Background

Zoonoses are those complications which are transmissible between human and animal populations [1]. In this regard dogs and cats are considered as a public health concern, as they may harbor various pathogens such as zoonotic helminths including Toxocara species [2]. Toxocariasis is a worldwide parasitic infection, primarily rendered by T. canis in dogs, T. cati in cats and foxes and T. leonina in a wide range of carnivores [3]. Mature worms lay eggs in the intestinal lumen of their host, which are excreted into the environment via defecation and pass their developmental stages in optimum soil and climate conditions. Upon ingestion of embryonated eggs by another host, the larvae would emerge and invade the intestinal mucosa, then migrate through viscera such as lungs, liver, and kidneys. In addition, transplacental and transmammary transmission to puppies and kittens are important routes of infection. In an epidemiological perspective, animal hosts parasitized by adult worms in their gut can disseminate infection by shedding parasite eggs into environment [4]. In an epidemiological perspective, animal hosts parasitized by adult worms in their gut, can shed parasite eggs, hence considered as a source for dissemination of the infection [5]. Human infection occurs by accidental ingestion of eggs, and, to a lesser extent, via pica and devouring on the paratenic hosts, including chicken, cattle, lamb, pig, and earthworms [4, 6]. Consequently, developmentally-arrested larvae migrate through body organs, but don’t develop into mature worms; hence, they provoke an array of syndromes enclosing VLM, NLM, and OLM as well as covert infection and asymptomatic toxocariasis [7,8,9]. Although rare, cardiac-associated toxocariasis is a serious, life-threatening complication due to VLM which has recently been emphasized [10].

Most of the infected individuals manifest nonspecific symptoms such as a cough, rhonchus, dyspnea and pyrexia along with hepatomegaly and eosinophilic granuloma, which implicates diagnosis of the infection using more sensitive approaches such as immunological assays i.e., ELISA for screening and Western blot for confirmation, rather than histological or parasitological methods [4, 11].

Toxocariasis cause by T. cati and T. canis frequently impacts young cats and dogs from birth to 1 year old, entailing respiratory signs (coughing due to pulmonary larval migration), general failure to thrive (retarded growth, emaciation, debilitated body coat and arthralgia) and intestinal disorders (alternating diarrhea and constipation, pot-belly and vomiting). No remarkable trait is seen following Toxascaris infection in dogs and/or cats and it is usually well-tolerated [3,4,5].

One of the characteristic of helminthic parasites is the stimulation of the immune system that leads to increased Th2 response and high production of IL-4, IL-5, IL-9, IL-10, IL-13, eosinophils, and IgE. Toxocara larvae can causes severe hyper eosinophilia and allergic involvements with effect on IgE and IL-5. Consequently, the production of specific antibodies provides the most complete evidence for Toxocara infection, which is the base of diagnostic tests such as ELISA and Western blot for reactivity to larval TES antigen [11,12,13].

Iran, a Middle Eastern country, possesses several climatological areas with particular characteristics in each region; this would have a significant bias on the epidemiology of Toxocara/Toxascaris species. In the previous studies the infection of dogs and cats with Toxocara species in different parts of Iran has been shown [14]. Despite the prevalence of Toxocara canis in the most areas, molecular studies on cat nematodes in Shiraz, in south-central Iran showed that, the most prevalent one is T. cati [15]. Toxocara vitulorum is frequently found in ruminants. Its main hosts are cattle and buffalo in tropical and sub-tropical regions [16]. It has been reported that 16% (95% CI: 11–21%; 470 out of 3031 samples) of soil samples gathered from public parks of the Iran were positive for Toxocara spp. eggs [17].

On the other hand, due to increasing body of work on Toxocara prevalence in various human/animal hosts in Iran, a comprehensive review would be exceedingly beneficial for appraising progresses about this zoonosis. Therefore, this meta-analysis attempts to fill the current gaps and provides insights into parasite prevalence with respect to host type, Toxocara and Toxascaris species, and geographical region in the country.

