Parasitic diseases
Parasitic protozoans and helminths cause tissue damage through migration, feeding, and reproduction inside the host. They release enzymes that disrupt the GIT mucosa and immune responses. Chronic parasitemia triggers inflammation, fibrosis, and oxidative stress, leading to tissue damage. Organ dysfunction may persist even after parasite clearance, causing long-term complications such as lymphadenopathy and lipo-lymphedema, with significant morbidity (20).
Entamoeba histolytica (E. histolytica): Global estimates suggest that around 500 million people are infected with E. histolytica, with about 10% developing invasive forms of amebiasis, highlighting its significant public health impact (21). Pathogenesis involves adhesion, cytolysis, and immune evasion through lectin, amebapores, and cysteine proteases. Molecules like lipophosphopeptidoglycan, peroxiredoxin, and arginase enhance invasiveness. Virulent strains overexpress oxidative stress genes, aiding survival and suggesting therapeutic targets (22). Noninvasive intestinal amebiasis infections are often asymptomatic, with cysts passing in the stool. Invasive intestinal amebiasis occurs when trophozoites breach the intestinal lining, leading to symptoms like acute diarrhea, bloody stools, and abdominal tenderness (23). Severe cases may cause fulminant colitis, perforation, or amebomas, with right lower quadrant pain and bowel obstruction. Amebic colitis typically resolves within a month, but chronic forms may persist with intermittent diarrhea and weight loss. Extraintestinal complications include liver abscesses, cerebral and pleuropulmonary involvement (24). Diagnosis of amebiasis involves stool microscopy, antigen detection, Polymerase Chain Reaction (PCR), and serology. PCR is the gold standard, while Enzyme-Linked Immunosorbent Assay (ELISA) aids in rapid detection. Serology is useful for extraintestinal cases. Imaging supports liver abscess diagnosis. Colonoscopy may reveal flask-shaped ulcers. Combining methods improves accuracy and helps distinguish pathogenic from nonpathogenic Entamoeba species (23). Genetic analysis of E. histolytica isolates from different endemic regions helps link parasite genotypes to infection outcomes, aiding in improved diagnosis and treatment (25). All E. histolytica infections require treatment to prevent transmission and recurrence. Effective management involves a tissue amoebicidal (e.g., metronidazole) followed by a luminal agent (e.g., paromomycin). Combination therapy is superior to monotherapy. Follow-up stool PCR confirms clearance. Prevention includes hygiene, safe food practices, and treating contacts if positive (26). Corticosteroids and antimotility drugs are contraindicated. Follow-up stool testing is advised post-treatment (24).
Giardia lamblia: Giardiasis is the most common enteric protozoal infection worldwide, affecting about 2% of adults and 8% of children in developed nations (27). It exerts its pathogenic effects in the upper small intestine by adhering to the epithelial brush border using its ventral disk, leading to disruption of brush border enzymes, tight junctions, and epithelial barrier function (28). These changes result in malabsorption, increased intestinal permeability, and apoptosis, often mediated by caspase-3 (29). Histopathological findings may include villous atrophy and crypt hyperplasia, particularly in symptomatic cases (27). Giardia consumes host arginine, limiting nitric oxide synthesis and epithelial cell proliferation, which may aid parasite persistence. Although inflammation is often minimal, the functional impact is significant (30). The disease severity and pathology vary depending on parasite strain, host nutrition, and microbiota composition. Giardia alters the gut microbiome, enhancing the virulence of certain commensals and prolonging GI symptoms post-infection. These multifactorial interactions underline Giardia’s ability to cause both acute and chronic intestinal dysfunction (30). Giardiasis causes symptoms like diarrhea, bloating, cramps, malabsorption, and weight loss. If it is left untreated, it can become chronic and leads to growth delay, anemia, and cognitive issues in children. Chronic infection is linked to conditions like IBS, food allergies, and fatigue (31). Though it often does not cause severe diarrhea, it may increase the risk of persistent diarrhea in children. It has been incidentally found in patients with liver and pancreatic diseases, suggesting possible associations with certain cancers (32). Zinc sulfate flotation is a low-cost, effective test for the diagnosis of Giardiasis, especially with serial stool samples. While immunochromatographic tests are sensitive and specific, they are costly and limited to Giardia detection. PCR is useful for epidemiology but may miss light infections in asymptomatic carriers or animals with low parasite levels (33). Tinidazole and nitazoxanide are FDA-approved treatments for giardiasis, both offering high efficacy and good safety profiles. Tinidazole is preferred for its single-dose regimen, while nitazoxanide is available in suspension and causes few side effects. Metronidazole, though not FDA-approved, is also effective and less expensive, but has more side effects and requires multiple doses over several days (34).
