Blood and Tissue Parasites and Antiprotozoal Drugs WS PDF

Overview This session will focus on some parasites that may be found in blood and various tissues and which may directly or indirectly affect the cardiovascular system. The biological characteristics of, and the clinical manifestations of infection caused by these organisms will be discussed. Infect...

Overview This session will focus on some parasites that may be found in blood and various tissues and which may directly or indirectly affect the cardiovascular system. The biological characteristics of, and the clinical manifestations of infection caused by these organisms will be discussed. Infections of the cardiovascular system discussed here are due to protozoal hemoflagellates of the genera Trypanosoma and Leishmania, tissue sporozoan Plasmodium and Babesia and various types of filarial worms. Other protozoa and metazoa that may be found in blood are discussed elsewhere as determined by the site at which they may cause significant pathology such as the skin, the gastrointestinal tract, or the central nervous system. Malaria is an ancient disease that has continued to defy universal eradication efforts. Indeed, it has remained a worldwide problem for centuries, and it is a useful model for the study of the epidemiology, pathophysiology, and management of vector-borne parasitic diseases. This session will cover the life cycle of the malaria parasite with a focus on the tissue-specific forms and their pathologic effects. The principles of intervention strategies will be discussed. Learning Objectives By the end of this session, you will be able to meet the following learning objectives: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Outline the general classification of parasites. Given the name of any parasite, state its class and/or subclass. Recall the scientific and common names for each parasite. State the general geographical distribution of each parasite. State the parasitic form that causes disease in humans (the infective form). State the body site where the parasite is primarily located. Describe the means by which each infection occurs. State the name of the disease produced. Describe the most common symptoms of the disease caused by each parasite. Recognize and describe the diagnostic stage for each parasite. State the appropriate specimen to be examined and list the laboratory tests that may be of value for diagnosis. Describe graphically the basic life cycle of each parasite. Identify methods used for the epidemiological control of parasitic infections and discuss stages in the life cycle that are most susceptible to intervention. Given a case scenario, name the most probable parasite involved, and discuss the method for making a diagnosis. Discuss the main features of immunological responses to protozoal and helminthic infections. Explain the molecular mechanism of action of drugs used to treat protozoal infections. Describe the spectrum of action and clinical use of each drug, by listing the main protozoa sensitive to it and the related disease. Describe the route of administration, distribution and elimination of drugs used to treat protozoa infections. Describe the main adverse effects and contraindications of the drug used to treat protozoa infection. Blood and Tissue Parasitic Infections The microbiology lectures on the cardiovascular system are not meant to cover the clinical presentation of CVS disease, as fascinating as that might be. That is the domain of ICM. Neither are they meant to discuss the morphological changes that accompany CVS disease which is a task for the pathologists. Rather, microbiologists and infectious disease specialists are expected to discuss those microbes that may contribute to CVS disease. The focus should be on describing those features that characterize microbial induced pathology and on determining how we, as clinicians and diagnosticians, may distinguish between diseases with strikingly similar appearance. The challenge is to be able to definitely state the cause of a disorder as this would be necessary for effective treatment and eradication as opposed to mere suppression of the symptoms. This section will cover the parasitoses, and we will first discuss the protozoa that cause CVS disease and then the helminthes. It would be useful to recall the major differences between these two classes of parasites and the manner by which the body responds to each type of parasite. Various parasites may be found in human blood and tissues. Many are tissue parasites that pass transiently through the blood while others may infect blood cells and induce frank hematological pathology. Biting or blood-sucking insect vectors transmit most parasites found in the blood. These parasites appear to have originated as insect pathogens or to have become highly adapted to their insect hosts and may require the insect for the