Introduction

Methods

Results

The systematic search was conducted on 18.06.2024. Searches on PubMed and Google Scholar identified a total of 1,064 publications (Fig 1). PubMed identified 287 results and Google Scholar 777. After assessing titles and abstracts of these articles for eligibility the analysis population was reduced to 42 articles. Subsequently, the full texts of these 42 manuscripts were reviewed and further twelve articles were excluded. Finally, 38 articles were added by being identified through the reference list of respective full texts. Data was then extracted and compiled from a total of 68 publications amounting to 111 cases of oro-facial filariasis.

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Fig 1. Flow Chart–Literature Review.

https://doi.org/10.1371/journal.pntd.0012610.g001

No registered study on oro-facial filariasis was found on clinicaltrials.gov or the Pan-African Clinical Trials Registry (PACTR).

As anticipated from a preliminary search, we only detected published articles on case reports, case series or review articles which had already partially compiled existing case reports. Published data on oro-facial filariasis was identified from as early as 1864 until 2022 (Tables 1 and 2). It seems that oro-facial filariasis can affect people of any age, as indicated by a median 39 years with an age range of 1 year to 80 years. It appears that both sexes are equally often affected, as demonstrated by 49% (54/110) cases being female and 51% (56/110) being male; sex was not reported for one case. The vast majority of identified cases was on oro-facial dirofilariasis (92%, 102/111), followed by lymphatic filariasis (2.5%; (3/111)) and lymphatic filariasis with squamous carcinoma (2.5%; 3/111), followed by onchocerciasis (1%, 1/111). Two articles mentioned filariasis, however, did not further specify the disease or filarial pathogen (2%, 2/111).

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Table 1. Descriptive statistics on all detected case reports.

https://doi.org/10.1371/journal.pntd.0012610.t001

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Table 2. Detailed case descriptions sorted by publication year, country and diagnosis.

https://doi.org/10.1371/journal.pntd.0012610.t002

Dirofilariasis was most commonly reported from the WHO European Region (53.9%; 55/102), and the WHO South-East Asian Region (37.3%; 38/102) followed by a few reports from the WHO Region of the Americas (4.9%; 5/102), the WHO Eastern Mediterranean Region (2.9%; 3/102) and the WHO Western Pacific Region (1%; 1/102) (Table 1). The median age of dirofilariasis cases was 39 years (IQR: 28 to 52 years) and females and males were equally often affected (49% [49/101] and 51% [52/101], respectively). Oro-facial dirofilariasis was almost exclusively caused by D. repens (98%; 81/83) and only two cases were caused by D. tenuis (2%); however, it is of mention that definitive Dirofilaria species diagnosis was not performed in 18.6% of cases (19/102). The most commonly affected oro-facial site was the cheek (63.7%; 65/102), followed by the face (17.7%; 18/102), the lip (7.8%; 8/102) and the jaw (6.9%; 7/102); furthermore, there was each a case with involvement of the nasolabial region, the oral cavity, the soft palate and the tongue, respectively. Although in 37% (38/102) of articles there was no clear description of the main pathology of oro-facial dirofilariasis, among the remaining 64 articles asymptomatic manifestations constituted almost 80% (50/64) and only about 20% (14/64) of articles described a symptomatic case. Among asymptomatic manifestations 58% (29/50) were nodules and 42% (21/50) were swellings. On the contrary, among the symptomatic manifestations there were more swellings than nodules (71% [10/14] and 29% [4/14], respectively) and pain was the main reported symptom in 64.3% (9/14) in symptomatic oro-facial dirofilariasis cases, followed by pruritus (28.6%; 4/14) and dysesthesia (7.1%; 1/14). Therapy was not reported in almost half of oro-facial dirofilariasis cases (46%; 47/102). Cases for whom therapy was reported (n = 55) mostly underwent surgical removal (89%; 49/55) or surgical removal including anti-filarial treatment (5%; 3/55). In two cases the swelling was squeezed, and a worm was recovered and lastly in one case the nodule developed into an abscess, which burst and revealed a white worm. Further details are denoted in Table 2.

