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InternalMed_Harrison. The drug of choice for treatment is praziquantel (Table 259-2). Other medical or surgical management may be needed for pulmonary or cerebral lesions.


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InternalMed_Harrison. For residents of nonendemic areas who are visiting an endemic region, the only effective preventive measure is to avoid ingestion of local plants, fish, or crustaceans; if their ingestion is necessary, these items should be washed and cooked thoroughly. Instruction on water and food preparation and consumption should be included in physicians’ advice to travelers (Chap. 149). Interruption of transmission among residents of endemic areas depends on avoiding ingestion of infective stages and disposing of feces and sputum appropriately to prevent hatching of eggs in the environment. These two approaches rely greatly on socioeconomic development, health education, and significant behavioral change. In countries where economic progress has resulted in financial and social improvements, transmission has decreased. The third approach to control in endemic communities entails selective use of chemotherapy for individuals posing the highest risk of transmission (i.e., those with heavy


InternalMed_Harrison

InternalMed_Harrison. transmission has decreased. The third approach to control in endemic communities entails selective use of chemotherapy for individuals posing the highest risk of transmission (i.e., those with heavy infections). The availability of praziquantel—a broad-spectrum, safe, and effective anthelmintic agent—provides a means for reducing the reservoirs of infection in human populations. However, the existence of most of these helminthic infections as zoonoses in several animal species complicates control efforts.


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InternalMed_Harrison. A. Clinton White, Jr., Peter F. Weller Cestodes, or tapeworms, are segmented worms. The adults reside in the gastrointestinal tract, but the larvae can be found in almost any organ. Human tapeworm infections can be divided into two major clinical groups. In one group, humans are the definitive hosts, with the adult tapeworms living in the gastrointestinal tract (Taenia saginata, Diphyllobothrium, Hymenolepis, and Dipylidium caninum). In the other, humans are intermediate hosts, with larval-stage parasites present in the tissues; diseases in this category include echinococcosis, sparganosis, and coenurosis. Humans may be either the definitive or the intermediate hosts for Taenia solium. Both stages of Hymenolepis nana are found simultaneously in the human intestines.


InternalMed_Harrison

InternalMed_Harrison. The ribbon-shaped tapeworm attaches to the intestinal mucosa by means of sucking cups or hooks located on the scolex. Behind the scolex is a short, narrow neck from which proglottids (segments) form. As each proglottid matures, it is displaced further back from the neck by the formation of new, less mature segments. The progressively elongating chain of attached proglottids, called the strobila, constitutes the bulk of the tapeworm. The length varies among species. In some, the tapeworm may consist of more than 1000 proglottids and may be several meters long. The mature proglottids are hermaphroditic and produce eggs, which are subsequently released. Because eggs of the different Taenia species are morphologically identical, differences in the morphology of the scolex or proglottids provide the basis for diagnostic identification to the species level.


InternalMed_Harrison

InternalMed_Harrison. Most human tapeworms require at least one intermediate host for complete larval development. After ingestion of the eggs or proglottids by an intermediate host, the larval oncospheres are activated, escape the egg, and penetrate the intestinal mucosa. The oncosphere migrates to tissues and develops into an encysted form known as a cysticercus (single scolex), a coenurus (multiple scolices), or a hydatid (cyst with daughter cysts, each containing several protoscolices). The definitive host’s ingestion of tissues containing a cyst enables a scolex to develop into a tapeworm. The beef tapeworm T. saginata occurs in all countries where raw or undercooked beef is eaten. It is most prevalent in sub- Saharan African and Middle Eastern countries. T. asiatica is closely related to T. saginata and is found in Asia, with pigs as intermediate hosts. The clinical manifestations and morphology of these two species are very similar and are therefore discussed together.


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InternalMed_Harrison. Etiology and Pathogenesis Humans are the only definitive host for the adult stage of T. saginata and T. asiatica. The tapeworms, which can reach 8 m in length with 1000–2000 proglottids, inhabit the upper jejunum. The scolex of T. saginata has four prominent suckers, whereas