completion of their life cycle. Infections of the cardiovascular system discussed here are due to protozoal hemoflagellates of the genera Trypanosoma and Leishmania, tissue sporozoa Plasmodium and Babesia and various types of filarial worms. Other protozoa and metazoa that may be found in blood are discussed elsewhere as determined by the site at which they may cause significant pathology such as the skin, the gastrointestinal tract or the central nervous system. Trypanosoma and Leishmania Trypanosome and leishmania parasites may be found in the blood, lymph, cerebrospinal fluid or tissue. They are classified as hemoflagellates because they may be seen in blood as free forms with flagella and undulating membranes. The hemoflagellates exist in four distinct morphologic forms called the amastigote, the promastogote, the epimastigote and the trypomastigote. The most significant forms in humans are the amastigotes found as short stumpy forms within cells and tissues and the trypomastigotes that are found as motile forms in plasma. The demonstration of these forms in humans is of diagnostic value. Trypanosomes are found in Africa and the Americas. African trypanosomes cause demyelinating encephalitis called sleeping sickness and are transmitted by the tsetse fly. T. gambiense is found in West Africa while T. rhodesiense is found in East Africa. These trypanosomes are discussed elsewhere. Treatment of Typanosom Medications for African Sleeping Sickness Medication for Chagas Disease Leishmaniasis The leishmania are obligate intracellular parasites that are found all over the world, especially in the tropics. They are transmitted by Phlebotomus sand flies. It is thought by some that leishmania were originally insect pathogens that have evolved into pathogens of vertebrates such as rodents, dogs and humans. The leishmania appear to belong to a large species and several subspecies differing in their degrees of virulence and temperature dependence in vivo. Leishmaniasis occurs in four basic clinical forms, each form arising from infection by a definite subspecies or subgroup. Click each title below to learn more about each form. Cutaneous or Dermal Leishmaniasis Cutaneous or dermal leishmaniasis is caused by parasites that replicate in macrophages of the skin, where the temperature is low. These subspecies (e.g. Leishmania tropica) are avirulent and cause infections that are self-limiting and resolve spontaneously without any treatment. More than 1.0 million infections are reported each year in more than 80 countries. Diffuse Cutaneous Leishmaniasis Diffuse cutaneous leishmaniasis is a disseminated form of dermal leishmaniasis that may be seen in individuals who are immunocompromised. This is also known as anergic leishmaniasis because humoral and cellular immune responses are absent. This form of anergy is specific; delayed type hypersensitivity to tuberculin is present. Lesions may cover many areas of the body, yet the organisms remain localized and there are no systemic manifestations. Mucocutaneous Leishmaniasis Mucocutaneous leishmaniasis is due to a moderately virulent strain of leishmania parasites (Leishmania brasiliensis) that replicate at the relatively warmer temperatures of the nasopharynx and may cause destruction of nasopharyngeal tissue. Visceral Leishmaniasis Visceral leishmaniasis is caused by Leishmania donovanii, the most virulent strain of the leishmania parasite. This disease is caused by organisms that prefer deep tissues at body temperature. The infection is characterized by irregular fever, hepatosplenomegaly, weight loss and pancytopenia. Amastigotes are present in many tissues including the liver, spleen and bone marrow. The presence of the parasite renders the organs dysfunctional leading to a rapidly fatal disease if untreated. Leishmaniavirus, a double stranded RNA virus, has been found in close association with the parasite. An emerging problem is the increasing incidence of Leishmania-HIV coinfection. Diagnosis The diagnosis of leishmaniasis is based on clinical presentation and upon evidence of exposure to sand flies. Diagnosis may be confirmed by the demonstration of amastigotes in skin scrapings or aspirate or on tissue biopsy or by culture of a suitable specimen. Since the organisms are obligate intracellular parasites, blood smears are not useful. The Montenegro test is a skin test for the demonstration of hypersensitivity reaction to leishmanin. Positive tests are generally seen in persons with cutaneous disease. Treatment of Leishmaniasis The choice of agent depends on the species of Leishmania, host factors, and resistance patterns noted in area of the world where the infection is acquired. Medications for Leishmaniasis The choice of agent depends on the species of Leishmania, host factors, and resistance patterns noted in area of the world where the infection is acquired. Malaria Malaria is