Balantidium coli is the largest pathogenic protozoan in humans and the only ciliate known to cause disease. Infection begins with the ingestion of cysts, which excyst in the small intestine. Trophozoites colonize the large intestine and invade the mucosa using enzymes like hyaluronidase and cysteine proteases, forming flask-shaped ulcers similar to those in amebiasis (35). Clinically, balantidiasis often mimics amoebic dysentery, presenting with bloody diarrhea, cramps, nausea, and fever. Severe cases may involve extraintestinal spread to the liver, lungs, or bladder, particularly in immunocompromised individuals. Host immunity, malnutrition, and comorbidities are critical in disease progression and dissemination (34, 36). Balantidiasis is often asymptomatic but can cause dysentery, abdominal pain, and tenesmus, especially in immunocompromised individuals. Severe cases may involve bloody diarrhea, intestinal ulcers, and rare complications like liver abscesses or spinal infections. The parasite can spread to other organs, including the lungs (34). A case report highlighted balantidiasis infection during pregnancy, likely due to immune suppression and contact with animals or raw vegetables (36, 37). For treating intestinal balantidiasis, tetracycline is the preferred option, but it is contraindicated in pregnancy and for children below 8 years. Other investigational drugs include iodoquinol, metronidazole, and nitazoxanide, with variable success from paromomycin and chloroquine (35).
Cryptosporidium spp.: This infection is commonly acquired from contaminated water, particularly in developed regions, where it can persist in water treatment facilities and swimming pools (38). It is the second most frequent cause of diarrheal disease and related mortality in children worldwide, after rotavirus (39). More than a million deaths from gastroenteritis linked to Cryptosporidium spp. have been recorded in the late 20th century and early 21st century (40). In individuals with HIV/AIDS, the infection can become chronic and difficult to treat. In healthy individuals, infection often causes self-limiting diarrhea, which may be accompanied by nausea, vomiting, abdominal pain, and low-grade fever (41). Immunocompromised patients may experience chronic or prolonged diarrhea, with potential extraintestinal spread to the biliary tree and pancreas (42). While stool microscopy is the gold standard for diagnosing Cryptosporidium spp., newer methods like multiplex PCR and antigen-based rapid diagnostic tests (RDTs) offer higher sensitivity and quicker results, with RDTs being particularly useful for rapid, point-of-care testing (43). Nitazoxanide is FDA-approved for treating cryptosporidiosis in immunocompetent individuals but is less effective in HIV patients, transplant recipients, and malnourished children (44). Emerging evidence suggests antiparasitic combinations, such as nitazoxanide with azithromycin and, in some cases, rifaximin, may be effective for treating cryptosporidiosis in transplant recipients. For HIV-infected individuals, restoring immune function with antiretroviral drugs (ARVs) is key to resolving the infection (44, 45).
