Introduction

Chikungunya fever is considered an abrupt onset arbovirus, transmitted by mosquitoes, and Aedes aegypti and Aedes albopictus are the main intermediate hosts of chikungunya virus (CHIKV). Since its resurgence in 2004, there is risk of CHIKV being imported into new areas due to the high levels of viremia in infected humans and the worldwide distribution of CHIKV transmission vectors [1].

CHIKV infection can cause acute (3 to 15 days), subacute (15 to 90 days), and chronic (>90 days) disease. When symptoms persist, they manifest mainly in the form of constant polyarthritis or polyarthralgia, accompanied by morning stiffness and asthenia, lasting from months to longer than 3 years from the onset of infection [2].

In addition to the main symptoms, studies have indicated that CHIKV fever can cause atypical manifestations, such as mucocutaneous lesions in the oral cavity, both in the acute and chronic stages of the disease [3]. Studies conducted in India during the chikungunya epidemic in 2010 showed a prevalence of 96.3% of oral manifestations, which may be located on the lips, tongue, floor of the mouth, and palate. The most frequent clinical manifestations were mucosal burning (96.3%) preceded by erythema (93.6%) and ulcers disseminated throughout the oral cavity (71.8%) [4].

Other oral manifestations were also reported such as macular depigmentation of the lips, lesions with lip crusting and lip commissures, oral mucosa pigmentation, thrush on the tongue, palate, and other areas of the oral mucosa, candidiasis on the tongue and palate, gingival pain, gingivitis, gingival bleeding, and temporomandibular joint (TMJ) arthralgia [3–5].

Although oral manifestations found in patients affected by chikungunya are similar to the pattern found in other viral infections, according to a study conducted in India in 2010, the presence of the clinical conditions of TMJ arthralgia, dysphagia, and ulcerations can be considered markers for chikungunya [4]. Patients with atypical mucocutaneous manifestations in the oral cavity should be referred for evaluation, treatment, and monitored for signs and symptoms.

In view of the foregoing, the aim of this study was to identify the main oral manifestations related to chikungunya fever, as well as describe the demographic characteristics of patients, by conducting a systematic review of the literature.

Methods

Eligibility criteria

We established the eligibility criteria according to the acronym PECOS (Population, Exposure, Comparator, Outcomes, and Study design). Details are described in Table 1.

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Table 1. Characteristics of studies used for determining the eligibility criteria.

https://doi.org/10.1371/journal.pntd.0009401.t001

With regard to the diagnosis of chikungunya, we can consider 2 different situations:

1. Confirmed cases: suspected cases with clinical and laboratory confirmation of the disease [7].
2. Suspected cases: patients who meet the clinical criteria and/or epidemiological criteria [7].

The clinical criterion establishes that patients must present fever >38.5°C with abrupt onset and severe acute onset arthralgia/arthritis not explained by other medical conditions. In turn, the epidemiological criterion stipulates individual resides or has visited an endemic or epidemic area within 15 days before the onset of symptoms or has an epidemiological link with a confirmed case. As a great deal of research has been carried out on epidemic peaks in chikungunya, this criterion is in accordance with the Brazilian Society of Rheumatology, which establishes that in epidemic situations, patients in the acute phase may have a diagnosis established based only on clinical–epidemiological criteria, without confirmatory serology or associated hematology [7].

Results

Study characteristics

The 27 articles selected were on studies conducted in India [4,10–21], Reunion Island [22–25], Sri Lanka [26], Germany [27], France [28], Colombia [29], Grenada [30], Bangladesh [31], Brazil [32–33], Pakistan [34], and Nicaragua [35], published from 2007 to 2020.

Initially, we present the characterization of all 27 studies included in Table 2.

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Table 2. Characteristics of the studies included.

https://doi.org/10.1371/journal.pntd.0009401.t002

Considering the 27 studies included in this systematic review, it was possible to survey data on a total of 7,023 suspected cases of chikungunya. We could extract data from 3,854 suspected cases of chikungunya reported in 8 studies [4,10,12–14,20,21,26] and from 2,611 laboratory-confirmed cases of chikungunya reported in 18 studies [11,15–19,22–25,27–30,32–35]. A study of 1,089 participants did not report the diagnostic criteria used for determining the disease [31].

Considering that chikungunya affects all ages and both sexes, it was possible to report studies covering all age groups, and in relation to gender, 3,369 cases were studied in male participants and 4,185 cases in female patients.

In this review, we could highlight the description of the following oral manifestations identified in chikungunya fever. Among the 7,615 participants of the 27 included studies, 1,297 presented oral ulcers and thrush, the most prevalent types of manifestations reported. Among the injuries identified in over 100 patients, we observed 273 cases of mouth opening pain, 162 pain and burning of oral mucosae, 157 cervical lymphadenopathy, 148 loss of taste, 147 TMJ arthralgia, 126 dysgeusia, 123 gingivitis, 110 gingival bleeding, 105 dysphagia, 103 erythema, and 100 cases of gingival edema. Finally, the less common manifestations were cases of the following: 90 bitter taste, 32 difficulty with chewing, 22 halitosis, 17 glossitis, 13 cheilitis, 10 hypersalivation, 8 interdental mucosal desquamation, 8 herpes, and 4 cases of pigmentation of lips, tongue, and hard palate. The table showing the combined proportion of oral manifestations separated into the subgroups of suspected and confirmed cases may be found in the Supporting information (S1 Data).

