2. Cellular and tissue protozoans.pdf

# Trypanosomatidae: African sleeping sickness This topic focuses on the parasitic protozoa of the family Trypanosomatidae, specifically the *Trypanosoma brucei* subspecies responsible for causing African sleeping sickness, detailing their life cycle, disease manifestation, diagnostic methods, prevention strategies, and treatment options [3](#page=3). ### 1.1 Introduction to Trypanosomatidae The family Trypanosomatidae comprises pathogenic flagellates that can reside in the blood (hemoflagellates) or tissues of humans. All species within this family necessitate an arthropod intermediate host for their life cycle. These organisms exhibit distinct morphologies depending on their location within both the human host and the arthropod vector [3](#page=3). ### 1.2 Trypanosoma brucei and African Sleeping Sickness The genus *Trypanosoma* includes several subspecies relevant to human health. Specifically, *T. brucei rhodesiense* and *T. b. gambiense* are the causative agents of East and West African sleeping sickness, respectively. These parasites are transmitted by the tsetse fly (*Glossina*), with the organisms being injected into humans during a blood meal taken by an infected fly. The characteristic trypanosome form can be observed in human blood smears or within tissues, particularly in lymph nodes and the central nervous system (CNS) during later stages of the disease [4](#page=4). > **Tip:** The geographical distribution of the subspecies influences the presentation and progression of the disease, with *T. b. gambiense* generally leading to a more chronic infection than *T. b. rhodesiense* [10](#page=10) [4](#page=4). ### 1.3 Morphology of Trypanosomes Trypanosomes present in humans and their vectors have distinct forms: * **Trypomastigote form:** This is a slender form, measuring 15-33µm, characterized by a single large nucleus and a long flagellum that runs along the cell body, connected by an undulating membrane. The kinetoplast and kinetosome are typically located at the posterior end of the cell. This is the diagnostic stage found in peripheral blood, lymph nodes, and CNS fluid [12](#page=12) [5](#page=5) [7](#page=7). * **Epimastigote form:** This form, found in the tsetse fly, possesses a shorter flagellum and undulating membrane. The kinetoplast and kinetosome are located closer to the anterior pole. This form multiplies within the fly's gut [5](#page=5) [7](#page=7). > **Tip:** The kinetoplast is a unique organelle found in kinetoplastids, containing mitochondrial DNA [2](#page=2). ### 1.4 Life Cycle The life cycle of *Trypanosoma brucei* involves two hosts: humans and the tsetse fly [7](#page=7). 1. **Infection of Tsetse Fly:** The tsetse fly ingests trypomastigotes when it takes a blood meal from an infected human [7](#page=7). 2. **Replication in Fly:** Inside the fly's gut, the trypomastigotes transform into epimastigotes, which then multiply [7](#page=7). 3. **Migration to Salivary Glands:** The epimastigotes migrate to the fly's salivary glands, where they develop into the infective trypomastigote stage [7](#page=7). 4. **Infection of Human:** When an infected tsetse fly bites a human, it deposits trypomastigotes from its salivary glands into the skin, initiating the infection [7](#page=7). Additionally, transmission can occur through breastfeeding and transplacental routes [7](#page=7). ### 1.5 Stages and Symptoms of African Sleeping Sickness African sleeping sickness progresses in two distinct stages: #### 1.5.1 Haemolymphatic stage (Stage One) This initial stage occurs 1-3 weeks after the tsetse fly bite and involves non-specific, generalized symptoms. Symptoms include enlarged lymph nodes, fever, headache, and joint and muscle pain [12](#page=12) [9](#page=9). #### 1.5.2 Meningoencephalitic stage (Stage Two) This stage develops after the trypanosomes invade the central nervous system (CNS). The progression to this stage differs between the subspecies [9](#page=9): * *T. b. gambiense* infection typically progresses to stage two after an average of 300-500 days [10](#page=10). * *T. b. rhodesiense* infection progresses more rapidly, with an estimated 21-60 days [10](#page=10). Invasion of the CNS leads to a variety of neuropsychiatric manifestations, often accompanied by a decrease in fever. The hallmark symptom is the reversal of the normal sleep/wake cycle, leading to daytime somnolence and nocturnal insomnia, earning it the name "African sleeping sickness." Other neurological and psychological symptoms include [10](#page=10): * **Mental:** Hallucinations, delirium, anxiety, emotional lability, attention deficit, apathy, aggression, mania, and confusion [10](#page=10). * **Motor:** Motor weakness, abnormal tone, gait disturbance, ataxia, tremor, and speech difficulties [10](#page=10). * **Sensory:** Paresthesia, hyperesthesia, anesthesia, pruritus, and visual problems [10](#page=10). * **Neurologic:** Abnormal reflexes, seizures, and coma [10](#page=10). > **Tip:** The distinction between West African Sleeping Sickness (*T. b. gambiense*) and East African Sleeping Sickness (*T. b. rhodesiense*) is crucial for treatment decisions, particularly regarding which medications are most effective [10](#page=10). ### 1.6 Diagnosis Diagnosis of African sleeping sickness involves the examination of biological samples for the presence of trypanosomes [12](#page=12). * **Blood Smears:** A thick blood smear can increase the likelihood of detecting trypanosomes. The trypanosomal form in plasma is the diagnostic stage [12](#page=12). * **Other Samples:** In later stages of infection, trypanosomes may be found in lymph node aspirates or cerebrospinal fluid (CSF) obtained from the CNS [12](#page=12). ### 1.7 Prevention Preventive measures against