Authors:
Ellis Kobina Paintsil Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), South-End, Asuogya Road, 039-5028 Kumasi, Ghana
Department of Theoretical and Applied Biology, Kwame Nkrumah University of Science and Technology, 039-5028 Kumasi, Ghana

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Wycliffe O. Masanta Maseno University Medical School, Department of Medical Microbiology, Private Bag, 40105 Maseno, Kenya

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Annika Dreyer Institute for Medical Microbiology and Virology, University Medical Center Göttingen, 37075 Göttingen, Germany

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Leonid Ushanov Institute of Veterinary Medicine, Agricultural University of Georgia, 0159 Tbilisi, Georgia

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Stella I. Smith Department of Molecular Biology and Biotechnology, Nigerian Institute of Medical Research, Yaba, Lagos 101212, Nigeria

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Hagen Frickmann Department of Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg, 20359 Hamburg, Germany
Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, 18057 Rostock, Germany

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Andreas E. Zautner Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
Health Campus Immunology, Infectiology and Inflammation (GCI), Medical Faculty, Otto-von-Guericke University Magdeburg, 39104 Magdeburg, Germany

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https://orcid.org/0000-0003-0984-013X
Open access

Abstract

Campylobacter infections and campylobacteriosis-associated post-infectious sequelae are a significant global health burden that needs to be addressed from a specific African perspective. We conducted a comprehensive literature search on NCBI PubMed to compile a comprehensive narrative review article on Campylobacter infections in Africa, focusing on key aspects in human and veterinary medicine as well as food hygiene. We specifically focused on the epidemiology of enteropathogenic Campylobacter spp. in sub-Saharan and North Africa considering antimicrobial susceptibility. The most significant sequela resulting from molecular mimicry to Campylobacter surface structures is the Guillain-Barré syndrome, which was mainly examined in the context of limited studies conducted in African populations. A dedicated subsection is allocated to the limited research on the veterinary medically important species Campylobacter fetus. There are significant differences in the composition of the gut microbiome, especially in rural areas, which affect the colonization with Campylobacter spp. and the manifestation of campylobacteriosis. There may be a problem of overdiagnosis due to asymptomatic colonization, particularly in the detection of Campylobacter using molecular biological techniques. To reduce the colonization and infection rate of Campylobacter, we propose implementing several control measures and urge further research to improve the current understanding of the peculiarities of campylobacteriosis in Africa.

Abstract

Campylobacter infections and campylobacteriosis-associated post-infectious sequelae are a significant global health burden that needs to be addressed from a specific African perspective. We conducted a comprehensive literature search on NCBI PubMed to compile a comprehensive narrative review article on Campylobacter infections in Africa, focusing on key aspects in human and veterinary medicine as well as food hygiene. We specifically focused on the epidemiology of enteropathogenic Campylobacter spp. in sub-Saharan and North Africa considering antimicrobial susceptibility. The most significant sequela resulting from molecular mimicry to Campylobacter surface structures is the Guillain-Barré syndrome, which was mainly examined in the context of limited studies conducted in African populations. A dedicated subsection is allocated to the limited research on the veterinary medically important species Campylobacter fetus. There are significant differences in the composition of the gut microbiome, especially in rural areas, which affect the colonization with Campylobacter spp. and the manifestation of campylobacteriosis. There may be a problem of overdiagnosis due to asymptomatic colonization, particularly in the detection of Campylobacter using molecular biological techniques. To reduce the colonization and infection rate of Campylobacter, we propose implementing several control measures and urge further research to improve the current understanding of the peculiarities of campylobacteriosis in Africa.

Introduction

Campylobacteriosis, the most common form of bacterial enteritis worldwide [1, 2], is responsible for a range of post-infectious complications such as reactive arthritis and, most notably, Guillain-Barré syndrome [3]. While the status of campylobacteriosis in Europe and America is well established, it exhibits several unique characteristics in Africa, including its epidemiology, habitats of origin in agriculture and environment, clinical manifestation, and the scientific study situation. Compared to other regions, the research on campylobacteriosis in Africa is still limited in many aspects. In this review article, we provide an overview on the epidemiology of enteropathogenic Campylobacter spp. in sub-Saharan Africa and North Africa, the antimicrobial resistance situation, and propose Campylobacter control measures, based on the current state of scientific literature. Additionally, we examined the significance of the microbiome in the manifestation of campylobacteriosis in Africa, particularly considering factors such as diverse dietary habits, varied water sources, and living closely with domestic animals as well as farm animals, thereby comparing urban and rural areas. Furthermore, we explore the research and experiences regarding the most significant post-infectious sequela of campylobacteriosis, the Guillain-Barré syndrome, in Africa. We also consider the role of Campylobacter fetus, an important microbial species in veterinary medicine, globally as well as in African countries, especially in the light of its recent subdivision into three subspecies. In the final part of this article, we address the challenges in diagnosing campylobacteriosis and the etiological relevance of positive Campylobacter spp. detections for human disease in the sub-Saharan African tropics. This is particularly important due to the significantly higher asymptomatic colonization rate in populations in resource-poor high-endemicity settings compared to industrialized countries.

Epidemiology of Campylobacter in sub-Saharan Africa

Prevalence of Campylobacter in farm animals and humans in sub-Saharan Africa

Campylobacteriosis is considered a significant public health problem in many parts of sub-Saharan Africa [4, 5], but the precise burden of the disease in the region is unknown due to limited surveillance. The estimated prevalence among humans in the sub-Saharan region is between 8.5% and 14.1% [5]. When examining specific risk groups, it was found that children under 5 years of age have a prevalence rate of 50.6% [5], patients with HIV of 45.0% [6], and patients with diarrhea of 20.3% [7]. The prevalence of the bacteria in farm animals varies widely, ranging from 2% in beef from Kenya to as high as 90% in sampled chicken from Cameroon [8]. Notably, certain studies have indicated particularly high rates, exceeding 50%, among pigs [9, 10] and poultry [11, 12]. Campylobacter jejuni and Campylobacter coli are the most common species isolated from both farm animals and humans [5, 6, 8]. Nonetheless, a study conducted in South Africa reported significantly more C. jejuni (n = 232) than C. coli (n = 25) among children aged 0–24 months. These two species of Campylobacter have adeptly evolved to survive and persist in diverse environmental settings, including high temperature zones, soil, water sources, as well as surfaces and equipment found within food processing environments [13].