Discussion

In this review, we mapped the evidence that described oral manifestations identified in chikungunya fever. The oral manifestations inclued a miscellaneous of lesions such as oral ulcers and thrush, gingival bleeding, gingivitis, oral mucosal pain and burning, erythema, and pigmentation of the lips, tongue and hard palate, herpes, cheilitis, glossitis, interdental mucosa desquamation, dysphagia, dysgeusia, difficulty with chewing, metallic taste, TMJ arthralgia, cervical lymphadenopathy, hypersalivation and halitosis.

We observed that the frequency and worsening of oral mucosal lesions occurred with increasing age and higher predominance in females. However, many studies pointed out that the majority of oral manifestations such as ulcerations were more often observed in the acute phase of the disease, with complete remission occurring 3 to 10 days after the onset of the symptoms.

Patients with chikungunya may have several oral manifestations simultaneously and varying degrees of severity. Oral symptoms are very distressing, causing considerable pain and suffering, negatively impacting the patients’ quality of life and well-being [3]. Although it is a self-limiting disease, palliative measures to alleviate the patients’ suffering and discomfort should be used, and, as a follow-up routine, we recommend that patients should be referred to a dentist for evaluation, treatment, and monitoring of signs and symptoms.

Although oral manifestations are still considered atypical manifestations of chikungunya, the high number of records, particularly of ulcers, shows that they are much more common than is supposed. Furthermore, studies generally included the analysis of these manifestations only as a secondary outcome, a fact that made it likely that they were underestimated [3]. Most studies have not measured oral lesions or considered them an uncommon manifestation of this disease. Only 5 studies in the literature [15,20,33–35] consulted dealt exclusively with determination of the oral manifestations of this viral fever. A study conducted in India in 2010, with the aim of verifying the prevalence of oral manifestations in chikungunya patients, found a positive outcome in 96.37% of the 110 suspected cases and 100% of the 37 confirmed cases [4].

Since 1963, the Indian population has suffered from outbreaks of chikungunya. In December 2005, during a major epidemic that started with 180,000 confirmed cases, the African genotype of CHIKV was isolated in the country for the first time. In this same epidemic, it was shown that the prevalence of mucocutaneous manifestations in chikungunya patients was observed from a series of cases. These included various patterns of hyperpigmentation, vesicobullous lesions, aphthous ulcers, lesions, vasculitis, and lichenoid reaction. Hypothetically, these findings could be attributed to the entry of the African CHIKV genotype during this outbreak, in contrast with previous outbreaks caused by the Asian genotype, in which these types of manifestations had not previously been reported [13].

Ulceration and aphthous lesions were observed predominantly during the acute phase of the disease (2 to 7 days) [4,12,16–18,21] and could be isolated; they were multiple, inflammatory, painful, and small (2 to 5 mm in size) [12], with remission without sequelae in periods lasting from 3 to 10 days [16–18]. The onset of oral ulcers normally associated with erythema in the affected region was reported, and no part of the oral cavity appeared to be immune to these manifestations. Soft palate ulcers were the most common, followed by those in the hard palate, tongue, and floor of the mouth. Palatine erythema was invariably associated with multiple ulcers [4]. Identifying and treating these injuries are important to ensure that the patient is able to eat properly.

Although hemorrhagic manifestations are considered uncommon in patients with chikungunya [14], in one study with 97 confirmed chikungunya, we observed the report that 54.32% patients tested suffered from bleeding in the oral cavity, causing chewing discomfort [15]. Several studies also reported the presence of hemorrhagic manifestations in the oral cavity, especially gingival bleeding [4,14,15,20,22,24–30,35]. However, these episodes tended to be much less severe compared with those observed in dengue patients [12,16,18].

It is important to note the presence of active CHIKV in the saliva of human patients with acute infection. This evidence claims that the viral agent in saliva may be associated with hemorrhagic lesions in the nasal/oral cavities during the viremic period and points out the importance of the relationship for clinical practice and management of the patient with chikungunya by the dentist [32–35]. In a study with 105 confirmed cases for chikungunya, CHIKV was isolated in the saliva of 27% of the cases with the presence of oral manifestations [32].

Chikungunya also compromised patients’ oral hygiene status. This may be because severe gingival pain could have prevented patients from performing thorough tooth brushing. When 97 confirmed chikungunya patients were compared in terms of oral hygiene status, gingival status, and plaque accumulation during the different stages of the disease, severe gingivitis was observed in 64.7% patients with chronic disease, while mild to moderate gingivitis was found in 64.7% patients in the acute stage. However, no significant associations were observed regarding oral hygiene status and plaque scores. The difference can probably be attributed to the inability of chronic patients to clean the oral cavity properly for a longer time, which was reflected in the higher plaque scores in these patients [15].

