Monkeypox and oral lesions associated with its occurrence: a systematic review and meta-analysis

Background A zoonotic, double-stranded DNA virus belonging to the genus Orthopoxvirus, the mpox virus (MPXV) is most common in tropical regions of Central and West Africa. The frequency of monkeypox (mpox) cases, however, has sharply climbed globally since May 2022. Objectives To establish the threat of mpox in terms of the oral lesions caused in sufferers. Materials and methods After a thorough study of the literature identified in the PubMed, Web of Science, and Cochrane library databases using the PRISMA framework, 103 papers were found. Using inclusion and exclusion criteria, we chose research that was relevant for our review before shortlisting 14 papers that conformed to the review's guidelines. Results In the 14 selected studies, it was found that oral lesions were among the first clinical signs of a mpox affliction, with ulcers on the dorsal surface of tongue lips being the most common areas affected. Conclusion The rarely observed oral lesions of mpox infection may help in the diagnosis and management of this condition. It is critical to keep in mind that recognising and detecting oral lesions in mpox patients opens the door to more research and efficient patient management.


Objectives
To establish the threat of mpox in terms of the oral lesions caused in sufferers.

Materials and methods
After a thorough study of the literature identified in the PubMed, Web of Science, and Cochrane library databases using the PRISMA framework, 103 papers were found.Using inclusion and exclusion criteria, we chose research that was relevant for our review before shortlisting 14 papers that conformed to the review's guidelines.

Introduction
The mpox virus (MPXV) is not an uncommon zoonotic disease.The mpox virus (MPXV) is the name for the virus causing the disease monkeypox (mpox).Both the smallpox and mpox viruses (MPXV) are members of the Orthopoxvirus genus in the Poxviridae family.In the Democratic Republic of the Congo, the first case of mpox on a human was documented in 1970. 1 Since that time, mpox has spread over western and central Africa.Up until recently, 47 nonendemic nations in Europe, North and South America, Asia, North Africa, and Australia had reported cases of the disease.More than 4,100 confirmed cases had been reported as of 2022, the count increasing by the minute.Notably, 87% of occurrences have happened in nations in Europe. 2 It is thought that the termination of smallpox vaccination, which offered some cross-protection against mpox but was not the primary cause of the new outbreak, led to an increase in human-to-human transmission.Generally speaking, human-to-human transmission happens when contaminated objects including linens, bedding, electronics, and clothing come into direct physical contact with an infected person's ulcerated skin or mucosa, respiratory droplets, or both.Through the placenta, pregnant women can spread the virus to unborn children. 3 mpox virus (MPXV) airborne transmission is still a contentious topic.Even if it does, it could not be the primary method of transmission.The incubation period for mpox infection lasts for 7-14 days or 5-21 days and is not contagious.Patients do not have any symptoms during this time. 4ble 1 represents the clinical characteristics of mpox as generally observed in sufferers.Notably, lesions in patients with mpox in non-endemic locations are more confined and have a different distribution of rashes, whereas symptoms in patients with mpox in endemic regions are more severe and result in a certain proportion of fatalities.Since at this moment 157 deaths have been reported. 5e beginning phase of mpox includes a fever, chills, headache, backache, myalgia, asthenia, and lymphadenopathy.Patients that are infected may be contagious during the prodromal stage.It's interesting to note that the fundamental distinction between the symptoms of mpox and smallpox is that smallpox does not result in lymphadenopathy but mpox does.Submandibular, cervical, axillary, and inguinal lymph nodes may be bilaterally or unilaterally affected in mpox. 6Lesions may form in the mouth, oropharynx, or throat after the prodrome before spreading to the skin.The face and extremities, such as the palms of the hands and soles of the feet, are typically where the skin rash is more intense.The lesions develop in stages, going from macule to papule to vesicle to pustule to crust.Until all lesions have crusted over, patients are deemed contagious.The sores are frequently characterised as hurting initially, then becoming irritating.After scabs have peeled off, scars with hyper/hypopigmentation may develop.Usually, the disease lasts 2-4 weeks.Patients in the latest outbreak's non-endemic areas present with unusual symptoms that are very dissimilar from those in western and central Africa.Genital, perianal, and perioral/oral rash, fever, lymphadenopathy, and swallowing pain are a few of these.Lesions on the oral mucosa and vaginal region may first emerge before or without spreading to other body areas, pointing to sexual contact as the likely mode of

