CHAPTER 133 Parasitic Infections

CHAPTER 133 Parasitic Infections Bruce M. Becker and John D. Cahill PERSPECTIVE Challenge Parasitology has become increasingly important in the practice of emergency medicine. There has been a dramatic increase in immigration from Southeast Asia, Central and South America, and Africa into the United States during the last few decades. Many of the people in transit have left their countries of origin under dire circumstances, fleeing civil unrest, war, famine, economic hardship, political persecution, and environmental devastation; they often lived in regions where parasitic infections were endemic. Business and adventure travel, including ecotourism, frequently transports immunologically naïve and vulnerable hosts to sites rich in parasitic disease (Fig. 133-1). Patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) who travel to countries where parasitic illnesses are endemic are at higher risk of contracting these illnesses. Patients with AIDS who immigrate or travel to the United States or Europe may harbor a number of devastating parasitic illnesses. There is a significant prevalence of endemic parasitic disease in many rural areas of the southeastern and southwestern United States and in some parts of Europe. Often, patients with parasitic illness initially seek treatment in the emergency department (ED). Correct diagnosis of and prompt chemotherapy for parasitic illness often lead to rapid recovery (Table 133-1); mismanagement can be disastrous. Osler wrote, Early in the course of disease, diagnosis is difficult and treatment easy; late in the course, diagnosis is easy and treatment difficult. Parasitic illness often begins insidiously; without appropriate treatment, the disease will pursue a chronic course, resulting in damage to the host s end organs, severe morbidity, and even death. To diagnose parasitic infection, the emergency physician must play detective, obtaining a thorough travel history, performing a detailed physical examination, and ordering appropriate laboratory studies. This information must be integrated into a strong understanding of the basic life cycles of parasites, the usual and unusual presentations of infection, and the intersecting geography of the organism and the host. The incubation period for the development of symptoms for parasitic diseases ranges from s (falciparum malaria) to months (vivax malaria) to years (filariasis). Uncovering parasitic illness depends heavily on Osler s principle to make the diagnosis, the clinician must first think of the diagnosis. Travel History Parasitic illness should be considered in the differential diagnosis of almost every sign or symptom imaginable, particularly in patients who recently have spent time in areas of the world with endemic parasitic illnesses (Table 133-2). Accordingly, a travel history should be included in the evaluation of most if not all patients presenting to the ED. Some of the most important questions are summarized in Box 133-1. For patients who have recently immigrated to the United States, the history should elicit additional information specific to the country of origin, also summarized in Box 133-1. PRINCIPLES OF THERAPY New and more effective antiparasitic agents are continually being developed. The list of drugs used to treat parasitic infestations is large and varied. Table 133-3 includes some of the newest pharmaceutical agents along with other older medications that are still recommended but have become almost obsolete because of toxicity or mediocre efficacy. The newer antiparasitic drugs are less toxic and more effective. Parasite biochemical pathways are different from those in the human host, permitting selective metabolic interference by using relatively small doses of chemotherapeutic agents. In many instances, single-dose treatment can eradicate an entire parasite burden, leading to implementation of effective mass treatment programs in infected populations in endemic areas. Treatment and disposition in the ED focus on the individual patient and the particular disease entity. The evolutionary goal of the successful parasite is to live with and at the expense of the living host; a parasite that kills its host has no survival advantage. Most parasitic infections (with certain important exceptions, such as falciparum malaria) pursue a chronic course and are not acutely life-threatening. Nevertheless, alterations in host immune function can change the virulence and morbid course of more benign infections (i.e., strongyloidiasis can become fulminantly disseminated in patients receiving immunosuppressive medication after organ transplantation or after the initiation of long-term steroid therapy). Because of the subacute or chronic nature of most parasitic infections, the clinician should first make a diagnosis and initiate chemotherapy, then arrange careful follow-up and repeated laboratory examinations to ensure that the patient is cured. When the parasites are not eliminated promptly, repeated doses or alternative drugs may be needed because drug resistance among parasitic organisms is becoming increasingly common. In cases of suspected drug resistance, referral to a geographic medicine or infectious disease clinic is indicated. A patient who appears clinically ill or has presumptive falciparum malaria (by symptoms or travel history) will usually require hospitalization for initial diagnosis, treatment, and observation. 1768

Schistosoma Schistosoma haematobium mansoni Red blood cell Schistosoma japonicum Taenia spp. 0 50 100 150 200 µm Ascaris lumbricoides Clonorchis sinensis Paragonimus westermani Fasciola and Fasciolopsis hepatica buski Normal Decorticated Embryonated Unfertilized Trichuris trichiura Enterobius vermicularis Fresh Ancylostoma duodenale Developed Figure 133-1. Eggs of major parasitic worms causing disease in humans. PRESENTING SYMPTOMS Fever Malaria Principles of Disease. The febrile patient with shaking chills and a time-appropriate history of travel to an endemic region requires evaluation for malaria. Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, and Plasmodium malariae are the species responsible for human malaria. More than 41% of the world s population lives in malaria-endemic areas (e.g., parts of Africa, Asia, Oceania, Central America, and South America). Approximately 300 million to 500 million clinical infections occur annually, resulting in 1.5 million to 2.7 million deaths. 1 Approximately 1500 cases of malaria are diagnosed yearly in the United States. The female Anopheles mosquito is the arthropod vector that transmits malaria after ingestion of gametocytes from infected persons. After sexual reproduction in the gut of the mosquito, sporozoites are released from the salivary glands into the human host during a blood meal. Sporozoites rapidly penetrate the liver parenchymal cells of their host. The protozoans, now termed cryptozoites or exoerythrocytic schizonts, multiply rapidly. Eventual lysis of the hepatic cells results in the release of merozoites into the bloodstream, which invade erythrocytes. In P. vivax and P. ovale infection, dormant hypnozoites can reside in hepatocytes; recrudescence of infections can occur many months to years later. After invading red blood cells (RBCs), the merozoites transform into trophozoites, which feed on the hemoglobin in RBCs. Trophozoites mature into schizonts, which divide asexually into additional merozoites. The RBCs undergo lysis, releasing merozoites into the blood. Although some merozoites are destroyed by the BOX 133-1 Chapter 133 / Parasitic Infections 1769 Comprehensive Travel History for Evaluation of Parasitic Disease in the Emergency Department Questions for All Patients What were the exact dates of travel? What countries did the patient visit? How much time was spent in each country? What was the patient doing in the country, and where was he or she living? Was the patient a tourist, an adventure traveler, or a worker? Did the patient stay in cities or rural villages? Was the patient sleeping in hotels or tents? Did the patient engage in protected or unprotected sexual intercourse? What did the patient eat and drink? What were the patient s activities (e.g., swimming in fresh water leads to schistosomiasis)? Did the patient receive prophylactic immunizations before travel? Did the patient take malaria chemoprophylaxis and comply with the regimen? Did the patient use mosquito repellent and netting? Does the patient have underlying chronic medical problems? What medications does the patient take? When did symptoms start, and what has been the chronology of symptoms, particularly fever and diarrhea? Questions for Patients Who Are Recent Immigrants to the United States When did the patient arrive and from where? What acute and chronic illnesses did the patient have previously while living in the country of origin? What treatment did the patient receive there? If a refugee, what countries did the patient pass through, and what were the living conditions (especially relevant for persons who have lived in numerous refugee camps)? What was the season during the patient s stay or travel in the countries (e.g., monsoon versus dry)? What animal exposures and bites has the patient experienced? Has the patient had exposure to fresh water, in either work or recreational activities? host s immune system, many enter new erythrocytes. After several repetitions of this erythrocytic cycle, the cyclic process changes, and male microgametocytes or female macrogametocytes may develop instead of merozoites. These gametes subsequently complete the reproductive cycle by fusion, which is accomplished sexually within the gut of a new female Anopheles mosquito after she has taken a blood meal from an infected host. Most people contract malaria after being bitten by an infected vector mosquito in an endemic region. Other mechanisms of transmission have been reported, including blood transfusions, injection drug use with contaminated syringes, maternal-fetal perinatal transmission, transmission from infected organs after transplantation (worsened by immunosuppression), and so-called airport malaria. Airport malaria has been reported in people who have never been in an endemic area but live near or work in an international airport. The infected mosquito is transported from the endemic region and released when the plane arrives at its destination. The mosquito survives long enough to transmit the parasite, although it does not establish itself in the new location. 2 Clinical Features. Most patients with malaria present with cyclic or irregular fevers. Other signs and symptoms include anemia, headache, nausea, chills, lethargy, abdominal pain, and upper respiratory complaints. 3 The important difference between P. falciparum and the other malaria species is the capacity of P. falciparum to cause severe organ system damage and death. RBCs infected with P. falciparum are rendered sticky and Text continued on p. 1776