an ancient disease that has plagued mankind for thousands of years. The name is derived from ‘mal air’ or bad air in reference to the foul odor from stagnant waters that are the breeding ground for the vector of the disease. Approximately 3.0 million people die each year from malaria, most of them children in endemic regions. The incidence of malaria is about one billion worldwide with many more people at risk. More than 1,000 new cases are reported in the United States each year. This disease is clearly one of the greatest health problems facing mankind today. The disease is caused by parasites of the genus Plasmodium. These are typical tissue sporozoa that exhibit two different life cycles in two different hosts. The asexual or schizogonous cycle takes place in the vertebrate intermediate host while the sexual or sporogonous cycle occurs in the definitive host, the female Anopheles mosquito. Several species of Plasmodium are known, and each is specific for its vertebrate host due to the requirement for a receptor on host cells to which the parasite’s apical end may bind. The species that infect humans are Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax. Many other host-specific species exist, such as Plasmodium berghei (rat) and Plasmodium yoelii (mouse). Of recent interest is the finding that the primate parasite Plasmodium knowlesi may cause human disease. Life Cycle The life cycle of the malaria parasite begins when the Anopheles mosquito vector bites a human. The mosquito injects sporozoites that circulate briefly in the blood before they enter the liver parenchymal cells to initiate the pre-erythrocytic or exo-erythrocytic or the hepatic cycle of schyzogonous replication. At the end of the hepatic cycle, merozoites are released from schizonts into the blood. Merozoites enter the erythrocytes where there is abundant hemoglobin for their development. They undergo rapid schizogonous replication in the red blood cells becoming schizonts that rupture and release more merozoites to invade more erythrocytes. This cycle of invasion, replication, and rupture results in the infection and destruction of massive numbers of erythrocytes leading to severe hemolytic anemia. A few of the merozoites do not develop into schizonts but become sexual forms known as gametocytes. The gametocytes circulate in the blood without any further development until they are taken up by the female Anopheles mosquito. Once in the mosquito, the gametocytes develop and mate to initiate the sporogonous cycle of replication. At the end of this cycle, sporozoites are formed and they migrate to the insect’s salivary glands from where they may be injected into humans when the insect takes the next blood meal. Latency At times, the sporozoite does not develop into merozoites but become hypnozoites that remain dormant in the liver for long periods. When these dormant forms become reactivated, they may cause relapses in persons who are thought to have been cured of malaria. This occurs in infections by P. vivax and P. ovale and may be seen months or years after the primary infection. Latency must be distinguished from recrudescence, which may occur following infection by P. falciparum and P. malariae. The disease recurs a few weeks after the primary infection presumably due to drug failure and/or re-infection. Latency occurs without any evidence of re-infection. Epidemiology The global distribution of malaria depends on the ability of the Anopheles mosquito to survive and reproduce. Thus, malaria is endemic in those tropical regions where warmth and moisture facilitate the development of the vector. It has been clearly established that the elimination of standing water, the breeding ground for mosquitoes, is the single most effective means of stopping the spread of malaria. Clinical Malaria The clinical phases of malaria fever follow parasite invasion and rupture of erythrocytes and the production of cytokines such as TNF-α. Classical malarial paroxysms include chills, fever and sweating. These may occur periodically as erythrocytes rupture in synchrony. Headache, malaise, nausea and vomiting may also occur. The occurrence of fevers at two-day (tertian) or three-day (quartan) intervals was once used to classify clinical malaria as a tertian fever (P. ovale, P vivax) or a quartan fever (P. malariae). Plasmodium falciparum causes the most severe form of malaria (malignant malaria) and tends to produce almost continuous fever without the distinct afebrile periods seen with the other species. It has also been observed that synchrony is difficult to maintain in natural infections, and as a result, periodicity might not be a reliable indication of the species responsible for an infection. Molecular methods are now available for such a determination. With time, various syndromes may develop. The rupture of erythrocytes may lead to severe hemolytic