African sleeping sickness focus on controlling the vector and treating infected individuals [14](#page=14). * **Vector Control:** This includes the application of insecticides, the use of repellents, and the implementation of mosquito nets to avoid tsetse fly bites [14](#page=14). * **Treatment of Infected Individuals:** Prompt diagnosis and treatment of infected persons interrupt transmission cycles [14](#page=14). * **Chemoprophylaxis:** This may be considered for individuals traveling to endemic areas [14](#page=14). * **Reservoir Host Management:** Wild animals serve as reservoir hosts for the parasite, and their management can play a role in prevention [14](#page=14). ### 1.8 Treatment Treatment strategies for African sleeping sickness are divided based on the stage of the disease and the subspecies involved [15](#page=15) [16](#page=16). #### 1.8.1 Stage One Treatments Two primary antimicrobial medications are used for early-stage infections: pentamidine and suramin [15](#page=15). * **Pentamidine:** Primarily used for stage one West African sleeping sickness, administered via injection or intravenously. It is generally well-tolerated but can cause side effects such as hypoglycemia and gastrointestinal upset [15](#page=15). * **Suramin:** Used to treat East African sleeping sickness and administered intravenously. Side effects are common but usually mild and temporary [15](#page=15). * **Fexinidazole:** A newer drug approved in 2019 for West African sleeping sickness, effective for both stage one and early stage two. It is taken orally as a daily pill for 10 days. It is contraindicated in the first trimester of pregnancy and for children under 6 years old. Common side effects include nausea, vomiting, and headache [15](#page=15). #### 1.8.2 Stage Two Treatments For infections that have progressed to the CNS (stage two), three medications are recommended: eflornithine, melarsoprol, and nifurtimox [16](#page=16). * **Eflornithine:** Treats stage two West African sleeping sickness and is administered intravenously four times daily for two weeks. Its demanding administration schedule in rural settings sometimes leads to its combination with nifurtimox for less frequent dosing [16](#page=16). * **Melarsoprol:** The only available treatment for stage two East African sleeping sickness, though it can also treat West African sleeping sickness. It is administered intravenously with a complex dosing regimen and is known for its toxicity, potentially causing severe neurological issues or death in 5-10% of cases [16](#page=16). * **Nifurtimox:** Typically used for American trypanosomiasis, it is sometimes combined with eflornithine for the treatment of West African sleeping sickness [16](#page=16). > **Example:** A patient diagnosed with stage two East African sleeping sickness would require treatment with melarsoprol due to the lack of alternative options for this specific presentation and stage [16](#page=16). --- # Trypanosoma cruzi: Chagas disease Trypanosoma cruzi is the protozoan parasite responsible for Chagas disease, also known as American trypanosomiasis, a significant public health concern in endemic regions [17](#page=17) [19](#page=19). ### 2.1 Forms of Trypanosoma cruzi *T. cruzi* exists in several forms, with specific stages associated with vector development, human infection, and diagnosis [18](#page=18): * **Promastigote and Epimastigote:** These forms develop within the insect vector and can occasionally be found in humans [18](#page=18). * **Trypomastigote:** This is the extracellular, motile stage observed in the blood and tissues of infected humans, measuring 15-30µm and characterized by a larger kinetoplast compared to *T. brucei*. The trypomastigote form found in the feces of the bug is the infective stage for humans. Occasionally, trypomastigotes can be found in blood smears [18](#page=18) [21](#page=21). * **Amastigote:** These are ovoid or spherical intracellular forms, measuring 1.5-4µm, and are typically found in clusters within macrophages and tissues, particularly the heart muscle, where they multiply. The amastigote form is considered the diagnostic stage [18](#page=18) [19](#page=19) [21](#page=21). > **Tip:** Visualizing these forms is crucial for understanding the parasite's life cycle and for diagnostic purposes. The amastigote form in tissue is a key diagnostic indicator, while the trypomastigote in the bug's feces is the infective stage [21](#page=21). > **Example:** Figure shows neonatal rat cardiomyocytes infected with *T. cruzi* trypomastigotes, where actin myofilaments are labeled green, the trypomastigote is labeled red, and nucleic acids are labeled blue [24](#page=24). ### 2.2 Transmission and Pathology of Chagas disease *T. cruzi* is primarily transmitted by blood-sucking triatomine bugs, commonly known as "kissing bugs". The transmission cycle involves the bug ingesting blood containing the trypomastigote form from an infected host. While feeding, the bug defecates near the bite wound, and the infective trypomastigotes in the feces are inadvertently rubbed into the wound or mucous membranes when the bite is scratched [19](#page=19). Besides vector-borne transmission, *T. cruzi* can also be transmitted vertically from mother to child during pregnancy (transplacentally) or through breastfeeding [21](#page=21). Once inside the human host, *T. cruzi* invades cells, particularly macrophages, where it transforms into the amastigote form and multiplies within the tissues. The parasite preferentially targets muscle cells, including those of the heart, esophagus, and colon. This parasitic invasion and subsequent inflammatory response can lead to significant tissue damage and organ dysfunction, resulting in a debilitating condition [19](#page=19). The