InternalMed_Harrison

InternalMed_Harrison. T. asiatica has an unarmed rostellum. Each gravid segment has 15–30 uterine branches (in contrast to 8–12 for T. solium). The eggs are indistinguishable from those of T. solium; they measure 30–40 μm, contain the oncosphere, and have a thick brown striated shell. Eggs deposited on vegetation can live for months or years until they are ingested by cattle or other herbivores (T. saginata) or pigs (T. asiatica). The embryo released after ingestion invades the intestinal wall and is carried to striated muscle or viscera, where it transforms into the cysticercus. When ingested in raw or undercooked meat, this form can infect humans. After the cysticercus is ingested, it takes ~2 months for the mature adult worm to develop.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations Patients become aware of the infection most commonly by noting passage of proglottids in their feces. The proglottids are often motile, and patients may experience perianal discomfort when proglottids are discharged. Mild abdominal pain or discomfort, nausea, change in appetite, weakness, and weight loss can occur. Diagnosis The diagnosis is made by the detection of eggs or proglottids in the stool. Eggs may also be present in the perianal area; thus, if proglottids or eggs are not found in the stool, the perianal region should be examined with use of a cellophane-tape swab (as in pinworm infection; Chap. 257). Distinguishing T. saginata or T. asiatica from T. solium requires examination of mature proglottids. All three species can be distinguished by examining the scolex. Available serologic tests are not helpful diagnostically. Eosinophilia and elevated levels of serum IgE may be detected. A single dose of praziquantel (10 mg/kg) is highly effective.


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InternalMed_Harrison. A single dose of praziquantel (10 mg/kg) is highly effective. Prevention The major method of preventing infection is the adequate cooking of beef or pork viscera; exposure to temperatures as low as 56°C for 5 min will destroy cysticerci. Refrigeration or salting for long periods or freezing at −10°C for 9 days also kills cysticerci in beef. General preventive measures include inspection of beef and proper disposal of human feces. The pork tapeworm T. solium can cause two distinct forms of infection in humans: adult tapeworms in the intestine or larval forms in the tissues (cysticercosis). Humans are the only definitive hosts for T. solium; pigs are the usual intermediate hosts, although other animals may harbor the larval forms. T. solium is found worldwide in areas where pigs are raised and have access to human feces. However, it is most prevalent in Latin America, sub-Saharan Africa, China, India, and


InternalMed_Harrison

InternalMed_Harrison. T. solium is found worldwide in areas where pigs are raised and have access to human feces. However, it is most prevalent in Latin America, sub-Saharan Africa, China, India, and Southeast Asia. Cysticercosis occurs in industrialized nations largely as a result of the immigration of infected persons from endemic areas.


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InternalMed_Harrison. Etiology and Pathogenesis The adult tapeworm generally resides in the upper jejunum. The scolex attaches by both sucking disks and two rows of hooklets. The adult worm usually lives for a few years. The tapeworm, usually ~3 m in length, may have as many as 1000 proglottids, each of which produces up to 50,000 eggs. Proglottids are released and excreted into the feces, and the eggs in these proglottids are infective for both humans and animals. The eggs may survive in the environment for several months. After ingestion of eggs by the pig intermediate host, the larvae are activated, escape the egg, penetrate the intestinal wall, and are carried to many tissues; they are most frequently identified in striated muscle of the neck, tongue, and trunk. Within 60–90 days, the encysted larval stage develops. These cysticerci can survive for months to years. By ingesting undercooked pork containing cysticerci, humans acquire infections that lead to intestinal tapeworms. Infections that cause


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InternalMed_Harrison. develops. These cysticerci can survive for months to years. By ingesting undercooked pork containing cysticerci, humans acquire infections that lead to intestinal tapeworms. Infections that cause human cysticercosis follow the ingestion of T. solium eggs, usually from close contact with a tapeworm carrier. Autoinfection may occur if an individual with an egg-producing tapeworm ingests eggs derived from his or her own feces.


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InternalMed_Harrison. Clinical Manifestations Intestinal infections with T. solium may be asymptomatic. Fecal passage of proglottids may be noted by patients. Other symptoms are infrequent.


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InternalMed_Harrison. In cysticercosis, the clinical manifestations are variable. Cysticerci can be found anywhere in the body but are most commonly detected in the brain, cerebrospinal fluid (CSF), skeletal muscle, subcutaneous tissue, or eye. The clinical presentation of cysticercosis depends on the number and location of cysticerci as well as on the extent of associated inflammatory responses or scarring. Neurologic manifestations are the most common (Fig. 260-1). Seizures are associated with inflammation surrounding cysticerci in the brain parenchyma. These seizures may be generalized, focal, or Jacksonian. Hydrocephalus results from CSF flow obstruction by cysticerci and accompanying inflammation or by CSF outflow obstruction from arachnoiditis. Symptoms of increased intra-cranial pressure, including headache, nausea, vomiting, changes in this problem can be overcome by using 1431 the more specific immunoblot assay. An immunoblot assay using lentil lectin purified glycoproteins is >99% specific and


