Nationwide Awareness Campaign and Call for Dental Screening for HHT in Germany

Background: HHT is a rare, systemic, inherited disorder in which patients suffer from telangiectasias, especially of the facial skin, lips and oral mucosa, as well as visceral vascular malformations (VM). The diagnosis of HHT is often delayed for decades. However, early detection of VMs can reduce morbidity and mortality. Methods: In 2018 a nationwide awareness campaign addressing all dentists in Germany consisted of one published article and two reminders about HHT. As a proxy for the effectiveness of the campaign, researchers measured the number of rst-time inquiries from patients and physicians about HHT documented by the German HHT self-help group from September 2016 until September 2019. Results: A total of 411 rst contacts with the German self-help group were documented, mainly via internet platforms (internet forum (n = 130) and Facebook ® (n = 189)). For 9% of those patients (n = 36/411) the physician or dentist (physician: (n = 31/36, 86%; dentist: n = 5/36, 14%) informed patients about the disease HHT and the self-help group. Before publishing the rst article about HHT no dentist referred patients to the German self-help group; afterwards, 5 patients received information about HHT from their dentist and contacted the patient organization for the rst time. After each publication in June, September and December 2018 the number of new contacts increased. Contacts via phone and e-mail had the highest relative increase. Conclusions: The repeated call for dental screening for HHT in Germany lead to increased awareness of this rare disease; more patients with possible HHT received information about the condition. The authors conclude that targeted campaigns may contribute to a shorter diagnostic latency resulting in increased quality of life and life expectancy in HHT.


Background
Hereditary haemorrhagic telangiectasia (HHT) is a systemic, autosomal dominant, inherited disorder resulting in vascular malformations. With an estimated prevalence of 1-2 individuals per 10.000 the disease is a "relatively frequent" rare disorder [1,2]. Patients suffer from recurrent bleedings and problems arising from blood shunting due to visceral vascular malformations. Most patients develop recurrent epistaxis and multiple typical telangiectases of the skin or mucosa, in particular on their face, tongue, and lips ( Fig. 1). Visceral vascular manifestations most commonly affect patients' lungs, livers, and brains [3]. Pulmonary arteriovenous malformations (PAVMs) can lead to disturbed lter function of the lungs resulting in abscesses and infarctions of visceral organs like the brain, liver and spleen [4][5][6][7]. Therefore, in patients with likely HHT, screening for PAVMs is recommended [8,9]. The diagnosis of HHT is based on genetic testing and / or the International Clinical Diagnostic Criteria, also known as the Curaçao Criteria. Genetic testing can reveal the diagnosis HHT in most cases but not all disease-causing mutations have been detected [10]. Using the Curaçao Criteria based on patients' family history and the history of epistaxis, telangiectasia and visceral lesions the diagnosis HHT can be established. The presence of at least three out of these four clinical criteria is required in order to diagnose HHT [3,8].
German public health insurances recommend that every adult should visit a dentist at least once a year. To reinforce this recommendation, a bonus system has been established: persons following this recommendation receive higher reimbursement in case of dental repair [11]. Therefore, many Germans (70%) follow this recommendation [12].
Dentists, as health care professionals, routinely examine the mucosa of the mouth. The detection of typical telangiectases on the patients' oral mucosa and perioral skin during these examinations is likely. By asking additional questions about the family history and recurrent epistaxis the diagnosis of HHT could be considered. In this study the results of a nationwide German HHT awareness campaign and call for dental screening were analysed.
Previous studies have shown that both early HHT diagnosis and screening for pulmonary involvement, at least, reduced morbidity and mortality in patients with HHT. Referral to an interdisciplinary centre specialized in HHT is advantageous for these tasks [13,14]. Patients with HHT and pulmonary arteriovenous malformations (and those where this has not been screened yet) should be informed about the recommendation to use an antibiotic prophylaxis for certain medical procedures [15][16][17]. This important information was published in articles and reminders for dentists and was further distributed via special patient cards containing this information by the German HHT patient organization. Adoption of these measures by patients with HHT can help prevent complications such as strokes and abscesses [8], which was a major goal of our awareness campaign.
In 91 cases (91/411, 22%) the source of information about the self-help group was known: in 36 cases (36/91, 40%) doctors -mostly general practitioners -informed patients with possible HHT about the self-help group and patients received information about the disease HHT (Fig. 3). 48% of the patients (n = 44/91) did independent internet research about HHT, 9 patients (9/91, 10%) were informed by family members, and 2 patients (2/91, 5%) by friends and members of another self-