Plasmodium spp. (Malaria): Despite being preventable and treatable, malaria continues to have a devastating impact on human health. It is endemic in 83 countries, most of which are located in tropical and subtropical regions, causing approximately 263 million infections and 597,000 deaths annually worldwide (46, 47). Species that commonly infect humans include Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, and Plasmodium knowlesi. Among these, P. falciparum and P. vivax are the most important due to their widespread prevalence and clinical significance (48). Malaria causes GIT pathophysiology by sequestration of infected red blood cells (iRBCs) in the GIT, including the stomach, colon, jejunum, and ileum, resulting in epithelial detachment, villous shortening, and increased intestinal permeability. As a result, ruptures and leakage of iRBCs occur, contributing to intestinal bleeding and dysbiosis (49). Moreover, malaria is a well-known risk factor for invasive bacterial diseases, which are predominantly caused by invasive enteropathogens. Among these, non-typhoidal salmonella (NTS) is particularly significant (50). GIT symptoms of malaria include abdominal pain, anorexia, heartburn, nausea, vomiting, diarrhea, and hepatic dysfunction (51–53). Artemisinin-based combination therapies (ACTs) are the main treatment for falciparum malaria, but emerging resistance is a concern, particularly in young children and those in low transmission areas (54). Side effects of antimalarial drugs are generally mild, with some risk of hematologic issues like hemolysis. Severe malaria may require blood transfusion, with guidelines recommending 30 mL/kg for afebrile children and 20 mL/kg for febrile children. Exchange blood transfusion may be considered for severe cases, but there is no strong evidence supporting its use. The high number of affected children and limited treatment options make this a significant public health concern (55).
Trypanosoma cruzi: More than 7 million people around the world, primarily in Latin America, are believed to be infected with Trypanosoma cruzi, the parasite responsible for causing Chagas disease (56). The chronic infection primarily affects the cardiac tissues, esophagus, and colon, leading to severe GI complications. Pathophysiology involves the destruction of enteric nervous system neurons and a reduction in interstitial cells of Cajal, causing megavisceral presentations like abdominal pain, nausea, vomiting, megacolon (severe chronic constipation, abdominal bloating, abdominal pain, fecaloma, risk of volvulus or bowel obstruction) and megaoesophagus (Dysphagia, odynophagia, regurgitation, chest pain, weight loss, aspiration pneumonia), and hepatosplenomegaly. Patients may experience malnutrition and weight loss over time (57, 58). Mixed mechanisms, including parasitic invasion, autoimmune responses, microvascular changes, and autonomic denervation, contribute to damage. Parasites persist in the GIT, especially in chronically infected individuals, with evidence of parasite DNA found in 20-50% of megaesophagus cases. Animal models show the colon and stomach as major reservoirs for the parasite, highlighting ongoing infection in the digestive tract (59). During the acute phase, high parasitemia allows direct detection through microscopy or PCR. In the chronic phase, low parasite levels require indirect methods like serologic tests (IgG detection) and molecular amplification techniques (60). Diagnostic strategies for Trypanosoma cruzi depend on disease stage. During the acute or reactivated phase, direct parasitological tests are preferred. Microscopy methods like fresh drop, thick drop, and buffy coat are low-cost and simple, but may miss low parasitemia and require trained staff. Microhematocrit and Strout techniques offer better sensitivity. Xenodiagnosis, though sensitive, is slow and impractical. Blood culture allows parasite isolation and typing, but is time-consuming and unsuitable for routine or urgent use (61). Treatment includes antiparasitic drugs—benznidazole or nifurtimox—which are most effective during the acute or early phases. However, these drugs often cause side effects such as nausea, vomiting, neuropathies, and central nervous system disturbances, leading to therapy discontinuation in 10–30% of cases. Nifurtimox is better tolerated in children (62).