1770 PART III Medicine and Surgery / Section Twelve Infectious Diseases Table 133-1 TYPE OF DRUG EXAMPLES* USEFUL IN THE TREATMENT OF Anthelmintics Thiabendazole Mebendazole Albendazole Ivermectin (Stromectol) Ascaris, Enterobius, hookworm, Strongyloides, Trichuris, hydatid disease (long-term therapy) Many nematodes of humans (except hookworms) Filariasis Onchocerciasis Trematodicides Praziquantel (Biltricide) Schistosomes Most other flukes, such as Clonorchis, Paragonimus, Fasciolopsis (many tapeworms of humans) Antiprotozoals Antimalarials Drug Classes and Modes of Action of Agents Used for Treatment of Parasitic Disease Metronidazole (Flagyl) Tinidazole Niridazole Amebiasis Balantidiasis Giardiasis Schistosoma haematobium LIKELY TARGET IN THE PARASITE Tubulin polymerization GABA-sensitive neuromuscular interface Surface structure Carbohydrate metabolism Molecular electron transport systems Acetylcholine recycling systems PROPOSED EFFECTS ON TARGETS Blocks cellular structural integrity and egg production; secondary effects on mitochondrial fumarate reductase and on glucose uptake Flaccidity or contraction (a tightbinding drug effective at low dose) Vacuolization and surface disruption followed by immune attacks by the host; contraction of the muscles due to flooding of calcium through a permeable tegument; initial increase of glucose metabolism followed by shutdown Failure to sustain energy-producing systems Binds to acetylcholinesterase, inactivating normal neuromuscular function Chloroquine phosphate (Aralen) Many species of susceptible malaria Parasite digestive vacuole hemoglobinase Local ph is changed so that enzyme becomes inoperative Mefloquine Many species of susceptible malaria Proguanil-atovaquone Many species of susceptible malaria Mitochondrial electron transport prevents the Works on both the erythrocytic and hepatic stages Doxycycline Many species of susceptible malaria normal function of the apicoplast Kills Plasmodium falciparum GABA, γ-aminobutyric acid. *Some drugs may be available only from the CDC Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333; telephone: 404-639-3670 (nights, weekends, and holis: 404-639-2888). Table 133-2 Parasites Causing Human Disease: Geographic Location and Portal of Entry PARASITE GEOGRAPHIC DISTRIBUTION COMMON INFECTIVE STAGE AND PORTAL OF ENTRY Protozoa Entamoeba histolytica Cosmopolitan, especially prevalent in warm climates Cyst via mouth Balantidium coli Warm climates Cyst via mouth Giardia lamblia Found all throughout temperate and warm climates Cyst via mouth Trichomonas vaginalis Cosmopolitan, United States Trophozoite via vulva or urethra Leishmania tropica Mediterranean area to western India Bite of sandfly introducing promastigote via skin leads to visceral disease Leishmania infantum Southern Europe and Mediterranean Bite of sandfly introducing promastigote via skin leads to visceral disease Leishmania donovani China, India, Africa, Mediterranean area, continental Latin America Bite of sandfly introducing promastigote via skin leads to visceral disease Leishmania chagasi South America Bite of sandfly introducing promastigote via skin leads to visceral disease Leishmania braziliensis South America and Central America Bite of sandfly introducing promastigote via skin leads to cutaneous or mucocutaneous disease Leishmania major and L. tropica Africa and Asia Bite of sandfly introducing promastigote via skin leads to cutaneous disease Leishmania mexicana, L. amazonensis, L. guyanensis, and L. costaricensis Central and South America Bite of sandfly introducing promastigote via skin leads to cutaneous disease Trypanosoma gambiense West and Central Africa Trypanosome via skin from bite of the tsetse fly

Chapter 133 / Parasitic Infections 1771 Table 133-2 PARASITE GEOGRAPHIC DISTRIBUTION COMMON INFECTIVE STAGE AND PORTAL OF ENTRY Trypanosoma rhodesiense Central and East Africa Trypanosome via skin from bite of the tsetse fly Trypanosoma cruzi Continental Latin America Trypanosome via skin from reduviid bug Plasmodium vivax Warm and cooler climates Sporozoite via skin from Anopheles mosquito Plasmodium ovale Warm and cooler climates Sporozoite via skin from Anopheles mosquito Plasmodium malariae Warm climates Sporozoite via skin from Anopheles mosquito Plasmodium falciparum Warm climates Sporozoite via skin from Anopheles mosquito Nematodes Trichinella spiralis Cooler and temperate climates Encysted larva in pork or bear via mouth Trichuris trichiura Warm, moist climates Embryonated egg via mouth Strongyloides stercoralis Warm, moist climates Filariform larva via skin Necator americanus Common in warm climates Filariform larva via skin Ancylostoma duodenale Common in warm climates Filariform larva via skin Enterobius vermicularis Cosmopolitan, common in the United States Embryonated egg via mouth Ascaris lumbricoides Global distribution, common in the United States Embryonated egg via mouth Wuchereria bancrofti Prevalent in warm climates Filariform larva via skin from bite of Anopheles or Culex mosquito Brugia malayi Asia Filariform larva via skin from bite of Anopheles or Culex mosquito Onchocerca volvulus Tropical Africa, Mexico, Central America, and northern South America Filariform larva via skin from bite of the blackfly Loa loa Tropical West Africa Filariform larva via skin from bite of the Chrysops fly Dracunculus medinensis Increasingly rare Ingestion of larva by copepod via mouth Cestodes Taenia saginata Taenia solium Adult worm Cysticercus stage Echinococcus granulosus Global distribution, uncommon in the United States South America, Central America, Mexico, East Africa, India, China, Indonesia Mediterranean, Russian Federation and neighboring countries, China, Central Asia, North and East Africa, and South America Cysticercus in beef via mouth Cysticercus in pork via mouth Eggs in human infections via mouth Eggs from canines via fecal-oral transmission Echinococcus multilocularis Central Europe, northern Asia, Alaska Eggs from foxes, dogs, and cats via fecal-oral transmission Hymenolepis nana Warm climates Eggs in human infections via mouth Hymenolepis diminuta Warm climates Larva in arthropod host via mouth Diphyllobothrium latum Trematodes Parasites Causing Human Disease: Geographic Location and Portal of Entry cont d U.S. Great Lakes region and Alaska, Scandinavia, Russia, Japan, Pacific Coast of South America, and Uganda Sparganum larva in fish flesh via mouth Fasciola hepatica Sheep-raising countries Larva on vegetation via mouth Fasciolopsis buski Asia Larva on water nuts Clonorchis sinensis Asia Larva encysted in freshwater fish Opisthorchis felineus Europe, Asia Larva encysted in freshwater fish Opisthorchis viverrini Thailand Larva encysted in freshwater fish Paragonimus westermani Primarily Asia, also South America and Africa Larva encysted in crabs or crayfish via mouth Schistosoma japonicum China, Southeast Asia, Philippines Cercarial larva in water via skin Schistosoma mansoni Africa, Latin America, Middle East, Caribbean Cercarial larva in water via skin Schistosoma haematobium Africa, Middle East Cercarial larva in water via skin Modified from Beaver PC, et al: Clinical Parasitology, ed 9. Philadelphia, Lea & Febiger, 1984.

1772 PART III Medicine and Surgery / Section Twelve Infectious Diseases Table 133-3 INFECTION DRUG* ADULT DOSAGE PEDIATRIC DOSAGE Amebiasis (Entamoeba histolytica) Asymptomatic drug of choice: Iodoquinol 650 mg tid 20 s 30 mg/kg/ in 3 doses 20 s alternatives: Diloxanide furoate 500 mg tid 10 s 25-35 mg/kg/ in 3 doses 7 s or Paromomycin 25-30 mg/kg/ in 3 doses 7 s 25-30 mg/kg/ in 3 doses 7 s Mild to moderate intestinal disease drug of choice: Metronidazole (followed by 750 mg tid 10 s 35-50 mg/kg/ in 3 doses 10 alternative: Severe intestinal disease, hepatic abscess drug of choice: Drainage of liver abscess alternative: paromomycin or iodoquinol) Tinidazole (followed by paromomycin or iodoquinol) Metronidazole (followed by paromomycin or iodoquinol) Tinidazole (followed by paromomycin or iodoquinol) s 2 g/ 3 s 50 mg/kg (maximum 2 g) qd 3 s 750 mg IV or PO tid 10 s 35-50 mg/kg/ in 3 doses 10 s 2 g/ 5 s 50 mg/kg or 60 mg/kg (maximum 2 g) qd 3 s Amebic meningoencephalitis, primary (Naegleria spp.) drug of choice: Amphotericin B 1 mg/kg/ IV, uncertain duration 1 mg/kg/ IV, uncertain duration Anisakiasis (Anisakis) treatment of choice: Drug Regimens for Treatment of Parasitic Infections Surgical or endoscopic removal Ascariasis (Ascaris lumbricoides): roundworm drugs of choice: Mebendazole 100 mg bid 3 s 100 mg bid 3 s Albendazole 400 mg one dose Older than 6 years, same dose as for adult Nitazoxanide 500 mg bid 3 s 200 mg bid 3 s Ivermectin 150-200 µg/kg for one dose Should be avoided in young children Balantidiasis (Balantidium coli) drug of choice: Tetracycline 500 mg qid 10 s 40 mg/kg/ in 4 doses 10 s (maximum 2 g/) alternatives: Iodoquinol 650 mg tid 20 s 40 mg/kg/ in 3 doses 20 s Metronidazole 750 mg tid 5 s 35-50 mg/kg/ in 3 doses 5 s Cutaneous larva migrans (creeping eruption) drug of choice: Ivermectin 200 µg/kg once daily 1 or 2 s Dracunculus medinensis (Guinea worm) drug of choice: Worm also needs to be extracted Metronidazole 750 mg tid 5-10 s 25 mg/kg/ (maximum 750 mg/ ) in 2 doses 10 s alternative: Thiabendazole 50-75 mg/ in 2 doses 3 s 50-75 mg/kg/ in 2 doses 3 s Enterobius vermicularis (pinworm) drugs of choice: Albendazole A single dose of 400 mg; repeat after 2 weeks Mebendazole A single dose of 100 mg; repeat after 2 weeks 11 mg/kg once (maximum 1 g); repeat after 2 weeks A single dose of 100 mg; repeat after 2 weeks Filariasis Wuchereria bancrofti, Brugia malayi drug of choice: Diethylcarbamazine Day 1: 50 mg PO Day 1: 1 mg/kg PO Day 2: 50 mg tid Day 2: 1 mg/kg tid Day 3: 100 mg tid Day 3: 1-2 mg/kg tid Days 4-21: 6 mg/kg/ in 3 doses Days 4-21: 6 mg/kg/ in 3 doses Loa loa drug of choice: Diethylcarbamazine Day 1: 50 mg PO Day 1: 1 mg/kg PO Day 2: 50 mg tid Day 2: 1 mg/kg tid Day 3: 100 mg tid Day 3: 1-2 mg/kg tid Days 4-21: 9 mg/kg/ in 3 doses Onchocerca volvulus drug of choice: Ivermectin 150 µg/kg PO once, repeated every 3-12 months Days 4-21: 6 mg/kg/ in 3 doses 150 µg/kg PO once, repeated every 3-12 months