Methods

Study area

Iran has a population of approximately 80 million (as of 2015), and is located between 25°3ʹ and 39°47ʹN and 44°5ʹ and 63°18ʹE, which covers a wide territory in the Middle East area (1,648,195 km2). The country borders Afghanistan and Pakistan to the east, Iraq and Turkey to the west, the Persian Gulf and Oman Sea to the south, and Azerbaijan, Armenia, and Turkmenistan to the north. The Iranian plateau climate is generally hot and dry, however the Caspian Sea coast in northern parts, comprising Golestan, Mazandaran and Guilan provinces, is Mediterranean-like, demonstrating heavy rainfalls, vegetation-enriched, surrounded by dense forests and a diverse range of carnivorous animals These geo-ecological features would provide a well-established setting for most parasites, e.g. soil-transmitted helminthiases, to localize in the area and parasitize many canid species. Also, the country is a mountainous region with several mountain ranges, mostly located at the western and northern parts such as Zagros mountain ranges with colder winters and heavy snowfalls. The annual precipitation is 680 mm in the eastern part of the plain and more than 1700 mm in the western parts [18,19,20,21].

Search strategy

The PRISMA protocol (preferred reporting items for systematic reviews and meta-analysis) was employed to conduct this meta-analysis [22]. In order to assess the prevalence of T. canis, T. cati and T. leonina in humans and carnivores of different parts of Iran, we investigated the available online articles of both Persian (SID, Iran Medex, Magiran, Iran Doc) and English (PubMed, Science Direct, Scopus, Ovid) databases. The search include between April 1969 and June 2019. Also, the articles that presented in held Parasitology congresses of Iran were involved. A combination of the following search terms were employed in our literature searches as follows: (“Toxocariasis” OR “Toxocara infection” OR “Toxocara canis” OR “Toxocara cati” OR “Toxascaris leonina”) AND (“Carnivora” OR “Human”) AND (“Prevalence” OR “Epidemiology”) AND (“Iran”).

Study selection and data extraction

After hand searching in bibliographic list of obtained full-text records for any related literature as well as removing duplicates, two independent reviewers screened the titles and abstracts for initial inclusion. A third reviewer was also involved for consensus in the case of any disagreements. Finally, those records that met the following inclusion criteria were eligible to enter our meta-analysis: (A) Peer-reviewed originally-published papers both in English or Persian; (B) Being available online between April 1969 till June 2019; (C) Cross-sectional investigations that assessed the prevalence of Toxocara spp. in various carnivores and human populations in Iran; (D) Studies that detected Toxocara infection using at least one of the parasitological, serological and molecular methods; (e) exact total sample size, positive samples and the respective prevalence rates were available. Empirical studies and any kind of review papers were excluded and failed for further analysis. A detailed variable of each of articles, including: province, year of publication, study design, sample size, detection method, and prevalence rates, in addition to animal species and sampling method for animal-based investigations were gathered. In this study, the JBI critical appraisal checklist for prevalence studies was employed [23].

Study quality assessment

The JBI checklist was used for quality assessment of the included articles. This checklist contains eight questions with four options including, Yes, No, Unclear, and Not applicable (Additional file 1: Figure S1). Briefly, a study can be awarded a maximum of one star for each numbered item. The papers with a total score of ≤6 and ≥ 7 points were specified as the moderate and high quality, respectively. Based on the obtained score, the authors have decided to include and exclude the papers [23].

Meta-analysis

Briefly, meta-analysis was yielded as a forest plot representing the prevalence estimates and related confidence intervals of each study along with summary measures. Also, the heterogeneity was analyzed using STATA statistical software (Version 8.2) to calculate Cochran’s Q and I2 statistics. I2 values of 25, 50, and 75% were considered as low, moderate and high heterogeneity, respectively [24]. Furthermore, the funnel plot based on Egger’s regression test illustrates publication bias and small study effects. In the current study, I2 was substantial; therefore, we used a random effects model at a 95% CI, to give a more conservative estimate of the Toxocara infection prevalence.