Schistosoma spp.: The WHO seeks to eliminate schistosomiasis as a public health concern by 2030 (63). Species of the genus Schistosoma are digenetic trematodes responsible for the NTD, schistosomiasis. This parasitic disease ranks second only to malaria in terms of socioeconomic impact. Over 220 million people are currently infected worldwide, with 90% of cases occurring in sub-Saharan Africa (64). Katayama syndrome, an acute phase of schistosomiasis, typically occurs 2–6 weeks post-exposure. It presents with fever, fatigue, myalgia, cough, urticaria, and eosinophilia. Severe cases may involve neurological, cardiac, or pulmonary complications (65, 66). Chronic intestinal schistosomiasis, mainly caused by S. mansoni and S. japonicum, leads to inflammation, granulomas, ulcers, and fibrosis in the colon and rectum (67). Symptoms include abdominal pain, diarrhea, weight loss, and anemia. Polyps and, rarely, intestinal obstruction may occur. Hepatosplenic schistosomiasis causes portal hypertension, splenomegaly, anemia, and fibrosis with preserved liver function, often complicating diagnosis and monitoring (68). However, current morbidity indicators show weak correlation with infection intensity, posing challenges for effective disease surveillance and assessment. Even light-intensity infections contribute to both short-term and long-term schistosomiasis-related disability, affecting health-related quality of life (69). This raises concerns about the current WHO elimination strategy, which primarily targets the reduction of heavy infections, potentially overlooking the broader burden of disease (69, 70). Diagnosis requires high suspicion, especially in endemic-area patients. Despite its low sensitivity, microscopy remains the gold standard for diagnosing schistosomiasis. While several diagnostic approaches have been explored—based on circulating parasite proteins, genetic markers, egg morphology, and paramagnetic properties—none have yet proven robust enough to fully replace microscopy (71). However, protein-based biomarkers such as circulating cathodic antigen (CCA), circulating anodic antigen (CAA), and antibodies are widely used targets for detecting Schistosoma infection. Among these, the point-of-care CCA (POC-CCA) test is recommended by the WHO for surveillance of S. mansoni, offering a practical alternative, particularly in endemic regions (72). Antibody-based diagnostics for schistosomiasis face limitations in specificity and in distinguishing past from current infections. Nanobody technology, derived from the heavy chain of IgG antibodies, offers a promising alternative (73). Schistosomiasis treatment relies heavily on praziquantel, but its short-term effect and inability to prevent reinfection limit its impact. Drug repurposing and combination therapies targeting multiple parasite stages are essential to improve outcomes and reduce resistance. Integrated, multifaceted strategies are needed to effectively combat this NTD (74).
Fasciola spp.: It is estimated that between 2.6 million and 17 million people are infected with Fasciola spp. Globally. It primarily affects the hepatobiliary system, but it also has indirect effects on the GIT (75). The pathogenesis of acute fascioliasis is mainly caused by mechanical damage from the parasite’s tegument causes abrasion, tissue digestion, and damage from its suckers as it moves within the liver (76). The parasites’ suckers cause significant tissue damage, attaching to bile duct walls and puncturing blood vessels for feeding. These actions create hemorrhagic migratory lesions in the liver parenchyma (77). The new infective juveniles manipulate the host’s immune system, preventing a Th1-mediated response and promoting a Th2 immune response, aiding parasite survival (76). After 3 to 4 months, the parasites mature in the bile ducts and begin egg production. Chronic infections may be asymptomatic but can lead to biliary obstruction, abdominal pain, and other complications. Over time, adult parasites cause bile duct damage, leading to chronic inflammation, cholangitis, and cholecystitis (78). The pathological signs include fibrotic lesions, micro-abscesses, and necrotic tracts in the liver, with rare ectopic migration to other tissues like the lungs or brain. Early Fasciola spp. infection presents as white or gray liver nodules, progressing as the parasite invades the bile ducts. Its movement and spiny surface damage the biliary epithelium, causing fibrosis, necrosis, abscesses, and cholangiohepatitis. Severe cases can impair nutrition, lead to cholangiocarcinoma, or result in death (67, 75). Fascioliasis detection is essential for disease control, with direct and indirect methods used for diagnosis. Direct methods, such as fecal egg count, are effective in chronic infections but have limited sensitivity in the early stages. Improved flotation-sedimentation-based techniques like Flukefinder® and Mini-FLOTAC® enhance sensitivity for low egg burdens (79). Indirect methods, including ELISA, detect antibodies or antigens and offer early detection, though they can be costly and prone to false results. Molecular techniques like PCR provide high sensitivity and species-specific identification but require specialized equipment, limiting their field application (80). Triclabendazole is highly effective against both adult and immature flukes, but its overuse has led to resistance in some regions (81). Other drugs like albendazole, rafoxanide, and clorsulon also show varying effectiveness depending on the host species and infection stage.
Clonorchis sinensis and Opisthorchis spp.: Clonorchis sinensis infection causes biliary epithelial irritation, leading to hyperplasia, metaplasia, and mucinous bile production. This results in bile stasis, recurrent cholangiohepatitis, fibrosis, and possible stone formation. Though biliary cirrhosis is rare, chronic infection increases the risk of cholangiocarcinoma due to prolonged epithelial changes and carcinogen exposure (82). Chronic Opisthorchis spp. infection increases the risk of cholangiocarcinoma, recognized as a category I carcinogen. Persistent infection leads to bile duct dilation, fibrosis, metaplasia, and hyperplasia. Carcinogenesis may involve mechanical irritation, parasite metabolites, and carcinogenic nitrosamines, with host cytokine gene polymorphisms further enhancing susceptibility to malignancy (83).
