see also: Otolaryngology COVID 19 Resources
Definitions
1. Long Covid
A World Heath Organization (WHO) working group (Soriano et al 2022) through an intensive Delphi process engaged 265 patients, researchers and WHO staff to name and define the condition of illness associated with Long COVID:
Long COVID = "post-COVID-19 condition", "chronic COVID-19", "post-COVID syndrome", "postacute sequelae of SARS-CoV-2 infection"
Long COVIDWorld Heath Organization (WHO) working group (Soriano et al 2022) |
History of probable or confirmed SARS-CoV-2 infection |
Usually three months from the onset of symptoms |
Symptoms that last for at least two months |
Symptoms that can't be explained by an alternative diagnosis(not limited to fatique, shortness of breath and cognitive dysfunction - include symptoms generally impacting daily functioning) |
These investigators (Soriano et al 2022) identified that it may be overly ambitious to provide a single definition for Long COVID for use in all care levels and severities. They also identify that 'not only timing and duration, but the symptoms are susceptible to subjectivity and bias" - and that the definition of long COVID will likely change as new evidence emerges.
Others support the concept that long COVID (Chronic COVID) as most appropriately classified with symptoms extending beyond 12 weeks (Greenhalgh 2020) - although debate continues regarding terminology and classification (Fernández-de-Las-Peñas 2021).
As per NEJM Journal Watch (2023) reivew of Lundber-Morris et al: Long COVID, aka 'PCC' (post-COVID-19 condition) "has been hypothesized to be a function of viral persistence, aberrant immune responses, and/or organ damage."
Pinkhofer et al (2023) through a matched cohort study comparing patients hospitalized for COVID with hospitalized controls without COVID found the brain health to be equally compromised in both groups. They concluded that long-term associations of COVID with cognitive, neurological and psychiatric impairment were similar to a carefully matched group of hospitalized patients with non-COVID-19 illness (including penumonia, mycocardial infaction and other). They identify that changes to brain health may not be specific to COVID in hospitalized patients - but rather resulting from severe illness as a less specific cause.
2. Xerostomia
Xerostomia is generally defined as the subjective complaint of a dry mouth and is not always accompanied by diminished salivary flow (Millsop 2017). The subjective complaint of dry mouth in the face of documented normal salivary flow has been ascribed to altered visco-elastotic properties of whole saliva potentially related to diminished minor salivary gland secretion (van der Putten 2011). Others suggest altered perception by the patient may be responsible for the complaint of dry mouth in the face of normal salivary measurement (Eveson 2011)
Hyposalivation is congruent with diminished salivary flow and, as per Villa et al (2014), diagnosed when the unstimulated salivary flow rate is ≤ 0.1 mL/min and the stimluated salivary flow rate is ≤ 0.5-0.7 mL/min. These investigators report normal unstimulated salivary flow rate to be approximately 0.3-0.4 mL/min and normal stimulated salivary flow rate to average 1.5-2.0 mL/min.
Some investigators support subclassifying the disorders by discriminating 'true xerotomia' ('objective xerostomia') associated with malfunction of the salivary glands from 'symptomatic xerostomia' ('subjective xerostomia') wherein there is a subjective impression of oral dryness that may be present despite normal salivary gland secretion as assessed by measurement of salivary production (Tanasiewicz 2016, Eveson 2011).
3. Sialadenitis
The terminology associated with salivary swelling is confusing through use of terms that includ sialosis, sialadenosis, sialadenitis. Our preference for terminology (HH) is listed below.
Sialadenitis reflects inflammation of the salivary gland and may be acute or chronic and caused by a broad range of processes including infection (bacterial/viral), obstruction (stone/stricture/foreign body), autommune (Sjogrens/IgG4RD), medication induced ('iodine mumps'/clozapine) and irradiation (I131,external beam). (Moore 2023, Hoffman 2023).
Sialosis (or sialadenosis) is a multifocal (usually bilateral), noninflammatory, non-neoplastic enlargement of the salivary glands (typically the parotid glands) that is often associated with systemic metabolic conditions (Hoffman 2023).