Chapter 133 / Parasitic Infections 1773 Table 133-3 Drug Regimens for Treatment of Parasitic Infections cont d INFECTION DRUG* ADULT DOSAGE PEDIATRIC DOSAGE Fluke, hermaphroditic Clonorchis sinensis (Chinese liver fluke) drug of choice: Praziquantel 25 mg/kg/ in 4-6 doses 1 25 mg/kg/ in 4-6 doses 1 Fasciola hepatica (sheep liver fluke) drug of choice: Bithionol 30-50 mg/kg on alternate s 10-15 doses Fasciolopsis buski (intestinal fluke) drug of choice: Praziquantel 25 mg/kg/ in 4 to 6 doses 1 Opisthorchis felineus drug of choice: Praziquantel 25 mg/kg/ in 4 to 6 doses 1 Paragonimus westermani (lung fluke) drug of choice: Praziquantel 25 mg/kg/ in 4 to 6 doses 2 s alternative: Bithionol 30-50 mg/kg on alternate s 10-15 doses 30-50 mg/kg on alternate s 10-15 doses 25 mg/kg/ in 4 to 6 doses 1 25 mg/kg/ in 4 to 6 doses 1 25 mg/kg/ in 4 to 6 doses 2 s 30-50 mg/kg on alternate s 10-15 doses Giardiasis (Giardia lamblia) drug of choice: Metronidazole 250 mg tid 5 to 7 s 15 mg/kg/ in 3 doses 5 to 7 s alternatives: Nitazoxanide 500 mg bid 3 s 200 mg PO bid 3s (older than 4 years) Tinidazole 2 g as a single dose 50 mg/kg as a single dose Hookworm infection (Ancylostoma duodenale, Necator americanus) drugs of choice: Albendazole 400 mg one dose or Mebendazole 500 mg one dose 500 mg one dose or Pyrantel pamoate 11 mg/kg (maximum 1 g) 3 s 11 mg/kg (maximum 1 g) 3 s Leishmaniasis (Leishmania braziliensis, Leishmania mexicana, Leishmania tropica, Leishmania donovani [kala-azar]) drug of choice: Miltefosine Not indicated in those 12 years or younger or Stibogluconate sodium 20 mg/kg/ IV or IM 20-28 s alternative: Amphotericin B 0.25-1 mg/kg by slow infusion daily or every 2 s for 8 weeks Malaria, treatment of (Plasmodium falciparum, P. ovale, P. vivax, and P. malariae) All Plasmodium species except chloroquine-resistant P. falciparum Oral drug of choice: Chloroquine phosphate 600 mg base (1 g), then 300 mg base (500 mg) 6 hr later, then 300 mg base (500 mg) at 24 and 48 hr Parenteral drugs of choice: Quinine dihydrochloride 20 mg/kg loading dose in 10 mg/ kg 5% dextrose during 4 hr, followed by 10 mg/kg during 2-4 hr q8h (maximum 1800 mg/ ) until oral therapy can be started or Quinidine gluconate or Artesunate for treatment failure or adverse reactions from quinidine or quinine, available from the CDC 10 mg/kg loading dose (maximum 600 mg) in normal saline slowly during 1-2 hr, followed by continuous infusion of 0.02 mg/ kg/min for 3 s maximum 2.5 mg/kg/ PO 28 s 20 mg/kg/ IV or IM 20-28 s 0.25-1 mg/kg by slow infusion daily or every 2 s for 8 weeks 10 mg base/kg (maximum 600 mg base), then 5 mg base/kg 6 hr later, then 5 mg base/kg at 24 and 48 hr Same as adult dose Same as adult dose Continued

1774 PART III Medicine and Surgery / Section Twelve Infectious Diseases Table 133-3 Drug Regimens for Treatment of Parasitic Infections cont d INFECTION DRUG* ADULT DOSAGE PEDIATRIC DOSAGE alternative: Chloroquine hydrochloride 200 mg base (250 mg) IM q6h if oral therapy cannot be started 0.83 mg base/kg/hr 30 hr continuous infusion or 3.5 mg base/kg q6h IM or SC Chloroquine-resistant P. falciparum Oral drugs of choice: Quinine sulfate 650 mg tid 3 s 25 mg/kg/ in 3 doses 3-7 s plus Doxycycline 100 mg bid 7 s or Clindamycin 900 mg tid 3-5 s 20-40 mg/kg/ in 3 doses 3-5 s alternative: Mefloquine 1250 mg once 25 mg/kg once (<45 kg) Atovaquone-proguanil 1000/400 mg qd 3 s Artemether-lumefantrine 4 tabs bid 3 s Parenteral drugs of choice: Quinine dihydrochloride Same as above Same as above or Quinidine gluconate Same as above Same as above or Artesunate Same as above Same as above Prevention of relapses: P. vivax and P. ovale only drug of choice: Primaquine phosphate 15 mg base (26.3 mg)/ 14 s or 45 mg base (79 mg)/wk 8 weeks Malaria, prevention of drug of choice: Chloroquine phosphate 300 mg base (500 mg salt) PO, once a week beginning 1 week before and continuing for 4 weeks after last exposure Chloroquine-resistant areas drugs of choice: Mefloquine 250-mg tablet PO once a week 4 weeks, then every other week, continuing for 4 weeks after last exposure or Atovaquone-proguanil or Doxycycline 250/100 mg qd 1 before travel, each in endemic region, and for 1 week afterward 100 mg daily during exposure and for 4 weeks afterward Schistosomiasis Schistosoma haematobium drug of choice: Praziquantel 20 mg/kg/ in 4 to 6 doses 1 Schistosoma japonicum drug of choice: Praziquantel 20 mg/kg/ in 4 to 6 doses 1 Schistosoma mansoni drug of choice: Praziquantel 20 mg/kg/ in 4 to 6 doses 1 0.3 mg base/kg/ 14 s 5 mg/kg base (8.3 mg/kg salt) once a week, up to adult dose of 300 mg base, same schedule as for adult Same schedule as for adults with the following dosing guidelines: 15-19 kg: ¼tablet 20-30 kg: ½tablet 31-45 kg: ¾tablet >45 kg: 1 tablet >8 yr: 2 mg/kg/ PO, up to 100 mg/ 20 mg/kg/ in 4 to 6 doses 1 20 mg/kg/ in 4 to 6 doses 1 20 mg/kg/ in 4 to 6 doses 1 alternative: Oxamniquine 15 mg/kg once 20 mg/kg/ in 2 doses 1 Schistosoma mekongi drug of choice: Praziquantel 20 mg/kg/ in 4 to 6 doses 1 20 mg/kg/ in 4 to 6 doses 1 Strongyloidiasis (Strongyloides stercoralis) drugs of choice: Ivermectin 200 µg/kg/ 1-2 s 200 µg/kg/ 1-2 s or Thiabendazole 50 mg/kg/ in 2 doses (maximum 3 g/) 2 s Tapeworm infection, adult (intestinal stage) Diphyllobothrium latum (fish), Taenia saginata (beef), Taenia solium (pork), Dipylidium caninum (dog) drug of choice: Praziquantel 5-10 mg/kg once 5-10 mg/kg once Hymenolepis nana (dwarf tapeworm) drug of choice: Praziquantel 25 mg/kg once 25 mg/kg once 50 mg/kg/ in 2 doses (maximum 3 g/) 2 s