Results

Hosts

Following systematic search of eight databases, totally 28 records human studies and 56 animal investigations were found eligible regarding Toxocara/Toxascaris (Fig. 1). During a 19-years period, 11,781 human individuals were examined and the calculated weighted prevalence was 9.3% (95% CI: 6.1–13.1%) (Tables 1 and 2). The trend line of human Toxocara/Toxascaris infection demonstrated that the prevalence has declined in spite of increased bulk of work on human population (Additional file 2: Figure S2). Most records (10 studies) were conducted in both rural and urban circumstances, however seroprevalence was mostly predominant in urban regions with 14% (95% CI: 5.6–25.3%) (No showed data). People under 20 years old were mostly examined by serodiagnosis approach, indicating 8.2% (95% CI: 4.6–12.7%) seroprevalence rate (Additional file 3: Figure S3).

Fig. 1
figure 1

Flowchart describing the study design process

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Table 1 Pooled prevalence of Toxocara infection among human and animals in Iran
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Table 2 Baseline characteristics of included studies for human toxocariasis in Iran
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A number of 29 entries contributed to prevalence of Toxocara/Toxascaris in dogs (Canis familiaris), showing a prevalence of 24.2% (95% CI: 18.0–31.0%). The weighted prevalence of Toxocara/Toxascaris was higher in 20 investigations which examined cats (Felis catus) [32.6% (95% CI: 22.6–43.4%)] (Tables 1 and 3). Interestingly, one study also used serodiagnosis in cats indicating a 53.8% (95% CI: 39.5–67.8%) seroprevalence (Additional file 4: Figure S4).

Table 3 Baseline characteristics of included studies for animal toxocariasis in Iran
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Four studies (all necropsy-based) dedicated to prevalence of Toxocara/Toxascaris in jackal (Canis aureus), representing a 23.3% (95% CI: 7.7–43.2%) frequency. A high prevalence among examined carnivores in Iran was observed in two studies of red fox (Vulpes vulpes) with 69.4% (95% CI: 60.3–77.8%) and one study of wildcat (Felis silvestris) with 62.5% (95% CI: 24.5–91.5%) (Tables 1 and 3).

According to the detection method, the highest total prevalence of T. canis in feces was related to the formalin-ether method [10.5% (95% CI: 5.8–16.3%)] (Additional file 5: Figure S5). Also the most total prevalence of T. cati in feces was related to the formalin-ether method [13.4% (95% CI: 9.7–17.7%)] (Additional file 6: Figure S6).

Parasite species

Among Toxocara/Toxascaris species examined through included studies in Iran, T. cati possessed the highest prevalence rate with 28.5% (95% CI: 20.0–37.7%) (25 records), whereas the pooled prevalence of T. leonina (20 records) and T. canis (31 records) infections were 14.3% (95% CI: 8.1–22.0%) and 13.8% (95% CI: 9.8–18.3%), respectively (Figs. 2, 3 and 4 and Table 3). Necropsy was the method of choice for detection Toxocara/Toxascaris spp., implicating in 31.3% (95% CI: 20.6–43.0%) prevalence of T. cati, 18.8% (95% CI: 10.2–29.1%) frequency of T. leonina, and 17.2% (95% CI: 9.8–26.1%) prevalence of T. canis (Figs. 5, 6 and 7).

Fig. 2
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The total prevalence of T. cati infection in carnivores of Iran

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Fig. 3
figure 3

The weighted prevalence of T. leonina in Iran carnivores by study method

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Fig. 4
figure 4

The total prevalence of T. canis infection in carnivores of Iran

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Fig. 5
figure 5

The weighted prevalence of T. cati in Iran carnivores by study method

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Fig. 6
figure 6

The weighted prevalence of T. leonina in Iran carnivores by study method

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Fig. 7
figure 7

The weighted prevalence of T.canis in Iran carnivores by study method

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Geographical characteristics

There was no statistically significant association between the estimated pooled prevalence of Toxocara/Toxascaris infection in human population and mean temperature (P = 0.49), humidity (P = 0.49), longitude (P = 0.7), and latitude (P = 0.27). Among three parasite species, only humidity (P = 0.023) and latitude (P = 0.032) for T. canis were statistically significant, while others were not remarkably involved (Fig. 8).

