social isolation, 34 (19.4%) of the patients experienced a cough, wheezing, fever, nausea, or diarrhea. Half of the symptomatic patients presented to the hospitals for these reasons, but none of them were diag-nosed with COVID-19. All of the patients agreed to comply with hygiene rules. Parents who were wearing masks at home while caring for their children were very few (17%), but a vast majority of parents demonstrated high hand-washing rates, at more than 10 times a day (73.7%)

No statistically significant difference was found be-tween two groups for usage of additional dietary supple-ments with the concern of getting sick (p=0.409). In addition, there was no signiﬁcant difference for frequency of washing hands and wearing a mask during childcare and frequency of washing hands between OC and FC (p=0.483 and p=0.773).

Discussion

During the period when routine patient follow-up was suspended due to COVID-19, most chronic patients had problems about accessing healthcare. We conducted an anonymous questionnaire study to determine the current situation and its effects on patients. To the best of our knowledge, this is the first study that aims to determine the problems faced by patients with IMDs during COVİD-19 period.

Patients with IMDs have a very dynamic metabolism, and they need frequent regular blood controls and physical examinations. PKU is one of the most common metabolic disorders in Turkey, and in this survey, it is the most common disease group (40%). Since strict blood phenyl-alanine control is related to a better neurodevelopmental outcome in PKU, patients need more frequent blood con-trols than do other IMD groups [4]. The common technique used for measuring blood phenylalanine level in our clinic is taking small volumes such as 1–2cc of capillary blood on Guthrie papers. By using this method, patients and their parents might easily continue their frequent blood level follow-ups. During this period, 56% of PKU patients claimed that they had difﬁculty getting routine blood controls. Besides in this group, this difﬁculty rate was found 61.7% in among all participants. This may be

attributed to PKU patients being accustomed to giving blood samples more frequently.

Moreover, although routine outpatient clinics were canceled, our laboratory continued to work, and a per-manent team stayed in the clinic to answer the questions and results received via e-mail. However, that the curfew applied to people under 20 years of age in our country and public transportation rarely ran may have made it difficult for patients to come to the hospital to give blood samples. Despite the struggles expressed by some of the parents, the number of phenylalanine–tyrosine analysis that our lab-oratory made between March 23, 2020, when the restriction starts, and May 30, 2020, was 500. During the same period of the previous year, this number was 569. Decrease be-tween these two periods is not clinically significant and shows that patients somehow deliver the blood to the laboratory despite all the difficulties.

The frequency of coming to the hospital may be thought to create psychological stress on the patients’ caregivers. The concern about exposure to viruses during transportation or in the hospital can aggregate patients’ concern of become sick. When we compared OC group and FC group for handwashing rates, wearing a mask during childcare, and using additional dietary supplements, no significance was found. This result may be attributed to the style of questions being asked. Although the use of many extra supplements, such as vitamin c, Quercetin, and propolis, was encouraged on social media to prevent becoming ill during the COVID-19 period, very few of the patients (16.6%) tried to use extra vitamins. The complexity of diseases and fear of unfavorable side effects of using unknown supplements might prevent families from taking extra pills.

Most of the IMDs do not have a curative treatment, in most IMDs special supportive treatments and lifelong challenging diets are used. In these diets, most foods are restricted and to measure the compliance, frequent blood controls are needed, and better diet compliance leads to better outcomes. However, diet compliance is a chal-lenging problem, and there are lots of reasons for dietary incompliance, including cognitive, emotional, and psy-chological factors; inconvenience and cost of dietary treatment [5].

A study by Haynes reported that only 50% of chronic disease patients in developing countries seek treatment recommendations [6]. Although most of the participants in our study had a special diet, 53% of them reported they had difﬁculties with their diet during COVID19 pandemic. Although our rate is similar to the rates from Haynes study, it is not possible to clearly discuss this issue since diet compliance in routine period is not known. In addition, the

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majority of patients did not have trouble obtaining special and expensive dietary products. The reason may be that Health System in Turkey provides any special products and formulas with full coverage for IMD patients. During this time, all the products were covered without any prescrip-tion needs, and patients received all formulas and medi-cines from pharmacies directly. Likewise, this also applied to special medicines, and the majority of patients did not have a problem accessing their medication.