chronic phase of Chagas disease can manifest as: * Enlarged heart (cardiomegaly), potentially leading to cardiac muscle destruction and heart failure [19](#page=19) [22](#page=22). * Enlargement of the esophagus (megaesophagus) and colon (megacolon) due to neuronal damage and muscle dilation [19](#page=19) [22](#page=22). * Other symptoms may include fever, edema of the eye and face (Romaña's sign), enlargement of the spleen, liver, and lymph nodes, and general weakness [22](#page=22). * Severe cases can be fatal [19](#page=19). ### 2.3 Diagnosis of Chagas disease Diagnosis of Chagas disease relies on identifying the parasite or detecting the host's immune response to the infection [21](#page=21) [22](#page=22): * **Microscopic Examination:** * **Blood Smear:** Examining blood for the presence of trypanosomes. Thick blood smears are recommended to increase the chances of diagnosis [22](#page=22). * **Tissue Biopsy:** Identifying amastigotes within tissue samples, such as heart muscle biopsies, is a definitive diagnostic method for the chronic phase [21](#page=21). * **Xenodiagnosis:** This involves allowing uninfected laboratory-reared bugs to feed on the patient's blood. The feces of these bugs are then examined for the presence of *T. cruzi* trypomastigotes, indicating a successful infection from the patient's blood [22](#page=22). * **Serological Tests:** Antibody detection methods, such as indirect hemagglutination antibody tests, are commonly used to diagnose chronic Chagas disease by identifying antibodies produced by the patient against the parasite [22](#page=22). ### 2.4 Geographical Distribution Chagas disease is endemic in Mexico, Central America, and South America [22](#page=22). ### 2.5 Prevention and Treatment Preventing Chagas disease involves a multi-pronged approach targeting vectors, infected individuals, and potential transmission routes [27](#page=27): * **Vector Control:** * Application of insecticides to eliminate domestic and peridomestic bug populations. * Use of repellents and insecticide-treated bed nets to reduce vector exposure. * **Treatment of Infected Individuals:** Identifying and treating infected individuals can help reduce the parasite reservoir and prevent transmission. * **Chemoprophylaxis:** This may be considered for individuals traveling to endemic areas, although its widespread implementation is challenging [27](#page=27). * **Reservoir Host Management:** The presence of wild animals as reservoir hosts for *T. cruzi* makes complete eradication of the parasite difficult [27](#page=27). **Chagas disease treatment** is primarily focused on antiparasitic chemotherapy, although treatment options have limitations [28](#page=28): * **Effective Drugs:** Benznidazole and nifurtimox are two drugs known to be effective against *T. cruzi* [28](#page=28). * **Drug Approval and Toxicity:** Benznidazole is approved by the Food and Drug Administration (FDA) in some regions. However, both drugs can cause significant toxicity [28](#page=28). * **Efficacy:** If administered early in the course of the infection, these drugs can be nearly 100 percent effective in treating Chagas disease [28](#page=28). > **Tip:** Early diagnosis and treatment are crucial for maximizing the effectiveness of antiparasitic drugs and preventing the development of severe chronic complications of Chagas disease. --- # Leishmania complex: Leishmaniasis This section details the Leishmania complex, focusing on pathogenic species, their life cycle, diagnostic methods, clinical presentations, and geographical distribution. ### 3.1 Pathogenic species of Leishmania The genus Leishmania comprises three primary pathogenic species that cause leishmaniasis in humans [29](#page=29). * **L. tropica:** Primarily causes cutaneous leishmaniasis [33](#page=33). * **L. braziliensis:** Responsible for mucocutaneous leishmaniasis [33](#page=33). * **L. donovani:** Leads to visceral leishmaniasis [33](#page=33). ### 3.2 Transmission and life cycle All Leishmania species are transmitted by sand flies of the genera *Phlebotomus* and *Lutzomyia*, which act as intermediate hosts. Wild and domestic animals can serve as reservoir hosts and carriers [29](#page=29) [30](#page=30). #### 3.2.1 Morphological forms * **Amastigote:** Ovoid or spherical with a rod-like kinetoplast, typically found in human hosts. These forms reside within macrophages [30](#page=30) [32](#page=32). * **Promastigote:** Slender in shape, possessing a kinetoplast and kinetosome at the anterior end, with a single free flagellum. This form is found in the insect vector [30](#page=30). #### 3.2.2 Life cycle stages 1. An infected sand fly bites a human, regurgitating promastigotes into the wound site [32](#page=32). 2. Promastigotes invade host tissues and transform into amastigotes [32](#page=32). 3. Amastigotes enter and multiply within macrophages [32](#page=32). 4. The diagnostic stage is the amastigote found within macrophages. *L. tropica* and *L. braziliensis* primarily invade skin-lesion macrophages, while *L. donovani* also infects macrophages in the bone marrow, liver, and spleen [32](#page=32). 5. A biting sand fly ingests infected macrophages containing amastigotes [32](#page=32). 6. Within the vector's gut, amastigotes transform into promastigotes [32](#page=32). 