The frequency and distribution of Campylobacter spp. in environmental samples vary significantly between different regions and countries [1]. In sub-Saharan Africa, factors such as agricultural practices, livestock management, water quality, and sanitation infrastructure have been identified to impact the transmission of Campylobacter spp. (Fig. 1) [1415]. It was observed in South Africa that free-roaming sheep and cattle spread Campylobacter spp. in the farm environment [14]. Campylobacter spp. have been detected in milk products from Tanzania [16], Ethiopia [17] and South Africa [18]. Due to the high Campylobacter contamination of farms, the occurrence of Campylobacter spp. in milk is difficult to avoid, hence effective heat treatment before consumption is highly recommended in order to reduce health risks associated with raw milk consumption [19]. Similarly, Campylobacter contamination of fresh vegetables has been reported in some sub-Saharan African countries [20, 21]. Contaminated irrigation water and animal manure are the main sources identified as the source of Campylobacter spp. contamination in vegetables (Fig. 1) [22].

Fig. 1.
Fig. 1.

Transmission routes of Campylobacter infection in humans. Created with Biorender.com (accessed on 15 August 2023). Campylobacter spp. naturally resides within the gastrointestinal tract of farm animals and primarily infects humans through the consumption of contaminated farm products. Campylobacter transmission can also spread through the environment via fecal contamination from reservoir hosts. Drinking contaminated water or its use for irrigation could lead to the contamination of crops that are later consumed by humans.

Citation: European Journal of Microbiology and Immunology 13, 4; 10.1556/1886.2023.00043

Even though it is well known that Campylobacter infections do occur throughout the year, a few studies conducted in sub-Saharan Africa have observed a higher frequency of the bacteria in the rainy season than in the dry season [6, 23]. The authors argue that poor agricultural practices, the combination of heavy rainfall and inadequate drainage systems which are common in various areas of sub-Saharan Africa, play a role in increasing the occurrence of Campylobacter contamination in water sources, including drinking water. Research conducted in rural sub-Saharan Africa, involving both food-producing animals and human populations [6, 9, 11, 17], has reported rural Campylobacter spp. prevalence rates similar to those recorded in urban areas [7, 10, 18, 24]. However, different factors might impact the prevalence and transmission of Campylobacter spp. in these distinct settings. It has been suggested that the widespread involvement of rural residents in crop farming and animal husbandry activities might increase their vulnerability to Campylobacter spp. transmission [25]. While farming activities are less prevalent in urban areas, the higher population density can result in sanitation infrastructure challenges. Additionally, the food environment and increased levels of food processing and distribution within urban settings could also play a role in contributing to the Campylobacter burden [26].

Antimicrobial resistance (AMR) patterns of Campylobacter spp. in sub-Saharan Africa

Campylobacter infections in humans are frequently self-limiting, often resolving without requiring antimicrobial intervention. However, in immunocompromised patients as well in the case of severe or prolonged diarrhea, antimicrobials may be needed. Due to the indiscriminate use of antimicrobials in humans and veterinary medicine, antimicrobial-resistant Campylobacter spp. strains have emerged [27]. To address the growing public health concern, it is highly recommended worldwide to decrease the use of antimicrobials in both human and veterinary medicine [28–30]. Reports of Campylobacter spp. isolates resistant to ciprofloxacin, erythromycin, and tetracycline have been documented in several sub-Saharan African countries [6, 7, 24, 31–34]. These antibiotics are the recommended drugs for treating campylobacteriosis, and the emergence of resistance poses challenges to ensure effective treatment within the region. Ciprofloxacin resistance in Campylobacter spp. isolated from poultry has been reported to be 95.4%, 71.0%, 67.3% and 40.8% in studies conducted in South Africa [32], Kenya [33], Ghana [6] and Ivory Coast [31], respectively. Similarly, high levels of erythromycin and tetracycline resistance in Campylobacter spp. strains isolated from poultry have been reported from Ghana [6, 7] and South Africa [32]. Compared to farm animals, lower levels (0–14%) of resistance to ciprofloxacin and erythromycin in Campylobacter spp. isolates from human patients have been observed in Uganda [24], Burkina Faso [34], and Nigeria [35]. The higher prevalence of antibiotic resistance in farm animals compared to humans can be attributed to several factors including dense animal populations on farms and limited regulation and oversight of antibiotic use in farm animals [27, 36].

Campylobacter species, particularly C. jejuni and C. coli, have shown the ability to develop multidrug resistance (MDR) (here defined as resistance to the antibiotics typically used for the treatment of campylobacteriosis, i.e., erythromycin, tetracycline, and ciprofloxacin). In sub-Saharan Africa, studies have documented MDR in Campylobacter spp. strains isolated from humans and poultry [6, 10, 37]. The emergence of multidrug-resistant Campylobacter strains is a significant public health concern as it limits the effectiveness of recommended antibiotics for treatment. Very few studies have been conducted in sub-Saharan Africa to identify antibiotic resistance genes and virulence makers. Nonetheless, the following antibiotic resistance genes: tet(O), blaOXA-61, aadE, and ermB and the virulence makers: ciaB, cdtA, cdtB, cdtC, cadF have been reported by different studies in various sub-Saharan African countries [6, 10].

Proposed Campylobacter control measures in sub-Saharan Africa

According to Taha-Abdelaziz and coworkers, Campylobacter-specific control strategies can be categorized as pre- and post-harvest interventions [38]. The pre-harvest measures encompass: (a) implementing food hygiene measures to minimize Campylobacter spp. exposure in the environment, (b) enhancing avian host immunity through vaccination, and (c) employing antibiotic alternatives to reduce or eliminate the infection burden in chicken [38]. In contrast, post-harvest interventions comprise procedures like (a) cleaning and sanitizing slaughterhouses, (b) decontaminating carcasses, and (c) sanitizing eggshells [38].

Most of the Campylobacter studies conducted in sub-Saharan Africa have proposed pre-harvest measures, especially the enhancement of farm hygiene and improvement of infection control measures, to reduce Campylobacter spp. occurrence [6, 17, 21, 39]. There has been limited research conducted on utilizing vaccines, probiotics, and bacteriophages to manage the prevalence of Campylobacter spp. in sub-Saharan Africa. Nonetheless, some studies have been performed on employing antibiotic alternatives in order to reduce or eliminate the infection burden. Hlashwayo and coworkers have reported on the examination of 47 medicinal plants belonging to 28 families, from six sub-Saharan countries, for in vitro activity against Campylobacter spp. Out of the 47 tested plants, Cryptolepis sanguinolenta and Terminalia macropter exhibited the highest levels of antimicrobial activity against Campylobacter spp. [40]. Nevertheless, the persisting high prevalence of Campylobacter spp. infections in sub-Saharan Africa emphasizes the need for additional research in order to establish appropriate control measures within the region.

