Keywords
long COVID-19 - orthodontic tooth movement - orthodontically-induced inflammatory
root resorption
Introduction
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) identified in 2019.[1] The global number of people infected by COVID-19 surpassed 526 million with a prevalence
of 43%.[2] The COVID-19 infection leads to a variety of symptoms such as headache, fatigue,
cough, shortness of breath, muscle and joint pain, altered taste and smell, cognitive
impairment, and diarrhea; and may even lead to severe pneumonia and death especially
in patients with underlying medical conditions.[3] The average recovery time from acute COVID-19 infection ranges between 2 and 3 weeks.[4] This is generally followed by a subacute phase that deals with symptoms that last
between 4 and 12 weeks after the onset of illness.[5]
[6] Symptoms that persist after the acute and subacute infection phases (beyond 12 weeks
up to an undefined period) lead to what is currently known as post-COVID-19 syndrome
or long COVID-19 (LC).[7]
Symptoms of LC include anxiety, fatigue, myalgia, cognitive impairment, sleep disturbances,
among others.[3]
[8] Fatigue and cognitive impairment have a lower incidence in children than adults.[9] Risk factors of LC include being female, older age, high body mass index, history
of chronic respiratory disease, and having a severe reaction to COVID-19 during the
acute phase.[10] In addition, the presence of more than five symptoms in the first week of acute
infection was shown to be significantly associated with the development of LC, independent
of the patient's age or sex.[11]
Pooled estimates indicate about 226 million individuals are currently experiencing
or have experienced persistent symptoms from COVID-19.[2] A recent meta-analysis reported that 80% of people who suffered from COVID-19 experienced
one or more long-term symptoms.[12] However, accurate reporting of the epidemiology of LC is restricted by several factors
including inconsistencies in the diagnostic criteria, reporting systems, follow-up
durations, and demographic characteristics of the examined populations.[7] Nonetheless, the incidence of LC has been reported to range between 30 and 96% depending
on the examination times after the acute infection.[7]
[13]
[14]
The pathophysiological mechanism for LC is poorly understood. However, a potential
reason for persistent symptoms could be an overall hyperinflammatory response.[6] In particular, when a patient experiences fatigue due to LC it may persist because
of direct viral encephalitis, neurological inflammation, hypoxia, and cerebral vascular
disease.[9] From a mental health perspective, animal models and brain analyses of COVID-19 patients
postmortem provided evidence that SARS-CoV-2 can also penetrate the blood–brain barrier.[15] This can then result in the brain triggering an immune response that releases interleukins
(IL), tumor necrosis factor α (TNF-α), and nitric oxide.[15] In addition, hyperinflammatory state, oxidative stress, cytokine storm, and DNA
damage have been hypothesized.[16] The LC can also be a sequalae of harboring the virus in tissue reservoirs across
the body, leading to reactivation; there may be cross reactivity of COVID-19 antibodies
with host proteins, leading to autoimmune problems; and there could be delayed viral
clearance due to immune system exhaustion, an overall mitochondrial dysfunction, and
alterations in the microbiome leading to long term health consequences.[6]
Various methods have been suggested for the diagnosis/detection of COVID-19 including
routine clinical screening for the detection of symptoms and clinical manifestations,
and confirmation with laboratory detection methods such as nucleic acid amplification
test, real-time reverse transcription-polymerase chain reaction test, rapid antigen
detection tests, serological techniques, and computed tomography scan.[17]
[18] However, accurate and early detection and identification of LC remain problematic,
which highlights the need for developing new validated screening questionnaires and
interviewing methods to identify persisting symptoms such as fatigue, mood and stress
disorders, and other mental health conditions associated with LC.[19]
It can be a challenge to manage persistent LC symptoms; this is partly due to the
overlap of persistent symptoms that could be a result of mental health problems from
the pandemic socially or emotionally leading to fatigue, headache, and other symptoms.[20] Also, it can be a challenge to distinguish between the populations' baseline and
their actual LC symptoms, especially for symptoms that present with relatively low
prevalence.[21] Thus, it will be very important to consider patients' pre-COVID-19/baseline state.
LC in Orthodontic Populations
LC in Orthodontic Populations
Orthodontic treatment (OT) is commonly performed in children, adolescents, and adults
for the improvement of dentofacial esthetics, oral function, and occlusion.[22]
[23] Since OT and LC are prevalent in the general population (including both growing
patients and adults), it is reasonable to assume that a growing number of individuals
with LC are currently undergoing or will undergo OT. It has been reported that patients
who experience mild or even asymptomatic COVID-19 infection exhibit a prolonged inflammatory
and stress response even after 40 days postinfection.[24] In this regard, the authors of the present editorial speculate that the biology
and outcomes of orthodontic tooth movement (OTM) might be altered in patients with
LC compared with nonpreviously infected or fully recovered individuals. Several studies
have assessed the disruption of OT during the COVID-19 pandemic and related lockdown.[25]
[26]
[27] These included the disruption of regular patient visits and management of orthodontic
emergencies, extended treatment durations, and patient distress and decreased satisfaction
with OT during the pandemic. Since it is likely that COVID-19 will continue to have
an impact on patients' general and oral health in the foreseeable future, the next
section aims to discuss the potential impact of LC on the biological mechanisms of
OTM, orthodontically-induced inflammatory root resorption (OIIRR), and periodontal
tissue response of patients undergoing OT.