anemia. Parasite and red cell debris also accumulate and are taken up by cells of the reticuloendothelial system causing RES hyperplasia and evidenced by hepatomegaly and splenomegaly. Anemia is due to red cell destruction by parasite replication and also due to clearance of infected erythrocytes and other immune mechanisms. Infected red cells are known to adhere to microvascular endothelium. This may cause obstruction of capillaries of the brain (cerebral malaria) and the heart (congestive heart failure, myocardial infarction) and other organs (e.g. acute respiratory distress). The kidneys are also adversely affected (blackwater fever, nephrotic syndrome) due in part to immune complex deposition. It has been proposed that ICAM-1, E-selectin and VCAM-1 are some of the molecules responsible for the adherence of parasites to vascular endothelium. Glucose utilization by the parasite may induce hypoglycemia and hyperlactatemia (acidosis). Malaria induced cytokine production may also have several effects, such as decreased red cell production due to TNF. There are suggestions that therapies aimed at blocking cytokine production may reduce pathology due to malaria without affecting the level of parasitaemia. Protective Factors Several factors are thought to protect against malaria. These are explained on the basis of the absence of a parasite specific receptor or innate inability to support parasite growth or survival. Malaria parasites are known to bind specifically to receptors on host cells. Cells that lack receptors are therefore immune to infection. Human parasites do not infect other animals, and vice versa. The specific receptor complex for Plasmodium vivax includes the Duffy blood group antigen (Fya/Fyb). Duffy negative cells (Fy/Fy) are unable to receive the parasite. Therefore, individuals who are Duffy negative are not infected by Plasmodium vivax. Cells that do not contain required nutrients also do not support parasite development. Malaria parasites thrive on normal adult hemoglobin (HbA), so, cells that contain ‘abnormal’ hemoglobin, such as HbS or β-Thal, are resistant to infection. Cells that lack certain enzymes are also not infected. Diagnosis Presumptive diagnosis may be easily made upon clinical presentation (fever, chills, sweats, myalgia, arthralgia, malaise, jaundice) and evidence or suspicion of exposure. Infection is confirmed by examination of stained blood smears showing intraerythrocytic parasite forms. Serologic and/or molecular techniques may be employed for further identification. Treatment Life Cycle –Therapeutic Targets Life cycle of malaria parasites. Only the asexual erythrocytic stage of infection causes clinical malaria (symptoms). All effective antimalarial treatments are blood schizonticides that kill this stage. Gametocytes In Blood and Sexual Forms Schizonts: Blood schizonts and Tissue schizonts Hypnozoites: In Liver and Latent or Dormant Stage 1. Transmission to Human Host: An infected mosquito injects sporozoites into the human's bloodstream. 2. Liver Stage (Exoerythrocytic Stage): Sporozoites enter the liver, infect hepatocytes and mature into merozoites. 3. Release from Liver: Merozoites are released from the liver into the bloodstream. 4. Blood Stage (Erythrocytic Stage): Merozoites invade erythrocytes and mature to trophozoites. 5. Blood Stage (Erythrocytic Stage) continued: Trophozoite multiplies, producing new merozoites, until the infected red blood cells rupture, releasing more merozoites into the bloodstream. 6. Gametocyte Formation: Some merozoites develop into male and female gametocytes, which circulate in the bloodstream. 7. Ingestion: When a mosquito takes a blood meal from an infected human, it ingests these gametocytes. Drugs effective against erythrocytic form: Artemisinin, Atovaquone/proguanil, Chloroquine, Quinine, Mefloquine, Pyrimethamine Drug effective against gametocytic form: Primaquiine Drug effective against exoerythrocytic form: Primaquine Therapeutic considerations In P. falciparum and P. malaria infections, only one cycle of liver cell Invasion and multiplication occurs. Liver infection ceases spontaneously in 4 weeks. Thus, treatment that eliminates erythrocyte parasites will cure these infections. In P. vivax and P. ovale infections, a dormant hepatic stage (hypnozoites) can cause relapses after therapy directed against erythrocyte parasites. Treatment against of both erythrocytic and hepatic parasites is required to cure these infections. Pharmacologic Treatments Artemisinins (Artesunate(IV); Artemether-lumefantrine(PO)) Artemisinins have become the commonly prescribed therapy to treat all forms of malaria. Its mechanism of action is not fully understood but most likely involves free radical production that damages proteins within the parasite. Side effects produced are generally considered to be mild and allergic reactions are rare. Caution should be