Epidemiology of C. jejuni and C. coli in North Africa

Data from North Africa indicate that infections with C. jejuni and C. coli occur predominantly among the pediatric population. Especially in less developed rural areas, C. jejuni infections are widespread due to frequent contact to farm animals, particularly poultry [41, 42]. Moreover, consumption of raw chicken meat and contaminated drinking water as well as limited access to sanitation are well-recognized risk factors [43–46]. Thereby, animal-sourced foods play an important role in the decrease of undernutrition in several African regions [47, 48]. The emergence of antibiotic resistances in C. jejuni isolates is of high concern.

The exact prevalence rates might vary across countries and regions within North Africa. More reports about Campylobacter in animal-sourced foods are reported than in humans [49]. However, the WHO estimates that 70% of foodborne diseases in the Arabic and North-African region is caused by Campylobacter spp., but also by diarrheagenic Escherichia coli, Salmonella enterica and norovirus [2].

The majority of reports examining the prevalence of Campylobacter spp. in North Africa have been conducted in Egypt, while there is a limited number of studies available from other countries in this region (Table 1). One assessment from Egypt showed that Campylobacter spp. were isolated from 6.4% of healthy children and 16.8% of children that were suffering from diarrhea in Alexandria [50]. In Cairo, Campylobacter spp. were isolated from 15.2% of healthy children while it was found in 25.9% of children suffering from diarrhea [51]. Furthermore, genotyping of different C. jejuni isolates demonstrated that the main source for C. jejuni in Egypt is broiler meat [45, 46, 52]. Moreover, it was suggested that several antibiotic resistance genes are present in C. jejuni isolated in North Africa [46]. Especially erythromycin, nalidixic acid, streptomycin, chloramphenicol, tetracycline, ciprofloxacin, gentamicin and ampicillin-resistant strains were detected in an Egyptian assessment [53].

Table 1.

Reports of C. jejuni or C. coli in northern African countries. Table adapted from Habib et al., 2021; n.d. = not detected

CountrySource (number of samples)C. jejuni [%]*C. coli [%]*
Egyptbroiler (101)n.d.4
slaughterhouses (104)n.d.3.9
fresh chicken meat (30)46.746.7
frozen chicken meat (30)46.740
raw milk (50)2020
kareish cheese (50)1414
yoghurt (50)88
Tunisiabroiler (590)n.d.n.d.
chicken meat (149)16.13.4
Turkey meat (101)13.81.9
Sudangoats (336)5.769.6
Moroccobroiler (105)n.d40
raw poultry (850)n.d.n.d.

* The percentage (%) of Campylobacter species was calculated from the positive samples (isolated target bacteria) by Habib et al., 2021.

In Tunisia, next to several virulence factors of Campylobacter strains, resistances against the following antibiotics was found: quinolones (ciprofloxacin or nalidixic acid, or both), erythromycin, β-lactams (ampicillin or amoxicillin/clavulanic acid or both), tetracycline and gentamicin [54].

Studies showed that the prevalence of C. jejuni and C. coli in Egypt is similar in chicken meat products either frozen or fresh, ranging between 40.0% and 46.7% [49, 55]. In Morocco, there is a higher reported incidence of C. coli, although this discrepancy may be due to a lack of comprehensive investigations [49, 56]. In Sudan, C. jejuni and C. coli were detected in goats among other facultatively pathogenic bacterial species [49, 57]. Tunisia reported a greater prevalence of C. jejuni in chicken and Turkey meat compared to C. coli [49, 58].

However, the lack of studies from North African countries other than Egypt and Tunisia makes it challenging to provide a comprehensive understanding of the Campylobacter spp. prevalence across the entire region.

Campylobacter spp. and the human microbiome

An introduction into the topic

Once consolidated, the human gut microbiome is known to provide a robust protection against colonization with exogenous microbial agents and infections with pathogenic microorganisms [59–62]. This phenomenon has been labeled as “colonization resistance”. As shown a decade ago [63], the microbiome composition can partly recover even after severe disturbances as they may be associated with infectious gastroenteritis on international travel in resource-poor settings. Discussed components of microbiome-associated colonization resistance comprise secretion of antimicrobial active components, competition for nutrients, stabilization of the integrity of the gut barrier and spreading of bacteriophages [59]. However, the gut microbiome's protective properties can be directly or indirectly compromised by disturbances due to drugs like antibiotics, proton pump inhibitors, antidiabetics and antipsychotics [59]. Further, co-evolution of entero-invasive microorganisms like C. jejuni has led to several virulence mechanisms which can overcome colonization resistance [59, 64]. In turn, alteration of the human gut microbiome due to severe enteric infection with microorganisms like Campylobacter spp. has been associated with increased odds of developing future inflammatory bowel disease [65].

The current knowledge on interactions between Campylobacter spp. and the gut microbiome, both based on animal studies and human assessments, is summarized in the following.

Experience with animals

In mouse experiments, rich abundance of Escherichia coli and Bacteroides spp. has been found to be associated with increased Campylobacter spp. colonization rates [66]. While mouse microbiomes are known to prevent C. jejuni infections in mice, inflammatory responses in the animals occur associated with C. coli challenges [67]. However, compared to mouse-specific enteric microbiota, human microbiome compositions in the animals' gut have been associated with even increased enteric inflammation in case of artificially induced colonization of the animals' guts with C. coli [68]. In turn as a consequence of C. coli infections in the gut of mice, enteric microbiome changes with an increased abundance of Enterobacterales have been recorded [69].