Fig. 8
figure 8

The meta-regression graph for the prevalence of T. canis according to humidity and latitude (P = 0.023), to (P = 0.032), respectively

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Discussion

The current systematic review and meta-analysis was aimed to elucidate the prevalence of Toxocara spp. infection in animal and human hosts in Iran. The human infection was highly concentrated in two northern provinces (Mazandaran and East Azerbaijan) (Fig. 9), highlighting optimum geo-ecological milieu in those parts of the country because of high percentage humidity due to vicinity to the Caspian Sea as well as considerable rainfall during the year; notwithstanding, we didn’t found any statistically significant correlation between human Toxocara/Toxascaris seroprevalence studies and geographical parameters comprising mean temperature, humidity, longitude and latitude (Fig. 8). Despite of equal records of Toxocara/Toxascaris infection from rural and urban areas, seroprevalence was partly elevated in urban regions rather than rural territories, resulting from the likely heterogeneity among studies and/or lack of sufficient records; care must be taken in interpreting such result as rural areas are naturally considered as higher risk areas than urban [9, 11, 17, 20].

Fig. 9
figure 9

Distribution map of human Toxocara/Toxascaris prevalence by province in Iran

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Toxocariasis due to several species of Toxocara and/or Toxascaris roundworms is still a seriously notifiable public health issue, particularly due to its intricate transmission routes [25]. In human this infection is caused by T. canis, in particular, and T. cati renders several issues comprising VLM, OLM, NLM and covert disease, each of which is represented by manifestations of the involved organ [26, 27]. Toxocara/Toxascaris infection in human populations is considered as a chronic parasite in nature which is distributed worldwide, particularly in tropical underdeveloped countries [28]. Several risk factors are supposed to play a major role in Toxocara/Toxascaris distribution among the human population, consisting of habitation in rustic areas, soil contact, consuming the undercooked meat of the infected paratenic host, insufficient and unhygienic water repositories, poor housing and low education as well [29,30,31,32]. Furthermore, owing to the adventurous nature of children, such as tasting any objects, eating soil and/or earthworms and being in the vicinity of dogs and cats, they are considered as a substantial risk group regarding toxocariasis [4, 33]. Hence, public places in which children may walk around such as parks, playgrounds, beaches and sandboxes are crucial territories for the acquisition of the infection [28, 31]. Since most individuals do not manifest any pathognomonic symptoms, the actual prevalence rate of the infection remains to be elucidated, even in industrialized nations [34, 35]. Considering that Toxocara parasites do not develop into adult stage in humans, coproscopy is unnecessary; thus, biopsy and direct parasite observation are the gold standard methods [36]. However, such examination is invasive and relies on the larval load and the infection phase [28]. Therefore, routine diagnosis of infection and/or exposure in human cases can be done by ELISA to detect specific antibody against TES antigens, which should be further validated by immunoblotting [37, 38]. As previously mentioned, TES-based ELISA tests are mostly used for human seroprevalence studies. Despite having proper immunogenicity, native TES antigens may cross-react with antibodies elicited against other helminths specifically Ascaris lumbricoides which decreases test specificity [39]. Therefore, the results may be regarded as suspicious, particularly when no immunoblotting confirmation is done, specifically in endemic regions where there exists the possibility of helminth co-infections. Alternative detection methods in paratenic or accidental hosts are including pathological inspection, larvae morphometry as well as PCR-based experiments [4]. A great deal of effort has been devoted to revealing the seroprevalence of human Toxocara/Toxascaris infection worldwide. In Africa, elevated seroprevalence rates of infection were detected, encompassing 6% in Egypt to 60% in Gabon and 92% in Réunion Island [5, 40]. Additionally, the seroprevalence ranges in Asia and South America included 11 -84.6% and 7.3–66%, respectively [41,42,43]. Comparable to other territories, rates of seropositive human cases were relatively low in European and North American countries [3], implicating improved hygiene practices and public awareness in industrialized nations.