Chapter 133 / Parasitic Infections 1775 Table 133-3 INFECTION DRUG* ADULT DOSAGE PEDIATRIC DOSAGE Tapeworm infection, larval (tissue) stage Echinococcus granulosus (hydatid cysts) drug of choice: Albendazole 400 mg bid 28 s, repeated as necessary Echinococcus multilocularis treatment of choice: Cysticercus cellulosae (cysticercosis) Surgical excision 15 mg/kg/ 28 s, repeated as necessary drug of choice: Praziquantel 50 mg/kg/ in 3 doses 15 s 50 mg/kg/ in 3 doses 15 s alternative: Surgery Trichinosis (Trichinella spiralis) drugs of choice: Drug Regimens for Treatment of Parasitic Infections cont d Steroids for severe symptoms plus Mebendazole 200-400 mg tid 3 s, then 400-500 mg tid 10 s Trichomoniasis (Trichomonas vaginalis) drug of choice: Metronidazole 2 g once or 250 mg tid or 375 mg bid PO 7 s Same as adult dose 15 mg/kg/ PO in 3 doses 7 s Trichuriasis (Trichuris trichiura, whipworm) drugs of choice: Mebendazole 100 mg bid 3 s 100 mg bid 3 s or Albendazole 400 mg once 400 mg once Trypanosomiasis Trypanosoma cruzi (South American trypanosomiasis, Chagas disease) drug of choice: Nifurtimox 8-10 mg/kg/ PO in 4 doses 120 s 1-10 yr: 15-20 mg/kg/ in 4 doses 90 s 11-16 yr: 12.5-15 mg/kg/ in 4 doses 90 s alternative: Benznidazole 5-7 mg/kg/ 30-120 s Same as adult dose Trypanosoma brucei gambiense, Trypanosoma brucei rhodesiense (African trypanosomiasis, sleeping sickness), hemolymphatic stage drug of choice: Suramin 100-200 mg (test dose) IV, then 1 g IV on s 1, 3, 7, 14, and 21 20 mg/kg on s 1, 3, 7, 14, and 21 alternative: Pentamidine isethionate 4 mg/kg/ IM 10 s 4 mg/kg/ IM 10 s Late disease with central nervous system involvement drug of choice: Melarsoprol 2-3.6 mg/kg/ IV 3 s; after 1 week, 3.6 mg/kg/ IV 3 s; repeat again after 10-21 s alternatives (T. b. gambiense only): Tryparsamide plus Suramin One injection of 30 mg/kg (maximum 2 g) IV every 5 s to total of 12 injections; course may be repeated after 1 month One injection of 10 mg/kg IV every 5 s to total of 12 injections; course may be repeated after 1 month 18-25 mg/kg total during 1 month; initial dose of 0.36 mg/kg IV, increasing gradually to maximum 3.6 mg/kg at intervals of 1-5 s for total of 9-10 doses Unknown Unknown Visceral larva migrans (toxocariasis) drug of choice: Diethylcarbamazine 6 mg/kg/ in 3 doses 7-10 s 6 mg/kg/ in 3 doses 7-10 s alternatives: Mebendazole 100-200 mg bid 5 s Same as adult dose or Albendazole 400 mg bid 3-5 s 400 mg bid 3-5 s Modified from Drugs for parasite infections. Med Lett Drugs Ther 37:99, 1995. *Some drugs may be available only from the CDC Drug Service, Centers for Disease Control and Prevention, Atlanta, GA 30333; telephone: 404-639-3670 (nights, weekends, and holis: 404-639-2888).

1776 PART III Medicine and Surgery / Section Twelve Infectious Diseases sludge in small arterioles and capillaries, causing ischemia in the host s metabolically sensitive organs. Acute falciparum infection may have any of the following manifestations: cerebral malaria with cerebral edema and encephalopathy, hypoglycemia (especially in children), metabolic acidosis, severe anemia, renal failure, pulmonary edema, disseminated intravascular coagulation, and death. In chronic malaria, increased cellularity from the host s exuberant immune response may lead to hepatosplenomegaly. Within the liver, parasites and malarial pigment distend the Kupffer cells. Parasitized RBCs also adhere to the sinusoidal system of the spleen, reducing its immunologic effectiveness. Anemia results from acute and chronic hemolysis. So-called blackwater fever hemoglobinuria caused by severe hemolysis may occur in patients with either chronic or acute falciparum malaria. Diagnostic Strategies. Light microscopic examination of thick and thin blood films is the gold standard approach to diagnosis of malaria. The clinician may have to view several slides and multiple fields to make the diagnosis if the parasite burden is small. Peripheral blood smears are stained with Giemsa or Wright stain and examined with ordinary light microscopy. The diagnosis can be made in a simply equipped laboratory. Even if the parasite is not visualized in the smear, treatment of malaria is indicated if the disease is suspected on clinical grounds. The U.S. Food and Drug Administration has approved the use of an antigen-based rapid diagnostic test for screening of patients. Microscopy should still be performed for all patients who have positive antigen test results to determine species and the severity of parasitemia. Management. In the past, chloroquine phosphate was the treatment of choice for acute, uncomplicated attacks of malaria. Resistance to chloroquine has been steadily increasing, and the drug is now recommended only in regions of known chloroquine sensitivity: Haiti, Dominican Republic, Central America, and limited regions of the Middle East. For uncomplicated malarial infections in patients from chloroquine-resistant regions, oral quinine and doxycycline given together may be used. Another suitable alternative combination is proguanil-atovaquone. For complicated P. falciparum infection (e.g., cerebral malaria, involvement of multiple organ systems, inability to tolerate oral medication), intravenous quinine (not available in intravenous form in the United States) or quinidine is used. Rapid infusion of intravenous quinine can cause profound hypoglycemia. Patients should not receive intravenous quinine without cardiac monitoring. The artemisinin agents are excellent antimalarials and are available in enteral and parenteral preparations. They have a rapid onset of action and are well tolerated. An oral agent known as artemether-lumefantrine (Coartem) is now available for uncomplicated malaria. The other artemisinins are not approved for use in the United States; however, parenteral artesunate is available as an investigational drug for patients who have complicated malaria not responding to quinidine. To obtain this drug, contact the Centers for Disease Control and Prevention (CDC) Malaria Hotline at 770-488-7788 or, during off hours, at 770-448-7100. 4 Primaquine is used to eliminate the hepatic phases of P. ovale and P. vivax to prevent recrudescent disease. Primaquine therapy is contraindicated in patients with glucose-6-phosphate dehydrogenase enzyme deficiency because it will precipitate severe hemolysis. Untreated falciparum malaria can lead to coma and death; early treatment reduces morbidity and mortality. Babesiosis Babesiosis is a malaria-like illness that is becoming increasingly prevalent in the northeastern United States (Babesia microti), the northwestern United States (Babesia gibsoni), and Europe (Babesia divergens). Babesiosis is endemic on Martha s Vineyard and Nantucket and is suspected, along with ehrlichiosis and Lyme disease, in patients on the cape and islands presenting with the summer flu. The organism is a protozoan, similar in structure and life cycle to the plasmodia. It is transmitted by the deer tick Ixodes dammini, the vector of Lyme disease. Several cases have been attributed to transfusions with infected blood. 5 Patients with babesiosis experience fatigue, anorexia, malaise, and emotional lability, with myalgia, chills, high spiking fevers, sweats, headache, and dark urine. Other manifestations include hepatosplenomegaly, anemia, thrombocytopenia, leukopenia, elevated liver enzymes (particularly the transaminases), and signs of hemolysis with hyperbilirubinemia and decreased haptoglobin. In an otherwise healthy person, the disease may remit spontaneously. In asplenic, elderly, and immunocompromised patients (especially patients with AIDS and those taking corticosteroids), up to 85% of RBCs may contain organisms. Clinical syndromes in these patients include massive hemolysis, jaundice, renal failure, disseminated intravascular coagulation, hypotension, and adult respiratory distress syndrome. Diagnosis is based on clinical suspicion, multiple thin and thick blood smears (Babesia organisms resemble plasmodia in blood smears), and serologic testing (convalescent titers may not be positive for several weeks after the infection). The treatment of choice consists of quinine plus clindamycin. 6 Patients infected with B. divergens tend to be sicker and require more supportive care. Coinfection with Borrelia burgdorferi, the agent of Lyme disease, results in more severe and prolonged illness. Other Parasites Causing Fever Other parasitic illnesses that commonly cause significant fever include schistosomiasis, fascioliasis, African and American trypanosomiasis, leishmaniasis, toxoplasmosis, and amebic liver abscess. Katayama fever may be the initial phase of schistosomiasis. Infected patients report brief exposures to fresh water in endemic areas. Clinical manifestations include spiking fevers, diaphoresis, and cough. Eosinophilia is common. 7 Fascioliasis, caused by the liver fluke Fasciola hepatica, is endemic throughout Asia, the former Soviet Union, southern Europe, and South America. Infection begins with ingestion of the metacercariae often found in watercress. Within 6 weeks, patients exhibit right upper quadrant abdominal pain, fever, and eosinophilia. 8 American trypanosomiasis (Chagas disease) is endemic to Central and South America. The vector, the reduviid bug, sheds trypomastigotes in its feces proximal to the bite site. The host responds to local inflammation and infection by excoriating the site, inoculating the wound with trypomastigotes and initiating systemic spread. Acute Chagas disease begins with a chagoma, an infected and swollen bite site, often periorbital, and quickly progresses to fever, malaise, facial swelling, and pedal edema. Parasitization of cardiac muscle leads to the dysrhythmias and ventricular dysfunction that are classically found in late disease (chronic Chagas cardiopathy). 9 Leishmaniasis is spread to humans by the sandfly and is found in the Middle East, in India, in East Africa, along the Mediterranean coast, and in Brazil. Although leishmaniasis can involve the skin (cutaneous) and the mucosa (mucosal), fever is seen only in visceral leishmaniasis in immunocompetent persons. Signs and symptoms also include massive hepatosplenomegaly, neutropenia, and weight loss. 10 The patient who has amebic liver abscesses from Entamoeba histolytica infection presents with high fevers, right upper quadrant pain, and elevated white blood cell count. 11 Neurologic Symptoms Cerebral Malaria Principles of Disease and Clinical Features. Cerebral malaria is a common, life-threatening complication of P. falciparum infection.