Salivary Symptoms
Persisting symptoms reported to often co-occur in association with COVID-19 have been reported to include (Tsuchiya 2023)
- Impaired taste (ranging from complete loss to mild or altered)
- Dry mouth (xerostomiawith oral function)
Salivary swelling in association viral infection (viral sialadenitis) is well documented for multiple viruses but not as conclusively studied for SARS-CoV-2 (COVID-19).
Viruses known to be associated with salivary gland swelling include paramyxovirus (causing mumps), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes simplex virus (HHSV-8), hepatitis C virus (HVC), human papilloma virus (HPV), cocksackie virus, influenza virus and echovirus. (Schreiber 2009, Elbadawi 2018 ).
Publications addressing COVID-19 associated salivary swelling - often diagnosed as 'sialadenitis' - are limited to case reports and small series ( Fisher 2021, Maegawa 2022, Chern 2020). More extensive reporting addresses xerostomia associated with COVID-19 and should be interpreted with the understanding that there are multipe causes that my contribute to the common complaint of dry mouth.
Epidemiology
Xerostomia in general
Xerostomia is a common complaint - identified by Villa (2015) to occur in 5.5% to 46% of the population. It occurs more commonly in women and the elderly with multiple causes including the common use of xerogenic medication, systemic disease (endocrine/autoimmune/infectious/granulomatous) and local factors (radiation/lifestyle) (Millsop 2017)
Xerostomia following COVID
Through systematic review, Tsuchiya et al (2023) identified salivary secretory sequelae to COVID - defined by terms: dry mouth, hyposalivation, xerostomia -were "reported by 2-40% of COVID-19 survivors followed up to 28-230 days"
The prevalence of dry mouth of 14.4% was reported by Biadsee et al in 97 subject assessed 8 months after recovery from COVID-19 (Biadsee 2021)
Another study identified an overall high prevalence (~30%) of xerostomia among 100 patients 7 months after recovery from infection but no stastistically significant difference the proportion with xerostomia when comparing those whose COVID symptoms were mild (25.7%), severe (19.5%) and critical (37.5%) (Anaya 2021)
The COVID variants Alpha, Bta, Gamma and Delta have been report to be associated with xerostomia more commonly than the Omicron variant - with xerostomia rarely reported after an Omicron variant infection (Jia 2022, Tsuchiay 2023)
Sialadenitis in General
Estimates regarding the prevalence of non-tumor salivary gland swelling are largely imprecise and likely under-reported. A evaluation by Żurek et al (2021) of a national health data set in Poland from 2010 to 2019 identified 230,000 patients with 'salivary gland pathologies" of whom 85% were non-neoplastic (Żurek 2021). These investigators suggested that the prevalence of salivary gland inflamatory lesions is about 1.2% of the general population and identified that salivary stones are reponsible for up to 50% of such inflamatory sialadenitis. Varying estimates identify salivary gland stones to affect 1% of the population via autopsy study (Williams 1999), 1 per 15,000 to 30,000 population based on an English hospital admission statical analysis (Escudier 1999) and an incidence of 1 per 10 - 20,000 population as a personal observation by Dr. Marchal (Marchal 2003).
Calcifications identified by CT imaging of the parotid glands that occur in the parenchyma and are not associated with sialadenitis are not considered 'sialoliths'. Buch et al (2014) identified 4% of patients had incidental parotid calcifications through review of non-contrast head CT scans done on 1,571 patients for reasons other than sialadentitis associated with the presence of calcifications were: HIV, alcoholism, chronic kidney disease, autoimmune disease and elevated alkaline phosphatase
Sialadentiis associated with COVID
Although salivary swelling reflecting sialadenitis has been reported as an 'early' symptom associated with COVID infection (Maegawa 2022 and others), Lechien identified the perceived salivary swelling may not reflect a sialadenits, but rather intra-parotid lymphadenitis are reported in 3 patients with acute documented COVID infection and cheek swelling with normal parotid parenchyma but with enlarged intraparotid lymph nodes ( Lechien 2020). These investigators report: "Our findings support the hypothesis that the parotitis-like symptoms might be attributable to intraparotid lymph node enlargement, which is different from a primary parotitis."