7. Promastigotes multiply in the vector's gut and develop into the infective stage [32](#page=32). ### 3.3 Diagnosis Diagnosis of leishmaniasis relies on identifying the amastigote stage, with the location of recovery varying by species [33](#page=33). * **L. tropica:** Recovery of amastigotes in macrophages of skin lesions [33](#page=33). * **L. braziliensis:** Recovery of amastigotes at the periphery of the lesion [33](#page=33). * **L. donovani:** Recovery of amastigotes in early skin lesions, and later in the spleen, lymph nodes, bone marrow, and liver [33](#page=33). > **Tip:** In certain clinical cases, diagnostic material can be collected from ulcers using impression preparations (placing a glass slide on the wet content) or smears of scrapings from the lesion's border. Staining with Giemsa's dye allows for visualization of amastigotes, characterized by a nucleus and a kinetoplast. While morphological features can suggest Leishmania, definitive species identification may require cultivation and DNA analysis [100](#page=100) . ### 3.4 Disease manifestations The clinical presentation of leishmaniasis differs significantly based on the infecting species, leading to distinct disease names [33](#page=33). * **L. tropica:** * **Disease name:** Cutaneous leishmaniasis, oriental sore, Baghdad boil [33](#page=33). * **Manifestation:** An ulcerated lesion on the body, often with pus. Typically self-healing [34](#page=34). * **Geographical distribution:** Mediterranean area, Asia, Africa, and Central America [34](#page=34). * **L. braziliensis:** * **Disease name:** Mucocutaneous leishmaniasis, uta, espundia [33](#page=33). * **Manifestation:** A red, itchy ulcer that is initially self-healing. Chronic mucosal ulceration can lead to disfigurement of the nose and ears years later [34](#page=34). * **Geographical distribution:** Central and South America [34](#page=34). * **L. donovani:** * **Disease name:** Visceral leishmaniasis, kala-azar, Dumdum fever [33](#page=33). * **Manifestation:** An initial ulcer at the bite site, followed by systemic symptoms including malarial-like spiking chills and fever, sweating, diarrhea, dysentery, and enlargement of the spleen and liver (splenomegaly and hepatomegaly). This form can be fatal if left untreated [34](#page=34). * **Geographical distribution:** East Africa, Asia, Mediterranean area, and South America [34](#page=34). > **Example:** A patient presenting with a non-healing ulceration on the hand, which began after a trip to Egypt and the Middle East, could be a case of cutaneous leishmaniasis. The ulcer's characteristics (flat, red border, bunded, wet center with scabs) and lack of response to initial topical treatments are suggestive [99](#page=99). ### 3.5 Treatment and Prevention #### 3.5.1 Treatment Information on specific treatments is limited in the provided pages, with a section simply titled "Leishmaniasis treatment". However, the general approach to managing leishmaniasis involves addressing infected individuals [42](#page=42). #### 3.5.2 Prevention Preventive measures against leishmaniasis target vector control and protecting individuals from bites [40](#page=40). * **Elimination of vectors:** Efforts to reduce or eradicate sand fly populations [40](#page=40). * **Treatment of infected individuals:** Reducing the reservoir of infection by treating infected persons [40](#page=40). * **Repellents and nets:** Using personal protective measures such as repellents and bed nets against sand flies [40](#page=40). --- **Summary of species and their primary disease:** | Species | Primary Disease | Key Manifestation(s) | Geographical Distribution | | :----------------- | :------------------------------------------------ | :------------------------------------------------------------------- | :------------------------------------------------------- | | *L. tropica* | Cutaneous leishmaniasis | Ulcerated lesion, self-healing | Mediterranean, Asia, Africa, Central America | | *L. braziliensis* | Mucocutaneous leishmaniasis | Red, itchy ulcer; later mucosal erosion (nose, ear) | Central and South America | | *L. donovani* | Visceral leishmaniasis (Kala-azar) | Systemic: fever, hepatosplenomegaly; potential fatality if untreated | East Africa, Asia, Mediterranean, South America | --- # Plasmodium: Malaria Malaria is a life-threatening disease caused by Plasmodium parasites transmitted through the bites of infected Anopheles mosquitoes [44](#page=44). ### 4.1 Overview of Plasmodium and Malaria Malaria is caused by blood parasites belonging to the genus *Plasmodium*. While there are approximately 156 named species of *Plasmodium* that infect various vertebrates, four species were traditionally known to infect humans: *P. falciparum*, *P. vivax*, *P. ovale*, and *P. malariae*. Recently, genetic methods have revealed that *P. ovale* consists of two subspecies: *P. ovale curtisi* and *P. ovale wallikeri*. A new species, *Plasmodium knowlesi*, a primate malaria parasite common in Southeast Asia, has also been identified and can infect humans, although it typically infects long-tailed macaques [44](#page=44) [45](#page=45) [46](#page=46). Malaria primarily occurs in tropical, subtropical, and temperate climate regions, though it can emerge around airports in Europe due to population movements. Globally, an estimated 300-500 million people are infected annually, with 1.5-3 million deaths. Malaria, along with AIDS and tuberculosis, is considered one of the most significant diseases worldwide, with over 45% of the global population living in malaria risk areas. Africa accounts for the majority of malaria cases, with one child dying every 30 seconds in Africa due to the disease [47](#page=47) [48](#page=48). The geographic distribution of malaria is influenced by environmental conditions that support parasite multiplication in the vector, typically tropical and subtropical areas. Climatic changes, particularly global warming, and population movements can alter this distribution. *P. falciparum* is the predominant species globally. *P. ovale* is more prevalent in Sub-Saharan Africa, while *P. vivax* is found in other regions. Distinguishing *P. ovale* and *P. vivax* solely on morphological characteristics can be challenging, often requiring molecular tools for accurate identification and distribution mapping. *P. malariae* has a widespread distribution across South America, Asia, and Africa [48](#page=48). Late, incorrect, or missed diagnoses are highly alarming and contribute to significant mortality [49](#page=49). #### 4.1.1 Life cycle of Plasmodium The life cycle of Plasmodium involves both a mosquito definitive host and a human intermediate host [44](#page=44). 