In a systematic review of the association between oral manifestations and dengue, the hypothesis was that the occurrence of associated comorbidities and/or the previous presence of dental biofilm or calculus on the tooth surfaces may have synergistically led to the oral manifestation of dengue hemorrhagic fever in some of the reported cases [36].

A study in India, with 97 cases of confirmed chikungunya, reported 57.7% cases of severe pain and burning sensation in the oral mucosa. The description of oral mucosal pain included a burning sensation, erythema, and gingivitis that could occur from 1 to 2 days before or after the onset of clinical symptoms of the disease. The burning sensation associated with the erythema of parts or the entire oral cavity was the symptom most reported by the patients studied, with the lips, tongue, floor of the mouth, and palate being the structures most frequently involved [4].

In the majority of patients, the interdental gum was commonly affected by bulbous edema. Other nonspecific findings included interdental mucosal peeling, which may coincide with the onset of viral infection [4].

The effect of CHIKV infection on connective tissue was reported, stating that in these cases, there was increased excretion of urinary proline and hydroxyproline, which suggested a high degree of renewal in connective tissue. Whether this affected the integrity of gingival tissue and alveolar bone, causing changes in gingival and periodontal health, has not yet been confirmed. Further studies with associated radiographic examination could help determine the effects on the alveolar bone and periodontal complex in more detail [37].

Patients expressed their inability to chew varieties of food and had to limit their diet to soft, semisolid, and only liquid foods in some more severe cases. Moreover, these chewing discomforts occurred mainly during the acute phase of the disease [15] and may be closely related to cases of TMJ arthralgia, which has been found to be clinically significant in seropositive patients, with a prevalence of 83.78% [4].

Relative to the causes of dysphagia, these can be directly associated with the presence of multiple palatal erythema accompanied by ulcers and/or erythema associated with burning sensation of the oral structures. In addition, in a study with 37 confirmed chikungunya cases in India in 2010, the presence of signs and symptoms of TMJ arthralgia, dysphagia, and ulcerations was statistically significant in chikungunya seropositive cases. Thus, the authors proposed the introduction of the term “Gunya stomatitis” to represent this clinical condition [4].

Chikungunya viral fever can also induce transient immune depression, leading to the entry of potential opportunistic infections, such as candidiasis, herpes, and stomatitis (multiple ulcers), which may cause discomfort and pain during the patients’ chewing process [16,23,33]. Another clinical feature that may negatively affect masticatory function and causes dysphagia is cervical lymphadenopathy due to sublingual and submandibular lymph node edema [4,20,23,33].

The profile of chikungunya-infected patients hospitalized due to the worsening of the clinical condition consisted of older patients with a history of associated comorbidities. Chronic diseases, such as diabetes, hypertension, ischemic heart disease, lung and kidney problems, and obesity, among others, played a decisive role in the outcome of cases, prolonging the length of these hospitalizations or even causing the death of these patients [22,24,25,27,29]. Chikungunya probably played an indirect role in these fatalities, indicating that further studies of its pathogenicity are clearly needed, taking the presence of preexisting comorbidities into consideration [22].

Exacerbation or recurrent acuteness of preexisting dermatoses, such as psoriasis, lichen planus, pityriasis rosea, pityriasis alba, allergic contact dermatitis, stasis eczema, Hansen type 1, and pemphigus vulgaris, has been well documented in association with chikungunya fever [12,16,18].

There are a variety of other clinical manifestations that may be associated with chikungunya infection in addition to the well-known classical symptoms, as previously described in the literature. However, many of these symptoms are nonspecific and may be present in several other viral infections. Some of these clinical symptoms may also correspond to the decompensation of underlying conditions and iatrogenic effects such as polypharmacy, emphasizing that more specific studies on the subject are needed [24].

As limitations of the studies included, we could highlight intentional sample or nonrepresentative cases recruited from the population, increasing risk of selection bias. Furthermore, some studies used samples with suspected cases, with diagnosis established, based only on clinical–epidemiological criteria, without confirmatory serology or associated hematology.

Moreover, we point out one of the problems of assessing the cause of oral manifestations, either by virus–host interaction, drug therapy, or association with preexisting comorbidities. We were also unable to assess whether oral manifestations are prodromal symptoms or a part of the systemic involvement of viral fever. Some studies included reported oral manifestations as a secondary outcome, presenting only the percentage and number of cases of their occurrence; therefore, we were unable to perform meta-analysis or any type of statistical inference regarding the prevalence of oral manifestations.

Due to the relevance of the topic and increasing number of infections worldwide, we reiterate the need for robust studies with representative samples and comparator groups.

Conclusions

Based on the 27 studies included, we were able to identify the main oral manifestations such as ulcers and oral thrush, gingival bleeding, pain and burning in the oral mucous membranes, arthralgia of the TMJ, opportunistic infections, and changes in taste.

Finally, we concluded that relative to oral manifestations that cause discomfort when chewing, such as ulcerations, there seems to be a predominance in the acute phase of the disease, with complete remission occurring 3 to 10 days after the onset, apparently mostly affecting women and older persons. These oral manifestations can be compatible with basic viral infections related to inflammatory response and transitory immunosuppression.

Supporting information