**4. Discussion**

The Italian Government's emergency declaration on 9 March, 2020, drastically changed our lives. Every action, behavior, or even gesture was filtered by the COVID-19 alert. "Stay at home" was mandatory for all people, except for medical doctors, all health operators, and patients needing urgent medical care (www.salute.gov.it).

This study emerged from the observation of different reactions in patients with lysosomal disorders dealing with pandemic outbreak. LSDs are genetic, multisystem diseases [2]. To date, some of the rare LSDs are susceptible to ERT, which has been shown to at least delay progression, allowing a better quality of life in terms of disabilities. Although, we offered a regular and COVID19-controlled service for these patients, who deserved to be regularly treated despite the emergency period, we observed that patients and their parents were extremely scared and worried about coming to the Hospital, fearing a higher risk for COVID contamination. Thus far, most of them missed their scheduled ERT. Conversely, those patients who had already been treated with home therapy refused treatment by the dedicated team because they felt that this could represent a potential source of the infection.

In this regard, Sechi et al. (2020) analyzed data collected by a questionnaire from 102 patients on ERT therapy for LSDs in Italy [5]. They found that almost 50% of patients who were receiving therapy at a hospital (61.8%) had disruptions, especially for personal feelings (fear of infection).

In the present study, we analyzed behavioral and emotional profiles of our patients with LSDs during the pandemic, compared to healthy controls. For this reason, a structured interview was created and administered online by a trained psychologist, already known to all patients as working in the Centre. Since we thought and developed the interview in light of this extraordinary event, the tool could not have been previously validated. The interview was made during the first week of lockdown, when both patients and controls were experiencing the same uncertainty resulting from the special situation. This study certainly may have some limits due to the small sample size, but this is the rule dealing with patients with rare diseases who are referred to a single center. Although no significant quantitative differences were observed in the type of response between clinical and control groups, there were some qualitative differences between the two groups in all investigated areas.

In general, all people forced to stay at home and freeze their jobs and who were far from common relationships, but too close to the familial nucleus members, experienced an increase in anxiety, worries, and uncertainty fostered by incessant media updates on virus lethality and virulence, underlining its invisible presence in our environment and in our lives.

Nevertheless, peculiar differences emerged in social relations and perception of "others". The clinical group, always accustomed to dealing with diversity, exclusion, and unawareness of others with respect to their lives of illness, perceived "others" mostly in a negative way, as dangerous, disrespectful, and not empathetic and to be avoided. The control group, although having the same negative perception, experienced "others" as frightened, insecure, suspicious, and elusive.

In the clinical group, daily routine was marked from the issues of illness and its treatment, while for the control group, main problems were related to difficulty in maintaining, according to an orderly sequence, rules, spaces, times, and sleep–wake rhythm.

On the other hand, it is singular that, in the percentage of positive representation of the routine changes, subjects in the clinical group believed that the positive element was the opportunity of a better relationship with family members, while among controls, positive elements relied on the possibility of being alone and doing something for themselves.

Data about future perception evidenced that, while the control group directed its attention to a future focused on economic, social, and environmental issues, patients prefigured a future always oriented by their critical situation being aware of their limits, in terms of treatment opportunities and life expectation.

We focused on the COVID-19 pandemic effects on medical care and health status of patients with LSDs. The real risk of contagion once again highlighted the vulnerability of patients with chronic rare diseases such as LSDs, the difficulty of coping with his or her defenses, and the need to trust and rely on others. In this case, the subjects preferred to refuse treatment, the only chance to improve their condition. They gathered all their defenses and tried to put in place all the resources and strategies available, such as resist and wait, for example, for home treatment, rather than face unarmed an unknown, enigmatic, and dangerous "enemy".

In our sample, a striking similarity emerged between the two groups, equally forced to stay at home and experience the same profound feeling to be excluded (Isolation and Inclusion, *The Lancet Psychiatry* 2020) [6] by normal life. The pandemic, which represented a scary event, suddenly occurring in the daily life, destabilizing, and giving rise to uncertainty, had the same impact as a diagnosis of a chronic rare disease.

The control group experienced the feeling to be involved in a mutual fight against a common enemy, thus enhancing brotherhood with others. The patients with lysosomal disorders and their families felt that COVID-19 opened the curtains, revealing their human condition of chronic exclusion and impairing their liberty to go out, walk, meet others, love, and breath without fear of death as all the others normally do. Especially the mothers of our patients reacted with strength and determination, feeling that other people can know understand their withdrawn lives to assist their sons. They could now teach others how to face isolation with dignity, aware of fragility, as they usually do: "I can't help from sadly smiling when my neighbors complain because their children are sad as they cannot go outside ... don't say it to me, please, my child and I do not go out since he was born and he is 4 years old. Now we are all the same, all confined at home ... you are not different from us, you also are vulnerable, now we all fear death".

The outbreak of COVID-19 evidenced the vulnerability of the patients with such rare diseases and their needs in terms of adhesion to the therapy schedule. Thus far, a special license for home therapy was approved by AIFA (Agenzia Italiana del Farmaco (Italian Medicines Agency), DET. 341/2020), including those drugs prescribed and dispensed only at hospitals. This determination allowed home treatment for most of our patients. The COVID-19 emergency revealed LSD patients' strength in terms of improved relationships, such as adhesion to the patients' group, family members, and community and their observance of imposed rules and precepts, trust in authority and doctors, and hope for improvement.

**Author Contributions:** Conceptualization, A.F. and G.L.; Data curation, G.L., A.A., A.S. and F.R.; Formal analysis, A.S. and R.B.; Investigation, G.L.; Methodology, G.L.; Supervision, A.A.; Validation, P.P.; Writing – review & editing, A.F., A.P. and R.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors wish to thank the patients, their families, Battista Mangani, and Nefri Basile for their collaboration. The family association "Bacodirame" is deeply acknowledged for financing the University Research Grant for the Psychologist.

**Conflicts of Interest:** The authors declare no conflict of interest.