Parasitized RBCs express malarial cell surface glycoproteins called knobs that are sticky. They adhere to capillary walls, causing sludging in the cerebral microvasculature, localized ischemia, capillary leak, and petechial hemorrhages. Clinical manifestations include fever, altered mentation including obtundation, coma, and occasionally seizures. A careful history and early diagnosis and therapy are essential to prevent severe morbidity and death. Management. Treatment of cerebral malaria consists of intravenous quinine, quinidine, or artemisinin (if it is available); supportive care, including mechanical ventilation for comatose patients and patients with noncardiogenic pulmonary edema; antiepileptics; and correction of acidosis and hypoglycemia (associated with quinine use and cerebral malaria). The mortality rate is high, especially in children, but if the patient recovers, neurologic sequelae are rare. Corticosteroids, including dexamethasone, provide no benefit and can worsen outcome in cerebral malaria. Cysticercosis Principles of Disease. Cysticercosis is caused by the larval form of Taenia solium, a common central nervous system (CNS) pathogen in many tropical areas. Cysticercosis is acquired by humans who eat undercooked pork containing the larval cysts. The adult worm matures in the small intestine; the larval forms may penetrate through the gut wall and end up anywhere in the body. They are trophic for the CNS, muscle, and soft tissue. Clinical Features. In the brain, the cluster of larvae of T. solium forms an expanding cyst that induces an intense immunologic reaction from the host, including inflammation, fibrosis, and ultimately calcification. Neurologic abnormalities develop when neural tissue cannot accommodate the enlarging cyst. Seizure activity often is the first indication of cysticercosis, which should be considered in the differential diagnosis of new-onset seizures in adults. The diagnosis of T. solium infection is established by the finding of characteristic proglottids (gravid segments) or scolices (worm heads) in stool preparations. Diagnostic Strategies and Management. Cranial computed tomography (CT) with contrast enhancement or magnetic resonance imaging may reveal an enhancing ring lesion. These lesions can mimic a CNS abscess, metastatic malignant disease, or a primary tumor such as glioblastoma multiforme. Albendazole is the therapeutic agent of choice, and corticosteroids and antiepileptics may be necessary during therapy, particularly if CNS cysts are present. 12,13 Neurosurgical consultation should be sought in the treatment of neurocysticercosis because acute obstructive hydrocephalus can occur. Echinococcosis Principles of Disease and Clinical Features. Echinococcus granulosus is another tapeworm capable of causing CNS disease. Cerebral hydatid cysts are loculated structures containing E. granulosus scolices (heads) and the remains of the germinal epithelium, termed hydatid sand. Common types of exposure include ingestion of food or water contaminated by the ova from feces of sheep or cattle infected by the adult worm and close contact with an infected sheep-herding dog that is shedding ova. Infection results in the liberation of the embryo oncosphere into the small intestine. After penetrating the intestinal wall, the larvae travel through the bloodstream to multiple sites for encystment. The liver is the target organ in nearly two thirds of cases, but 7% of patients have brain involvement; infected patients may present with seizures or focal neurologic signs. Diagnostic Strategies and Management. The diagnosis of hydatid cyst disease is suggested by the appearance and localization of the cyst on ultrasound examination or CT scan. Serologic Chapter 133 / Parasitic Infections 1777 Figure 133-2. Hydatid cysts removed surgically. Figure 133-3. Additional hydatid cysts removed surgically. evaluation of serum or cerebrospinal fluid (CSF) may help confirm the diagnosis. Aspiration of the cyst should not be attempted because of the risk of seeding the host s body with metastatic cysts. Treatment options include albendazole and surgical resection. Resection of the cyst may cause an anaphylactoid reaction if there is spillage of hydatid sand, which contains parasite antigenic proteins (Figs. 133-2 and 133-3). 14 African Trypanosomiasis Principles of Disease. African sleeping sickness is caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. This infection is endemic in limited areas of West and East Africa. Several recent cases have been reported in returned travelers who were on safari in East Africa. The motile organisms are transmitted by the bite of the Glossina (tsetse) fly, which introduces the infective form of the trypanosome into the host s blood. A small lesion or boil may develop and persist for several s. The flagellated organism travels throughout the bloodstream, invading the lymph nodes and spleen. Clinical Features. Winterbottom s sign, which is posterior cervical lymphadenopathy, usually is apparent at the time of initial treatment. The patient generally is febrile, and trypanosomes are visible in a thick peripheral blood smear. A maculopapular rash can be seen in fair-skinned people. Once the parasite invades the CNS, cerebral inflammation causes severe headache. Patients may display a change of mental status, psychiatric symptoms, and eventually extreme sleepiness and lethargy. Coma and death from starvation and trypanotoxins are inevitable in untreated patients. 15

1778 PART III Medicine and Surgery / Section Twelve Infectious Diseases Diagnostic Strategies and Management. An appropriate exposure history and characteristic symptoms should prompt the clinician to obtain diagnostic studies. Trypanosomes in peripheral blood, CSF, or lymph node and bone marrow aspirates establish the diagnosis. The presence of parasites in the CSF indicates advanced progression of the disease. Suramin sodium is the treatment of choice for early infection with T. b. rhodesiense. Pentamidine isethionate is the preferred treatment of early T. b. gambiense infection. Trivalent arsenicals, such as melarsoprol, which can penetrate the blood-brain barrier, are used in advanced disease with neurologic sequelae. Other Parasites Causing Neurologic Symptoms CNS involvement with Trichinella spiralis has been reported in severe cases; larval migration of this parasite into the brain and meninges leads to meningitis, encephalitis, seizures, paresis, coma, and death. The pathophysiologic changes may reflect obstruction of small cerebral arterioles by migrating larvae, with subsequent vasculitis or cerebral edema resulting from inflammatory immunologic reaction to the larvae or larval fragments. Therapy for trichinosis with severe muscle or CNS involvement includes mebendazole or thiabendazole as well as steroids, which depress the host s inflammatory response to infection. 16 Amebic abscess of the brain or meningoencephalitis caused by E. histolytica is a rare complication of infection with this intestinal parasite. Infestation occurs after ingestion of amebic cysts. Spread of amebae to the brain or meninges from the colonized large bowel wall is rare but should be considered in any patient with amebiasis and subsequent neurologic impairment. The diagnosis may be made by microscopic identification of trophozoites (motile amebae) in CSF; however, biopsy of affected tissue is more specific. CNS amebiasis is treated with intravenous metronidazole but may require neurosurgical intervention. Naegleria and Acanthamoeba are free-living freshwater amebae that infect patients while they are swimming and diving in ponds and lakes. The amebae invade the CNS through the olfactory neuroepithelium or compromised corneal epithelium that has been violated by abrasion or contact lens wear, leading to amebic meningoencephalitis. The pharmacologic regimen of choice is amphotericin B and miconazole together when these motile amebae are identified in CSF. 17 Strongyloides stercoralis infection is a common disease in the tropics. The worm enters through the skin and migrates to the small bowel. Infection with Strongyloides is more clinically significant in immunosuppressed patients, who may suffer larval dissemination with subsequent encephalitis and pyogenic meningitis in the CNS. Strongyloides infection is treated with thiabendazole or albendazole. Ivermectin has recently been found to be as effective with fewer side effects. 18 Granulomas may occur in the brain from egg deposition by Schistosoma. In general, they do not cause major symptoms; however, several cases of transverse myelitis with paraplegia have been reported when the immunogenic and inflammatory eggs have lodged in the spinal cord of infected patients. Anemia Malaria Malaria infection often is associated with anemia, especially in children younger than 5 years (Fig. 133-4). Anemia may develop quickly, from massive hemolysis in acute infection, or it may have a more insidious onset, developing during months. Mature merozoites lyse parasitized RBCs. Uninfected RBCs undergo immune destruction from cell surface antibodies produced in Figure 133-4. Five-year-old child with severe life-threatening anemia (hematocrit of 9) in association with chronic malaria. response to parasite-associated changes in RBC surface proteins. This process of destruction is abetted by increased reticuloendothelial activity. The reticulocyte response in infected persons is blunted by inhibition of erythropoietin secretion. The antimalarial drug primaquine can precipitate hemolysis in patients who have glucose-6-phosphate dehydrogenase deficiency, which is common in many Africans and some Asians. Whipworm and Hookworm Infestation by the whipworm Trichuris trichiura and especially by the two human hookworms Necator americanus and Ancylostoma duodenale is a major cause of iron deficiency anemia worldwide. Adult worms penetrate into intestinal mucosa and feed, causing significant ongoing luminal blood loss. The host s feces contain eggs that mature in the soil through a rhabditiform larval form to the infective filariform larva. These larvae penetrate the human skin, usually through the feet. In trichuriasis, anemia is seen only with massive parasite infestation. Ova from the whipworm are ingested through stool-contaminated food and water. Diagnosis of these infections requires identification of characteristic ova in the stool. As with most helminthic infections, peripheral eosinophilia is common. Mebendazole or albendazole effectively controls trichuriasis and hookworm infections in adults and children. 19 Anemic patients should receive iron supplementation. Tapeworm Infection with the fish tapeworm Diphyllobothrium latum is associated with pernicious anemia. This tapeworm competes with the human host for absorption of vitamin B 12. When the host ingests raw freshwater fish that contains the embryo plerocercoid larvae in its muscle fibers, the large adult tapeworm develops within the human small intestine. The diagnosis is made by identification of the ova in the feces. Praziquantel is the drug of choice in adults and children. 20