1. **Infection of Mosquito:** An *Anopheles* mosquito bites a human and ingests male micro- and female macro-gametes from the blood [50](#page=50). 2. **Gametogenesis and Fertilization:** In the mosquito's gut, the male gametocyte fertilizes the female gamete, forming a zygote [50](#page=50). 3. **Ookinete Development:** The zygote develops into an ookinete, which moves outside the stomach wall [50](#page=50). 4. **Oocyst and Sporozoite Formation:** The ookinete develops into an oocyst, which then forms numerous sporozoites [50](#page=50). 5. **Migration to Salivary Glands:** These sporozoites migrate to the mosquito's salivary glands, representing the infective stage [50](#page=50). 6. **Infection of Human:** When the infected mosquito bites another human, it injects the sporozoites through its saliva, thus infecting the human [50](#page=50). #### 4.1.2 Stages in the Human Host Within the human host, the Plasmodium life cycle has two main phases: * **Exoerythrocytic Phase (in liver):** * Each sporozoite penetrates a liver cell [52](#page=52). * Within the liver cell, asexual multiplication occurs, leading to the formation of merozoites [52](#page=52). * **Erythrocytic Phase (in blood):** * Merozoites are released from the liver cells and invade red blood cells (RBCs) [52](#page=52). * Inside the RBC, the parasite develops into a trophozoite [52](#page=52). * The trophozoite matures into a schizont, which contains multiple merozoites [52](#page=52). * The schizont ruptures, releasing merozoites, each of which invades a new RBC [52](#page=52). * This asexual multiplication is called schizogony [44](#page=44). * Some merozoites develop into gametes (male microgametocytes and female macrogametes) which are then taken up by the mosquito to complete the cycle [52](#page=52). > **Tip:** The exoerythrocytic phase occurs in the liver and is not directly detectable in peripheral blood, but it is crucial for establishing the infection and can lead to relapses in certain species due to the presence of hypnozoites [52](#page=52) [54](#page=54). ### 4.2 Diagnostic Stages and Symptoms Identifying Plasmodium species is crucial for diagnosis and treatment [65](#page=65). #### 4.2.1 Morphological Diagnostic Stages Different Plasmodium species have characteristic morphological features in infected red blood cells: * **P. falciparum:** * **Trophozoites:** Typically appear as small ring forms, often with more than one ring per RBC, and may have double chromatin dots [53](#page=53) [93](#page=93). * **Gametocytes:** Crescent-shaped [53](#page=53). * **Schizonts:** Not usually seen in peripheral blood due to sequestration of mature forms in capillaries of internal organs [53](#page=53). * **Maurer's clefts:** Membranous vesicles that can be seen in infected RBCs [61](#page=61). * **P. vivax:** * **Trophozoites:** Large, irregular ring forms, and infected RBCs are enlarged and may exhibit Schüffner's dots [53](#page=53) [92](#page=92). * **Schizonts:** Contain 12-24 merozoites [53](#page=53). * **Gametocytes:** Round [53](#page=53). * **Schüffner's dots:** Small, red dots visible in infected RBCs under a light microscope, caused by tiny caveolae [60](#page=60). * **P. ovale:** * Similar to *P. vivax*, infected RBCs are enlarged and often oval-shaped with fimbriated edges. * Also exhibits Schüffner's dots [60](#page=60). * **P. malariae:** * Trophozoites are compact and may form band-like shapes across the RBC. * Schizonts typically contain 6-12 merozoites arranged in a rosette pattern. * Infected RBCs are not enlarged. > **Tip:** The presence of Schüffner's dots helps distinguish *P. vivax* and *P. ovale* infections from *P. falciparum*. Maurer's clefts are indicative of *P. falciparum* infection [60](#page=60) [61](#page=61). #### 4.2.2 Symptoms and Clinical Presentation Malaria symptoms can be non-specific and easily missed, leading to delayed diagnosis and potentially fatal outcomes. Key symptoms include fever and chills, headache, myalgia (muscle aches), arthralgia (joint pain), weakness, vomiting, diarrhea, anemia, and spleen enlargement. Patients may experience paroxysms of fever [53](#page=53) [56](#page=56). The clinical presentation varies depending on the infecting species, parasitemia level, and the patient's immune status [57](#page=57). * **P. vivax:** Paroxysms of fever typically occur every 48 hours (tertian malaria), characterized by a cold phase (chills), a hot phase (fever, headache, vomiting, convulsions), and a recovery phase. Relapses can occur years after the initial infection due to the presence of hypnozoites (dormant forms) in liver cells. Complications include splenomegaly, and rarely, splenic rupture [53](#page=53) [54](#page=54) [57](#page=57). * **P. falciparum:** Paroxysms are less regular, and patients often feel unwell between fever spikes. This is the most virulent species, capable of causing high parasitemia (over 65% infected RBCs). Infected RBCs tend to adhere to capillary walls, leading to obstruction of blood flow. Severe complications can arise rapidly, including cerebral malaria (central nervous system involvement), acute renal failure, severe anemia, and adult respiratory distress syndrome. Bloody urine, massive hemolysis, and brain damage from RBC clumping can lead to rapid death [54](#page=54) [56](#page=56) [57](#page=57). * **P. malariae:** Associated