InternalMed_Harrison

InternalMed_Harrison. nausea, vomiting, changes in this problem can be overcome by using 1431 the more specific immunoblot assay. An immunoblot assay using lentil lectin purified glycoproteins is >99% specific and highly sensitive. However, patients with single intracranial lesions or with calcifications may be seronegative. With this assay, serum samples provide greater diagnostic sensitivity than CSF. All of the diagnostic antigens have been cloned, and assays using recombinant antigens are being developed. Antigen detection assays using monoclonal antibodies to detect parasite antigen in the blood or CSF may also facilitate diagnosis


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InternalMed_Harrison. FIGuRE 260-1 Neurocysticercosis is caused by Taenia solium. Neurologic infection can be and patient follow-up. These assays are onlyclassified on the basis of the location and viability of the parasites. When the parasites are in the now becoming available for patient care.ventricles, they often cause obstructive hydrocephalus. Left: Magnetic resonance imaging show-Studies have demonstrated that cliniing a cysticercus in the lateral ventricle, with resultant hydrocephalus. The arrow points to the cal criteria can aid in diagnosis in selected scolex within the cystic parasite. Center: CT showing a parenchymal cysticercus, with enhance-cases. In patients from endemic areas who ment of the cyst wall and an internal scolex (arrow). Right: Multiple cysticerci, including calcified had single enhancing lesions presentinglesions from prior infection (arrowheads), viable cysticerci in the basilar cisterns (white arrow), with seizures, a normal physical examinaand a large degenerating


InternalMed_Harrison

InternalMed_Harrison. single enhancing lesions presentinglesions from prior infection (arrowheads), viable cysticerci in the basilar cisterns (white arrow), with seizures, a normal physical examinaand a large degenerating cysticercus in the Sylvian fissure (black arrow). (Modified with permission tion, and no evidence of systemic disease from JC Bandres et al: Clin Infect Dis 15:799, 1992. © The University of Chicago Press.) (e.g., no fever, adenopathy, or chest radio- vision, dizziness, ataxia, or confusion, are often evident. Patients with hydrocephalus may develop papilledema or display altered mental status. When cysticerci develop at the base of the brain or in the sub-arachnoid space, they may cause chronic meningitis or arachnoiditis, communicating hydrocephalus, hemorrhages, or strokes.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis The diagnosis of intestinal T. solium infection is made by the detection of eggs or proglottids, as described for T. saginata. More sensitive methods, including antigen-capture enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and serology for tapeworm stage-specific antigens, are currently available only as research techniques. In cysticercosis, diagnosis can be difficult. A consensus conference has delineated absolute, major, minor, and epidemiologic criteria for diagnosis (Table 260-1). Diagnostic certainty is possible only with definite demonstration of the parasite (absolute criteria). This task can be accomplished by histologic observation of the parasite in excised tissue, by funduscopic visualization of the parasite in the eye (in the anterior chamber, vitreous, or subretinal spaces), or by neuroimaging studies demonstrating cystic lesions containing a characteristic scolex (Fig. 260-1). With improving resolution of neuroimaging studies, the


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InternalMed_Harrison. vitreous, or subretinal spaces), or by neuroimaging studies demonstrating cystic lesions containing a characteristic scolex (Fig. 260-1). With improving resolution of neuroimaging studies, the scolex can now be identified in many cases. In other instances, a clinical diagnosis is based on a combination of clinical presentation, radiographic studies, serologic tests, and exposure history.


InternalMed_Harrison

InternalMed_Harrison. Neuroimaging findings suggestive of neurocysticercosis constitute the primary major diagnostic criterion (Fig. 260-1). These findings include cystic lesions with or without enhancement (e.g., ring enhancement), one or more nodular calcifications (which may also have associated enhancement), or focal enhancing lesions. Cysticerci in the brain parenchyma are usually 5–20 mm in diameter and rounded. Cystic lesions in the subarachnoid space or fissures may enlarge up to 6 cm in diameter and may be lobulated. For cysticerci within the subarachnoid space or ventricles, the walls may be very thin and the cyst fluid is often isodense with CSF. Thus, obstructive hydrocephalus or enhancement of the basilar meninges may be the only finding on CT in extraparenchymal neurocysticercosis. Cysticerci in the ventricles or subarachnoid space are usually visible to an experienced neuroradiologist on MRI or on CT with intraventricular contrast injection. CT is more sensitive than MRI in identifying


InternalMed_Harrison

InternalMed_Harrison. in the ventricles or subarachnoid space are usually visible to an experienced neuroradiologist on MRI or on CT with intraventricular contrast injection. CT is more sensitive than MRI in identifying calcified lesions, whereas MRI is better for identifying cystic lesions, scolices, and enhancement.