undertaken with use during the first trimester of pregnancy. Artemisinins are highly effective against blood schizonts and against gametocytes of all malarial species. However, it has no effect on hepatic stages. Rare reports of resistance have been seen (SE Asia). Chloroquine Chloroquine has historically been the most utilized treatment in the fight against malaria. Chloroquine prevents the polymerization of heme, causing a buildup of the toxin which lyses the parasite and the RBC. Chloroquine has rapid gastrointestinal absorption and excellent bioavailability. Although overall it is well tolerated, rare serious adverse reactions include: Hemolysis (G6PD), impaired hearing, confusion, visual changes, psychosis, retinopathy, ECG changes, agranulocytosis, and exfoliative dermatitis. Chloroquine is a highly effective blood schizoticide of all malaria species but has no effect on the hepatic stage. High levels of resistance are seen in many parts of the world and limits its modernday use. Mefloquine The mechanism of action of mefloquine is unknown but it demonstrates effective killing of blood schizonts of all malarial species. However, it is not active against hepatic stages or gametocytes. Resistance to mefloquine is common in SE Asia. Mefloquine is well absorbed orally, is metabolized by the liver, and has a wide volume of distribution. The major adverse effect of mefloquine is neuropsychiatric and should be avoided in patients with schizophrenia, bipolar disease, depression and other like conditions. Other potential adverse effects include: Nausea/vomiting, Diarrhea, Dizziness, Sleep disturbance, and cardiac arrhythmias. Quinine and Quinidine Like mefloquine, the mechanism of action of quinine and quinidine against malaria species is not well understood. These drugs are effective blood schizonticides of all malarial species. They are also effective against gametocytes of P. vivax, P. malariae, and P. ovale. They do not have efficacy against hepatic stages of the infection. These drugs are also well absorbed from the GI tract and quinidine is also available as an intravenous dosage form. Of note, quinine has a very long half-life of nearly 2 months. Quinine and quinidine have an extensive list of potential adverse effects including: Hematologic and cardiac arrhythmias, Allergic reactions, and Hypoglycemia. Cinchonism is a cluster of adverse effects associated with these drugs and includes tinnitus, headache, nausea, vomiting, dysphoria, and visual disturbances. A complication of malaria called “blackwater fever” which includes hemolysis, severe anemia, and hematuria, is most commonly seen with treatments involving quinine and quinidine compared to other anti-malarial agents. Patients with G6PD and long QT syndrome should avoid the use of these agents. Atovaquine-Proguanil Atovaquone is believed to inhibit mitochondrial electron transport in Plasmodium species and is effective at killing blood schizonts of all species. It does not have activity against hepatic stages of the disease. It is given orally and is generally well tolerated with reported side effects being, nausea, headache, insomnia, and rash. Folate Inhibition – Pyrimethamine, Proguanil, Sulfadoxine/ Pyrimethamine Sulfadoxine provides inhibition of plasmodial dihydropteroate synthase while Pyrimethamine leads to inhibition of plasmodial dihydrofolate reductase. The combination of these mechanisms provides inhibition of plasmodial DNA synthesis. This therapy has a slow action against merozoites of all malarial species while providing some activity against primary tissue schizonts. Resistance is common in many areas, particularly to P. falciparum. Folate inhibitors are generally well tolerated but are related to rare cases of hemolytic anemia, agranulocytosis, liver necrosis, and serious dermatologic rashes (SJS, TEN). Primaquine Primaquine is active against primary tissue schizonts and gametocytes of all malarial species. It is the only active agent against hypnozoites of P. vivax and P. ovale. However, primaquine has no activity against blood merozoites. Some P. vivax species show resistance. The mechanism of action of primaquine is unknown and it is generally well tolerated. Use should be avoided in G6PD deficiency. Rare side effects include agranulocytosis and cardiac arrhythmias. Summary – Killing Activity of Antimalarial Drugs Malaria Vaccine The Malaria RTS,S/AS01 Vaccine Consists of a recombinant fusion protein created based on an antigen target consisting of a repetitive sequence of four amino acids in the circumsporozoite antigen on the surface of the P. falciparum sporozoite. "RTS" stands for "repeat T epitopes" derived from the circumsporozoite protein "S" stands for the S antigen derived from hepatitis B surface antigen (HBSAg) AS01 is a proprietary adjuvant In efficacy studies: 40% reduction in malaria episodes, Reduction in severe malaria, and 1 life