Antimicrobially induced depletion of enteric microbiomes in mice as well as complete lacking of enteric microbiomes facilitate both enteric and systemic inflammation in the animals in response even to C. jejuni challenges [70–75], but C. jejuni-specific colonization resistance in the gut of mice can at least partly be restored by fecal microbiota transfer (FMT) [76] and even FMT from susceptible animal donors is associated with a protective effect [77]. In case of C. jejuni colonization in mice with a human gut microbiome, in contrast, increased TH-2 lymphocyte and autoimmune responses as well as Guillain Barré syndrome-associated antibody induction were observed in a C. jejuni strain-dependent manner [78]. Toll-like receptor 4 (TLR 4) and TLR 9 have been shown to be major mediators of such C. jejuni-mediated inflammation [79–81]. Compared to humans, TLR 4 responses in healthy mice challenged with C. jejuni are 10.000× times lower, which is considered as a major factor of colonization resistance [82]. The iron-chelating compound desferoxamine reduces inflammation and promotes shifts towards asymptomatic colonization [83]. Even in mice harboring a human enteric microbiome, FMT with mouse-borne microbiota but also exposure to probiotic lactobacilli and bifidobacteria result in a decrease of C. jejuni colonization or infection [84, 85]. In contrast, immature mouse microbiomes which are abundant shortly after weaning in very young animals were shown to be insufficient to medicate colonization resistance in mice and even severe entero-colitis caused by C. jejuni was seen in such instances [86].

Focusing on wild mice, their species is considered to be of relevance for the animals' potential of harboring Campylobacter spp. in their gut. While Mus minutus was shown to carry considerable proportions of Campylobacter spp. DNA in its gut, enteric microbiota of Mus musculus were characterized by high abundance of Lactobacillus spp. DNA but absence of nucleic acid sequences of Campylobacter spp. in a Korean assessment [87].

In chicken as well, the importance of the gut microbiome for the control of C. jejuni-associated virulence has been shown. Chicken with lacking or antimicrobially depleted gut microbiomes were demonstrated to be more vulnerable to C. jejuni in terms of enteric colonization intensity, invasiveness of the pathogen and inflammation [88, 89]. Colonization of the gut of chicken with C. jejuni has been shown to be associated with the absence of Peptococcaceae as well as several genera of the family Ruminococcaceae. More than this, bacteria of the Christensenellaceae R-7 group and C. jejuni were suggested to obviously compete for the same substrate in the chicken's gut [90]. On the other hand, spontaneous decolonization of C. jejuni from the gut of chicken has been associated with increased detection of Clostridiaceae, Ruminococcaceae, Lachnospiraceae, and Peptococcaceae sequences in the birds' enteric microbiomes [91]. In addition, effects on the birds' microbiomes have been shown to at least partially depend on the time of exposition to C. jejuni [92], while the microbiome composition is also affected by the time of infection [93]. Enrichment of the chicken's gut microbiome with presumedly protective microorganisms like lactic acid bacteria has been discussed as an option for the reduction of the colonization with Campylobacter spp. [94, 95]. On a mechanistic level, the application of deoxycholic acid (DCA) but not of other bile acid derivates like lithocholic acid or ursodeoxycholic acid was associated with reduced colonization of chicken guts with C. jejuni. DCA-associated reduced Firmicutes and increased Bacteroidetes proportions within the animals' gut microbiomes were considered as mediators of such increased colonization resistance. Also, the transplantation of DCA-modulated anaerobes made the birds less vulnerable to C. jejuni colonization [96]. The latter phenomenon has been confirmed for the mouse model as well [97]. Of note, the influence of bile acids on microbiome-associated colonization resistance of chicken towards C. jejuni has been repeatedly demonstrated [91] and microbially synthesized short-chain fatty acids have also been proven to influence gene expression patterns with relevance for persistence and virulence of C. jejuni [98]. Of note, short-chain fatty acids were still able to reduce Campylobacter spp. colonization in chicken at late stages of colonization when applied as feed additives [99]. Other compounds resulting in a decrease of Campylobacter spp. as part of the enteric microbiomes of chicken comprise biochar, bentonite and zeolite as 4% feed additives each [100] as well as the essential oil carvacrol [101]. In chicken pretreated either with C. jejuni lysate or Poly-D,L-lactide-co-glycolide polymer nanoparticles containing CpG oligodeoxynucleotides, increased microbiome diversity and increased proportions of Firmicutes and Bacteroidetes were found to be associated with reduced proportions of Campylobacter spp. as part of their enteric microbiomes [102].

Interestingly, however, experiments including reciprocal microbiota transfer suggested that the microbiome compositions only partly explain differences of Campylobacter spp.-specific colonization resistance in birds [103].

Experience with human individuals

A US-military medical investigation based on a controlled human infection model for C. jejuni, which had also provided evidence for lacking effect of rifaximin prophylaxis against C. jejuni infection, recently suggested a mild association between beta-diversity of the human enteric microbiome and vulnerability towards C. jejuni-associated gastroenteritis [104]. As shown for Swedish poultry abattoir workers with a high pre-test probability of developing Campylobacter spp. infection, the gut microbiome of individuals developing Campylobacter spp.-associated gastroenteritis was characterized by a higher abundance of Bacteroides spp., Escherichia spp., Streptococcus spp. and Phascolarctobacterium spp. but a lower abundance of sequences of Clostridiales, Lachnospiraceae and Anaerovorax spp., respectively, compared to a matched control population without Campylobacter spp. infections. In the same study, long-term effects of Campylobacter spp.-infections on the human microbiome were confirmed, indicating interaction in both directions [66]. Thereby, the dimension of C. jejuni infection-associated alteration of the human gut microbiome seems to be variable. Particularly low diversity of the human enteric microbiome after C. jejuni infections with high proportions of Proteobacteria, Fusobacteria and Gammaproteobacteria as well as reduced levels of several taxa of Firmicutes, especially of the order Clostridiales and the family Ruminococcaceae, were found to be associated with postinfectious bowel dysfunction. High fiber consumption seemed to have a protective effect and was associated with lower abundance of Gammaproteobacteria [105]. Even in Southern-American high endemicity settings, where Campylobacter spp. are often recorded as asymptomatic colonizers in the gut of local children, their abundance was associated with altered enteric microbiome compositions [106].

In low-income countries in general, C. jejuni infection-associated affection of the human enteric microbiome has been proposed to be associated with multiple effects on children, including malabsorption and growth reduction, but also immune impairment, cognitive reduction and even increased mortality. As admitted by the authors themselves, however, evidence is still low and future research is needed [107]. Focusing on Africa, increased abundance of Campylobacter spp. sequences was detected in stool samples of children from Guinea-Bissau co-infected with enteric protozoa like nonpathogenic Entamoeba coli and Endolimax nana as well as with pathogenic Giardia duondenalis and Entamoeba histolytica irrespective of clinical symptoms. It was speculated that the protozoa might shape the children's enteric microbiome in a way that colonization of Campylobacter spp. is facilitated [108].