In total, seroprevalence data integration in epidemiological investigations is not reasonable for several reasons, comprising sampling disparities, antigen preparation, and quality, different cutoff levels, cross-reactivity especially in the tropics were polyparasitism exist and inability to explicitly distinguish the infection by various Toxocara spp. Therefore, expanding our evidence based on human Toxocara infection would be corroborated by a better understanding of parasite biology, in particular, the immune evasion mechanism of larvae, and utilization of advanced, species-specific diagnostic tools [30].

The calculated total prevalence of infection in cats (Felis catus) was higher [32.6% (95% CI: 22.6–43.4%)] than in dogs (Canis familiaris) [24.2% (95% CI: 18–31%)] in the country (Table 1). Similar to human seropositive cases, carnivores in northern Iran were the most frequent hosts being parasitized by Toxocara spp., whereas minimum animals were infected in central parts [12% (95% CI: 8–17%)]. Among wild canine species in Iran, only jackal (Canis aureus) and red fox (Vulpes vulpes) were diagnosed with Toxocara/Toxascaris infection, with 23.3% (95% CI: 7.7–43.2%) and 69.4% (95% CI: 60.3–77.8%), respectively (Table 1).

Moreover, it was deduced that the weighted prevalence of T. canis, T. cati, and T. leonina in Iran were 13.8% (95% CI: 9.8–18.3%), 28.5% (95% CI: 20.0–37.7%), and 14.3% (95% CI: 8.1–22.0%), respectively. Given geographical characteristics, only humidity (P = 0.023) and latitude (P = 0.032) were significantly linked to T. canis infection. Increasing latitude would likely result in decreased mean temperature and more temperate climates than the equator area. Water vaporization and condensation in northern parts of the country due to the vicinity to the Caspian Sea and high mountain ranges and humid weather substantially implicate in Toxocara/Toxascaris larval development, as proved in the laboratory [17, 20].

The survey of the infection in carnivores is usually made via traditional parasitological methods (e.g. floatation technique) to detect eggs as well as intestinal necropsy of dead carcasses [44, 45]. Nevertheless, each detection method may provide a prevalence rate different from other modalities, which this issue would implicate potential biases in reporting and/or interpreting data. As we stated in the results section, necropsy has been shown as a better and efficient detection tool than fecal examination. For instance, more than 2-fold prevalence of Toxocara/Toxascaris spp. in dogs was obtained using necropsy [34.3% (95% CI = 26.4–42.8%)] than fecal examination [15.6% (95% CI = 9.8–22.4%)]. Also, necropsy was the most efficacious method in cats with 37.4% (95% CI = 23.5–52.4%) than fecal examination [20.4% (95% CI = 9.4–34.2%)]. On an international scale, different studies have documented the prevalence of Toxocara/Toxascaris in stray/domestic dogs (Canis familiaris) and cats (Felis catus). In Europe, T. canis prevalence in dogs ranged from 1% in Germany to 76% in Albania. Also, the prevalence of T. cati infection was up to 34.5% in Spain in this continent [46,47,48,49]. In dogs dwelling in the Americas, T. canis infection prevalence varied from 12.7% in Canadian provinces to 18% in Cuba. Also, T. cati was mostly prevailed in Argentina and Brazil with 61 and 25%, respectively [50,51,52,53]. The highest T. canis and T. cati infection rates in Asia were dedicated to Russia and China with 63 and 36.5%, respectively [54, 55]. Additionally, mild Toxocara species infections were identified in African domestic carnivores [56,57,58,59].

Globally, the highest T. leonina prevalence (up to 38%) was observed in domestic dogs from Russia [52]. Wildlife probably plays a critical role in the epidemiology of Toxocara species, as they may be considered as potent reservoir for these enigmatic roundworms [60].