REVISED Amendments from Version 1
The introduction has been revised to align with updated nomenclature, now referring to the disease as "mpox" and the virus as "mpox virus (MPXV)".Additionally, Table 1 has been updated to reflect current data, with the inclusion of 157 reported deaths from non-endemic regions.A reference to the study published in The Lancet Microbe, which described viable virus in saliva (doi: 10.1016/S2666-5247( 22)00291-9), has been incorporated to support the relevant assertion.Furthermore, the manuscript now includes the study by Hernaez et al. (Monitoring monkeypox virus in saliva and air samples in Spain: a crosssectional study), with appropriate citation, which involved 44 confirmed mpox patients from the 2022 outbreak in Madrid and detailed clinical symptoms, including oral lesions, available in supplementary materials (Hernaez et al., 2023).
Any further responses from the reviewers can be found at the end of the article transmission. 7Many individuals first had pustules before becoming feverish.Patients with a few small, isolated skin lesions sometimes show no signs of pain.It's interesting to note that the same people can have lesions in various stages.Pain, haemorrhage, proctitis, and tenesmus can all result from anus and rectum lesions.
Patients in the endemic area have never before reported having these symptoms.Patients in the current outbreak locations generally experience milder symptoms than those in the endemic zone.There haven't been many documented hospitalizations, and the two most common causes were pain management and subsequent infection care. 8Prior to skin rashes, mpox might present with oral and oropharyngeal lesions.It is stated that mouth sores, along with fever and enlarged lymph nodes, are common symptoms in mpox patients.Notably, the CDC stated that lesions in the mouth and on the tongue were seen in 70% of people.These findings imply that the virus can be carried in the saliva and spread via oral-skin and/or oral-anogenital contact.Therefore, it's crucial for dentists and other dental professionals to be aware of and able to identify mpox oral lesions.Starting with macule, papule, vesicle, and pustule, the progression of oral lesions should resemble that of skin lesions. 9ceration with pseudomembrane occurs after the roofs of the vesicle or pustule break off.A male patient who was a returning tourist from Nigeria experienced right cervical lymphadenopathy, multiple 2-4-mm pustules, and central umbilication of the skin, particularly on the face, neck, and hands.The oral lesions were described as a single intact pustule on the lower labial mucosa and a few round 2-3 mm erosions on the mucosa, indicating that the original vesicles or pustules have already broken off. 9nce, by the means of this systematic review and subsequent meta-analysis, we aimed to establish the threat of mpox in terms of the severity of oral lesions that are caused due to it.

Protocol employed
This systematic review was performed as per the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) strategy and rules from the Cochrane group and the book Orderly reviews in Health care: Meta examination. 10e also utilised the PICO strategy to identify and evaluate the relationship between mpox and oral lesions.The population of interest included individuals with confirmed cases of mpox.The intervention of interest was the presence of mpox, while the comparison group consisted of individuals without mpox.The outcome of interest was the occurrence of oral lesions associated with mpox.

Review hypotheses
This systematic review aimed to analyse, by the means of selecting studies, to review the correlation between the incidence of mpox and the oral lesions occurring in patients because of it at various stages of the disease.

Study selection
There were a total of 103 documents discovered after extensive search on the online journals and 54 of the papers were selected initially.Following that, 22 similar/duplicate articles were eliminated, which resultantly made 32 separate papers available at first.The abstracts and titles of submissions were then reviewed, and a further 18 papers were eliminated.Finally, 14 documents that met the inclusion and exclusion criteria were chosen, which included study articles and randomised/non-randomised control trials (Figure 1).

Eligibility criteria
For this systematic review, we employed the PICOS (Participants, Interventions, Comparison, Outcome, Study design) framework for assessment of studies fit for our investigation.
The following were excluded from the scope of our systematic review: incomplete data, individuals in whom antimicrobial treatment had begun only recently, seminar presentations, scholarly articles, placebo controlled studies, and opinion articles.
Since the literature available on this topic is quite scant in volume, we did not limit our search in terms of the time period when the studies were published i.e. we took into account all the papers that were published with context to our topic (where the number of papers itself was found to be quite sparse in number).
Placebo-controlled studies were not included in the analysis.Also excluded were literature reviews and cases published in languages other than English.

Search strategy
Using relevant keywords, reference searches, and citation searches, the databases PubMed-MEDLINE, Web of Science, Cochrane, and Scopus were all searched."Monkeypox," "Oral lesions," "Saliva," "Zoonotic viruses" and "Oral manifestations" were the search terms used to access the database.

Data selection and coding
Two independent reviewers located the relevant papers by using the right keywords in various databases and online search tools.The chosen articles were compared, and a third reviewer was brought in if there was a dispute.
After choosing the articles, the same two reviewers independently extracted the following data: author, year of publication, country, kind of publication, study topic, population demographics (n, age), outcome measure(s), relevant result(s), and conclusion (s).The data was compared and any differences were discussed with the third reviewer.The evaluation of risk analysis was also performed, the detail of which have been furnished in Figure 2.