Chapter 133 / Parasitic Infections 1779 Peripheral Edema Elephantiasis Principles of Disease. Elephantiasis, or filariasis, is manifested in the host by the development of massive peripheral edema with distention and thickening of the overlying epidermis, which acquires the appearance and texture of elephant skin. Elephantiasis is caused by infection with the filarial worm Wuchereria bancrofti or Brugia malayi. The infection is confined to humans and is widely distributed in the equatorial regions of the world, including Africa, Asia, South America, and Oceania. More than 90% of all infections are found in Asia, where the disease has reached epidemic proportions. Even in endemic regions in which most residents are infected, the disease is rare among travelers. Infected mosquitoes introduce microfilariae into the bloodstream of the human host during a blood meal. After infecting the host, the worms migrate into the lymphatic system and mature into coiled, gravid adults. The adult worm triggers a robust inflammatory reaction in the lymphatic vessels, particularly in the lower extremities and genitalia. The macrophages, lymphocytes, plasma cells, giant cells, and eosinophils migrate to the inflamed and fibrotic lymphatic vessel, which becomes erythematous, edematous, and tender, suggesting the diagnosis of filariasis. Clinical Features. Chronic manifestations of filariasis include fibrosis of a lymphatic vessel containing a dead or calcified worm. Subsequent mechanical blockage of the lymphatic system leads inevitably to severe lower extremity and genital edema accompanied by thickening of the skin. Recurrent cellulitis is common in these patients; prevention of superinfection requires meticulous skin care. Diagnostic Strategies and Management. The adult female worm produces microfilariae, which reach the peripheral blood through the lymphatics, whereupon the patient experiences shaking chills and fever. Thick peripheral blood smears may show infection, particularly at night, when the release of microfilariae is most common. Diethylcarbamazine rapidly clears the microfilariae from the peripheral blood and slowly sterilizes the gravid female nematode. Combined therapy with diethylcarbamazine and albendazole, or ivermectin and albendazole, may be more effective. 21 Established elephantiasis of the scrotum can be successfully treated surgically. Chronic lymphatic obstruction of the limbs rarely responds to operative intervention. Dermatologic Symptoms Cutaneous Leishmaniasis Principles of Disease. Cutaneous leishmaniasis is one of the most important causes of painless chronic ulcerating skin lesions in the world. Leishmania braziliensis and Leishmania mexicana are responsible for New World leishmaniasis; Leishmania tropica and Leishmania major commonly cause Old World leishmaniasis. The female Phlebotomus sandfly transmits the promastigotes during a blood meal, which are ingested by host macrophages and survive in their leishmanial form in the skin. Clinical Features. Skin papules and nodules are seen early in the course of infection at the site of the insect bite. A raised macule also can appear, which subsequently develops painless central ulceration and a raised border. Lymphocyte and macrophage invasions of the epidermis and dermis cause the induration that occurs at the ulcer border. Secondary bacterial infections of these ulcers increase the associated scarring. L. braziliensis braziliensis (subspecies of L. braziliensis) attacks the mucocutaneous skin borders (i.e., in tissues of the nose and mouth). Mutilation of the face occurs after massive tissue and nasal cartilage destruction. The larynx and trachea also can be involved, compromising the airway. Disseminated cutaneous leishmaniasis (L. mexicana amazonensis in South America and L. tropica aethiopica in Ethiopia) is characterized by diffuse nodules and papules resembling those of lepromatous leprosy (Fig. 133-5). Persons with this manifestation of leishmaniasis are thought to have a defect in their cell-mediated immunity response. Diagnostic Strategies and Management. Definitive diagnosis of leishmaniasis is made by direct visualization of the parasite with light microscopy. Diagnosis also can be made by an indirect fluorescent antibody test. Results of intradermal skin testing often are negative during the acute stages of the disease. Many forms of cutaneous leishmaniasis, especially L. tropica and L. mexicana infection, are self-limited and require no treatment unless the wounds become secondarily infected. Treatment options for advanced disease include sodium stibogluconate, meglumine antimoniate, and amphotericin B. An oral drug, miltefosine, has been used with success for treatment of both the visceral and the cutaneous forms of leishmaniasis. 22 These treatments are rarely initiated in the ED setting. Dracunculiasis Figure 133-5. Cutaneous leishmaniasis. Principles of Disease and Clinical Features. Dracunculus medinensis, the fiery serpent, appears in the host as the adult worm migrates through the subcutaneous tissues of the leg. The head of the gravid adult female erodes through the skin of the leg and releases larvae into the water when the host wades in a pond or open well. The larvae promptly infect the Cyclops water flea. Humans who drink water containing the infected crustacean complete the cycle of infection. The patient may complain of rash, intense pruritus, nausea, vomiting, dyspnea, and diarrhea before the female worm erupts through the skin. Management. The classic treatment in developing countries has been to wind the worm around a stick and slowly extract the parasite from the skin during the course of 1 or 2 s. If the worm breaks while it is being extracted, the patient experiences an intense inflammatory reaction with cellulitis along the worm track. The diagnosis is confirmed when microscopic larvae are found in the fluid of the cutaneous ulcer or when the adult female worm is identified extruding from the skin. The use of metronidazole to shorten the time of extraction is controversial. The World Health Organization set a goal to eradicate this disease through public health awareness: encouraging the covering of wells, filtering well water to remove the fleas, and keeping infected persons with active skin lesions out of potable water. These efforts have had a tremendous impact on the eradication of dracunculiasis from Africa. 23

1780 PART III Medicine and Surgery / Section Twelve Infectious Diseases Other Parasites Causing Dermatologic Symptoms Cutaneous larva migrans, the creeping eruption, occurs in the host s epidermis when the skin is penetrated by Ancylostoma braziliense (dog or cat hookworm) larvae. Exposure usually occurs after walking barefoot or lying on beaches or other warm soil contaminated by animal feces. The diagnosis is suggested by the presence of a characteristic meandering erythematous track on the skin surface caused by larval migration. Visceral larva migrans occurs in young children after ingestion of soil containing ova from the dog ascarid Toxocara canis. Thiabendazole, ivermectin, or albendazole may be used for treatment of cutaneous larva migrans, and antipruritics give symptomatic relief. Diethylcarbamazine treats visceral larva migrans. An alternative is thiabendazole. 24 Swimmer s itch is a dermatitis that occurs when skin is penetrated by the nonhuman schistosome of avians and mammals, usually from swimming in northern U.S. freshwater lakes. The infection spontaneously resolves when the nonhuman schistosome is destroyed by the human host s immune system. A similar dermatitis also can occur after infection with schistosome species that are trophic for humans. Treatment is symptomatic. Strongyloides can cause a transient, pruritic rash that may appear and then disappear within hours. Taenia solium can cause cysts in the soft tissues and muscles. These cysts often are an incidental finding. Onchocerciasis (from Onchocerca volvulus), which is commonplace in West Africa and parts of South America, can cause severe pruritus and the development of nodules on bone protuberances. Visual Symptoms Onchocerciasis Principles of Disease. Onchocerciasis is a major cause of blindness in the world. Ninety-five percent of all cases occur in Africa. The parasite is found only in humans and is transmitted by the bite of the Simulium fly. These flies live near rivers, hence the common name of the disease, river blindness. Microfilariae of O. volvulus are released by adult nematodes, which coil in subcutaneous nodules in the infected host; the microfilariae then migrate through the dermis and epidermis. The presence of adult worms stimulates a brisk immune response, including the infiltration of lymphocytes, macrophages, plasma cells, and eosinophils. Clinical Features. The skin becomes chronically edematous and pruritic; it then atrophies, resulting in loose, thin folds of skin. River blindness is more likely to develop in patients with nodules in proximity to the eyes. When the microfilaria dies during its migration in the eye, the foreign tissue that is deposited in the iris musculature incites an immune sclerosing keratitis, which is the major cause of the ocular destruction and subsequent blindness (Fig. 133-6). Diagnostic Strategies and Management. The diagnosis of onchocerciasis requires identification of characteristic microfilariae in skin snipped from the patient. Ivermectin is the therapeutic drug of choice. In many countries in which the disease is endemic, the manufacturers of ivermectin have donated the drug in an attempt to eradicate the disease. 25 Surgical excision of the subcutaneous nodules is recommended when they are located on the head. Loiasis Principles of Disease and Clinical Features. Another filarial infection that causes ocular problems is loiasis. Loiasis is confined to forest areas in West and Central Africa. Transmission of Loa loa occurs through the bite of flies of the genus Chrysops. The edema initially associated with migration of the worm is called a Calabar Figure 133-6. Patient with onchocerciasis or river blindness. swelling. The disease is caused by migration of the adult worm in the subcutaneous tissue. The adult worm occasionally migrates through the subconjunctival tissues of the eye and can be surgically excised from the conjunctiva. Although it is upsetting to the patient, the disease is generally fairly benign. The adult worm releases sheathed microfilariae into the peripheral bloodstream during the time. Diagnostic Strategies and Management. Microfilariae can be detected in a thick blood smear, securing the diagnosis of loiasis. The treatment of choice for L. loa infection is diethylcarbamazine. Corticosteroids or antihistamines should be used to supplement specific chemotherapy because of the intense allergic reaction that occurs when the killed adult worms and microfilariae disintegrate. Other Parasites Causing Ocular Symptoms Toxocara canis has a trophism for the host s eyes. Toxocariasis is a roundworm infection found in urban dogs. Humans ingest eggs by the fecal-oral route. The larvae migrate and often enter the retina, where they become trapped. They stimulate an immune response that culminates in granuloma formation. These granulomas can impair vision and sometimes are mistaken for retinal tumors. There is no means of direct diagnosis except tissue biopsy. Although serologic tests are available, results need to be interpreted with caution. Infection is treated with albendazole and steroids; larvae visible in the retina can be destroyed with a laser. Toxoplasma gondii infection can precipitate a vitreal inflammation with retinal hemorrhages. Immunocompromised patients may have chorioretinitis and optic neuritis with visual field defects and ocular palsies. Erythrocytes with sticky knobs from P. falciparum infection can cause retinal vascular congestion and ischemia with hemorrhage, exudate, infarction, and macular destruction. Cerebral malaria can produce cortical blindness. Mucocutaneous leishmaniasis can involve the eyelids, tear glands, retina, or iris and may result in total ocular destruction. Acanthamoeba can cause a dangerous keratitis in contact lens wearers. The patient complains of severe pain, tearing, and photophobia. Early infection may be misdiagnosed as herpetic keratitis. The infection may become chronic and necessitate keratoplasty for preservation of vision. Many different worms migrate to or through the eye, causing inflammation, tissue destruction, and blindness. Echinococcus and Cysticercus can initiate destructive cystic lesions in the eye. Pulmonary Symptoms Patients with P. falciparum malaria initially may seek treatment for fever and cough. Early in the course of treatment for severe

