Contrary to our concerns that people with PWS might be more seriously affected than the general population due to their known risk factors, the parents/carers who responded to our survey reported generally very mild or no symptoms and the outcomes for people with PWS were positive. No one in the survey required lengthy hospital admission, intensive care treatment, or died as a result of a COVID-19 illness. The cohort included people with PWS with additional risk factors, such as obesity, and an age range up to the mid-fifties. They were not, however, a group with reported high levels of respiratory co-morbidity. Whilst this observation indicates that severe outcomes are not inevitable in this group of people, the question arises as to whether these findings can be generalised to the whole population of people with PWS, particular in countries not represented in the survey. Our aim had been to obtain responses from different countries with varying economic status and variations in access to health care; however, the reports were predominately from Europe and North America and we are not able to determine whether outcomes were different in less well-resourced countries. The survey was available in four European languages but not in other languages of relatively common usage, such as Arabic and Mandarin, or in the many minority languages. Despite our efforts our survey numbers were not as robust as we would have desired. For this and other reasons the sample cannot be considered to be representative of the global population of people with PWS who acquired COVID-19. In addition, the weaknesses of our survey were that the individuals with PWS were not tested regularly and therefore asymptomatic individuals would have been missed. However, if asymptomatic cases were missed this would not alter the fundamental proposition that people with PWS may have some innate protection against COVID-19, if anything it supports this conclusion. A number of those with PWS included did not have COVID-19 testing to prove the diagnosis and a small number of informants did not know whether those they supported had had genetic testing for PWS.
These findings could be explained by recruitment bias for a number of reasons: first, parents and other carers may have been too upset to complete the survey if the person with PWS they cared for had been severely ill or died; second, more adverse outcomes may have occurred in parts of the world where the survey was not known about, a significant language barrier existed, or there was no internet access; and third, if those providing support also had had COVID-19, their illness may have prevented them from completing the survey or affected their motivation. It is also possible that some of these cases were in fact more severe than reported but this was not obvious because of the high pain threshold and perhaps a reluctance on the part of the person with PWS to report their feelings. The first two of these possibilities are supported by unofficial reports from colleagues who heard of deaths and hospitalisations in America and South Africa but these were very much minority reports.
A very important drawback to interpretation is that this study cannot address the question as to whether or not people with PWS were more or less exposed to COVID-19. Lack of exposure may be a partial explanation for the low response rate, especially as in many countries the policy was for people with intellectual disabilities to be shielded and because of this or because of the general preference of people with PWS for lone pursuits, they may not have in fact come into long and close contact with infected people. Moreover, if exposed, the viral load may have been small for the same reasons. In a study comparing 15 fatal, 133 symptomatic and 138 asymptomatic cases of COVID-19 illnes, a high viral load was associated with more severe illness and poorer outcomes [14]. However, the qualitative data from this study would indicate that even where the whole family developed COVID-19, which is likely to have led to high levels of family exposure to the virus, the outcomes for those with PWS were still mild. Some limited support for suggesting that people with PWS might have some protection against severe disease following COVID-19 illness comes following more recent enquiries, specifically about serious illness or the deaths of people with PWS. These enquires were made close to the end of study through the global contacts of IPWSO and via the IPWSO Professional Providers and Caregivers Board (representing organisation providing care to people with PWS) to ask if they had knowledge of the deaths of people with PWS from COVID-19. Representatives from seven countries responded reporting little direct knowledge of deaths and a very small number of deaths in total and these were invariably in people with PWS who were very obese or had had very severe respiratory illness. Although in this study the number of surveys completed is small and the nature and extent of bias is difficult to quantify, when all the evidence is taken together we conclude that people with PWS are certainly not, as we had feared, more severely affected by COVID. Furthermore, it is possible that they have some protection from severe disease, except where they are extremely obese or their health is severely compromised for some other reason. This observation contrasts with some evidence from data linkage studies investigating COVID-19 illness in people with intellectual disabilities. Although findings from these studies have differed, on balance they indicate that people with intellectual disabilities are both more likely to be infected with COVID-19 and more likely to have negative outcomes, including increased mortality rates. This may be particularly the case for people with ID who have Down syndrome where a tenfold increase in mortality has been reported [15]. Such data linkage studies have the benefit of large numbers but their findings are not broken down according to the many other specific and often rare causes of a person’s intellectual disabilities. The term ‘intellectual disability’, as recorded in medical records, refers to an extremely heterogeneous group varying not only in the cause of, but also the severity of disability, and in the extent of co-morbidities. Increasingly it is recognised that, whilst people with specific genetically determined neurodevelopmental disabilities may have in common the presence of an intellectual impairment, they also differ fundamentally in their biology and the associated risks for specific physical illness. If the finding that people with PWS are protected against serious outcomes of COVID-19 illness is correct, the question arises as to how the specific genetics of PWS and the resultant phenotype might give rise to some protection and whether there are important lessons for the population as a whole.