saved for every 200 children vaccinated. Best results observed with continued use of netting and avoidance measures. Vaccine Schedule: For children > 5 months of age, 3 doses given 1 month apart, 4th dose 15-18 months post third dose Control Programs The World Health Organization has been very active for several decades in the global effort to eradicate malaria. The current program is called “Roll Back Malaria” and it is hoped that efforts will be directed at eliminating or at least, controlling the mosquito. Many pharmaceutical companies are also working on drug development and the Bill and Melinda Gates Foundation is actively funding the Malaria Vaccine Initiative but drugs and vaccines alone are unlikely to have the long lasting impact of sweeping environmental changes Babesiosis Babesiosis is a common rodent and cattle disease that may occasionally affect humans. The disease has gained prominence because it is so easily confused with malaria on clinical grounds alone. Babesiosis is caused by Babesia spp. and is transmitted by the Ixodes tick. This is the same tick that transmits Lyme disease. The two diseases are therefore found in the same geographic areas and may be transmitted together (co-infection). Infection is transmitted by several species of ticks in which sexual replication occurs. Human infection is usually caused by Babesia microti in the United States and Babesia divergens in Europe. Infection is usually asymptomatic except in immunocompromised or splenectomized individuals in whom it may be severe. Typical symptoms include general malaise, fever, shaking chills, profuse sweating, myalgia, fatigue and weakness. Diagnosis Babesiosis is clinically similar to malaria but may be distinguished on the basis of exposure to ticks. Examination of blood smears may reveal the characteristic tetrads or Maltese cross. Identification may be confirmed by the demonstration of specific IgM, by immunofluorescence or by molecular techniques. Treatment of Babesiosis Antibiotic treatment is recommended only for patients with symptomatic disease. For most patients, the recommended therapy is a combination of atovaquone and azithromycin. An alternative option is the combination of clindamycin plus quinine. In pregnant patients, the use of clindamycin and quinine is the preferred treatment. Summaries of the drug regimens can be found in the table below. Lymphatic Filariasis Lymphatic filariasis is cause by tissue nematodes that reside in the subcutaneous tissue, deep connective tissue, lymphatic system, or other body cavities of humans. Insects are generally responsible for parasite transmission and the infections follow a chronic course, requiring years before significant pathologic changes become evident. Endomyocardial fibrosis may result from chronic filarial-induced eosinophilia. The major filarial nematodes are Wuchereria bancrofti, Brugia malayi and Brugia timori (elephantiasis), Onchocerca volvulus (river blindness), Loa loa (Calabar swellings) and Dracunculus medinensis (guinea worm). Elephantiasis Elephantiasis is a chronic debilitating disease of humans transmitted through mosquito bite. The disease occurs mostly in the tropics and subtropics and may affect up to 120 million people, up to 40 million of who may become disfigured. Wuchereria is restricted to humans while Brugia may be maintained in a zoonotic cycle. Infective microfilariae are injected into the skin or blood when the mosquito bites. After a period of several months, the worms mature into adults and migrate to the lymphatics. The adult female then produces microfilariae that enter the blood and may be picked up by the mosquito. The microfilariae mature into infective forms in the mosquito. The early pathology of lymphatic filariasis is due to host immune reaction to the migrating microfilariae. There is acute inflammation and hypereosinophilic response to the larvae. It has also been shown that bacterial and fungal superinfections occur and are a significant contributor to overall pathology. In particular, bacteria of the genus Wolbachia are intimately associated with the microfilariae. It appears that these infections are due largely to lymph stasis. In late disease, adult worms may be found in the lymph nodes and in lymphatic channels. Lymphangitis and lymphadenitis may develop as a result of the physical presence of the parasite as well as intense repeated inflammatory reactions that lead to hyperplasia of the endothelium. Leakage of fluid into the surrounding tissue leads to lymphedema. The lymph nodes become filled with fibrous tissue and the lymph channels become stenotic, leading to the development of collateral lymph channels. Thus, the development of elephantiasis is a complex process and elephantoid tissue is a mixture of lymph and fat in a matrix of fibrous tissue. The skin shows hyperkeratosis and acanthosis with scarring and loss of