with quartan malaria, characterized by fever cycles every 72 hours. Complications include nephrotic syndrome [53](#page=53) [57](#page=57). * **P. ovale:** Causes ovale malaria with fever cycles typically every 48 hours [53](#page=53). > **Tip:** Always consider malaria in patients with a history of exposure, especially if they present with fever, as untreated infections can progress rapidly to severe, fatal forms [56](#page=56). #### 4.2.3 Pathological Byproducts * **Hemozoin:** Plasmodium parasites degrade hemoglobin to obtain nutrients, releasing heme molecules. Free heme is toxic to the parasite, so it is converted into an insoluble biocrystal called hemozoin. Hemozoin, a dark brown pigment, is visible in the parasite's food vacuole and later accumulates in organs like the spleen and liver. The formation of hemozoin is a target for some antimalarial drugs, such as chloroquine [59](#page=59). ### 4.3 Diagnosis of Malaria Diagnosis primarily relies on demonstrating the presence of Plasmodium parasites (trophozoites, schizonts, or gametocytes) in peripheral blood smears. Blood is ideally drawn when a paroxysm begins (during chills or fever) as parasite numbers are highest at this time [65](#page=65). * **Microscopy:** Microscopic examination of Giemsa-stained thin and thick blood smears is the gold standard for diagnosis and species identification. Morphological features of the parasites and infected blood cells are used to identify the species . * **Molecular Techniques:** Molecular diagnostic techniques, such as PCR, can complement microscopy, especially for accurate species identification, which can be challenging microscopically [65](#page=65). * **Immunologic/Biochemical Tests:** Antibody detection can indicate past infections but not necessarily active ones. Immunologic or biochemical detection of malaria parasite products are also available and under evaluation. Malaria antigen tests can confirm malaria, and some can indicate the presence of *P. falciparum*, though they may not rule out other species [65](#page=65). > **Example:** A microscopic examination of a blood smear on day 2 showed 1% RBC invasion, while on day 7, invasion increased to 32%. Diagnosis of *Plasmodium falciparum* was made based on morphological features and this progression. In another case, enlarged RBCs with Schüffner’s dots indicated *Plasmodium vivax* . ### 4.4 Prevention and Treatment #### 4.4.1 Prevention Strategies Prevention strategies focus on vector control and chemoprophylaxis: * **Vector Control:** * Elimination of *Anopheles* mosquitoes [67](#page=67). * Introduction of fish that consume mosquito larvae in water bodies [67](#page=67). * Use of insecticide-treated mosquito nets and repellents [67](#page=67). * **Medical Interventions:** * Treatment of infected individuals to reduce the reservoir of parasites [67](#page=67). * Chemoprophylaxis (preventive medication), although its effectiveness is limited by the emergence of drug-resistant strains [67](#page=67). #### 4.4.2 Antimalarial Vaccines The RTS,S/Mosquirix™ vaccine is an antimalarial vaccine designed to combat *P. falciparum*. RTS,S stands for a combination of *P. falciparum* circumsporozoite protein (CSP) central repeating regions (R), T-cell epitopes (T), and hepatitis B surface antigen (S). Its aim is to stimulate the body's immune system to prevent *P. falciparum* from infecting, maturing, and multiplying in the liver, thereby stopping it from re-entering the bloodstream and infecting red blood cells. The vaccine is primarily administered to children aged 5-9 months in regions of Africa with moderate to high parasite transmission. Developed in 1987, its efficacy was established in a phase 3 trial in 2014 [66](#page=66). #### 4.4.3 Treatment Treatment of malaria is crucial to prevent severe disease and death [68](#page=68). > **Example:** A patient with a positive malaria antigen test showing *P. falciparum* developed severe anemia and acute renal failure despite pharmacological treatment and died 11 days after symptom onset, highlighting the severe potential of *P. falciparum* infections. Another patient who traveled to Pakistan and used chemoprophylaxis developed a high fever 9 months later. Microscopic examination revealed enlarged RBCs with Schüffner’s dots, leading to a diagnosis of *Plasmodium vivax* . --- # Babesia: Babesiosis Babesiosis is a malaria-like disease caused by the eukaryotic parasite *Babesia*, a member of the phylum Apicomplexa, with human infections occurring primarily in temperate regions [69](#page=69). ### 5.1 Overview of Babesiosis Babesiosis is characterized as a disease resembling malaria, caused by infection with the parasite *Babesia*. The disease is most prevalent in the Northeastern and Midwestern United States and parts of Europe, with sporadic occurrences globally, particularly during warmer months [69](#page=69). ### 5.2 Transmission Modes Humans can contract babesiosis through several routes: * **Tick bites:** This is the primary mode of transmission for the human strain of babesiosis, often leading to co-infection with other tick-borne illnesses such as Lyme disease [69](#page=69). * **Blood transfusions:** Transmission via infected blood products is not uncommon and is a significant concern, especially for vulnerable individuals [69](#page=69) [72](#page=72). * **Congenital transmission:** An infected mother can transmit the parasite to her baby [69](#page=69). ### 5.3 Human Hosts and Pathogen Diversity Humans are generally considered a dead-end host for *Babesia* species, making conventional transmission from person to person unlikely. However, *Babesia* parasites are highly diverse, with over 100 known species. Four clades of *Babesia* species are known to infect humans [70](#page=70) [72](#page=72) [73](#page=73): * **Small *Babesia* (<3 µm):** * *B. microti* * *B. duncani* * **Large *Babesia* (>3 µm):** * *B. divergens* (primarily a cattle parasite observed in Europe) * *B. venatorum* (formerly known as EU1, a roe deer parasite, closely related to the large *Babesia* clade) The K01 strain, isolated in South Korea, also belongs to the large *Babesia* clade and can infect ungulates. Knowledge regarding specific pathogenic mechanisms in humans is limited due to the relative rarity of human cases [70](#page=70) [72](#page=72). ### 5.4 Geographic Distribution The worldwide distribution of *Babesia* species is closely tied to the geographical range of their competent *Ixodes* tick vectors [73](#page=73). ### 5.5 Prevention Strategies Preventing babesiosis largely focuses on minimizing tick exposure [76](#page=76): * **Avoidance:** Stay away from heavily wooded and grassy areas during peak tick activity seasons, typically from May to September [76](#page=76). * **Protective Clothing:** Wear long pants and long-sleeved shirts, tucking shirts into pants to prevent ticks from accessing the skin [76](#page=76). * **Repellents:** * **Permethrin:** Can be applied to clothing for a repellent effect on ticks, but should not be applied directly to skin [76](#page=76). * **DEET (N,N-Diethyl-meta-toluamide):** Based insect repellents offer some degree of tick repellency [76](#page=76). * **Tick Checks:** Since tick bites require at least 24 hours of attachment for transmission, thorough daily inspection of the body surface for ticks is crucial after activities with high tick exposure risk [76](#page=76). > **Tip:** Due to the potential for co-infection, if you present with symptoms after a tick bite in an endemic area, it is important to inform your healthcare provider about the possibility of both Lyme disease and babesiosis [69](#page=69). > **Example:** An individual spending time hiking in the woods during the summer months in the northeastern United States is at a higher risk of encountering ticks carrying *Babesia microti*, the most common species causing babesiosis in that region [69](#page=69). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Trypomastigote | A developmental stage of trypanosomes characterized by a free-moving, elongated body with a kinetoplast at the posterior end and a flagellum running along an undulating membrane. This is often the diagnostic stage in blood smears. | | Epimastigote | A developmental stage of trypanosomes found in the insect vector, where the kinetoplast is located near the anterior end, and the flagellum is attached along a short undulating membrane. | | Promastigote | A developmental stage of trypanosomes and leishmania, characterized by a slender body with the kinetoplast and kinetosome at the anterior end, from which a single free flagellum emerges. This is the infective stage for Leishmania. | | Amastigote | A small, ovoid or spherical intracellular stage of trypanosomes and leishmania, typically found within host cells like macrophages. It is often a diagnostic stage within tissues. | | Kinetoplast | A dense granule containing mitochondrial DNA, located at the base of the flagellum in trypanosomatids. It is a characteristic feature of these protozoan parasites. | | Hemoflagellate | Protozoan parasites that have a flagellum and live in the blood or other tissues of vertebrates. Trypanosomes are a common example. | | Intermediate host | An organism that harbors the larval or asexual stage of a parasite. For trypanosomes and leishmania, arthropods like tsetse flies and sand flies often serve as intermediate hosts. | | Central Nervous System (CNS) | The part of the nervous system comprising the brain and spinal cord. Invasion of the CNS by trypanosomes leads to severe neurological symptoms in African sleeping sickness. | | Haemolymphatic stage | The initial stage of African sleeping sickness where the trypanosomes multiply in the blood and lymphatic system, causing generalized, non-specific symptoms. | | Meningoencephalitic stage | The later stage of African sleeping sickness, occurring after trypanosomes invade the central nervous system, leading to severe neurological and neuropsychiatric manifestations. | | Tsetse fly | A biting fly found in sub-Saharan Africa that transmits trypanosomes, the causative agents of African sleeping sickness, to humans and animals. | | Glossina | The genus name for the tsetse fly. | | Vector | An organism, typically an arthropod, that transmits a pathogen from one host to another. | | Chemoprophylaxy | The administration of drugs to prevent disease, often used for infectious diseases like malaria or during travel to endemic areas. | | Xenodiagnosis | A diagnostic method used to detect parasites, such as Trypanosoma cruzi, by allowing uninfected vectors (e.g., bugs) to feed on a patient and then examining the vector's feces for the presence of the parasite. | | Indirect hemagglutination | A serological test used to detect antibodies in a patient's serum, often employed in the diagnosis of parasitic infections like Chagas disease. | | Sand fly | Small biting flies belonging to the genera Phlebotomus and Lutzomyia, which are vectors for Leishmania parasites causing leishmaniasis. | | Viscera | The internal organs of the body, especially those in the abdomen. Visceral leishmaniasis affects these organs. | | Cutaneous leishmaniasis | A form of leishmaniasis that primarily affects the skin, causing ulcerated lesions. | | Mucocutaneous leishmaniasis | A form of leishmaniasis that affects the mucous membranes of the nose, mouth, and throat, often leading to severe disfigurement. | | Visceral leishmaniasis | A severe form of leishmaniasis, also known as kala-azar, that affects internal