malaria, noncardiogenic pulmonary edema or acute respiratory distress syndrome may develop, necessitating mechanical ventilation with positive end-expiratory pressure. E. histolytica can cause sympathetic pleural effusions, pulmonary or pleural involvement by direct extension or rupture of an amebic liver abscess, or direct hematogenous seeding of the lungs, leading to considerable additional morbidity and mortality among patients with underlying amebic infection. Pneumocystis pneumonia, caused by Pneumocystis jiroveci (formerly Pneumocystis carinii), is one of the most common respiratory opportunistic infections in patients with HIV infection in the United States and Europe; surprisingly though, it is responsible for less than 10% of pulmonary opportunistic infections in Africa and the developing world. The reason for this discrepancy is unclear. Many patients with AIDS in these countries die with CD4 + cell counts that are higher than those associated with P. jiroveci pneumonia in the United States. 26 Löffler s syndrome, characterized by persistent and nonproductive cough, substernal chest pain, wheezing, rales, pulmonary infiltrates on the chest radiograph, and marked eosinophilia, often is seen when larvae from the roundworm Ascaris lumbricoides, the hookworms N. americanus and A. duodenale, and the threadworm S. stercoralis transit the lungs as part of their developmental cycles. Ascaris larvae penetrate the small intestinal wall to gain entry into the small venules of the gastrointestinal tract and then migrate to the lungs. Strongyloides and the hookworm filariform larvae penetrate through the skin of the feet, entering small cutaneous venules before migration to the lungs. The pulmonary infiltrates and symptoms are transient, resolving within 2 weeks. Diagnosis depends on discovery of larvae in sputum or gastric aspirates. Negative stool examinations initially are nondiagnostic because eggs do not appear in the stool for at least 1 month after initial infection. The patient s immune response to the microfilariae of W. bancrofti and B. malayi is the cause of tropical eosinophilic pneumonia. Affected persons present with malaise, weight loss, new-onset nocturnal wheezing and asthma, shortness of breath, and chest discomfort. Chest radiographs may show nodular or interstitial infiltrates, consolidations, or cavitation. Microfilariae can be seen in lung biopsy material. Untreated infection may result in obstructive or restrictive lung disease. Patients have marked eosinophilia and elevations of serum immunoglobulin E. Paragonimus westermani and echinococcal species are trophic for the lungs in their human hosts. P. westermani eggs are shed in stool, hatch in fresh water, and, as miracidia, infect a snail intermediary. After further development, cercariae are released from the snail, penetrating and encysting in freshwater crabs or crayfish. If the human host consumes raw or undercooked shellfish, the metacercariae excyst within the host s duodenum, penetrating the duodenal wall into the abdominal cavity. The larvae migrate from the peritoneal cavity through the diaphragm into the pleural cavity, finally migrating to the lungs, where they cause hemorrhage, necrosis, and a granulomatous response. Early in the process, patients may have infiltrates and eosinophilia; later disease is marked by bronchiectasis, chronic bronchitis, fever, hemoptysis, and cachexia. Pulmonary nodules and cysts may cavitate. Many of these patients may have a positive result on purified protein derivative testing, and their symptoms and chest radiographic findings may mimic tuberculosis. 27 Sputum often is blood streaked and flecked with dark brown particles containing ova. Finding of ova in sputum is diagnostic. Radiography, stool examination, and immune testing of sputum and blood are all helpful in making the diagnosis. Praziquantel is the therapeutic agent of choice. E. granulosus causes pulmonary hydatid cyst disease; the host remains asymptomatic until a cyst grows large enough to cause a mass effect, becomes superinfected, or leaks cyst material, which is highly immunogenic and causes a severe anaphylactoid reaction. Chapter 133 / Parasitic Infections 1781 Pulmonary hydatid cysts also can be associated with cough, expectoration of sandlike material, chest pain, and hemoptysis. Primary hydatid disease in the liver can metastasize to the lungs or brain. A thoracic CT scan may show a unilocular lung cyst; on a plain radiograph, a ruptured cyst is said to resemble a water lily, a pathognomonic finding. Cysts can be treated with careful surgical excision and pharmacotherapy. Early schistosomal disease, or Katayama fever, can be manifested with fever, cough, eosinophilia, and diffuse pulmonary nodules as the schistosomula pass through the lungs. In longstanding disease, ova shed from worm pairs can lodge in the vasculature of the lungs, causing pseudotubercles, granulomatous lung disease, pulmonary hypertension, and cor pulmonale. In patients with long-standing, latent, and asymptomatic S. stercoralis infections who are started on corticosteroids or immunosuppressive therapy, the helminth disseminates widely. Fatal, massive pulmonary infections with radiographic whiteouts and unsupportable respiratory failure have been reported in patients who have received organ transplants; this clinical disaster occurs more commonly in patients who emigrate from developing countries and receive organ transplants and immunosuppressive therapy without being evaluated for Strongyloides infection. 28 Strongyloides pulmonary infection can cause wheezing and cough, leading to an initial misdiagnosis of bronchospasm and asthma; if the patient is given steroids, the strongyloides may disseminate with markedly increased morbidity and mortality. 28 Cardiovascular Symptoms Chagas Disease Principles of Disease. Trypanosoma cruzi infection often leads to acute and chronic myocarditis. T. cruzi is endemic in South and Central America and causes Chagas disease. The vector is the reduviid bug or kissing bug that inhabits the walls and roofs of thatched dwellings built adjacent to forest. Urban transmigration has expanded the epidemiologic scope of Chagas disease, previously a disease of rural populations. The disease is not seen commonly in travelers. The reduviid bug s bite is no longer the only source of T. cruzi infection; transfusion with blood containing live trypanosomes from infected hosts is a growing source of infection. Oral transmission also has been reported. 28 The reduviid bug bites the patient, often around the eye, and excretes feces containing the trypomastigote of T. cruzi. The trypomastigote enters the inflamed bite wound or other mucosal or conjunctival surfaces, causing a local swelling called a chagoma. Romaña s sign (painless unilateral periorbital edema) is pathognomonic but rarely seen. The trypomastigote migrates to trophic tissues, including smooth muscle, cardiac muscle, and autonomic ganglia in the heart, esophagus, and colon, causing local inflammation and tissue destruction. Clinical Features. Acute infection is heralded by fever, facial and dependent extremity edema, hepatosplenomegaly, lymphadenopathy, malaise, lymphocytosis on peripheral blood smear, and elevated liver transaminases. At this stage, fatal left ventricular dysfunction and dysrhythmias are uncommon. Early illness lasts 1 to 2 months and resolves spontaneously, resulting in a latency known as the indeterminate phase, which can persist throughout the patient s lifetime. In approximately 25% of the cases, the infection progresses to chronic Chagas disease, principally with cardiomyopathy and gastrointestinal disease. Amastigotes invade cardiac muscle and the cardiac conduction system, causing chronic inflammation, mononuclear cell infiltration, and fibrosis. Patients whose disease involves the conduction system may present with atrial bradydysrhythmias, right and left bundle branch blocks, complete heart block, and ventricular dysrhythmias, including ventricular fibrillation. Cardiac muscle is replaced by fibrosis and