Altogether, epidemiological knowledge on associations of enteric microbiome composition and enteric colonization with Campylobacter spp. in Africa is still extremely scarce. Future research is required to shed light on this important topic.

Association of Campylobacter spp. infections and Guillain-Barré syndrome – experience from Africa

Background of Guillain-Barré syndrome-triggering by Campylobacter spp.

Probabilistic associations of Campylobacter spp. infections and the immune-mediated acute polyradiculo-neuropathy Guillain-Barré syndrome (GBS) with symmetrical flaccid paresis as a common clinical manifestation are considered as well established [109–113]. Etiologically, this association is driven by molecular mimicry between the pathogens' surface structures and axonal or myelin components of the central nervous system. C. jejuni, in particular, as well as Mycoplasma pneumoniae and human cytomegalovirus (CMV) are believed to induce about one third of the observed GBS cases [3] with the pathogen's lipooligosaccharide (LOS) stimulating Toll-like-receptor 4 as a molecular trigger. Some authors even assume a quantitively stronger association [114115], with estimations of Campylobacter-based induction of GBS-cases ranging between 5% and 42% [116117]. More than this, C. jejuni-associated GBS-cases were reported to be characterized by particular severity [3] and sometimes irreversible courses [118], represented by predominantly axonal degeneration in the more severe cases [119, 120]. In contrast to GBS associated with respiratory infections, the clinical onset has been reported to be slightly delayed [121]. Usually, GBS onset is reported one to three weeks after the diagnosis of C. jejuni infections [122].

Campylobacter-associated sialylated LOS comprises ganglioside-like epitopes which have been shown to induce anti-ganglioside auto-antibodies directed against peripheral nerves [120, 123–126]. GBS-associated anti-ganglioside antibodies of the IgG1 and IgG3 type indicate involvement of T-cell reactivity in the disruption of the blood-nerve-barrier [127]. In addition, it has been suggested that bacterial toxins might contribute to maintaining the host's inflammatory response occurring in GBS [128] and that C. jejuni infection can influence innate and adaptive pro-inflammatory pathways which contribute to overcoming immune tolerance, thus supporting autoimmunity [127]. Further, several host factors including the human leukocyte antigen type are believed to play important roles as interfering factors [129]. In a strain-dependent manner and affected by peculiarities of the human host's immune system, different types of auto-antibodies can occur, triggering either demyelinating GBS, also called acute inflammatory demyelinating polyneuropathy, or axonal GBS, also called acute motor axonal neuropathy [126]. The strain-dependence affects the probability of infection-associated GBS as well. While 1 out of 1058 Campylobacter infections were previously shown to trigger GBS in general, even 1 out of 158 Campylobacter Penner:Lior serotype HS:19 (heat-stable) infections had the same outcome [118]. Penner:Lior type HS:19, which is usually a relatively rare C. jejuni serovar, has initially been found to be overrepresented in Japanese patients with GBS [122]. Of note, a recent meta-analysis came to a similarly low general probability of GBS triggering after Campylobacter infection as described by Allos [118] in the 0.07% range [130]. Nevertheless, this baseline risk of GBS after Campylobacter infection is still about 70-fold to 100-fold higher than the GBS risk in the general population [127].

One of the best-studied molecular mechanisms of C. jejuni-strain-specific differences regarding the probability of GBS triggering is a polymorphism in the sialyltransferase (cstII) gene. This enzyme is a key factor in the synthesis of GBS-associated ganglioside-like lipo-oligosaccharides (LOSs) [131]. If the 51st amino acid, which determines the enzymatic activity of the 291 amino acid-long peptide, is threonine (Thr), so-called GM-1-like and GD1a-like LOSs are synthesized, triggering auto-antibodies associated with limb weakness. If the 51st amino acid is asparagine (Asn), GT1a-like and GD1c-like LOSs are expressed and respectively triggered auto-antibodies have been associated with ophthalmoplegia and ataxia [131].

Of note, Campylobacter-induced GBS can also be accompanied by other autoimmunity-induced medical conditions. For example, concomitantly occurring GBS and focal segmental glomerulosclerosis have been recently reported associated with a Campylobacter infection [132].

Experience from Africa

Studies on associations of Campylobacter infections and GBS on the African continent are scarcely available. International comparisons, which are still based on limited case numbers, at least suggest an internationally stabile association between GBS and preceding infections. However, there are regional differences in resulting clinical phenotypes, calling for further research on a larger scale [133]. The general occurrence of Campylobacter spp.-associated GBS in sub-Saharan Africa is accepted, but reliable data on the local quantitative relevance of this medical condition are widely lacking [5].

From South Africa, increased proportions of GBS in both children and adults were reported in association with a C. jejuni biotype 2 Penner-Lior serotpye HS:41 clone and highly similar isolates in the middle of 1990s, a serotype which is regionally relatively rare [134, 135]. Clinical GBS associated with these HS:41 isolates was reported as severe, the patients required prolonged hospitalization and automated ventilation [134, 135]. Sequence data from the South African GBS-associated HS:41 isolates have been provided [136] and the C. jejuni integrated element 1 (CJIE1, a Campylobacter Mu-like prophage) was described as a genomic element of regional importance [137]. Even in clonally related HS:41 isolates, minor expression differences in the ganglioside-like lipo-oligosaccharides GM1 levels were observed [138]. In a more recent South African study on GBS, Campylobacter spp. were identified in about 12% of GBS patients with about 3 out of 4 cases carrying C. jejuni, while the other campylobacteriosis cases were due to C. coli or C. jejuni/C. coli co-infections [139].

In the north of the African continent, a recent Egyptian assessment focused on regional differences of Campylobacter infection-associated GBS compared to previous western studies. The authors reported a comparably younger age of Egyptian GBS cases after Campylobacter spp. infection and history of infection with a broader spectrum of Campylobacter serotypes, while Campylobacter spp.-induced anti-ganglioside auto-antibodies were broadly abundant [140]. This finding matches the results of an international assessment which was not able to identify globally applicable epidemiological markers for GBS-associated C. jejuni isolates in HS:19 strains and others [141, 142].