Ascaris lumbricoides: Human ascariasis is a major NTD globally and remains a significant public health concern, particularly in low-resource settings, with 10.73% prevalence rate for studies published between 2018 and 2021 (84). In the GIT, Ascaris lumbricoides causes mechanical damage through its migration. Mature worms can obstruct the small intestine, leading to symptoms like abdominal pain, distention, nausea, and vomiting. Severe cases result in intestinal obstruction, necrosis, intussusception, or volvulus. Migration into the bile or pancreatic ducts can lead to biliary colic, obstructive jaundice, or pancreatitis (85). The most common method for diagnosing ascaris infection is the microscopic identification of eggs in stool samples (86). Although counting adult worms expelled after treatment is considered the “gold standard” for assessing infection intensity, this method is rarely used and typically limited to research studies rather than routine parasite surveillance or mass deworming program monitoring (84). A 2020 Cochrane review found that a single dose of albendazole, mebendazole, or ivermectin is a safe and effective treatment for ascariasis in both children and adults, achieving a 93% cure rate with minimal differences in effectiveness or side effects among the drugs (87).
Trichuris trichiura is a widespread intestinal parasite, commonly co-infecting with Ascaris. It often causes no symptoms, but children are more likely to develop symptoms such as growth delay, anemia, clubbing, colitis, and rectal prolapse (88). Adults with heavy infections may also suffer from inflammatory colitis, bloody diarrhea, and tenesmus. Severe cases are linked to increased tumor necrosis factor (TNF)-α production in the colon, which can cause appetite loss and wasting (89). Diagnosis is typically done through standard stool microscopy due to the high number of eggs shed, which appear barrel-shaped with distinctive plugs at both ends. Worms may also be seen during colonoscopy or in prolapse cases. PCR offers better species identification but with varied sensitivity. Eosinophilia may be present (89). A single dose of albendazole or mebendazole results in a cure rate of 25% to 33%. However, prolonged treatment with albendazole 400 mg for 3 to 7 days or mebendazole 500 mg daily or 100 mg twice a day for 3 to 7 days may be more effective in treating heavy infections with at least 1000 eggs per gram of stool (90).
Hookworm: Human hookworm infections are primarily caused by Necator americanus, A. ceylanicum and Ancylostoma duodenale. A. ceylanicum is a soil-transmitted helminth. A. ceylanicum is the second most common hookworm infecting humans in the Asia-Pacific region and is zoonotic, with dogs as the main reservoir. Unlike human-specific hookworms, it infects both animals and humans. The parasite has a direct life cycle, with infection occurring through ingestion or skin penetration of larvae from the environment. After entering the body, larvae migrate through the bloodstream and trachea before maturing in the small intestine (88, 91). Hookworm infections impose a substantial burden on endemic populations, with an estimated loss of 800,000–4 million disability-adjusted life years (92). Hookworm infections cause chronic intestinal blood loss through the feeding of adult worms, leading to anemia. The parasites disrupt the intestinal epithelium, affecting nutrient and iron absorption. Iron metabolism is altered, reducing iron availability and stimulating erythropoiesis. These effects contribute to anemia, especially in iron-deficient hosts (93). Hookworm-related blood loss occurs through capillary bleeding from feeding larvae and adults, and leakage at their intestinal attachment sites. The severity depends on the species and parasite load. Chronic bleeding, combined with poor iron intake and low iron stores, often leads to anemia, particularly in low-resource areas (94). Hepcidin (HAMP), a liver-derived peptide, plays a central role in this regulation by controlling the hepcidin-ferroportin axis, which is necessary for stabilizing serum iron levels. Factors like inflammation, low oxygen levels, and existing iron concentrations affect HAMP expression (95). During hookworm infection, HAMP is often downregulated, disrupting iron flow and influencing red blood cell production. This leads to increased erythropoietin release, which promotes red blood cell formation to compensate for oxygen loss (96). For uncomplicated cases, a 3-day regimen of mebendazole, with 100 mg taken twice daily 12 hours apart, is effective. Additionally, pyrantel pamoate, dosed at 11 mg/kg (up to a maximum of 1 g) daily for three days, is also effective in treating hookworm infections (97).
