Providing high-quality care remotely to patients with rare bone diseases during COVID-19 pandemic

The general recommendations from WHO are applicable to all individuals including those with RBD [7]. The main recommendations are:

Critically ill patients with SARS-CoV-2 pneumonia may develop Acute Respiratory Distress Syndrome (ARDS) and require supportive treatment [9]. Current supportive treatment includes the following:

A treatment algorithm based on a stepwise utilization of HFNC, NIV and ETI can be utilized to reverse hypoxemia in patients with OI who develop severe ARF associated to SARS-CoV-2 pneumonia (Fig. 1).

Access to therapies and specialists’ consultation has become challenging during the COVID-19 pandemic, with even more relevant problems for patients affected by rare disorders. Indeed, this fragile population is, by definition, more brittle and tend to suffer more from any additional health problem. Patients can “forget” their disease, being, instead, concentrated on avoiding the risk of infection. Moreover, patients might incautiously discontinue their treatments, especially if the disease is not immediately life threatening. For this reason, it is necessary to offer specific indications related to the treatments to RBD patients during this COVID-19 outbreak.

First, patients taking vitamin D and calcium, should continue their treatment, especially considering the postulated extra-skeletal effects of vitamin D on innate and adaptive immunological response. Indeed, vitamin D supplementation could protect against acute respiratory tract infection [16] and, even more interestingly for COVID-19, has been shown to reduce circulating IL-6 in critically ill patients [17]. In addition, quarantined individuals are usually less exposed to sunlight and, in turn, the synthesis of vitamin D is diminished [18]. Therefore, we suggest to adults to take more than the usually recommended 1000 IU of daily cholecalciferol [19] and to paediatricians to adjust the dosage in children as well [20]. With regards to calcium intake, we suggest to follow current recommendations on age-related calcium intake.

Children with vitamin D-dependent rickets type 1 and type 2 should continue the regimen of treatment with active vitamin D metabolites, such as calcitriol or alfacalcidol, in combination with calcium salts [21]. Furthermore, children with X-linked hypophosphatemic rickets receiving conventional treatment (calcitriol or alfacalcidol associated with inorganic oral phosphate salts) [21] or the recent new Burosumab therapy [22‐24] must be accurately followed by the bone specialist performing the scheduled checks.

Second, we recommend to patients on amino bisphosphonates (i.e., OI patients both adults and children) [25, 26] not to discontinue their treatment. Intravenous amino bisphosphonates infusions can be safely postponed, or, in exceptional situations, an oral substitutive agent can be offered to those that cannot delay the treatment. Nevertheless, bone specialists should be consulted through telehealth service and a shared decision-making strategy should be encouraged.

Finally, for patients under treatment with orphan drugs the therapy should be continued independently of the actual crisis with the agreement of the bone specialist.

In order to create COVID-19 emergency units, hospital settings were re-organized to free up resources (i.e. ICU beds, blood products, ventilators, personal protective equipment) and all elective orthopaedic procedures have been cancelled or postponed, with the only exception of tumour surgery.

Minor injuries (i.e. contusions, ankle sprains, simple wounds) should be treated by an Accident and Emergency (A&E) consultant without input of an orthopaedic surgeon. As well as, the cases that do not need treatment or need a simple bandage or splint application. Imaging exams should be performed in the A&E department and, if needed, the orthopaedic surgeon should review it remotely. If an orthopaedic consultation is necessary, it should be performed in the A&E department by the orthopaedic surgeon wearing full personal protective equipment (PPE) [27]. Procedures like conscious sedations for fracture reduction or reduction of dislocations should also be performed in the A&E department without transferring the patient to other areas of the hospital. Before discharge from the A&E department “at-risk” patients and their accompanying parent (if the patient is a child) should be offered a swab test for SARS-CoV-2 infection. Patients should be instructed to go home and respect a quarantine period until the result of the swab test is available. Contact number and address of the patient is forwarded to the local health authority for further follow-up in the community.

Major injuries or emergency cases requiring surgical treatment should be directly transferred from A&E to SARS-CoV-2 dedicated operating room through a dedicated entrance and elevator. Following surgery, patients are transferred to a dedicated multidisciplinary COVID-19 ward.

A pre-operative swab for SARS-CoV-2 should be performed in all “at-risk” trauma patients before surgery and every effort should be made to postpone surgery until the result of the swab is available. Thus, if the result is negative, the patient can be treated and transferred to the regular orthopaedic ward, and if it is positive, surgery is performed speedly and post-operative care is provided in the dedicated COVID-19 ward.

The adoption of the above mentioned guidelines has been recommended to all the orthopaedic units [27, 28] and has been successfully in place for the last 4 weeks at the Giannina Gaslini Children’s Hospital (Genoa, Italy) providing 24/7 coverage of all paediatric (< 14 years-old) trauma cases in the northern region and elective care treatment of all ailments of the musculoskeletal system below the age of 18 (including upper limb and lower limb reconstructive, tumour, and spinal surgery).