Discussion
To our knowledge this study describes the rst awareness campaign for HHT based on the inclusion of dentists. Every year more than 70% of the German population receive a professional tooth cleaning and examination by their dentists as it is supported by the German public health insurances [19,20]. Therefore, our approach had the potential for a nationwide population-based campaign. In HHT over 80% suffer from visible symptoms, like muco-/cutaneous telangiectasia, [3,[21][22][23] which could be detected by their dentists. Additionally, most patients and affected relatives suffer from recurrent nosebleeds, which can easily be assessed by taking a history directed speci cally at these points. The presence of telangiectases, nosebleeds and/or a positive family history are su cient to raise suspicion for HHT in the setting of a dental practice resulting in the appropriate referral for further evaluation. Early diagnosis and treatment achieved -like in this case through dental screenings -can lead to improved quality of life for HHT patients [14,24].
The results of the awareness campaign demonstrated a positive effect: our nationwide dental awareness campaign was associated with a higher frequency of persons contacting the self-help group for the rst time. However, the 10% increase in contacts for an equivalent time interval seems to be relatively small (187 rst contacts for the period from September 2016 to May 2018 in comparison to 222 contacts for the period from July 2018 to September 2019). Various explanations exist for the limited impact of the campaign. Our approach targeted dentists. In Germany, dentists normally do not write referrals which may have contributed to the limited effect. Only 9% of patients indicated that they were informed by their dentists or other physicians on the possibility of HHT. Before the campaign, no dentist referred patients to the German self-help group; afterwards, at least 5 patients received information about HHT by their dentists and mentioned this when they contacted the patient organization for the rst time. It is probable that this effect was related to the awareness campaign, which we interpreted as a limited success. However, it is interesting that 44% of patients stated that they were informed mainly by their general practitioners and only 14% by dentists. A higher rate of referrals by dentists was expected. The authors were not able to identify the reason for this but one possibility is that dentists rst referred to the general practitioner who then recommended that patients contact the self-help group.
Diagnosing rare diseases is challenging, as they are numerous and diverse in presentation. Therefore it is appropriate, that general practitioners and dentists have only limited knowledge of such diseases [25]. About 5000 rare diseases are known of which 700 involve dental, oral or craniofacial pathologies [26]. Given that an oral mucosal examination is a relatively simple and inexpensive screening tool, the World Dental Federation states that a systematic examination of the oral mucosa should be part of every dental examination procedure [27]. HHT is an autosomal inherited disease in icting female and male patients of various ages [28]. In Germany, dentists are the only primary health-care professionals treating patients of all ages and sexes. They are providers of primary oral healthcare and therefore essential gatekeepers for the management of patients who may have oral manifestations of systemic diseases, As such, they are often likely to be the rst clinicians to observe such abnormalities [24,29]. However, another study analysed the identifying rate of early oral cancer in the general dental practice and came to the conclusion that this is of limited effectiveness. Diagnostic screening systems also depend on qualitative factors -on primary health-care professionals using their discretion and clinical judgement for the screening process to work effectively. Although thorough screening might be challenging from a practical and economical point of view, clinical judgement should be encouraged in order to detect unexpected or rare diseases, like HHT [30]. As mentioned above, we identi ed speci c limitations to our approach with dentists. An consideration is that dentists are ooded with information and, even though the article was published in an important set book, this was only read by a limited number of dentists. We plan to increase awareness during future studies by asking the patients of self-help groups to print out the articles of the awareness campaigns and to present them to their dentists during their next visits.
Awareness campaigns for rare diseases like HHT are necessary in order to reduce the diagnostic latency and improve the medical care of these patients [31,32]. The German patient self-help group and different HHT centres and hospitals have been working toward heightened awareness of HHT in the general population and among healthcare professionals over the past years. However, the effect was limited and further measures seemed necessary [33]. In general, many problems in treating patients with rare diseases result from the lack of awareness or experience among healthcare professionals, low motivation, and barriers to changing practice or policies. One approach to increase awareness of and familiarity with rare diseases in healthcare is to target the postgraduate education of gatekeeper care providers, like dentists or primary care physicians. The goal of this education would be to help these providers differentiate rare diseases amidst the backdrop of the general population. Such education might be especially effective if it focuses on recognizable, core warning signs of rare diseases instead of on in-depth information. In this way, physicans might be more easily able to detect divergent patterns of diseases through their "gut feeling" pattern recognition [34]. Health promotion activities that focus on large populations such as smoking cessation campaigns may affect the health of many individuals which encourages engagement by primary care physicians and government agencies. However, mainly due to the lack of exposure or awareness of primary care providers or politicians the incentive to change practice or policy may be limited for rare diseases [35]. The "Shit Happens" campaign is an example of a parents-oriented research project for patients with the rare condition Hirschsprung's disease. The campaign demonstrated that social media can be a powerful and responsive tool to connect families with rare diseases [36].
To tailor the HHT awareness campaign to dentists as the target audience, we studied approaches taken by earlier campaigns targeting dentists. Two awareness campaigns, one in Brazil and the other in Florida, were implemented in order to improve the prevalence of hepatitis B vaccination among dentists and to inform dentists about diagnosing and treating patients with temporomandibular disorders. The campaigns were mainly based on online tools and resulted in low response rates amongst dentists [37,38]. Therefore, we developed a different approach by publishing repeated articles in a set book for all dentists in Germany. In our awareness campaign a case report about HHT together with instructions about disease management of HHT were published online and in print in the journal of the German dental association and the Federal Association of Fund Dentists of Germany which every dentist receives in Germany. This journal is a set book for all dentists in Germany with a total circulation of 77 621 copies in 2017. After publication of the article the number of rst contacts to the German self-help group via phone calls and emails increased, especially when comparing the time periods two months before and after the rst publication. Only these two means of communication were suggested in the publication, and subsequently, the increase in these routes were higher than in other channels like Facebook® or internet inquiries, suggesting that the rise in new contacts might be associated with our campaign. Interestingly, almost half of the patients answering to this question did an internet research about HHT and the German self-help group to access information on the disease. This underscores the fact that the internet has become a very popular source of health-related information for patients [39]. Likewise, many healthcare professionals use web-based tools for obtaining health-related information; however, defective synthesis of the available information can lead to diagnostic error [40].
Data was provided by the German HHT self-help group. Due to technical problems the documentation of the different communication channels for the whole period is only complete for rst-time contacts by phone. It should be noted that another limitation of the study was that neither patients' details (i.e. sex, age, clinical symptoms) nor a follow up of completed screening or necessary therapies could be documented due to data protection regulations. However, the cooperation of the self-help group for HHT and medical professionals during this study demonstrates the important role that patient involvement plays in the healthcare system [41,42].
The article on HHT was published in June 2018. On the beginning of July 2018, the new website of the German HHT selfhelp group was launched. Therefore, the effect of the new homepage might have been a confounding factor. However, a new website several years ago did not increase number of phone contacts at that time.
The development of a table showing oral manifestations and basic information, not just for HHT but also for other rare diseases, will be a task for our future work in order to facilitate the diagnostic process and to inform dentists about treatment options of different rare diseases.