All of the families reported complying with hygiene rules. Since this information is based on family state-ments, it is very hard to measure clearly. The vast ma-jority of the families (73.7%) claimed to wash their hands more than 10 times a day. According to a survey, the frequency of people washing their hands more than 10 times is 61.6% in Turkey [7]. As IMD patients are at risk of life-threatening acute decompensation even after regular infections, patients and their caregivers are used to following measurements for reducing risks of an infection on a routine basis. Moreover, this high rate may have been found due to the trainings that all of the patients receive in our clinic after diagnosis about food and medicine preparation and hygiene rules.

In our study, most of the participants had four or more people living at home. The average household population according to the Turkish Statistics Institute is 3.5 (Turkish Statistics Institute, 2018). Despite the pandemic and the curfew, 77.7% of the responders had to go to work (i.e., could not work from home). Although most people had to work outside of their homes and lived in more crowded houses, none of the patients had a COVİD-19 infection, and only three patients’ relatives had a COVID-19 infection. As of July 1, 2020, in Turkey, there have been 199,906 conﬁrmed cases and 5,131 deaths [8]. The lack of any COVID-19 infections among our patients might indi-cate that the patients and their relatives comply with hygiene rules.

There were several limitations to this study. First of all, our patient group consisted of a wide range of IMD patients. Since patients have different follow-up times, treatment schedules, and risks, our data do not have a homogeneous distribution. Also, IMDs other than PKU are represented poorly in our study, and this became a barrier for us to compare how different IMD disease groups affect the results. Secondly, as our patients live in different parts of Turkey (and two patients even live in Azerbaijan), they may be considered to have different problems because of their social-economic environments. Lastly, this is an on-line survey study and all data are based on family state-ments, and these factors are cause of several limitations such as selection and recall bias.

This period has been a challenging time not only for IMD patients, but also for every chronic patient. During this time, all of the clinics that follow chronic patients have had to make various arrangements. All of the unnecessary visits had to be postponed. As how long the pandemic will last, different strategies are needed to be developed to follow up patients. Tele medicine is one the most rational arrange-ments that can be made in this direction, but several blood controls are needed to monitor biochemical changes for IMD patients. In a study from Italy, home care services had been used to visit the patients at their homes and obtain blood tests and vital parameters. In addition, some of the non-COVID-19 beds might be reserved for hospital admis-sion requirements for patients with IMD or other chronic diseases [9].

The medical surge in this COVID-19 pandemic has changed our routine clinical practice in different ways. Every country, institution reacted with their own capacity and infrastructure. We expect to have similar surges in future result of new outbreaks or environmental disasters. Institutions should have prepared alternative plans to be ready for the worst-case scenarios.

Conclusion

Routine healthcare is affected in IMD clinics as are the other clinics that have provided follow-ups to chronic disease patients during COVID-19 pandemic. IMD patients’ medical follow-ups are very distinct and very important for their well-being. Our study reveals that IMD patients adapted to the changes even with difficulty. In the future, having plans for chronic disease clinics for medical surge periods will enable better patient follow-up during this period and prevent potential harm to the patients.

Research funding: None declared.

Author contributions: EOE and EK designed the study. EOE, SA, and DH prepared the survey. EOE, SA, ACAZ, TZ collected data. EOE, DH, TZ, ACAZ, EK wrote the manuscript. All authors critically reviewed the manuscript. Competing interest: All authors state they have no competitive (ﬁnancial) interests in this study.

Informed consent: Informed consent was obtained from all individuals included in this study.

Ethical approval: Approval was granted by the Ethics Committee of Istanbul University–Cerrahpasa and documented in case ﬁle 2020-83045809-604.01.02. All procedures followed were in accordance with the ethical

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standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.

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Supplementary Material: The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0441).