Strongyloides stercoralis: is a common parasitic roundworm that infects over 600 million people worldwide, especially in tropical climates. Despite its widespread presence, it remains largely ignored and is classified as a NTD due to insufficient awareness and limited research (98). This intestinal parasite can infect both humans and domestic animals such as cats and dogs, with potential for transmission between species (99). A particularly concerning feature of Strongyloides stercoralis is its capacity for autoinfection, where it reproduces inside the host without needing to exit, potentially leading to a dangerous condition called Strongyloides hyperinfection syndrome (100). This syndrome is especially deadly, with mortality rates surpassing 90 % in severe cases (101). Additionally, the parasite can weaken the host’s immune response, posing a serious risk to those with weakened immune systems, including individuals with HIV, those undergoing immunosuppressive treatment, people with alcoholism, and the malnourished (100). GI symptoms of Strongyloides hyperinfection syndrome range from mild discomfort to severe issues like hematemesis, distension, and shock. Diarrhea is common due to mucosal damage, enteritis, villous atrophy, and ulceration, potentially leading to sepsis. Though rare, liver and biliary complications include jaundice, papillary stenosis, and enzyme elevation, which can mimic graft-versus-host disease (102). Diagnosing this parasite is challenging because the number of larvae in the stool is often low and inconsistent, resulting in up to 70 % of cases being missed through routine fecal exams. Charcoal culture and agar plate culture also enhance sensitivity significantly. To increase diagnostic accuracy, a combination of methods such as duodenal fluid examination and serological testing is often needed (103). However, diagnostic techniques for strongyloidiasis lack standardization across methods (104). For uncomplicated strongyloides infection, ivermectin is preferred as it is effective against both larvae and adult worms. For patients who are not able to tolerate ivermectin, an alternative successful therapy consists of albendazole (400 mg for adults or 15 μg/kg for children twice a day for 3 to 7 days), which targets only the adult worms (105).
Bacterial infection
Vibrio cholerae (V. cholerae) is the causative agent of Cholera, which is an acute, watery diarrheal illness of a short incubation period (0.5–5 days) (106). Vibrio is a curved, rod-shaped, motile, Gram-negative bacterium that inhabits aquatic environments (107). It is classified into over 200 serogroups based on the structure of the O-antigen in its lipopolysaccharide (LPS). Among these, only strains from the O1 (three serotypes Ogawa, Hikojima, and Inaba) and O139 serogroups are capable of causing cholera and epidemics, as they produce cholera toxin (108). After ingestion, V. cholerae withstands the acidic environment of the stomach through an acid tolerance response. In the small intestine, it uses its flagellum to navigate the mucus layer and reach the epithelial cells, while evading host immune defenses and gut microbiota resistance. Successful colonization relies on the expression of key virulence factors, including toxin-coregulated pilus (TCP) and cholera toxin (CTX). Cholera is marked by profuse watery diarrhea and vomiting, which can quickly result in hypovolemic shock, metabolic acidosis, and death. Without treatment, the case-fatality rate may reach up to 50% (109). The infection can be confirmed using reliable and accessible diagnostic methods, such as PCR and RDTs. If not treated promptly, cholera can lead to severe dehydration and death. Management depends on the severity of the condition and may include oral rehydration salts (ORS), intravenous fluids, and antibiotics (108).