Studies on the association of Campylobacter infections and GBS from the middle of the African continent are widely lacking, although it is unlikely that GBS is an irrelevant medical condition in these regions. In resource-limited Ethiopia, health-related costs of an average GBS case were calculated to be 30 times higher compared to an average diarrhea case and GBS was estimated to account for 0.2% of the total national health-related costs of the country [143]. However, detection of associations between GBS and Campylobacter spp.-infections is only feasible if adequate diagnostic approaches for the identification of such infections are in place [121, 144]. This is frequently not the case in resource-limited tropical settings of sub-Saharan Africa, calling for future multinational cooperative epidemiological research approaches.

The role of C. fetus in African countries

Compared to other Campylobacter species, such as C. jejuni, C. coli and C. lari, C. fetus has received less attention from the scientific community. Nevertheless, there are quite a few publications pertaining the epidemiology and laboratory detection of this pathogen. The geography of these research efforts includes various countries of sub-Saharan and North Africa, where the health of cattle and other herd animals is essential for the well-being of local communities [145].

C. fetus comprises three subspecies: C. fetus subspecies fetus (CFF), C. fetus subspecies veneralis (CFV) - both associated with mammals - and C. fetus subspecies testudinum (CFT), which is associated with reptiles. Although CFV is mostly a bovine pathogen causing a venereal disease known as bovine genital campylobacteriosis (BGC) in cattle, there have been a few cases where it was isolated from humans, such as women with bacterial vaginosis [146]. CFV establishes a chronic infection in bulls where it is found in the penile epithelium, prepuce and urethra, without causing any obvious signs of infection [147]. A recent isolation of CFV from a fecal sample of a Rhesus monkey at a research center in the United States could suggest interspecies transmission potentially also affecting human individuals and the fact that this pathogen could be transmitted via the fecal-oral route [148]. Previously, two cases of CFF causing systemic disease and death due to liver damage of iatrogenic causes were described in immunocompromised Rhesus monkeys at another research center in the United States [149]. The human-to-animal transmission hypothesis of CFV was suggested earlier by another research group showing that CFV could have been present in humans as a pathogen in the early livestock domestication era. By jumping between species, CFV evolved solely as a venereal pathogen in cattle. In any case, many questions still remain unanswered regarding its transmission and etiological relevance [150]. Serious negative economic impact is caused each year globally for the profitability of the cattle industry due to CFV and other infectious agents causing pregnancy losses in cattle [147].

In contrast to CFV, CFF in humans is associated with extra-intestinal, systemic infections with a mortality rate up to 14% [151]. In animals, the transmission of CFF follows the fecal-oral route and, once an animal ingests the pathogen with food or water, the microorganism invades the mucosa resulting in transient bacteremia and abortion [152]. Evidently, CFF has a close affinity to blood, as in humans it often causes bloodstream-associated infections and is characterized with a hematogenous spread causing a wide range of conditions from dialysis-associated peritonitis to endocarditis and pneumonia [151]. In humans with chronic underlying illnesses, CFT has been associated with gastro-intestinal and extra-intestinal disease, including bloodstream infections. Generally, the symptoms of CFT infection may include fever, cough, epigastric pain, diarrhea and fatigue [153, 154]. The major distinction between the three subspecies of C. fetus is that CFF and CFV affect mammals, while CFT is associated with reptiles. In fact, both CFT and CFF have been associated with cases of human C. fetus ssp. infections acquired from squamates [154]. Like other Campylobacter spp., CFF can be found in both birds and reptiles [152]. In domestic animals such as cattle and sheep, CFF infrequently causes abortions, which results in prolonged calving season [148, 151]. Besides cattle, CFF has been reported as a commensal in other animals, such as monkeys and horses, having been isolated from feces of these animals. Escher and coworkers also noted in their 2016 study the identical genotypic and phenotypic characteristics between human and bovine strains of CFF. For example, 5 human strains from two host-specific clusters in this study were identical to bovine isolates suggesting the existence of a definitive link between the two hosts [151].

Research regarding C. fetus in Africa is scarce. In 1981, persistent infections with “C. fetus subspecies jejuni” in African children in the South African city Johannesburg were described. Whereas some of the infected children developed symptoms, others did not [155]. The actual microbial species classification “C. fetus subspecies jejuni” does not exist in the modern classification. As the bacterial isolates originated from fecal samples, the authors may have meant C. jejuni. Madoroba et al. identified that 1.9% of tested samples originating from South African cattle were positive for CFV [156]. Previously, Schmidt et al. described campylobacteriosis in South Africa as a significant infectious cause of reproductive disorders among cattle leading to poor calving [157].

C. jejuni and C. fetus were the most frequently identified Campylobacter spp. in a study conducted in Ethiopia in 2021 examining 519 samples originating from humans, livestock, chickens and water. C. fetus predominated in cattle and sheep feces, while C. jejuni predominated in human feces originating from Africa [158].

Various Campylobacter species were the object of 75 research studies originating in Africa between 1994 and 2019. South Africa, Tanzania and Nigeria were the countries where the majority of the studies took place [40]. Naturally, C. jejuni and C. coli were the most commonly researched Campylobacter species. However, in Nigeria — a key West African country — significant research on C. fetus has also been carried out. The majority of these studies (25 in total) from the region report a high prevalence of C. fetus in cattle, sheep, goats, donkeys, and other farm animals. This prevalence is linked to reproductive issues within these animal populations [40]. In Tanzania and the entire region of East Africa, CFV was reported as the cause of enzootic infertility among cattle in smallholder farms. In contrast, South Africa, a representative country of the region of Southern Africa, did not identify C. fetus as a major problem affecting local farms [40]. Many countries from sub-saharan Africa are considerably less developed compared to South Africa, with far less allocations into research financing. For example, some reports of C. fetus originating from these countries were not accompanied by antimicrobial testing [40].

From a clinical point of view, differentiation between the three C. fetus subspecies is essential, although extremely difficult, as more than 90% of the two species' genomes are identical [159]. Sequencing of the 16S rRNA gene is ineffective in distinguishing the three species. Consequently, genotyping, amplified fragment length polymorphism (AFLP) analysis, and specific PCR analyses have been preferred. With the implementation of Next Generation Sequencing (NGS), the task of subspecies identification of C. fetus isolates will probably become less challenging. Furthermore, MALDI TOF MS based proteotyping allows the discrimination of CFT from CFF and CFV, but differentiation between CFF and CFV was shown to be impossible due to the lack of specific biomarkers [160]. A method for direct detection of the three C. fetus subspecies from clinical samples with high sensitivity and specificity but without discrimination between them is based on fluorescent in situ hybridization (FISH) using a combination of two DNA probes [161].