Risk of bias assessment
The AMSTAR-2 protocol 11 was employed for the assessment of the risk of bias in our selected studies.As a critical evaluation tool for systematic reviews, AMSTAR 2 joins a number of other instruments that have been published for this purpose.It consists of a 16-point checklist, as shown in Table 2 below.The development of the original AMSTAR tool was based on two instruments that have received a lot of attention.Two instruments that have been released are exact copies of the original AMSTAR.The domains listed in the Cochrane risk of bias instruments for systematic reviews are identified by the AMSTAR 2 risk of bias items.These represent an agreement that was reached after input from more than 30 methodology specialists in each case.

Results
Table 3 as given below includes the findings of the systematic review as well as information on the 14 studies that were selected for the review.The results of the meta-analysis (conducted using RevMan 5 software) are displayed in Figures 3, 4 and 5 below in the form of a forest plot that reflects and ranks all the studies included in this systematic review.After data on the sample size, variables analysed, and various components of the investigations selected for our systematic review were entered into the Revman 5 programme, a forest plot illustrating the risk ratio, odds ratio, and risk difference was obtained as part of the meta-analysis for our study.
Figures 3, 4 and 5 represent the forest plots obtained after meta-analysis of the incidence of the oral lesions in patients of mpox that were a part of the studies that were selected for our systematic review.

Discussion
Many diseases, including chickenpox, measles, bacterial skin infections, scabies, syphilis, and medication-induced allergies, share characteristics of the mucocutaneous lesions with mpox. 26Based solely on the clinical appearance, it might be challenging to discern between these disorders in some cases.When comparing mpox to chickenpox or smallpox, lymphadenopathy during the prodromal stage might be used to make the distinction.Healthcare professionals should gather a sample if mpox is suspected so that it can be further examined using polymerase chain reaction (PCR), a method that has strong specificity and sensitivity for finding the mpox virus (MPXV). 27The fluid from vesicles, pustules, or dry crusts should be collected, preserved in a dry, sterile tube without viral transport media, and kept cold.An optional method for making the diagnosis is a biopsy. 28 evident by the finding mentioned in Table 3 depicting the selected studies, oral lesions are primarily present at the start of the mpox affliction.For example, in the study by Tarín-Vicent et al, 22 lesions in the oral and perioral area were present in 78 people (or 43%).In all the studies, oral lesions were present in some form or the other (as ulcers or vesicular rash most commonly around the tongue or lower lip area) during the prodromal stage of monkeypox which was accompanies by symptoms such as fever, myalgia, and general malaise and, in some cases, a pruritic rash.The case reviews by Iamaroon et al 14 and Samaranayake et al 20 also provide with literature evidence of oral lesions in monkeypox patients.One of the documented cases 29 in these reviews mention of a male patient who was a returning tourist from Nigeria experienced right cervical lymphadenopathy, multiple 2-4-mm pustules, and central umbilication of the skin, particularly on the face, neck, and hands.The oral lesions were described as a single intact pustule on the lower labial mucosa and a few round 2-3 mm erosions on the mucosa, indicating that the original vesicles or pustules have already broken off.In the study by Girometti et al, 13 oral mucosal enanthema were more frequently recorded among unvaccinated individuals than among those who had received vaccinations.This condition can occur in more than 70% of cases.This might represent the aspect of oral lesions occurring more in unvaccinated individuals which might prompt strengthening of the already stringent vaccination laws around the world especially in terms of traveling.Speaking of traveling, seven of the 14 studies that we selected for our review involved individuals who were traveling from one country to another which again warrants a separate investigation into the transmission of monkeypox or monkeypox-like infectious diseases within a particular defined area (such as a city, state or country) and how it might differ from the outcomes obtained in our investigation.
Figures 3, 4 and 5 represent the meta-analysis results of our investigation.Although the heterogeneity levels in the three different assessments are particularly high (91%, 89% and 97%), it is due to the fact that the studies that were selected had sample sizes that were lesser than what could be considered ideal and more importantly, the methodological differences in the studies selected contribute to the high levels of heterogeneity of the forest plots.The fixed effect model was employed in the odds ratio, risk ratio and the risk difference assessments so as to keep uniformity in terms of our interpretations and reduce bias that occurs resultantly after selection of studies with such variations in methodology and sample sizes.
The nasopharyngeal swab bio sample has been the gold standard for the detection of severe acute respiratory syndrome coronavirus 2 since the start of the COVID-19 pandemic (SARS-CoV-2).Saliva has recently become a practical and affordable bio fluid for COVID-19 diagnostics and may someday take the place of a nasopharyngeal swab. 30Saliva collection requires no specialised equipment, is non-invasive, and uses a straightforward approach.Since mpox infection   Only the first of the three cases-involving a 28-year-old woman who saw the doctor 15 days after developing fever, asthenia, headache, and sore throat-was found to have early lesions in her oral mucosa.This case also had several pruritic, papulovesicular lesions on the limbs and trunk.
Noe et al (2022) 16 2 males Observational study In order to emphasise the significance of recent advances for medical experts around the world and to share further observations regarding One patient described having trouble swallowing and having white patches on his tonsils.These oral sores on the tonsils were supposedly the patient's frequently appears in the oral cavity, patient saliva may contain mpox virions and hence might be used as a bio sample to identify the virus.These patients will greatly benefit from further research to validate the use of saliva for mpox diagnoses. 31