1782 PART III Medicine and Surgery / Section Twelve Infectious Diseases scarring, leading to the development of right and left ventricular dysfunction and dilated cardiomyopathy. Mural thrombi are common. The first indication of long-standing asymptomatic infection can be thromboembolic disease, such as pulmonary embolism, stroke, or peripheral arterial embolism. Congestive heart failure is generally rapidly progressive and fatal within months unless it is aggressively treated with pharmacologic intervention and transplantation. 29 Diagnostic Strategies. Acute Chagas disease can be diagnosed by the presence of motile trypomastigotes in anticoagulated blood specimens. The organism also can be cultured in special liquid media. Chronic Chagas disease can be diagnosed by one of several serologic tests, including complement fixation, enzyme-linked immunosorbent assay (ELISA), and indirect immunofluorescence testing. The assays are nonspecific, cross-reacting with malaria, syphilis, leishmaniasis, and some collagen vascular diseases. Polymerase chain reaction technology is improving and soon will provide the gold standard modality for diagnosis. 30 Management. Nifurtimox and benznidazole are used for treatment of T. cruzi infection. Cure rates rarely exceed 50%. The duration of treatment with nifurtimox is prolonged, and the drug has many serious side effects. Its production has been discontinued; however, it is the only antitrypanosomal medication available in the United States to and can be obtained from the CDC by calling 404-639-2888. Benznidazole has fewer side effects. It is now recommended for indeterminate-phase treatment. Late complications of chronic diseases are modulated by autoimmune activity and do not respond to antiparasitic pharmacotherapy. Chronic Chagas disease of the heart, esophagus, or colon is treated symptomatically. Automated implantable cardioverter-defibrillators decrease the incidence of sudden death in infected patients. 31 Patients receiving immunosuppressive therapy to prevent rejection after cardiac transplantation have developed recurrent disease in the transplanted myocardium. Other Causes Aberrant migration of Ascaris to the myocardium, causing myocarditis and pericardial effusions, is well described. E. histolytica abscesses of the liver also may cause pericardial effusions if they erode through the diaphragm. Gastrointestinal Symptoms Diarrhea Diarrhea is one of the most common symptoms for which travelers seek medical attention. Gorbach 32 wrote, Travel expands the mind and loosens the bowels. Diarrhea also is the leading cause of death in children younger than 5 years in developing countries and a major source of morbidity for older children and adults (Fig. 133-7). Most diarrheal disease is viral or bacterial; however, some clinically significant diarrheal disease is caused by parasites. Cryptosporidium parvum and Cyclospora cayetanensis are foodborne and water-borne coccidians that cause watery diarrhea. Both are particularly significant causes of morbidity in malnourished children and patients with AIDS. Cryptosporidial oocysts can be seen in stool when an acid-fast stain is used. ELISA and immunofluorescent assays of stool also are available for this organism. Paromomycin decreases diarrheal frequency in patients with AIDS who have cryptosporidial infections, who would have prolonged, disabling symptoms without treatment. Cyclospora oocysts can be detected in stool samples with a Ziehl-Neelsen stain. Trimethoprim-sulfamethoxazole treats this infection. 33 E. histolytica causes an invasive or inflammatory diarrhea. Patients complain of fever, tenesmus, abdominal pain, and watery Figure 133-7. Fecal-oral transmission of diarrheal agents occurring in a developing country. stool containing blood and mucus. Untreated disease can progress to widespread colitis and perforation of the bowel wall with peritonitis and death. Stool examination reveals mobile trophozoites containing ingested RBCs. Cysts noted on stool studies do not necessarily reflect active infection as there are nonpathogenic ameba species that can be found in the bowel of healthy adults. Immune assays of stool can now differentiate between E. histolytica and these nonpathogenic ameba species. Serologic tests may be useful in an infected patient from a nonendemic region but take a month for results to turn positive. Metronidazole is the drug of choice for treatment of amebiasis. Balantidium coli is the other protozoan that can cause invasive diarrhea. It has trophism for the terminal ileum, sometimes resulting in a clinical picture suggestive of appendicitis. Tetracycline and metronidazole are active against B. coli. Giardia lamblia can cause persistent diarrhea, abdominal bloating, cramps, flatulence, and significant weight loss. The organism is ingested and reproduces exponentially in the small bowel. In severe infection, the entire jejunum becomes covered with organisms, and the patient has malabsorption with steatorrhea. The organisms are rarely seen in fresh stool preparations because they quickly break down and become indiscernible. Accordingly, an antigen test often is used to confirm the diagnosis. Giardia has many animal reservoirs, including the beaver. Campers who drink unfiltered, pure mountain spring water in the United States commonly contract Giardia infection. Metronidazole, tinidazole, or nitazoxanide treats the disease. 33 S. stercoralis, Capillaria philippinensis, T. trichiura, and Schistosoma have been associated with diarrhea. Hyperinfection or dissemination of Strongyloides can cause persistent diarrhea, weight loss, and abdominal pain. Trichuris causes diarrhea when the parasite load in the intestine is high. Schistosomiasis can cause a chronic granulomatous colitis, which may resemble inflammatory bowel disease, or an acute, bloody, febrile colitis associated with Katayama fever in the immunologically naïve patient. In chronic schistosomiasis, worm pairs in patients mesenteric and portal venous systems lay eggs that become ensnared in the liver, causing intense local inflammation and scarring and the classic pipestem cirrhosis with periportal fibrosis. Clinical manifestations in these patients include portal hypertension, ascites, and esophageal varices (Figs. 133-8 and 133-9). Upper gastrointestinal bleeding is not as common as in patients with alcoholic cirrhosis; however, a high number of patients are infected with schistosomiasis in endemic regions, so variceal bleeding is an important cause of gastrointestinal hemorrhage in these populations.

Chapter 133 / Parasitic Infections 1783 Figure 133-8. Pipestem cirrhosis with extensive ascites in a patient with chronic schistosomiasis. appear clinically to have Meckel s diverticulum or acute appendicitis. Manifestations of the infection include nausea, vomiting, fever, abdominal pain localized to the right lower quadrant, and a tender mass. Surgical exploration may uncover abscesses, obstruction, or intestinal infarction. Anisakiasis is characterized by severe abdominal pain after ingestion of raw fish (sushi and sashimi primarily). Anisakis marina, a nematode that burrows into the intestine, is the pathogen. The liver fluke Fasciola hepatica causes a syndrome that mimics viral hepatitis: right upper quadrant pain, fever, nausea and vomiting, jaundice, tender enlarged liver, and elevated transaminases. Patients also have eosinophilia and urticaria. Imaging studies, including CT, show the tracks of burrowing flukes. Serologic testing establishes the diagnosis; the patient s stool may not contain eggs for several months after ingestion.36 The eggs of schistosomes become trapped in the portal venules, where they trigger an inflammatory response, leading to granulomatous liver disease, fibrosis, and cirrhosis. Hepatic granulomas also are seen in disseminated strongyloidiasis and aberrant biliary ascariasis. E. histolytica can cause hepatic abscesses. Affected patients typically do not have amebic dysentery and do not shed Entamoeba in their stool, but results of serologic studies almost always are positive. Patients have fever, weight loss, anorexia, and right-sided abdominal pain but no jaundice. Treatment is with metronidazole or tinidazole and a luminal amebicide, such as iodoquinol.37 E. granulosus produces hydatid cysts of the liver that on CT contain septations and so-called daughter cysts. Pharmacotherapy with albendazole and careful excision remain the treatments of choice. Leaking cyst material can initiate a severe anaphylactoid reaction in the host. Jaundice may result from hemolysis secondary to direct infection of RBCs with Plasmodium or Babesia or from biliary obstruction with pigmented stones. Ascaris can cause biliary colic, pyogenic cholangitis, pancreatitis, or liver abscess. Dead worms can be the nidus for gallstone formation. Biliary imaging and endoscopic retrograde cholangiopancreatography will show worms in the biliary tree. Mechanical removal by endoscopy combined with anthelminthic therapy is curative. Clonorchis sinensis and F. hepatica are trophic for the biliary tree. These worms can be present without producing symptoms for years before eventually precipitating cholecystitis, cholangitis, or cholangiocarcinoma. Pruritus Ani Figure 133-9. Extensive ascites in a child, which may be from schistosomiasis or kala-azar (leishmaniasis). Abdominal Pain Several parasites have been identified in pathologic examination of appendices of patients diagnosed with tropical appendicitis. These infections have included enterobiasis, amebiasis, ascariasis, trichuriasis, and taeniasis.34 A. lumbricoides can cause significant persistent or recurrent abdominal pain in adults and partial intestinal obstruction in children with significant worm loads. Anthelmintics and conservative, supportive therapy usually eliminate the problem, thereby avoiding surgical intervention. The diagnosis of ascariasis is made by the identification eggs in the stool. Patients with large worm loads may excrete adult worms, especially after therapy is started. Severe intestinal amebiasis can be complicated by colonic perforation and peritonitis.35 Angiostrongylus costaricensis, a nematode known as the rat lung worm, is common in Central America. Infected children may Enterobius vermicularis, or pinworm, causes pruritus ani, a syndrome of intense perianal itch occurring primarily in children. Autoinfection is common because children (and adults) scratch the pruritic anal area and then bite their nails or put their fingers in their mouth. The worm has a worldwide distribution. Diagnosis is clinical and is confirmed by finding the small adult worms wiggling about on the anal verge. Eggs are rarely seen in the stool but can be visualized by the tape test: transparent tape touched to the perianal region collects eggs, which can be seen with light microscopy. Albendazole or mebendazole is the drug of choice. PARASITIC COINFECTIONS IN PATIENTS WITH HIV INFECTION AND AIDS Perspective HIV infection and AIDS are prevalent in developing countries. Heterosexual transmission and perinatal transmission are common; young children and young adults of both sexes are primarily infected. Patients presenting to the ED may be coinfected with HIV and any other infectious agent, including all of the parasites discussed in this chapter. HIV coinfection may worsen the