Characteristics of the nine (n = 9) oro-facial non-dirofilariasis cases are listed in Table 1. All of them were reported from tropical or subtropical regions with active disease transmission: three out of three (100%) cases of parasitologically confirmed lymphatic oro-facial filariasis and one out of three (33%) cancer cases with parasitologically confirmed concomitant lymphatic oro-facial filariasis stem from the South-East Asian Region of the WHO; one out of one (100%) case of oro-facial onchocerciasis and two out of three (67%) cancer cases with parasitologically confirmed concomitant lymphatic oro-facial filariasis stem from the WHO African region. The age ranged from 13 years to 62 years and there were 5 males (56% and 4 females (44%). All cases of oro-facial lymphatic filariasis (with or without concomitant cancer) were caused by W. bancrofti. More than half of them caused asymptomatic manifestations (56%; 5/9). Among the symptomatic cases (n = 4) pain and ulcer were most common (50%; 2/4 and 50%; 2/4, respectively). The cheeks were the most frequently reported site of disease manifestation (56%; 5/9) followed by the jaw (11%; 1/9), the lip (11%; 1/9), the gingiva (11%; 1/9) and the floor of the mouth (11%; 1/9). All oro-facial, non-dirofilariasis cases had the worm removed by a medical procedure. Further details are denoted in Table 2.

The methodological quality of articles was favorable for two thirds of the included article population (66%; 73/111) and unfavorable (i.e. low) for a third (33%; 38/111). Among the articles rated favorable, the majority was rated as having high methodological quality (64%; 47/73) and 36% (26/73) had acceptable quality.

When looking at absolute numbers and relative percentages of oro-facial filariasis cases by time and WHO region it is apparent that between 1864 and 1989 most cases were reported by the WHO European Region (83.3%; 20/24), followed by the WHO African Region (12.5%; 3/24) and lastly, the WHO South-East Asian Region (4.2%; 1/24) (Table 3). Within the period of 1990 to 1999, the WHO European Region still reported about two thirds of the total global disease burden (63%; 17/27), followed by the WHO South-East Asian Region (29.6%; 8/27) and lastly, by the WHO Region of the Americas (7.4%; 2/27). During the time frame between 2000 and 2009, each 40% of cases were reported by the WHO European Region (10/25) and WHO South-East Asian Region (10/25), each 8% of cases were reported by the WHO Western Pacific Region (2/25) and the WHO Eastern Mediterranean Region (2/25), followed by 4% (1/25) in the WHO Region of the Americas. In the most recent time frame between 2010 until present, approximately two thirds were reported by the WHO South-East Asian Region (68.6%; 24/35), followed by the WHO European Region (22.9%; 8/35), the WHO Region of the Americas (5.7%; 2/35) and lastly, the WHO Eastern Mediterranean Region (2.9%; 1/35).

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Table 3. Number and relative percentage of oro-facial cases of filariasis per country and year.

https://doi.org/10.1371/journal.pntd.0012610.t003

Discussion

The impact of filariasis on oral health is still largely unknown and epidemiological research both on filarial diseases and oral health are neglected. This comprehensive systematic review corroborates this assumption. While the earliest reported cases stem from as early as 1864 since then, only case reports, case series or review articles about these cases were published, but not a single epidemiological or large clinical study. Similarly, not a single, registered study on oro-facial filariasis was identified on large clinical trial platforms. This indicates that the topic of filarial oro-facial disease is indeed a neglected research topic and that the true rate of people suffering from oro-facial filarial disease might be immensely underestimated by the published literature. Our systematic review on the published literature suggests that the vast majority of oro-facial filariasis is represented by oro-facial dirofilariasis caused by D. repens. This is followed by a small non-dirofilarial minority represented by W. bancrofti and O. volvulus.