Epidemiological and clinical study
A form of oral vesicular rash appeared in all 122 confirmed or probable cases, and 45 (58%) of the 77 confirmed patients also experienced sore throats.
A rash on the tongue and mucous membranes, as well as any sores or lesions on the tongue, in the oral cavity, or on the corners of the mouth, are common early signs of monkeypox.
superficial sores on the oral mucosa and lips.Recurrent lesions are more confined and frequently affect the keratinized oral mucosa and lip vermilion. 32Similar study findings imply that the virus can be carried in the saliva and spread via oralskin and/or oral-anogenital contact. 33  Fortunately, the majority of people with mpox infection recover on their own.To reduce gastrointestinal fluid losses, those with gastrointestinal symptoms (such as vomiting or diarrhoea) will need oral or intravenous rehydration.Several antivirals have been licenced for the management of smallpox based on animal models, but they may also be beneficial in treating mpox infections.Human dose studies for these medications have been carried out, but their effectiveness has not been fully explored.The first antiviral approved for the treatment of smallpox in adults and children weighing at least 3 kg is tecovirimat, and it is regarded as the preferred method of care. 34Dual therapy with tecovirimat and brincidofovir may be utilised in patients with advanced illness.By blocking the last steps in viral maturation and release from the infected cell, the viral envelope protein VP37-by which Tecovirimat functions-inhibits the transmission of the virus within an infected host. 35Although its effectiveness in treating mpox in people has not been investigated, investigations on animals treated with tecovirimat at various illness phases have shown better survival from lethal mpox virus infections in comparison to animals given with a placebo. 36,37The side-effect profile of the placebo was generally identical to that of tecovirimat in an enlarged safety study with 359 human volunteers given tecovirimat.Since June 2021, brincidofovir has also been authorised for the treatment of monkeypox in the US. 38An oral counterpart of the injectable medicine cidofovir, brincidofovir, may have a better safety profile than cidofovir, such as reduced renal damage. 39These medications function by preventing viral DNA polymerase. 40The effectiveness of brincidofovir against orthopoxvirus infections has been established, despite the paucity of studies examining its usage in treating mpox infections in animal models. 41The FDA has authorised the hyperimmune globulin known as Vaccinia Immune Globulin (VIG) for the treatment of specific vaccine-related side effects. 42These include vaccinia infections in people with skin disorders, aberrant infections brought on by the vaccinia virus, progressive vaccinia, severe widespread vaccinia, and eczema vaccinatum (except in cases of eye-related infections). 42 far as limitations go, our systematic review had a few to being with.For starters, the sample size observed in our selected studies were fewer than what would be considered ideal, but, since the number of articles which had documented the oral manifestations observed in patients suffering from mpox are very scarcely available, we selected the ones best suited for our objectives.Additionally, prior to the outbreak in May 2022, mpox had a limited clinical relevance, therefore it was frequently overlooked in the differential diagnosis.Other infectious illnesses could be in the differential diagnosis list.The countries of Central and Western African regions, where this disease is endemic, do not have a lot of data available on mpox due to the extremely limited number of studies performed, which as such necessitates the importance of documenting mpox and its effects observed in the form of symptoms such as the occurrence of oral lesions.

Conclusion
All the 14 articles selected in this review have reported the incidence of oral lesions in mpox sufferers, in at least the beginning stages of the disease, which have then blown up into full-fledged symptoms.As such, the identification and treatment of this illness may be aided by the seldom observed oral features of mpox infection.Acute onset oral signs (as seen in nearly all our selected studies) should be differentially diagnosed for mpox, especially in people who are more likely to experience this ailment.It is crucial to remember that recognising and identifying oral lesions in patients with mpox paves the way for additional research, effective care, and the prevention of cross-infection between patients and medical staff.

