Amoebiasis

The infection is caused by an intestinal protozoan, Entamoeba hystolitica, which occurs in nature in two forms:

• The cyst, a dormant form that allows the amoeba to survive in extreme conditions (such as those of extreme stomach acidity) and in which it infects the host organism;
• The trophozoite, the active form in which the amoeba, having arrived in the intestine, resumes vital functions such as feeding and movement and in which it can cause disease.

It has long been estimated that about 10% of the world's population was infected with Entamoeba hystolitica, but in fact almost all cases (90%) are due to other less dangerous species. In fact, we are aware of four morphologically identical Entamoeba species:

• E. histolytica (pathogenic)
• E. dispar (harmless colonizer, very common)
• E. moshkovskii (less common, pathogenicity uncertain)
• E. bangladeshi (less common, pathogenicity uncertain)

E. hystolitica can coexist with the host, receiving the nutrients necessary for its survival without causing harm (commensalism), or it can invade tissues causing intestinal or extra-intestinal infections and, thus, disease. Asymptomatic infections are the most common, but they can give rise to health problems under special circumstances, such as in the presence of other diseases or states of immunodepression.E. histolytica infection is multifactorial and depends on the interaction between the amoeba, the host, and the microbiota or pathogenic microorganisms. Much information has been obtained on the virulence factors, metabolism and pathogenicity mechanisms of this parasite. However, less is known about its relationship with the host during different stages of the disease.

Transmission occurs in most cases by ingestion of water or food on which mature cysts are present, but sexual transmission is also possible following oral-anal and oral-genital contact.
House flies can be vectors, capable of carrying cysts by storing them even in their intestines.

Amebiasis is widespread across the planet, with 35-50 million people infected with E. hystolitica, and causes between 40 and 100,000 deaths each year, making it the fourth leading cause of death caused by protozoan infection. However, the distribution of cases is not uniform: the prevalence varies widely among different regions of the planet, from only 1-2% in temperate climates to 50% in many countries in hot and humid regions, with higher numbers in nonindustrialized countries, where the spread is linked to access to water sources and the level of sanitation and where it is a major problem, particularly in children. As travel and migration to developed countries from endemic areas increases, the incidence and prevalence of amebiasis continues to rise. Because most patients are asymptomatic, diagnosis and treatment can be difficult for clinicians, potentially leading to the continued spread of the disease. Africa is the region of the world most affected by this infection, but it is a problem that remains unexplored, and the epidemiology of amebiasis remains highly uncertain in this part of the world. In Central and Latin American countries, the parasite shows endemic behavior mainly in Mexico, Brazil, and Ecuador. In Mexico, for example, the incidence rate of intestinal amebiasis from 1995 to 2000 was between 1,000 and 5,000 cases/100,000 population/year. The risk of amebiasis in Asian countries ( Japan, Taiwan, and South Korea ) has also increased in the last decade, particularly among men who have sex with men, probably due to oral-anal sexual contact.As for Europe, most cases are imported and affect travelers and immigrants from endemic areas. Mention should be made of the case of Spain, where this disease was often present in the last century but was virtually eradicated after improvements in sewage and drinking water infrastructure.

Normally, the host keeps the parasite under control by living in the intestinal lumen and feeding on bacteria, scattered host cells and residual food. However due to unknown signals, E. histolytica can lead to symptomatic infection called intestinal amebiasis (IA) with varying degrees of severity. In the course of infection, the parasite penetrates intestinal tissues and feeds on red blood cells and apoptotic and necrotic cells, causing symptoms ranging from abdominal pain and ulcerative colitis with mucus and blood (called amoebic dysentery) to appendicitis and ameboma (annular lesions of the cecum and ascending colon. It is possible in rare cases that the spread of amoeba is not limited to the intestine, causing diseases such as amoebic liver abscess (or ALA), pneumonia, purulent pericarditis, and even cerebral amebiasis, in which the infection affects the brain. Interestingly, AI has been compared on a cellular and molecular level with colon cancer metastasis, as both cancer cells and amoebas follow the same pathway to the liver and other organs and establish invasive microecosystems involving similar types of host cells and molecules.

Correct diagnosis of AI is essential to control the spread of amebiasis, however challenging it is because it is based on clinical symptoms and laboratory tests that lack high sensitivity and specificity. In developing countries, research has traditionally been based on the identification of mature cysts in stool samples. Although this is considered the gold standard test in the diagnosis of AI, microscopic observation has critical drawbacks, including poor sensitivity (about 60 percent) and the inability to distinguish pathogenic amoeba from non-pathogenic species. In addition, it can be difficult to differentiate these four amoeba species from others in the human colon and, even more so, from certain types of white blood cells. Several variables, such as storage condition, time taken for sample processing, fixed or nonfixed samples, and parasite density, influence the result of microscopic observation. ELISAs based on the capture of amoebic antigens in feces have been more successful. They have even enabled the development of commercial kits that can even differentiate E. histolytica from E. dispar. These diagnostic kits allow the generation of reliable results very quickly by following simple instructions, but they are expensive because of the use of monoclonal Abs (mAbs) for antigen capture and therefore are not routinely used in clinical laboratories.

Once the disease is diagnosed, a well-defined treatment plan must be followed. Numerous compounds have been used to treat AI, some of which have been removed from the market because of their toxicity. The antiamoebics exert their action at two different levels:

• at the luminal level they act only on the intestinal lumen and are used to treat nondysenteric amoebic colitis (e.g., diiodohydroxyquinoline, paromomycin and diloxanide)
• systemically they are absorbed into the blood and act in the tissues (such as nitroimidazoles) and are most useful in symptomatic cases.

Treatment of symptomatic amebiasis normally relies on metronidazole because it is effective and commercially available at low cost. This drug belongs to the group of nitroimidazoles, which are effective against various parasitic protozoa both in the intestine and tissue. These treatments are indicated in patients with symptomatic intestinal amebiasis and asymptomatic cyst carriers, but because of their rapid intestinal absorption, they are most effective against ALA. Nitazoxanide, a nitrothiazolyl-salicylamide derivative, is a broad-spectrum antimicrobial agent with activity against protozoa, nematodes, cestodes, trematodes, and anaerobic bacteria. Treatment of AI with nitazoxanide is more effective than metronidazole (70-90% cure rate). Although the mechanism of action is similar to that of metronidazole, the effectiveness of this drug may be due to the differences between the two molecules. Nitazoxanide interacts with and inhibits the enzyme pyruvate oxidoreductase, the same enzyme that reduces metronidazole and activates it, and the products of nitazoxanide activation do not induce DNA mutations as has been observed with those of metronidazole.

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Amebiasis could be easily avoided by adopting basic hygiene habits and having access to toilets and tap water. Only people who live in or travel to endemic areas are at risk. Although much effort has been devoted to the development of a vaccine against E. histolytica, there is still insufficient evidence to support effective and long-lasting protection against amoeba infection. Responses in animal models suggest that it may be possible to develop a viable human vaccine, advancing to go beyond the preclinical stage. Unfortunately, however, induction of long-term memory has not yet been demonstrated in animal models, a hallmark of a successful vaccine. The fact that some people are able to develop partial immunity against intestinal infection while remaining asymptomatic indicates that the potential for developing an effective vaccine is promising.