Conclusion
This study demonstrates that a nationwide awareness campaign and call for dental screening for HHT in Germany lead to an increased number of persons with possible HHT being informed about the disease. This might contribute to early diagnosis and treatment in HHT and consequently improvements in morbidity and mortality among HHT patients.

Methods
From September 2016 until September 2019 the German HHT self-help group documented all rst inquiries from patients and physicians about HHT. The self-help group was contacted directly via e-mail or phone. Additionally, a board member of the German HHT self-help group provided data from an internet forum (https://www.morbusosler.info/) and a closed Facebook® group on HHT (https://www.facebook.com/groups/1889282361305763/).
In June 2018, a case report of a patient with HHT and PAVM developing a liver abscess after professional tooth cleaning together with an explanation and instruction on disease management in HHT was published in the journal of the German dental association and the Federal Association of Fund Dentists of Germany [15]. This journal is distributed to all dentists in Germany and is a set book for them. In 2017 it had a total circulation of 77,261 [43]. Three and six months later a reminder was published in the same journal [16,17]. In these three articles, dentists were asked to pay attention to typical telangiectases of the oral mucosa and facial skin and -upon discovery -to ask the patients if they or other relatives have nosebleeds. If HHT is suspected, it was advised to recommend that the patient get in contact with a medical centre to clarify a potential diagnosis. The self-help group was recommended as a way for patients to nd the appropriate medical centre. Consent for publication: Not applicable.
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Authors' contributions: UG, CG and FD have made substantial contributions to the conception of the work, the acquisition, analysis, and interpretation of data. UG and FD have drafted the work. All authors have approved the submitted version (and any substantially modi ed version that involves the author's contribution to the study) and all authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Funding: This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors. Figure 1 Typical Telangiectasia of the skin and mucosa in a patient with HHT HHT = hereditary hemorrhagic telangiectasia