elasticity. Affected parts include the limbs (lower limbs more often than upper limbs), genitals and breasts. Diagnosis Diagnosis is difficult because infections are usually asymptomatic in the early stages. There may be fever and possibly lymphadenitis. Microfilariae may be demonstrated in the circulation, mostly at night (nocturnal periodicity) when the vector is most likely to feed. The microfilariae may be distinguished morphologically from other clinical important filariae. A high degree of suspicion is required to warrant clinical investigation. Hematologic and serologic findings include elevated eosinophil count, high IgE level and the presence of specific antifilarial IgM and IgG antibody. New circulating antigen detection methods (ELISA, card test) are available. Onchocerciasis Onchocerciasis, also known as river blindness, is of major public health concern. The causative organism Onchocerca volvulus, is a leading cause of blindness and may also cause lesions of the skin. Some 20 million people are infected worldwide. At least 500,000 suffer from serious visual impairment and up to 300,000 are completely blind. The disease is endemic in areas near fast flowing rivers that provide the environment for the development of the vector, the Simulium blackfly. Infection occurs when an infected blackfly bites and injects the larvae into the skin. These larvae develop into adult worms that may be found within fibrous tissue capsules in the dermis and subcutaneous tissue. Gravid females produce microfilariae, which invade the subcutaneous tissues, skin and eyes. Microfilariae are in the dermis and rarely appear in blood or urine. The female produces thousands of microfilariae each day and has a reproductive life span of up to 15 years. Clinical Disease The clinical signs of onchocerciasis are due to adult worms in subcutaneous tissue and millions of marauding microfilariae. The adult worms may be sequestered in subcutaneous nodules (the onchocercoma) on the trunk, particularly in the hip area (the iliac crest), or limbs, or on the scalp. The major clinical manifestations are due to millions of migrating microfilariae and immune response to them. The problem is further compounded when the microfilariae die and provoke a very strong inflammatory reaction. Both antibody and cell-mediated responses contribute to the pathologic picture. The principal sites affected are the skin and the eyes. Onchodermatitis Many individuals with onchocerciasis present with severe pruritus and disfiguring skin lesions. The skin may be hot and edematous and the itching may cause sleeplessness and fatigue. Repeated inflammation of the dermis may result in hypertrophy or thickening and severe wrinkling (craw craw). The skin may become hypo- or hyperpigmented giving rise to the condition known as ‘leopard’ skin Onchokeratitis Severe sclerosing keratitis and uveitis leading to blindness are serious sequelae of onchocerciasis. It appears that the development of ocular lesions requires infection by an appropriate parasite strain and depends on severity of infection. The lesions are clearly immune mediated as circulating antibodies to retinal antigen have been demonstrated in infected persons. Mast cells and basophils also seem to release amines and contribute significantly to onchoceral pathology following binding of cellular-IgE by parasite antigen. Diagnosis It is relatively easy to make a clinical diagnosis of onchocerciasis based on symptomatology and evidence of exposure. Skin snips may be taken from nodules to demonstrate the presence of microfilariae. Multiple snips are required for excellent results. Nodules may also be excised (nodulectomy) for diagnostic purposes. Slit-lamp examination of the eye may be useful for the demonstration of microfilariae in the anterior chamber. The Mazzoti patch test can be used when skin snips are negative to determine reactivity to diethycarbamazine, DEC. The appearance of a localized inflammatory reaction at the site of the patch indicates a positive test or presence of parasite. Loiasis The African eye worm, Loa loa, causes Calabar swellings or loiasis. This disease is limited only to a small part of West Africa and is of no public health importance. Eradication efforts currently underway should assure its quick exit. The parasite is transmitted by the mango fly or deer fly, Chrysops spp. The infective larvae are deposited in the skin and mature in about one year. The adult worms migrate through the subcutaneous tissues where they produce typical swellings. They then mate and produce microfilariae. The migration of adult worms is slow and causes no pain, only possibly causing some distress when they are seen meandering over the bridge of the nose or lazily finding their way across the conjunctiva. The swellings are due to an inflammatory reaction to the parasite or its products and may cause some pain, rash