The infection cycle of SARS-Cov-2 is well characterised. On exposure to the virus, the viral spike protein binds to the angiotensin 1-coverting enzyme 2 (ACE-2) receptors and can then enter the cell and replicate. This viral load results in an immune reaction with the release of cytokines and in some cases an enhanced pro-inflammatory response. The role of the ACE-2 receptor and the extent of the subsequent immune response appear central to understanding the risk for serious disease when exposed to the virus [16]. The fact that there was no difference in outcome depending on genetic type of PWS indicates that it is something specific relating to the core PWS genotype and the absence of expression of the maternally imprinted/paternally expressed genes located at 15q11-13 (MKRN3, NECDIN, MAGEL2, IPW, SNORD 116, SNORD 115) that results in some protection or, alternatively, such protection is a consequence of some additional aspect of the PWS phenotype, such as growth hormone and sex hormone deficiencies. This latter explanation seems unlikely as a significant proportion of the people with PWS included in the study were on replacement therapy.
Anecdotal evidence from parents of people with PWS suggests that they may have innate immunity to viral diseases because they either did not succumb to, or had a milder illness than, siblings for a range of childhood illnesses. In this survey, one respondent reported “All three adults in the household, including the person with PWS, were sick at the same time, however, the person with PWS had the mildest case of the three of us”. In a paper of 2010, Viordot et al. [17] concluded ‘PWS subjects compared to adiposity-matched obese subjects demonstrate similar insulin resistance but increased low-grade inflammation. The dissociation of inflammation and central adiposity suggests that activation of innate immunity may be either a specific genetic feature of PWS or linked to the commonly associated obstructive sleep apnoea syndrome, and might offer a treatment target to reduce cardiovascular disease.’ We suggest that our findings support the hypothesis of increased innate immunity in people with PWS.
Although people with PWS do not appear to have been severely medically affected by COVID, mental health may have suffered from constraints of lockdown while eating behaviours may have benefited from a positive effect of isolation. Somewhat opposing papers from Germany [18] and France [19] concluded: ‘The COVID-19 pandemic has had a significant effect on the mental health of individuals with PWS, evidenced by an increase in behaviours associated with PWS, including temper outbursts, food-seeking, and irritability, which again underlines their need for specialised care. Individuals living with their families were particularly vulnerable, indicating that they and their families are in special need of support.’ And ‘Lockdown during the COVID-19 pandemic was associated with positive effects for most French adults with PWS, with weight loss probably associated with a more favourable environment during this period. We observed no severe forms of COVID-19.’
Finally, what are the lessons for the present pandemic or any future pandemic? Clearly, other viruses may have more, or different, adverse effects and any future pandemic would still require vigilance with respect to people with PWS. For some countries, the support of adult children as well as young children rests almost entirely with the family, so where family members are severely affected in a pandemic the support needs of the person with PWS may not be met. Where people with PWS have been at risk for severe illness related to a viral infection it would appear to be when they are very severely obese. Whilst in many parts of the world access to early diagnosis and the availability of information about the importance of controlling the food environment means that parents can prevent severe obesity and can ensure that co-morbidities are treated, this is not the case for many countries. The health care of rare disorders, such as PWS, remain a neglected area in many parts of the world [20].