Potential Impact of LC on OTM
Potential Impact of LC on OTM
Orthodontically applied forces on teeth create tensile and compressive strains on
the surrounding periodontal tissues through a mechanism of mechanotransduction.[28] Specifically, force induced strains at the compression site of the periodontal ligament
(PDL) lead to a constriction of the microvasculature (focal necrosis), which manifests
histologically as an area of tissue hyalinization.[29] This results in the release of various proinflammatory cytokines including the receptor
activator of nuclear factor kappa B ligand (RANKL), TNF-α, IL-1, IL-6, and other prostaglandins
and lysosomal enzymes,[28]
[30] which mediate tissue resorption at the compression site of the PDL. On the other
hand, strains at the tension side of the PDL increase blood flow and stimulate alveolar
bone apposition by inducing osteoblast progenitor proliferation, reducing RANK signaling,
and inhibiting osteoclast activity and formation.[31] In other words, OTM depends on coordinated bone and periodontal tissue remodeling,
which is regulated by various biological processes including loading-induced fluid
flow, induced hypoxia, and chemical and electrical signaling within the PDL.[31]
[32] This aseptic inflammatory cascade induced by orthodontic force application is regulated
by cytokines, prostaglandins, osteoprotegerin, and other key factors,[31] which enables movement of teeth into the orthodontically-planned positions in patients
with malocclusion who undergo OT. Control of the inflammatory process is crucial in
patients undergoing OT as unregulated inflammation might lead to side effects including
OIIRR, alveolar bone loss, and damage to the dental and paradental tissues.[31] Various factors such as systemic diseases, medications, nicotine, obesity, and stress
may influence the inflammatory response to orthodontic force application,[33]
[34]
[35]
[36]
[37] indicating the need of potential patient counselling, close monitoring, and orthodontic
plan/mechanotherapy adaptation in susceptible patient populations.
There has been no substantive research on the impact of LC on OTM. One of the possible
routes on how it could affect OTM is via the use of medications to reduce inflammation.
Patients with LC are often prescribed long-term anti-inflammatory medications to counter
the systemic inflammation. Corticosteroids may also be prescribed in varying durations
and strengths.[38]
[39] The tooth movement pathway is reliant on inflammation, and multiple studies have
shown that reducing or blocking inflammation either genetically or through pharmaceutical
means can have a profound negative effect on the rate of OTM.[40]
[41] As such, patients who are on long-term anti-inflammatory drugs have a significant
risk of reduced OTM,[42] and this would be an important factor for the orthodontist to take into consideration
when formulating the appropriate treatment plan and creating realistic objectives
and end-goals for the patient. Furthermore, LC has been associated with a prolonged
inflammatory and stress response,[24] and it might affect periodontal tissue remodeling during OT altering the rate of
OTM and increasing the risk of periodontal tissue destruction. The above-mentioned
hypotheses focused on indirect relationships between LC and OTM. Direct association
must not be excluded either. Due to common pathways, LC could impact the biological
mechanisms of OTM. Further research is needed to validate these hypotheses.
Potential Impact of LC on OIIRR and Alveolar Bone Loss
Potential Impact of LC on OIIRR and Alveolar Bone Loss
OIIRR and alveolar bone loss are some possible side effects of OT. It has been shown
that root resorption can be affected by the amount of orthodontic force, direction
of force, and duration of OT.[43] It has also been reported that obesity, respiratory disease, infections, and chronic
inflammation can increase the risk of root resorption.[44]
[45] For these reasons, patients suffering from LC may be at greater risk of OIIRR. At
a cellular level, clastic cells such as osteoclasts and cementoclasts have both been
implicated in the resorption of the external root surface. It has been demonstrated
that there is a possible link between COVID-19 and inflammatory cytokines, especially
IL-1, IL-6, and TNF-α which stimulate osteoclast activity, favoring bone resorption
through the RANK/RANKL system. It has also been postulated that the COVID-19 virus
may also act directly on bone resorptive units.[39] Whether these create a direct risk to OTM and related OIIRR is still not clear;
however, the implications still need to be acknowledged.
Through these inflammatory and bone resorptive mechanisms, the risk of bone loss during
OTM in patients with LC may potentially be higher. In addition, a dysfunction and
alteration of the oral microbiome has been reported in patients with LC.[46] These patients had significantly increased populations of microbiota that induced
inflammation, such as members of the genera Prevotella and Veillonella, which are
bacterial species that produce lipopolysaccharides. This may also contribute to a
greater risk of bone loss and periodontal disease.
Challenges and Future Research
Challenges and Future Research
Undoubtedly, the long-term impact of COVID-19 in the form of LC is still being studied
in many fields of medicine and it is pertinent to understand its implications in dentistry
and orthodontics. Potential research may include but not limited to retrospective
data from orthodontic patients who have had COVID-19 infections and are still suffering
from its prolonged state as LC including radiographs or other forms of imaging that
may demonstrate impact on OIIRR and bone loss. Similar retrospective research may
also be conducted to see if patients with LC who had undergone OT were subjected to
longer treatment durations, poorer treatment outcomes, and poor oral hygiene. Furthermore,
developing validated screening methods of LC and implementing them in the clinical
orthodontic setting would be beneficial for the development of prospective clinical
studies that assess the impact of LC on clinical orthodontic outcomes in patients
undergoing OT. Such studies will help develop clinical protocols for the orthodontic
management of patients with LC to ensure successful orthodontic outcomes while managing
the risk of possible side effects.
Conclusion
The impact of LC on OTM and related parameters remains unclear. The authors of the
present review discussed potential biological mechanisms through which LC may influence
OTM, OIIRR, and periodontal tissue response to orthodontic force application highlighting
the need of further research in this respect.