Of note, only few African clinical laboratories are equipped with the latest and expensive technology. Fortunately, 1% glycine tolerance testing is a low cost, phenotypic test to differentiate two subspecies of C. fetus. CFF is tolerant to glycine, while CFV is not, with occasional exceptions [162]. For the species and subspecies identification of C. fetus isolates, one cost effective way is coupling biochemical methods with PCR and/or genotyping. This combined approach may be successfully used in diagnostic laboratories even in low-income countries.

Immunohistochemistry (IHC) and other antibody-based assays can also be used for fairly accurate identification of CFV. For example, Campero et al. correctly identified 13 CFV cases among other Campylobacter spp. infections present in formalin-fixed tissues applying this technique. Thus, the C. fetus IHC procedure using formalin fixed tissues can be used as a practical tool for the detection of C. fetus-associated with ovine and bovine abortions [147163]. Apparently, C. jejuni may also cause genital infections in cattle and sheep as evidenced by Li and colleagues, thus making the application of species-level differentiation techniques necessary for the correct identification of the infectious agent [164]. IHC procedures are associated with low costs and have thus been used for the identification of C. fetus and other Campylobacter spp. in African countries [40].

Summarized, infections with Campylobacter spp., including C. fetus, in animals and especially in cattle and poultry, are common in sub-Saharan Africa. Main reasons of high prevalence rates comprise poor hygiene when handling animals, as well as unregulated open markets and animal killing practices. The public health burden of C. fetus needs to be seriously evaluated. Due to the difficulties in isolation and identification of this bacterium, its prevalence may be relevantly underestimated. However, worldwide, the number of patients at risk of systemic infections due to such pathogens is on the rise. Evidence suggests that C. fetus has a propensity of being associated with human cases having underlying conditions, such as immunodeficiency. Many African countries affected by the HIV epidemic could benefit from technological and diagnostic improvements facilitating the reliable identification of systemic infections potentially caused by C. fetus [165].

Etiological relevance of diagnostic Campylobacter spp. detection for human disease in the sub-Saharan African tropics

Facultative pathogenicity of Campylobacter spp. and its epidemiological background in sub-Saharan Africa

The term “facultative pathogenicity” describes a microorganism's ability of causing either etiologically relevant infection or harmless colonization in response to host-specific factors. Insofar, this paradigm is in partial contradiction to the third historic Henle-Koch-postulate which suggests that pure cultures of an infectious agent should be sufficient conditions for the experimental induction of an associated infectious disease [166]. Nowadays, the fulfillment of this condition would be called “obligate pathogenicity” and is quite rarely the case in infectious disease medicine.

Although large-sized studies like MAL-ED [167] have proven increased risk of diarrhea in sub-Saharan children <2 years of age in case of diagnostic detection of Campylobacter spp., considerable proportions of children with Campylobacter spp. proven in their stool samples were in the asymptomatic control group. Insofar, Campylobacter spp. is no exemption from the rule of predominance of facultative pathogenicity. In smaller, regional studies in Africa with a broader age spectrum of study participants like in a 40-year-old assessment from the Central African Republic [168], a recent work from Ghana [169] as well as works form other African countries like Cameroon [170] and Northern African Tunisia [171], even significance for a minor increased risk of diarrhea can get lost in comparison of individuals with and without Campylobacter spp. detectable in stool. Obviously, this is not solely associated with more or less virulent species within the Campylobacter genus, because comparable findings were observed with C. jejuni-specific diagnostic assays in stool samples of Ghanaian children as well [172]. Even more than this, high proportions of asymptomatic Madagascan children showed colonization with C. jejuni in a previous assessment [173]. Admittedly, the above-mentioned findings were reported as results of cross-sectional assessments, while longitudinal studies on potential long-term persistence of Campylobacter spp. in stool samples of sub-Saharan African populations are lacking so far. Nonetheless, a colonization rate exceeding 20% in Madagascan infants, as recently reported, is indicative of a carrier state rather than the shedding of residual DNA following the successful clearance of a C. jejuni infection [173].

In spite of uncertain etiological relevance of Campylobacter spp. detection in human stool samples in sub-Saharan Africa due to asymptomatic colonization and carriage, its relevance as a causative agent of diarrhea, in particular in African children, is widely accepted [5, 174, 175]. This focus on very young infants is different in comparison to resource-rich industrialized settings, where Campylobacter spp.’s relevance as major causes of bacterial diarrhea remains more stable over the different age groups [176] associated with a low infection pressure. Interestingly, urban African infant populations have been associated with a later Campylobacter spp. infection peak compared to rural populations [177], potentially suggesting a higher transmission rate in the rural setting. Antimicrobial therapy in sub-Saharan Africa is challenged by partly high resistance levels [178, 179], e.g., up to 70% resistance against the macrolide azithromycin in Southern Africa [178].

Immune responses and microbiome effects as likely reasons for the highly variable clinical impact of Campylobacter spp. in sub-Saharan Africa

Various reasons are considered to influence the high variance of medical conditions following Campylobacter spp. transmission to human individuals in sub-Saharan Africa. Adaptive immune responses to high infection pressure are among those reasons. As early as in the late 1980s, a study in the Central African Republic on the association of Campylobacter spp. with diarrhea had shown that highest infection rates were observed between the first and third month of life and dropped significantly even as early as in the interval between the fourth and sixth month of life of the infants. The early switch from infections to carrier states was explained by frequent and early (re-)exposition in the tropical high endemicity setting [180]. This very early data matches with more recent observations on infectious diarrhea in infants on Zanzibar, suggesting a rapid circle of pathogen clearance and re-infection [181], leading to habituation and decreased disease severity resulting in some sort of “semi-immunity”. In contrast, previous attempts have failed to produce a robust and long-lasting vaccine-induced immune-protection in humans, as infection-induced protection early wanes without repeated exposure to different Campylobacter spp. strains [182, 183]. The latter finding is, unfortunately, quite discouraging for early implementation steps of infection prevention and control enforcement in resource-limited tropical settings, because the waning of semi-immunity might be associated with more severe symptoms in case of re-infections due to beginning but yet insufficient infection control procedures and a resulting decreased frequency of re-exposition. This leads to the seemingly paradox situation that “a little bit” infection control might lead to worse results than both adequate infection control and no implementation of infection control at all.