Patent T. canis infections are generally higher in young foxes (under 6 months of age); although, a relatively high prevalence rate have also been among adult foxes in endemic territories, representing weak immune status against intestinal [61]. The prevalence of T. canis in European foxes varies between 9.0% (in Italy) and 65.0% (in Denmark), as well as 32.5 and 71.0% prevalence in Canada and Japan, respectively [61]. The lowest and highest T. leonina prevalence in red fox was reported from Kirghizstan (5.9%) and the Slovak Republic (47.1%), respectively [60]. Regarding golden jackal (Canis aureus) moderate prevalence rates of Toxascaris leonina have been reported around the world, such as in Azerbaijan (31.8%), Bulgaria (36%) and Russia (43.5%). The prevalence of T. canis in this wildlife species ranges 40–61% in Asia and 20–54.5% in European countries, whereas T. cati was only detected in jackals dwelling in Russia (5–26%) [49, 62]. Considering that there are only 4 golden jackal studies and 2 red fox (Vulpes vulpes) studies, there exist paucity of data on Toxocara/Toxascaris prevalence in wild canine and feline fauna of Iran, which highlights more subtle investigations. Approximately, since the middle of previous century a periurban rise in European foxes population carrying Toxocara/Toxascaris worm burdens have posed a great environmental risk of contamination with parasite ova. On the other hand, they act a critical role in maintaining T. canis wildlife cycle with implications in constant transmission to human populations and pet dogs [63].

The findings of the present study indicated a mild seroprevalence in human population; also, infection in cats was higher than dogs, however unbalanced sampling may have influenced these findings. Most of the infected cases were from north of Iran, which possess a favorable ecological milieu for appropriate animal hosts and Toxocara egg development (i.e., 28–33 °C in laboratory-based conditions, during 2–6 weeks [64]. Despite the improved hygiene and health surveillance systems as well as a wide-range public awareness in developed countries, still Toxocara/Toxascaris infection remains a public health concern in those areas and the rest of the world as well. During the time, there have been established a close companionship between dogs and cats with humans, and during past decades it has been even strengthened. However, these associations, particularly in underdeveloped nations, have been accompanied with poor veterinary infrastructures. This, along with free-roaming or community-owned dogs and cats pose a serious threat for zoonoses transmission to human societies [65].

With respect to the constant infection cycle in carnivores and the life-threatening traits of human toxocariasis, revisiting the epidemiological strategies in companion animals enclosing anti-helminthic medication and screening plans such as the routine fecal examination is of utmost importance. In addition, it is highly emphasized that future human investigations focus on using recombinant TES antigens with high sensitivity and specificity and less cross-reactivity. Also, it is better to identify anti-Toxocara IgG4 coupled with TES rather than total IgG and employ western blot as a complementary diagnostic technique [28]. Moreover, it is recommended to educate laboratory technicians for accurate parasite detection, regularly deworm puppies and kittens to decrease the worm burden, perform pro-active chemoprophylaxis approach and cultivate knowledge among the public as well as physicians regarding the clinical consequences of the disease. The interwoven collaboration among blood banks, veterinary diagnostic laboratories and municipalities (control stray dog/cat populations in urban areas) would provide a more completed picture of disease seroprevalence and distribution in people and animals, giving us the opportunity for targeted intervention strategies and better management of this zoonotic enigma. In parallel to above-mentioned recommendations the WSAVA has recently found a One Health Committee to highlight the transmission potential of zoonotic infectious agents from dog/cat to human. Besides the OIE has recently extended the surveillance of wildlife diseases through WAHID in the world. All of these expanded fields of epidemilogical data would assist the global community towards better understanding of human-domestic animal-wildlife interplay and control of human zoonotic diseases [63].

Limitations

It is noteworthy to mention that some limitations constrained our findings en route performing current systematic review and meta-analysis, including 1) lack of risk factor appraisal, 2) absence of a standard, easy-to-use diagnostic tool in case of human studies to particularly discern the involved Toxocara spp., 3) lack of investigations considering different aspects of human Toxocara-induced complications such as VLM, OLM, and covert infection. Certainly, with these in hands, we could achieve the more complete picture of the current situation of Toxocara/Toxascaris infection in animal and human hosts of Iran.

Conclusion

In conclusion, this study revealed that Toxocara and Toxascaris infection in Iran among people is mild while in dogs and cats are high. Exclusive studies including human, animal and environmental health data should be conducted in different geographical regions of the country. The outcome of such studies will allow the government and non-government organization to set proprieties and design strategies, combining accurate surveillance and prevention of these zoonotic diseases.