Salmonella enterica: Typhoid fever presents as a severe systemic illness characterized by fever and abdominal pain. It is marked by potentially life-threatening fever with a multitude of clinical signs and symptoms. The primary causative agent is a gram-negative bacterium, Salmonella enterica serotype Typhi (formerly S. typhi), although other serotypes, such as Paratyphi A, B, and C, can produce a similar clinical picture. After an incubation period of 6–30 days, the primary symptom of enteric fever is high fever, often accompanied by nausea, abdominal pain, and altered bowel habits (110). Increasing fever begins with secondary bacteremia in established typhoid infection. The gallbladder is colonized via hematogenous or local spread, especially with gallstones or structural pathology. Lymphoid tissue in Peyer’s patches is involved in primary, reinfection, and chronic infection, leading to fecal excretion and transmission. Proliferation of lymphoid tissue can cause constipation, while endotoxin-induced necrosis may lead to intestinal bleeding, perforation, or tertiary bacteremia (111). Blood culture remains the gold standard for diagnosing typhoid fever, though its sensitivity is limited. While bone marrow culture offers higher sensitivity, it is invasive, difficult to perform, and not practical for routine use. The Widal test is a simple, low-cost serological method used to detect antibodies against Salmonella O and H antigens. However, it has low sensitivity, is highly operator dependent, and its accuracy varies by region (112). In response to multidrug resistance (MDR) S. Typhi, fluoroquinolones (ciprofloxacin, ofloxacin, fleroxacin, pefloxacin) became common treatments. However, reports of reduced fluoroquinolone effectiveness emerged in endemic regions and among travelers. In areas with high MDR and fluoroquinolone resistance, azithromycin or ceftriaxone are preferred treatments (113).
Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrheal disease, especially in children under five in endemic regions, contributing to around 100 million cases and 60,000 deaths in 2015. It is also a major cause of traveler’s diarrhea, with about one-third of affected travelers seeking medical care for GI symptoms (114–116). ETEC causes disease by producing heat-labile (LT) and/or heat-stable (ST) enterotoxins. A key step in ETEC infection is its attachment to the intestinal epithelium via colonization factors (CFs). After adherence, the enterotoxins trigger secretion of water and electrolytes into the intestinal lumen, leading to diarrhea (117–119). Diarrhea can lead to rapid dehydration and weakness, resembling cholera. Other symptoms may include vomiting, stomach cramps, headache, and occasionally mild fever (120). Beyond immediate illness, ETEC has been linked to long-term effects such as childhood stunting, weakened immunity, increased susceptibility to other infections, and impaired cognitive development (117). Traveler’s diarrhea caused by ETEC is also associated with post-infectious IBS (115). Management relies on adequate fluid intake, oral rehydration (or intravenous fluids if needed), avoiding sugary drinks, zinc supplementation, and antibiotics in severe cases. Recommended antibiotics include fluoroquinolones, macrolides, or rifaximin.
Leptospira: Leptospirosis, caused by Leptospira, is a worldwide zoonotic disease that is estimated to result in approximately 1 million cases and 60,000 deaths each year (121). Certain occupations, such as farming, ranching, veterinary work, rice farming, and military service, which involve exposure to animals or water, are linked to a higher risk of leptospirosis. In developed countries, travel-related infections and recreational activities have also emerged as significant sources of Leptospira infection. The clinical presentation of leptospirosis is often nonspecific, with symptoms ranging from asymptomatic cases to severe manifestations, including fatal multi-system organ failure (122). The incidence of leptospirosis in tropical regions is up to ten times higher than in other areas. This disparity is likely due to a combination of environmental and socioeconomic factors. Environmental factors, such as higher temperatures, humidity, and rainfall, create conditions that favor the survival of the causative organism. Socioeconomic factors, including poor sanitation and increased human contact with rodents and domestic animals, further contribute to the higher incidence in these regions (122, 123). The incubation period for leptospirosis typically ranges from 7 to 12 days. Leptospirosis typically begins with sudden fever, chills, muscle pain, and a throbbing frontal headache, resembling many other febrile illnesses. A hallmark sign is conjunctival suffusion (redness without discharge). GI symptoms like nausea, vomiting, diarrhea, and anorexia are common, and about half of the patients develop a dry cough. Aseptic meningitis occurs in up to 80% of cases. Less commonly, patients may experience hepatosplenomegaly, lymphadenopathy, or pharyngitis. Fulminant disease in leptospirosis can manifest as Weil’s disease, a severe form of the illness characterized by the triad of jaundice, renal failure, and hemorrhagic manifestations (124, 125). In many cases, clinical suspicion alone may justify the initiation of empiric antibiotic treatment. Definitive diagnosis of leptospirosis can generally be achieved through traditional microbiological methods, such as direct detection or culture, or through serological testing. Serological methods are the most widely used approach for confirming a diagnosis of leptospirosis. Among these, the microscopic agglutination test (MAT) is considered the “gold standard. For mild cases, oral antibiotics (doxycycline, azithromycin, ampicillin, or amoxicillin) are options. While in severe cases, intravenous antibiotics are preferred (126).