Pregnancy in woman with RBD may increase the risk of complications associated with the condition, such as cardiopulmonary and musculoskeletal problems. Thus, pregnant RBD patients have a high-risk pregnancy which requires a multidisciplinary follow-up [29‐31].

To date, there is no scientific evidence about an increased susceptibility of pregnant women to COVID-19. However, there is epidemiologic evidence that a small portion of pregnant women is at higher risk of severe illness from viral infections [32].

Pregnancy is a physiological state that predisposes women to respiratory complications of viral infection. Due to the physiological changes in their immune and cardiopulmonary systems, pregnant women are more likely to develop severe illness after infection with respiratory viruses [33]. Additionally, the presence of a pre-existing (or diagnosed during pregnancy) heart disease or respiratory problem, might increase the development of complications from COVID-19. Risk estimation for cardiovascular disease, in general, is mostly based on functional cardiopulmonary status. It was evident that pregnant women with other viral pneumoniae had an increased risk of preterm birth, fetal growth restriction and having a newborn with low birth weight [33].

Currently, there is no evidence that SARS-CoV-2 can be transmitted to the unborn child during pregnancy, or during childbirth (vertical transmission) [34‐36].

In light of the above, all pregnant women should be extra careful to avoid infection. Preventive actions include social distancing measures and washing hands often using soap and water or alcohol-based hand sanitizer [27]. Stringent measures are required for women with a severe cardiorespiratory complication secondary to RBD.

If a pregnant woman or anyone in her household has symptoms of cough, fever and difficult breathing, or has been diagnosed with COVID-19, it is necessary to contact the maternity service to organize the right place and time for the visits.

It should be kept in mind that maternity care is an essential service and should be planned along with other essential services. The risks of not attending care include harm to women, their baby or both of them, even in the context of COVID-19 global pandemic. Suspected, probable and confirmed cases of SARS-CoV-2 infection should be treated in hospitals with effective isolation facilities and protection equipment. Suspected/probable cases should be treated in isolation and confirmed cases should be managed in a negative-pressure isolation room. They are called negative pressure rooms because the air pressure inside the room is lower than the air pressure outside the room. This means that when the door is open, potentially contaminated air or other dangerous particles from inside the room will not flow out into the uncontaminated areas. A critically ill confirmed case should be admitted to a negative-pressure isolation room in the intensive care unit.

It is important that pregnant women with RBD continue to attend their scheduled routine care and follow-up for assessment for complications RBD-related. Management of SARS-CoV-2 infected pregnant women should be undertaken by a multidisciplinary team (obstetricians, maternal– fetal-medicine subspecialists, obstetric anaesthetists, midwives, virologists, microbiologists, neonatologists, infectious-disease specialists).

At delivery if the mother has COVID-19, the newborn should be test with pharyngeal swab.

For the newborn with skeletal disease with involvement of thorax and a potential reduction of compliance of lung, temporary separation of the newborn from a mother could be useful to reduce the risk of mother-baby transmission, until the result of neonatal swab.

If the swab is positive for coronavirus separation is not long necessary and the neonate can stay with mother. If the swab is negative, the risk and benefits of prolonging separation should be discussed with the mother by clinicians and decision should be made in accordance with mother’ desires. If separation is not accepted, the mother should take all possible precautions to avoid spreading the virus to her infant, including her hands before touching the infant and wearing a face mask while feeding at the breast.

We do not know whether mothers with COVID-19 can transmit the virus via breast milk, however the virus has been detected in the breast milk of woman with COVID-19 [37].

Whether and how to start or continue breastfeeding should be determined by the mother in coordination with her family and healthcare providers.

Children and adolescents are vulnerable to SARS-CoV-2 infection, but the disease appears to be less severe than in adults [38, 39]. The reason for this different severity remains to be determined. Differences in the clinical presentation of COVID-19 in children and adults have been reported [38, 40, 41]. Prevalence of clinical features among children and adults with COVID-19 is listed in Table 1.

Common abnormal laboratory findings that have been described in SARS-COV-2 infected patients are elevated creatine kinase MB, lymphopenia and leucopenia. Comparing children and adults, an elevated procalcitonin is described in pediatric patients and not common in adults, whereas adults present more often an increase in C-reactive protein than children. In pediatric patients, variables that are associated with severity of COVID-19 are radiographic presentation, decreased lymphocytes count, elevated body temperature, and high levels of procalcitonin, D-dimer, and creatine kinase MB [38, 41]. Most common radiologic findings are bilateral ground-glass opacities. Consolidation with surrounding halo sign may be considered as a typical sign in pediatric patients [38].