and itching. Microfilariae may be found in the blood where they exhibit diurnal periodicity, being present immediately before and right after the noon hour (11:00am – 1:00pm). The worms do not damage the eye. They do not cause blindness. Serious complications are not common but may include cardiomyopathy, encephalopathy and nephropathy. Encephalitis due to the massive microfilaremia is often fatal. Diagnosis Clinical diagnosis may be based on presentation and visualization of the worm and evidence of exposure to the vector. Confirmation is by examination of blood smears for the typical sheathed microfilariae. Antigen detection methods are also available Treatment of Lymphatic filariasis, Elephantiasis, Onchocerciasis, Loiasis Diethylcarbamazine Citrate (Dec) DEC is the drug of choice for filariasis, elephantiasis, and loiasis. It has also been used in some cases of onchocerciasis. DEC immobilizes microfilariae, alters the organism’s surface structure, and displaces the parasite from tissues. Once exposed, the host immune system is able to more easily eliminate the worm. The drug is given orally and has a wide body distribution. It is eliminated renally and requires dosage adjustments in patients with renal insufficiency. Side effects directly related to the drug are thought to be minor and transient and include, headache, nausea, and malaise. Reactions related to the release of proteins from the death of microfilariae and/or adult worms can potentially be severe in some infections both locally and systemically. Ivermectin Ivermectin is the drug of choice to treat onchocerciasis and could also be used as a second line agent or in combination with DEC for other infections. Ivermectin appears to paralyze nematodes and arthropods by intensifying γ-aminobutyric acid (GABA)-mediated transmission of signals in peripheral nerves. Ivermectin does not kill adult worms but blocks the release of microfilariae for several months after a single dose. With repeated dosing, the drug appears to permanently reduce microfilaria production. For onchocerciasis, after acute treatment, doses are repeated at 12-month intervals until the adult worms die which can be 10 years or longer. Ivermectin is administered orally, has a wide volume of distribution and is eliminated in the feces. Adverse effects of ivermectin are considered mild and are commonly associated with the killing of microfilariae. Effects start on initial day of treatment, peak on the second day and then begin to subside. Acute treatment is usually accompanied with a corticosteroid to lessen the adverse reactions. Guinea Worm The disease ‘guinea worm’ got its name from the Central African country where it was described in recent times even though the disease was well known in ancient times among the Egyptians, the Greeks and the Romans. The staff of the Roman god of medicine, Aesculapius, is believed to show the causative agent, Dracunculus medinensis, wound around a stick. This parasite is probably not a true filaria worm but is included here for convenience. Human infection occurs following the ingestion of infected water fleas, Cyclops, which are the vectors for the parasite. These crustacean copepods are found in contaminated water. Thus, the disease may be found in those areas of the world where water is ingested untreated. Simple boiling or filtration removes or kills the vector and prevents transmission. Following ingestion of an infected copepod, the larvae are released and they penetrate the duodenal mucosa and develop into adults in loose connective tissue. The female adult worm is very long, measuring up to 1m. When gravid, it migrates to the subcutaneous tissues of the skin and eventually forms a papule in the dermis. A blister eventually forms. Finally, the blister ulcerates and when immersed in water, the worm discharged large numbers of larvae, which are ingested by the copepod. Secondary bacterial infection of the blisters may occur. Diagnosis Diagnosis may be made when cutaneous lesions form and adult worms may be visible. Typically, the lesions are localized but may be quite debilitating. The blisters or ulcers may be very painful. Calcified worms may be seen on x-ray of subcutaneous nodules. The disease is limited to a few isolated areas of the world where it may reach epidemic proportions. Although there is no pharmacologic treatment available, the disease can be easily eradicated by removing the worm and caring for the wound. Miscellaneous Parasites Infections by many other parasites, such as Taenia solium, Trichinella spiralis, Toxoplasma gondii, Echinococcus granulosus, Necator americanus, Schistosoma mansoni and Entamoeba histolytica, may occasionally present with cardiovascular manifestations. These organisms are discussed elsewhere. Such infections may sometimes complicate diagnoses and should be considered whenever indicated by epidemiological factors.