Mechanisms
The ACE2 receptor and the transmembrane serine protease TMPRSS2 needed to allow the SARS-CoV-2 to enter host cells are present in the parotid, submandibular, sublingual and minor salivary glands (Jackson 2022)
Autopsy tisues from COVID-19 patients identifying viral particles consistent with Coronavirade in the ductal lining and acinar cell cytoplasm of these salivary glands (Matuck 2021)
References
COVID-19
Tsuchiya H. COVID-19 Oral Sequelae: Persistent Gustatory and Saliva Secretory Dysfunctions after Recovery from COVID-19. Med Princ Pract. 2023;32(3):166-177. doi: 10.1159/000531373. Epub 2023 Jun 3. PMID: 37271130; PMCID: PMC10601698.
Greenhalgh, Trisha, Matthew Knight, Maria Buxton, and Laiba Husain. "Management of post-acute covid-19 in primary care." bmj 370 (2020).
Fernández-de-Las-Peñas, César, Domingo Palacios-Ceña, Víctor Gómez-Mayordomo, María L. Cuadrado, and Lidiane L. Florencio. "Defining post-COVID symptoms (post-acute COVID, long COVID, persistent post-COVID): an integrative classification." International journal of environmental research and public health 18, no. 5 (2021): 2621.
Jia, Hongling, Hui Wang, Lan Cao, Zhisheng Lai, Zichun Cheng, Qingpei Chen, Tongzheng Liu et al. "Genetic analysis of a SARS-CoV-2 Omicron variant from a Chinese traveller returning from overseas." Emerging Microbes & Infections 11, no. 1 (2022): 306-309.
Anaya JM, Rojas M, Salinas ML, Rodríguez Y, Roa G, Lozano M, et al. Post-COVID syndrome. A case series and comprehensive review. Autoimmun Rev. 2021;20(11): 102947
Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102-e107. doi: 10.1016/S1473-3099(21)00703-9. Epub 2021 Dec 21. PMID: 34951953; PMCID: PMC8691845.
Villar JC, Gumisiriza N, Abreu LG, Maude RJ, Colebunders R. Defining post-COVID condition. Lancet Infect Dis. 2022 Mar;22(3):316-317. doi: 10.1016/S1473-3099(22)00060-3. PMID: 35218747; PMCID: PMC8865876.
COVID-19 Clinical Research Coalition Clinical epidemiology working group. https://covid19crc.org/research-areas/clinical-epidemiology/ (Clinical Epidemiology | CERCLE - Coalition for Equitable Research in Low-Resource Settings (cerclecoalition.org) accessed 11-24-2023)
Lundberg-Morris L et al. Covid-19 vaccine effectiveness against post-covid-19 condition among 589 722 individuals in Sweden: Population based cohort study. BMJ 2023 Nov 22; 383:e076990. (https://doi.org/10.1136/bmj-2023-076990. opens in new tab)
NEJM Journal Watch: Comment on-line addressing Lundberg-Morris et al Dec 15,2023 accessed 12-28-2023 <https://www.jwatch.org/na56865/2023/12/15/how-well-do-covid-19-vaccines-work-prevent-post-covid-19 >
Peinkhofer C, Zarifkar P, Christensen RHB, et al. Brain Health After COVID-19, Pneumonia, Myocardial Infarction, or Critical Illness. JAMA Netw Open. 2023;6(12):e2349659. doi:10.1001/jamanetworkopen.2023.49659
Xerostomia
Tanasiewicz M, Hildebrandt T, Obersztyn I. Xerostomia of Various Etiologies: A Review of the Literature. Adv Clin Exp Med. 2016 Jan-Feb;25(1):199-206. doi: 10.17219/acem/29375. PMID: 26935515.
Millsop JW, Wang EA, Fazel N. Etiology, evaluation, and management of xerostomia. Clin Dermatol. 2017 Sep-Oct;35(5):468-476. doi: 10.1016/j.clindermatol.2017.06.010. Epub 2017 Jun 27. PMID: 28916028.