Large Chinese pediatric case series have documented only two cases of death in children [42, 43], but in the last days, mass-media reported the death of some children and adolescents both in European countries and in the United States. Children may be a disease spreader for more vulnerable people, such as grandparents, therefore having a critical role in community-based viral transmission, even without showing symptoms [44, 45].

Reports about SARS-CoV-2 infection in children and adolescents with chronic diseases or RBD, are actually lacking. They may likely be infected in the same proportion as healthy children and adolescents. Nevertheless, children with RBD affecting chest wall development (Table 2), could be at higher risk of acute respiratory insufficiency even though affected by a mild form of the disease.

Chest wall malformations, including excessively stiff and narrow chest, can lead to a decreased functional residual capacity, exposing patients to severe respiratory insufficiency [46‐50]. These patients could, therefore, be susceptible to more severe complications related to SARS-CoV-2 infection than healthy subjects. For patients with chest wall malformations it is therefore recommended to seek for medical advice since the onset of fever and to access to hospital in case of persistent, severe cough, increased respiratory rate for age, worsening breathing difficulties, and/or oxygen saturation < 97% by pulse oximetry.

It is also important to consider that symptoms of SARS-CoV-2 infection overlap with symptoms of many other pediatric diseases, and that other pediatric diseases that have not disappeared. Access to Italian Emergency Departments has decreased dramatically, as hospitals are considered possible sites of infection for COVID-19. This is leading to late admissions of pediatric patients in advanced stages of other diseases.

All age groups are at risk infection by SARS-CoV-2, but elderly people are at the highest risk of developing a more severe infection, leading to a critical illness due to the physiological changes related to ageing, and the possible underlying health comorbidities [51]. Considering that European countries have an enormous concentration of elderly people and that over 95% of all deaths caused by COVID-19 occurred in individuals older than 60 years, following all recommendations to avoid infection is crucial [1]. Furthermore, smoking represents an important factor for COVID-19 disease severe outcomes and mortality, in particular for elderly males: according to WHO, the odds of disease progression is 14 times higher among people with a history of smoking compared to those without [52].

Despite their physical limitations and motor impairment, patients with RBD often present normal or higher degree of social, communicative and resilience skills. For example, people affected with OI often achieve high educational and employment levels [53‐55]. The Quality of Life of people with OI, from childhood to adulthood, show more restrictions regarding physical activities, whereas socio-cultural and mental QoL seem to be less affected [56‐58].

A high degree of resilience and a low incidence of depression are reported. Since childhood, they have learnt that their life will be marked by a long series of challenges and ups and downs [54, 59]. From that, a strong impulse to start over again after fractures or surgery, and to resume the goals previously achieved to try to overcome them emerges [53].

Behind their accomplishments and their remarkable abilities, however, an effective management of anxiety, fear of pain and risk of fractures is required. The need to feel safe in social contexts and the concern for a harm free physical contact with other people are persistent [60, 61]. Physical integrity is a source of continuous subliminal continuous stress [53].

During the recurring and extended hospitalizations for fractures and related surgeries up to home recoveries, families are involved together with healthcare professionals in the care and cure of their relatives with OI up to adult life, if total autonomy cannot be reached [58, 60, 61]. Children and adults with OI frequently don’t rely on those who do not know their bones brittleness and their functional limitations [62].

In the case of COVID-19 patients affected with RBD:

Patient Associations have always been a point of reference for their communities. The comparison and dialogue among associates are the main activity of the Associations and today this occurs more and more frequently through ways of communication such as video conferences or social networks. Face-to-face national or international meetings and conferences are important too, at the presence of clinicians, specialists and representatives of the Institutions.

These sharing tools or methods allow the Associations to create a complete and as comprehensive as possible perspective, relating to the needs of the patient himself, offering better data collection.

Currently many Associations have developed processes and methodologies to create an effective “empowerment” that allows its members to be fully prepared and involved in sectors such as research, biobanking and clinical studies and to participate in trials.

Collaboration among Associations is fundamental for their growth, as well as a direct comparison during congresses or video conferences among patients and specialists from Universities or research and clinical centers. Nowadays, the Associations are responsible for gathering the needs of the rare diseases patients in order to be able to:

The Associations also represent a point of reference in times of emergency, providing broad spectrum support to the members in need. Cases in which patients’ requests to the COVID-19 Helpline cannot be resolved from a medical / scientific point of view are referred to the Patient Associations. Thus, they can provide prompt responses to people who have expressed difficulties and place them in an extended network context that also includes legal, social and psychological support.

For this purpose, the COVID-19 Helpline is connected to other local networks, such as Uniamo’s SAIO Helpline (Listening, Information and Guidance Service) and an As.It.O.I. active phone number, with telephone, message service and voicemail available. In the COVID-19 emergency, the problems to be addressed can be different and can be summarized in:

The Associations provide real-time feedback on the treatments requested and obtained treatments, thus representing a litmus test for the institutions that must take care of the patients with a rare disease.