Shigella: Shigellosis caused by Shigella species (Shigella flexneri [commonest], Shigella sonnei, Shigella dysenteriae [most severe], and Shigella boydii) infect humans using virulence factors such as Shiga toxin (Stx), which is cytotoxic, neurotoxic, and enterotoxin, and a type III secretion system (T3SS) with effector proteins that cause the severe symptoms of shigellosis (127). The incubation period is 1–4 days, with an infectious dose of as few as 200 living organisms. Key challenges in controlling shigellosis include the high transmissibility of Shigella between individuals and its swift development of antimicrobial resistance (AMR). The most common symptoms of shigellosis include acute diarrhea (which may be watery, mucoid, or bloody), tenesmus, abdominal discomfort, nausea, and vomiting (128). Shigellosis-associated diarrheal diseases account for an estimated 125 million cases annually, leading to approximately 160,000 deaths worldwide (129). Besides travelers’ diarrhea, shigellosis has been associated with complications such as post-infectious IBS in travelers (130) and acalculous cholecystitis (131). Although most patients recover without complications within seven to ten days, serious outcomes can occur, including metabolic disturbances, sepsis, convulsions, rectal prolapse, toxic megacolon, intestinal perforation, and hemolytic-uremic syndrome (HUS) (128). Microscopy of fresh stool is a quick, inexpensive test for invasive bacterial diarrhea, with polymorphonuclear leukocytes (PMNs) suggesting a bacterial cause but not specific to Shigella. Definitive diagnosis requires stool culture and serotyping, as well as antimicrobial sensitivity testing. PCR methods are sensitive but not routine or useful for resistance testing (128, 132). Treatment primarily involves supportive care (hydration and electrolyte management). Antimotility drugs are contraindicated. Antimicrobial therapy is reserved for severe cases or high-risk patients, with fluoroquinolones, azithromycin, or third-generation cephalosporins as options. Increasing AMR, particularly to macrolides, penicillin, and cephalosporins, complicates treatment. In high-risk populations, carbapenems or colistin may be necessary. For pediatric cases, azithromycin is the empiric therapy, with cefixime as alternative (132).
Campylobacter: Campylobacteriosis is caused by Campylobacter which is a gram-negative, spiral-shaped, microaerophilic bacterium frequently linked to foodborne diseases. Over 95% of human infections are caused by C. jejuni and C. coli (133). The infectious dose of Campylobacter is relatively low, requiring only 500–800 bacteria to cause infection. Children below 4 years of age and elderly individuals aged 75 or older are more susceptible to the infection. Infection may lead to long-term complications such as IBS, arthritis, and Guillain–Barré Syndrome (GBS), septic thrombophlebitis, endocarditis, neonatal sepsis, pneumonia, sepsis, acute colitis associated with IBD, colorectal cancer, Barrett’s esophagus, carcinoid syndrome, and acute appendicitis (134–136). The isolation and identification of Campylobacter species depend on culture-based methods that use selective media with antibiotics, such as Skirrow’s medium, mCCDA, and Bolton broth. Antibiotics are not routinely recommended for healthy patients with Campylobacter infections, but may be considered for high-risk groups, such as immunocompromised or elderly individuals, and those with severe symptoms like fever, bloody stools, or significant abdominal pain. Immunocompromised patients may need multiple antibiotic courses. Antibiotics usually are not required; however, it is indicated if there is high fever, excessive bowel movements (>8 stools per day), bloody diarrhea, persistence of symptoms for longer than 1 week, pregnancy, or immunocompromised states. Macrolides (Azithromycin with a typical regimen of 500 mg/d for 3 days) are the preferred treatment due to rising AMR patterns (137).