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

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 non-endemic 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.⁴

Table 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.⁵

The 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.⁶ Lesions 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 transmission.⁷ Many 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.⁸ Prior 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.⁹

Ulceration 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.⁹

Hence, 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.

Methods

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).

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

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.

Figure 2. Risk analysis across selected studies.

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.

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. 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. 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.

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.²⁶ Based 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).²⁷ The 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

As 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 al¹⁴ and Samaranayake et al²⁰ also provide with literature evidence of oral lesions in monkeypox patients. One of the documented cases²⁹ 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.³⁰ Saliva collection requires no specialised equipment, is non-invasive, and uses a straightforward approach. Since mpox infection 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 Vesicular or pustular lesions are the terms used to characterise mpox oral symptoms. The ulceration occurs following the vesicle or pustule rupture. Mpox patients’ lesions may mirror those caused by other viral diseases of the oral cavity, such as COVID-19, chickenpox, measles, measles-mumps-rubella, measles, and herpes zoster. Vesiculobullous lesions predominate in mpox oral lesions. The vesicles/bullae readily separate, resulting in numerous uncomfortable, superficial sores on the oral mucosa and lips. Recurrent lesions are more confined and frequently affect the keratinized oral mucosa and lip vermilion.³² Similar study findings imply that the virus can be carried in the saliva and spread via oral-skin 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.³⁴ Dual 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.³⁵ Although 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.^36,37 The 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.³⁸ An oral counterpart of the injectable medicine cidofovir, brincidofovir, may have a better safety profile than cidofovir, such as reduced renal damage.³⁹ These medications function by preventing viral DNA polymerase.⁴⁰ The effectiveness of brincidofovir against orthopoxvirus infections has been established, despite the paucity of studies examining its usage in treating mpox infections in animal models.⁴¹ The FDA has authorised the hyperimmune globulin known as Vaccinia Immune Globulin (VIG) for the treatment of specific vaccine-related side effects.⁴² These 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

As 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.

Author contributions

Conceptualization, HA, AD, FB, NM, FA, OM, KPS, MAS, HA, MKA; methodology, HA, AD, MKA; software, HA, AD, MKA; validation, HA, AD, MKA; formal analysis, HA, AD, MKA; investigation, HA, AD, MKA; resources, HA, AD, MKA; data curation, HA, AD, MKA; writing—original draft preparation HA, AD, FB, NM, FA, OM, KPS, MAS, HA, MKA; writing— review and editing. HA, AD, FB, NM, FA, OM, KPS, MAS, HA, MKA; visualization, HA, AD, MKA; project administration, HA, AD, MKA; funding acquisition, none. All authors have read and agreed to the published version of the manuscript.

Reporting guidelines

Figshare. PRISMA flowchart. DOI: https://doi.org/10.6084/m9.figshare.23626704.v1

Figshare. PRISMA checklist. DOI: https://doi.org/10.6084/m9.figshare.23626695.v1