Mohamed LOUNIS
University of Ziane Achour, Djelfa, Algeria I would like to thank the authors for this interesting manuscript.However, after reviewing, I found that the manuscript has shown some gaps that have affected its quality: 1.The manuscript requires an extensive language editing.The grammar and the sequencing of the ideas is a lacking character of this manuscript.The introduction of the abstract did not provide information in relation with the subject and has not allowed to define the hypotheis.The results are not well described in the abstract.Introduction: in the first sentence : the mpox virus is a zoonotic agent (not a disease) The term mpox should be defined in the beginning of the sentence, not later.The introduction should be revised.it seems to be composed of multiple separated sentences (try to correlate between the sentences).Also, it has not alowed to define the hypotheis of the work.The results are very simplistically presented, despite the interesting results provided.They were not practically described either in the results or in the discussion.The same is true for the discussion, which contains two (simple paragraphs (2 and 3) and a second part (paragraphs 3 and 4), which has practically no relation to the work.The statisticall analysis are not fully described.At last, I have a concern that really bothered me, which is the fact that you included case reports and reviews in this systematic review Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? No
Is the statistical analysis and its interpretation appropriate?

Bruno Hernaez
Centro de Biologia Molecular Severo Ochoa (CBMSO) -Consejo Superior de Investigaciones Cientificas (CSIC), Nicolás Cabrera, Madrid, Spain I thank the authors for updating the nomenclature and naming the disease as "mpox", however I consider that this should also apply to the title to meet the WHO recomendations.Thus the title should be "Mpox and oral lesions associated with its occurrence: a systematic review and metaanalysis" Are the rationale for, and objectives of, the Systematic Review clearly stated?

Not applicable
Are sufficient details of the methods and analysis provided to allow replication by others?Not applicable

Is the statistical analysis and its interpretation appropriate? Not applicable
Are the conclusions drawn adequately supported by the results presented in the review?
Viable virus in saliva was first described by our group in a study published in The Lancet Microbe (doi: 10.1016/S2666-5247 (22)00291-9).The incorporation of this reference would support the affirmation " These findings imply that the virus can be carried in the saliva and spread via oral-skin and/or oral-anogenital contact".

3.
In line with this, I wonder why this study is not included in the present review.The study by Hernaez et al (Monitoring monkeypox virus in saliva and air samples in Spain: a crosssectional study) included 44 confirmed patients with mpox from the 2022 outbreak in Madrid (Spain), and the clinical symptoms (including the presence of oral lesions) can be found in an exhaustive table as Supplementary material.In my opinion the authors should contemplate its incorporation now, perhaps by adding the term "saliva" to the search strategy.Is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.

Are the conclusions drawn adequately supported by the results presented in the review? Yes
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Yes Competing Interests: No competing interests were disclosed.
Reviewer Expertise: poxvirus immune evasion I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Yes
If this is a Living Systematic Review, is the 'living' method appropriate and is the search schedule clearly defined and justified?('Living Systematic Review' or a variation of this term should be included in the title.)Yes Competing Interests: No competing interests were disclosed.
Reviewer Expertise: OMFS I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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Figure 2 .
Figure 2. Risk analysis across selected studies.

Figure 1 .
Figure 1.Representation of selection of articles through PRISMA framework.

Figure 3 .
Figure 3. Incidence of oral lesions in mpox sufferers as compared to other lesions in the selected studies on the basis of the odds ratio represented on a forest plot.

Figure 4 .
Figure 4. Incidence of oral lesions in mpox sufferers as compared to other lesions in the selected studies on the basis of the risk ratio represented on a forest plot.

Figure 5 .
Figure 5. Incidence of oral lesions in mpox sufferers as compared to other lesions in the selected studies on the basis of the risk difference represented on a forest plot.

4 . References 1 .
Hernaez B, Muñoz-Gómez A, Sanchiz A, Orviz E, et al.: Monitoring monkeypox virus in saliva and air samples in Spain: a cross-sectional study.Lancet Microbe.2023; 4 (1): e21-e28 PubMed Abstract | Publisher Full Text Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes Are sufficient details of the methods and analysis provided to allow replication by others?Yes

Table 1 .
Clinical presentation of monkeypox generally exhibited in patients.

Table 2 .
AMSTAR-2 16-point checklist of risk of bias assessment in selected studies.

Table 3 .
Tabular representation of the studies used for this systematic review.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.
Reviewer Report 12 March 2024 https://doi.org/10.5256/f1000research.162619.r252060© 2024 Hernaez B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.