Oro-facial dirofilariasis manifested exclusively as nodules or swellings in different tissue locations. This is in line with the biology of the adult stages of D. repens and D. tenuis, both of which are known to be most-commonly located in subcutaneous tissue [2]. While swellings (some of which can appear to migrate) are often described to be caused by the active migration of the adult worm, subcutaneous nodules are formed by adult worms whose migration is rendered stationary by the host’s immune system [17,78]. Characteristically, many case reports reported swellings of subcutaneous tissue for weeks to months, which often spontaneously increased and decreased in size and finally manifested into a single, mobile, soft, or firm nodule. Also, in line with the literature these nodules and swellings are mostly asymptomatic, however, can become painful if the immune system of the host attempts to clear the active infection [79]; again, this is congruent with our findings since pain and dysesthesia combined constituted 71% (10/14) of symptoms in symptomatic oro-facial dirofilariasis. Interestingly, most oro-facial dirofilariasis manifestations occurred in the cheek and face and to lesser frequency in the lip, jaw and elsewhere. However, it is believed that these are not true predilection sites, but artefacts resulting from categorizing the human body into anatomical regions, some of which are naturally larger than others. From this perspective the stochastic probability that a migrating worm is found in the larger tissue regions of the cheek or face is higher than in the comparatively smaller tissue regions of the jaw, or lip. Furthermore, virtually all cases had the worm removed, either iatrogenically (98%; 54/55) or spontaneously (2%; 1/55) which is again in line with the recommended treatment of general dirofilariasis caused by D. repens or D. tenuis which is surgical removal [79].

The vast majority of dirofilariasis was caused by D. repens (98%), followed by D. tenuis while no case was caused by D. immitis. This phenomenon can be explained via parasite biology since adults of D. immitis are described to inhabit the intravascular space primarily of pulmonary arteries, and not subcutaneous tissue (which is the case for adults of D. repens and D. tenuis) [2].

Interestingly, while D. repens is described to exclusively occur in the old world, there was one case of oro-facial dirofilariasis reported from the Americas caused by D. repens. The authors report that even despite careful questioning, the patient did not recall any insect bite, nor did she report any history of recent travel outside of the United States [33].

Similarly to D. repens and D. tenuis, also L. loa, O. volvulus and certain Mansonella spp. actively migrate through tissue. However, except for one detected onchocerciasis case we did not detect any case caused by the other above-mentioned filarial species. Although we did neither detect a single case of tooth pain nor a case of oro-facial loiasis, we recently submitted a secondary analysis of a large cross-sectional survey for publication indicating that L. loa can cause transient tooth pain [5]; we argued that a transient swelling of the periodontium or the soft tissue of the oral cavity may explain this symptom. While this phenomenon needs to be corroborated by further research it suggests that up to 25% of individuals with loiasis may suffer from transient tooth pain [80].

On the other hand, filarial pathogens, such as W. bancrofti, B. malayi and B. timori can block lymphatic vessels, thereby potentially exerting secondary damage onto other organs, for example, by causing severe lymphedema of the limbs, which is often accompanied by diffuse thickening of the skin and the subcutaneous tissue; this is then called elephantiasis. We did not detect any case of elephantiasis of filarial origin in the oro-facial region. Yet, we found one publication which described a case of filarial infection with lymphedema in the lip. However, we did not include this article in our analysis population, because the oro-facial pathology was highly likely caused by bacteria and not by the filarial infection [81].

Oro-facial filarial disease was more common in adults than in children. This is epidemiologically and biologically plausible due to two factors: first, the sometimes-long exposition period required to acquire active infection and second, the generally long induction time required for filarial infections to manifest in filarial disease [1,82,83].