organs like the spleen, liver, and bone marrow. | | Oriental sore | A common name for cutaneous leishmaniasis caused by Leishmania tropica, characterized by ulcerated skin lesions. | | Baghdad boil | Another common name for cutaneous leishmaniasis, particularly in the Middle East. | | Uta | A term for cutaneous leishmaniasis, especially in South America. | | Espundia | A term for mucocutaneous leishmaniasis, particularly in South America. | | Kala-azar | A common name for visceral leishmaniasis, characterized by fever, weight loss, and enlargement of the spleen and liver. | | Dumdum fever | An older term for visceral leishmaniasis. | | Schizogony | An asexual process of reproduction in protozoa, particularly Plasmodium, where the nucleus divides multiple times before the cytoplasm divides, resulting in merozoites. This occurs in the intermediate host. | | Sporozoites | The motile, elongated infective stage of Plasmodium that is transmitted to humans by the bite of an infected Anopheles mosquito. | | Merozoites | The infectious cells produced by the schizogony of Plasmodium, which invade red blood cells in humans. | | Trophozoite | The actively growing and feeding stage of a protozoan parasite, such as Plasmodium, within a host cell. | | Schizont | A mature schizont containing merozoites, which is formed during the asexual reproduction of Plasmodium in red blood cells. | | Gametocyte | The stage in the Plasmodium life cycle that develops into gametes within the mosquito host. | | Exoerythrocytic phase | The stage of the Plasmodium life cycle that occurs in the liver cells of humans, where sporozoites develop into merozoites. | | Erythrocytic phase | The stage of the Plasmodium life cycle that occurs in red blood cells, where parasites multiply asexually and cause the clinical symptoms of malaria. | | Paludism | An older term for malaria. | | Tertian malaria | Malaria characterized by fever paroxysms occurring every third day (approximately 48 hours), typically caused by Plasmodium vivax or Plasmodium ovale. | | Quartan malaria | Malaria characterized by fever paroxysms occurring every fourth day (approximately 72 hours), typically caused by Plasmodium malariae. | | Paroxysms | Sudden attacks or recurrences of symptoms, such as the chills and fever associated with malaria. | | Hypnozoites | Dormant forms of Plasmodium vivax and Plasmodium ovale that remain in the liver cells and can cause relapses of malaria months or years after the initial infection. | | Parasitemia | The presence of parasites in the blood, often expressed as a percentage of infected red blood cells. | | Cerebral malaria | A severe and potentially fatal complication of Plasmodium falciparum infection, characterized by neurological symptoms such as delirium, seizures, and coma, caused by blockage of capillaries in the brain. | | Splenomegaly | Enlargement of the spleen, a common symptom in various parasitic infections, including malaria and leishmaniasis. | | Nephrotic syndrome | A kidney disorder characterized by excessive protein loss in the urine, edema, and low blood protein levels, which can be a complication of Plasmodium malariae infection. | | Hemozoin | An insoluble biocrystal formed by Plasmodium species from toxic heme molecules released during hemoglobin digestion. It is often referred to as malaria pigment. | | Caveolae | Small, flask-shaped invaginations of the plasma membrane found in eukaryotic cells. Schüffner’s dots in malaria are thought to be related to these. | | Lipid raft | Small, dynamic domains within the cell membrane that are enriched in cholesterol and sphingolipids, playing roles in cell signaling and protein trafficking. | | Protein trafficking | The process by which proteins are transported to their correct locations within or outside the cell. | | Maurer’s clefts | Distinctive membranous structures found in erythrocytes infected with Plasmodium falciparum, involved in protein export from the parasite. | | Phlebotomids | A collective term for sand flies, the vectors of leishmaniasis. | | Circumsporozoite protein (CSP) | A major surface protein of the Plasmodium sporozoite stage, targeted by the RTS,S/Mosquirix antimalarial vaccine. | | T-cell epitopes | Specific regions on an antigen that are recognized by T-cells, playing a crucial role in the adaptive immune response. | | Hepatitis B surface antigen (HBsAg) | A protein found on the surface of the hepatitis B virus, used as a component in the RTS,S vaccine to stimulate an immune response. | | Babesiosis | A tick-borne parasitic disease caused by protozoa of the genus Babesia, which infect red blood cells and can cause malaria-like symptoms. | | Alveolate | A diverse group of eukaryotes characterized by the presence of alveoli (flattened sacs) beneath the plasma membrane. Plasmodium and Babesia are alveolates. | | Apicomplexa | A phylum of obligate intracellular parasitic alveolates, which includes Plasmodium, Babesia, and Toxoplasma. | | Congenital transmission | Transmission of an infection from a mother to her child during pregnancy, childbirth, or breastfeeding. | | Ixodes | A genus of ticks that includes common vectors for various pathogens, including Babesia and Lyme disease bacteria. | | Ungulates | Mammals with hooves, such as cattle, deer, and horses. | | Immunocompromised | Having a weakened immune system, making an individual more susceptible to infections. | | Splenectomized | Having had the spleen surgically removed. Individuals without a spleen are at higher risk for severe Babesiosis. | | DEET (N,N-Diethyl-meta-toluamide) | A common insect repellent that also has some repellent effect on ticks. | | Permethrin | A synthetic pyrethroid insecticide and acaricide that can be applied to clothing to repel ticks and other insects. |