Villa, Alessandro, Christopher L. Connell, and Silvio Abati. "Diagnosis and management of xerostomia and hyposalivation." Therapeutics and clinical risk management (2014): 45-51.
van der Putten GJ, Brand HS, Schols JM, de Baat C. The diagnostic suitability of a xerostomia questionnaire and the association between xerostomia, hyposalivation and medication use in a group of nursing home residents. Clin Oral Investig. 2011 Apr;15(2):185-92. doi: 10.1007/s00784-010-0382-1. Epub 2010 Feb 18. PMID: 20165967; PMCID: PMC3056013.
Eveson JW. Xerostomia. Periodontol 2000. 2008;48:85-91. doi: 10.1111/j.1600-0757.2008.00263.x. PMID: 18715359.
Xerostomia and COVID
Hao M, Wang D, Xia Q, Kan S, Chang L, Liu H, Yang Z, Liu W. Pathogenic Mechanism and Multi-omics Analysis of Oral Manifestations in COVID-19. Front Immunol. 2022 Jul 4;13:879792. doi: 10.3389/fimmu.2022.879792. PMID: 35860279; PMCID: PMC9290522.
Biadsee, Ameen, Or Dagan, Zeev Ormianer, Firas Kassem, Shchada Masarwa, and Ameer Biadsee. "Eight-month follow-up of olfactory and gustatory dysfunctions in recovered COVID-19 patients." American journal of otolaryngology 42, no. 4 (2021): 103065.
Matuck, Bruno Fernandes, Marisa Dolhnikoff, Amaro Nunes Duarte‐Neto, Gilvan Maia, Sara Costa Gomes, Daniel Isaac Sendyk, Amanda Zarpellon et al. "Salivary glands are a target for SARS‐CoV‐2: a source for saliva contamination." The Journal of pathology 254, no. 3 (2021): 239-243.
Sialadenitis
Schreiber A and Hershman G: Non-HIV Viral Infections of the Salivary Glands 2009 in Oral and Maxillofacial Surgery Clinics Volume 21, Issue 3
Moore J, Simpson MTW, Cohen N, Beyea JA, Phillips T. Approach to sialadenitis. Can Fam Physician. 2023 Aug;69(8):531-536. doi:
Elbadawi LI, Talley P, Rolfes MA, Millman AJ, Reisdorf E, Kramer NA, Barnes JR, Blanton L, Christensen J, Cole S, Danz T, Dreisig JJ, Garten R, Haupt T, Isaac BM, Jackson MA, Kocharian A, Leifer D, Martin K, McHugh L, McNall RJ, Palm J, Radford KW, Robinson S, Rosen JB, Sakthivel SK, Shult P, Strain AK, Turabelidze G, Webber LA, Weinberg MP, Wentworth DE, Whitaker BL, Finelli L, Jhung MA, Lynfield R, Davis JP. Non-mumps Viral Parotitis During the 2014-2015 Influenza Season in the United States. Clin Infect Dis. 2018 Aug 1;67(4):493-501. doi: 10.1093/cid/ciy137.
Hoffman H Savliary Gland Swelling: Evaluation and Diagnostic Approach UpToDate accessed 11 24 2023 < Salivary gland swelling: Evaluation and diagnostic approach - UpToDate (uiowa.edu)>
Żurek M, Rzepakowska A, Jasak K, Niemczyk K. The Epidemiology of Salivary Glands Pathologies in Adult Population over 10 Years in Poland-Cohort Study. Int J Environ Res Public Health. 2021 Dec 24;19(1):179. doi: 10.3390/ijerph19010179. PMID: 35010439; PMCID: PMC8750634.
Cascarini L, McGurk M. Epidemiology of salivary gland infections. Oral Maxillofac Surg Clin North Am. 2009 Aug;21(3):353-7. doi: 10.1016/j.coms.2009.05.004. PMID: 19608052.
Wilson KF, Meier JD, Ward PD. Salivary gland disorders. Am Fam Physician. 2014 Jun 1;89(11):882-8. PMID: 25077394.