Time trend analyses seem to indicate that the share of global oro-facial filariasis burden carried by the WHO European Region was about 80% until 1989 and gradually declined thereafter to approximately 20%. On the contrary, the share of global disease burden of the WHO South-East Asian Region was below 5% until 1989 and eventually increased to almost 70%. Other WHO regions consistently had comparatively low shares of global case burden over time. While the relative increase from South-East-Asian countries seems plausible, due to the co-endemicity of various filarial pathogens there, it seems puzzling that other regions, especially the WHO African Region reported such consistently low rates of oro-facial filariasis given that sub-Saharan African countries carry a comparatively rather high overall filarial case burden [84,85]. The most likely explanations for this phenomenon also represent the main limitations of this article. First, reported case numbers need to be interpreted with caution, since case counts do not stem from routine, standardized and objective surveillance systems but taken from the published literature. This means that the probability of case reporting depends much more on the interest and industriousness of a physician, or researcher than on the actual presence of oro-facial filariasis in a given setting. In other words, the subjective nature of case reporting does not only limit direct comparability of case burden among countries, but also across time. This highlights the importance of conducting large and objective epidemiological studies which should consider and ascertain all locally endemic filarial infections when assessing their potential impact on oro-facial health and the overall public health importance of oro-facial filariasis. Second, the scope of this review encompassed the whole world. Given the high global heterogeneity of the quality of health care systems in different countries this even further reduces comparability of case burden among countries, because it is more likely that articles get published in high-resource settings than in low-resource settings, owing to a relatively better research infrastructure.

It is of mention that in the majority of reported cases asymptomatic swellings, or nodules were the main symptom of oro-facial filarial disease. An important differential diagnosis for asymptomatic swellings, or nodules is cancer. In fact, three cases even had cancer and oro-facial filariasis at the same time. Unfortunately, due to a lack of published studies it is not clear whether oro-facial filariasis might lead to oro-facial cancer, or whether (even though it seems unlikely) cancer might pre-dispose to acquisition of filarial infection, or whether this was merely due to chance. Further prospective studies need to be conducted to investigate any potential causal relationship. However, the similarity of symptomatology indicates that cases of oro-facial filariasis should receive appropriate assessment for cancer and vice versa. Yet, most cases of overall filarial disease are almost exclusively reported from lower- and middle-income countries from the tropics, where health systems often suffer from a lack of resources. Thus, it might be problematic for the global majority of patients with oro-facial filariasis to receive adequate cancer care. Therefore, in the absence of adequate diagnostic facilities and diagnostic apparatus simple cross-sectional studies could be conducted in resource-limited settings to provide oral health providers with valuable information to be ultimately used for case management. First, the prevalence of oro-facial lesions, as well as, their causes should be investigated. Second, symptom scores could be computed which could be used to create guidelines for the medical expert to manage the given oro-facial health problem in a specific setting. Meanwhile, in the absence of adequate clinical and epidemiological research results, oral health providers should consider parasitological etiologies in oro-facial disease manifestations particularly in patients with high risk of carrying a specific parasitic infection. Unfortunately, oral health providers were often not exposed in dental medicine curricula to the idea that parasites can be an underlying cause of certain oro-facial diseases. This educational gap is even further complicated by the fact that parasite-specific characteristics (e.g. life cycles, risk factors, or disease manifestation) can be vastly different among parasitic diseases. Therefore, closing this gap would probably demand a disproportionate exposure of dental medicine students to parasitology at the expense of other relevant educational content in the syllabus. Whether this is justified needs to be judged by (dental) medical faculties depending on the geographical area of the respective university considering local parasitic disease transmission rates.

Conclusion

Although filarial diseases are to date not generally regarded as being associated with oral health problems this assumption might not be justified. This comprehensive systematic review was conducted to detect and collate all published studies on oro-facial filariasis. The fact that only case reports, or case series were identified, while not a single, large epidemiological or clinical study was detected suggests that this constitutes a neglected field of research. Cases identified in the published literature indicate that the vast majority of published oro-facial, filarial case reports were cases of dirofilariasis. However, it might well be that the phenomenon of oro-facial filariasis presents completely different in the context of large epidemiological and clinical studies if all locally endemic filarial infections are considered and ascertained in an objective and systematic manner. Therefore, such large studies are important and warranted to understand oro-facial filariasis better as well as its potential public health importance. Among the published studies, oro-facial filariasis manifested exclusively as nodules or swellings in different tissue locations. These nodules and swellings were mostly asymptomatic and therefore, cancer is an important differential diagnosis.