The precise nature of semi-immunity induced by rapid infection cycles is complex and yet poorly understood. The induction of humoral immunity is driven by both Campylobacter spp. infection and carriage as early shown in the Central African Republic [184]. Later reports pointed towards a likely protective effect of gamma-type interferon [182], while multi-functional cytokine responses of CD4+-type T cells triggered by campylobacteriosis were not found [185]. Epidemiological data provide further hints on the influence of an individuum's immunological state on the clinical impact of campylobacteriosis in Africa. Breastfeeding has been linked to a reduced risk of clinically apparent campylobacteriosis in infants younger than six months, even in areas where the disease is highly prevalent. This suggests that immunologically active components in breast milk, such as IgA antibodies, likely play a role in mitigating the disease [186]. In turn, malnourishment in African children and the associated immunocompromising effects were described to facilitate enteric campylobacteriosis [187].

Next to adaptive immune responses, microbiome effects have to be considered. While campylobacteriosis is known to relevantly affect the composition of the microbial flora in the human gut [104], there are also hints that specific compositions of the enteric flora show protective effects by reducing the likeliness of colonization or infection with Campylobacter spp. [61, 82, 94, 188, 189]. More than this, sub-Saharan African epidemiological assessments have suggested that the co-abundance of other enteric pathogens may affect the clinical courses of infection [190, 191] by the induction of immune responses and/or by specifical shaping of the enteric microbiome environment. The interplay of those factors is still poorly understood and a topic of ongoing research.

The interpretative dilemma regarding diagnostic results – when is a Campylobacter spp.-detection disease-associated in sub-Saharan Africa?

The uncertainty on the attribution of etiological relevance of Campylobacter spp. detections in human stool samples in high-endemicity settings as detailed above is a challenge for the interpretation of diagnostic results in sub-Saharan Africa. Therefore, it would be desirable to identify diagnostic strategies to overcome this challenge. As semi-quantification of pathogens in stool samples can be standardized with a realistic effort in times of real-time PCR-based diagnostics, quantitative pathogen abundance as reciprocally correlated with Ct-values in real-time PCR was early assessed for this purpose. Robust associations of the quantitative Shigella spp. burden in infant stool samples from sub-Saharan Africa and East Asia with the severity of enteritis as shown by the group of Lindsay and colleagues in 2013 made this hypothesis appear promising [192]. Subsequent attempts of transferring these findings to other bacterial causative agents of diarrhea were, however, less convincing. While reciprocal association of cycle threshold (Ct) values in real-time PCR for diarrhea-associated pathogens with clinical diarrhea could be confirmed for Shigella spp./EIEC (enteroinvasive Escherichia coli) and additionally shown for rotavirus and astrovirus in Tanzanian infants, the authors of the respective study failed to show such an association for Campylobacter spp. [193]. Partly contradictory results for C. jejuni- and C. coli-specific real-time PCR were shown by Liu and colleagues, who reported evidence for etiological relevance in case of Ct-value ranges from 20 to 25 and from 25 to 30, indicative of intermediate pathogen loads, but neither for Ct-values >30, indicative of a low pathogen load, nor for Ct-values <20, indicative for a high pathogen load [194]. More than this, low Ct-values of 20 for C. jejuni and of 17 for Shigella spp./EIEC as reported for stool samples from clinically inapparent Madagascan children [173] do not necessarily indicate clinical disease and so, results obtained with study protocols which automatically attribute clinical relevance based on quantitative abundance of enteric pathogens in high endemicity settings [195] should be interpreted with care.

If, however, sole quantity is not the whole story, the question arises which auxiliary parameters could be included in the diagnostic interpretation with realistic effort. As neither specific immunological profiles indicative of clinically apparent campylobacteriosis nor both specific and easy-to-obtain microbiome and/or co-infection profiles are available, the achievement of a high pre-test probability by considering clinical parameters prior to diagnostic testing seems most promising. In case of clinically apparent infection, Campylobacter spp. have been associated with invasive courses of enteritis with either visible blood [5] or increased numbers of red and white blood cells [196] in stool samples in Sub-Saharan African assessments. Also, dehydration of African children with enteric campylobacteriosis is common [186]. While specificity and predictive value of such clinical signs are admittedly still low, their lacking abundance might, however, provide more confidence to clinicians when denying likely etiological relevance of molecular Campylobacter spp. detections in stool samples due to insufficient matching with clinical findings.

Conclusions

The number of studies on Campylobacter spp. in Africa, both in the field of human medicine and veterinary medicine, is still limited to date. Such studies should be conducted more frequently in the near future, as they provide a basis for, e.g., drinking water and food hygiene procedure as well as other preventive medical approaches. This is particularly important due to the relatively high mortality rate of gastrointestinal infections in newborns and young children in Africa. Due to the different microbiome composition within the human intestine in African individuals living in rural areas compared to inhabitants of industrialized regions and due to the considerably higher Campylobacter spp.-colonization rate without patho-etiological significance, the diagnosis of campylobacteriosis remains a challenge, with culture-based methods, but also with highly sensitive molecular biological techniques. This challenge needs to be addressed in medical microbiology laboratories in African countries, calling for ongoing implementation research.

Funding

This research was funded by the Deutsche Forschungsgemeinschaft, grant number ZA 697/6-1.

Author Contributions

Conceptualization, A.E.Z.; methodology, E.K.P., W.O.M., A.D., L.U., S.I.S., H.F., A.E.Z.; software, E.K.P.; validation, A.E.Z., and H.F.; formal analysis, A.E.Z.; investigation, E.K.P., and W.O.M.; resources, A.E.Z.; data curation, E.K.P., W.O.M., A.D., L.U., S.I.S., H.F., A.E.Z.; software, E.K.P.; writing—original draft preparation, E.K.P., W.O.M., A.D., L.U., S.I.S., H.F., A.E.Z.; software, E.K.P.; writing—review and editing, E.K.P., W.O.M., A.D., L.U., S.I.S., H.F., A.E.Z.; software, E.K.P.; visualization, E.K.P.; supervision, A.E.Z.; project administration, A.E.Z., S.I.S.; funding acquisition, A.E.Z. All authors have read and agreed to the published version of the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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