Marchal F, Dulguerov P:Sialolithiasis management: the state of the art. Arch Otolaryngol Head Neck Surg. 2003 Sep;129(9):951-6
Escudier MP and McGurk M. Symptomatic sialoadenitis and sialolithiasis in the English population: an estimate of the cost of hospital treatment. Br. Dent J. 1999;186:463-466
Buch K, Nadgir RN, Fujita A, Tannenbaum AD, Ozonoff A, Sakai O. Clinical associations of incidentally detected parotid gland calcification on CT. Laryngoscope. 2015;125(6):1360-1365. doi:10.1002/lary.25095
Williams, M: Sialolithiasis in pp 819 - 835 The Otolaryngology Clinics of North America Salivary Gland Disease ed Rice DH and Eisele D Vol 32 number 5 October 1999
Sialadenitis and COVID
Fisher J, Monette DL, Patel KR, Kelley BP, Kennedy M. COVID-19 associated parotitis. Am J Emerg Med. 2021 Jan;39:254.e1-254.e3. doi: 10.1016/j.ajem.2020.06.059. Epub 2020 Jun 27. PMID: 32631770; PMCID: PMC7320680.
Maegawa K, Nishioka H. COVID-19-associated parotitis and sublingual gland sialadenitis. BMJ Case Rep. 2022 Dec 19;15(12):e251730. doi: 10.1136/bcr-2022-251730. PMID: 36535731; PMCID: PMC9764613.
Chern A, Famuyide AO, Moonis G, Lalwani AK. Sialadenitis: A Possible Early Manifestation of COVID-19. Laryngoscope. 2020 Nov;130(11):2595-2597. doi: 10.1002/lary.29083. Epub 2020 Sep 4. PMID: 32833242; PMCID: PMC7461412.
Lechien JR, Chetrit A, Chekkoury-Idrissi Y, Distinguin L, Circiu M, Saussez S, Berradja N, Edjlali M, Hans S, Carlier R. Parotitis-Like Symptoms Associated with COVID-19, France, March-April 2020. Emerg Infect Dis. 2020 Sep;26(9):2270–1. doi: 10.3201/eid2609.202059. Epub 2020 Jun 3. PMID: 32491984; PMCID: PMC7454100.
Gebretsadik HG. An update on oral clinical courses among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A clinical follow-up (a prospective prevalent cohort) study. PLoS One. 2022 Oct 21;17(10):e0275817. doi: 10.1371/journal.pone.0275817. PMID: 36269692; PMCID: PMC9586351.
Capaccio P, Pignataro L, Corbellino M, Popescu-Dutruit S, Torretta S. Acute Parotitis: A Possible Precocious Clinical Manifestation of SARS-CoV-2 Infection? Otolaryngol Head Neck Surg. 2020 Jul;163(1):182-183. doi: 10.1177/0194599820926992. Epub 2020 May 5. PMID: 32369434.
Gherlone, E. F., Polizzi, E., Tetè, G., De Lorenzo, R., Magnaghi, C., Rovere Querini, P., et al. (2021). Frequent and persistent salivary gland ectasia and oral disease After COVID-19. J. Dent. Res. 100, 464–471. doi: 10.1177/ 0022034521997112
Mechanisms
Jackson, Cody B., Michael Farzan, Bing Chen, and Hyeryun Choe. "Mechanisms of SARS-CoV-2 entry into cells." Nature reviews Molecular cell biology 23, no. 1 (2022): 3-20.
Hao M, Wang D, Xia Q, Kan S, Chang L, Liu H, Yang Z, Liu W. Pathogenic Mechanism and Multi-omics Analysis of Oral Manifestations in COVID-19. Front Immunol. 2022 Jul 4;13:879792. doi: 10.3389/fimmu.2022.879792. PMID: 35860279; PMCID: PMC9290522.
Alfaifi A, Sultan AS, Montelongo-Jauregui D, Meiller TF, Jabra-Rizk MA. Long-Term Post-COVID-19 Associated Oral Inflammatory Sequelae. Front Cell Infect Microbiol. 2022 Mar 2;12:831744. doi: 10.3389/fcimb.2022.831744. PMID: 35310855; PMCID: PMC8924417.