InternalMed_Harrison

InternalMed_Harrison. The second major diagnostic criterion is detection of specific antibodies to cysticerci. Although most tests using unfractionated antigen have high rates of false-positive and false-negative results, graphic abnormalities), the constellation of with no midline shift was almost always caused by neurocysticercosis. Finally, spontaneous resolution or resolution after therapy with albendazole alone is consistent with neurocysticercosis. Minor diagnostic criteria include neuroimaging findings consistent with but less characteristic of cysticercosis, clinical manifestations suggestive of neurocysticercosis (e.g., seizures, hydrocephalus, or altered mental status), evidence of cysticercosis outside the central nervous system (CNS) (e.g., cigar-shaped soft-tissue calcifications), or detection of antibody in CSF by ELISA. Epidemiologic criteria include 1. Absolute criteria a. Demonstration of cysticerci by histologic or microscopic examination of biopsy material b.


InternalMed_Harrison

InternalMed_Harrison. Demonstration of cysticerci by histologic or microscopic examination of biopsy material b. Visualization of the parasite in the eye by funduscopy c. Neuroradiologic demonstration of cystic lesions containing a characteristic scolex 2. Major criteria a. Neuroradiologic lesions suggestive of neurocysticercosis b. Demonstration of antibodies to cysticerci in serum by enzyme-linked immunoelectrotransfer blot c. Resolution of intracranial cystic lesions spontaneously or after therapy with albendazole or praziquantel alone 3. Minor criteria a. Lesions compatible with neurocysticercosis detected by neuroimaging studies b. Clinical manifestations suggestive of neurocysticercosis c. Demonstration of antibodies to cysticerci or cysticercal antigen in cerebrospinal fluid by enzyme-linked immunosorbent assay d. Evidence of cysticercosis outside the central nervous system (e.g., cigar-shaped soft-tissue calcifications) 4. Epidemiologic criteria a. b.


InternalMed_Harrison

InternalMed_Harrison. Evidence of cysticercosis outside the central nervous system (e.g., cigar-shaped soft-tissue calcifications) 4. Epidemiologic criteria a. b. Frequent travel to a cysticercosis-endemic area c. Household contact with an individual infected with Taenia solium aDiagnosis is confirmed by either one absolute criterion or a combination of two major criteria, one minor criterion, and one epidemiologic criterion. A probable diagnosis is supported by the fulfillment of (1) one major criterion plus two minor criteria; (2) one major criterion plus one minor criterion and one epidemiologic criterion; or (3) three minor criteria plus one epidemiologic criterion. Source: Modified from OH Del Brutto et al: Neurology 57:177, 2001. 1432 exposure to a tapeworm carrier or household member infected with T. solium, current or prior residence in an endemic area, and frequent travel to an endemic area.


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InternalMed_Harrison. 1432 exposure to a tapeworm carrier or household member infected with T. solium, current or prior residence in an endemic area, and frequent travel to an endemic area. The diagnosis is confirmed in patients with either one absolute criterion or a combination of two major criteria, one minor criterion, and one epidemiologic criterion (Table 260-1). A probable diagnosis is supported by the fulfillment of (1) one major criterion plus two minor criteria; (2) one major criterion plus one minor criterion and one epidemiologic criterion; or (3) three minor criteria plus one epidemiologic criterion. Although the CSF is usually abnormal in neurocysticercosis, CSF abnormalities are not pathognomonic. Patients may have CSF pleocytosis with a predominance of lymphocytes, neutrophils, or eosinophils. The protein level in CSF may be elevated; the glucose concentration is usually normal but may be depressed.


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InternalMed_Harrison. Intestinal T. solium infection is treated with a single dose of praziquantel (10 mg/kg). However, praziquantel occasionally evokes an inflammatory response in the CNS if concomitant cryptic cysticercosis is present. Niclosamide (2 g) is also effective but is not widely available.


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InternalMed_Harrison. The initial management of neurocysticercosis should focus on symptom-based treatment of seizures or hydrocephalus. Seizures can usually be controlled with antiepileptic treatment. If parenchymal lesions resolve without development of calcifications and patients remain free of seizures, antiepileptic therapy can usually be discontinued after 1–2 years. Placebo-controlled trials are clarifying the clinical advantage of antiparasitic drugs for parenchymal neurocysticercosis. Trends toward faster resolution of neuroradiologic abnormalities have been observed in most studies. The clinical benefits are less dramatic and consist mainly of shortening the period during which recurrent seizures occur and decreasing the number of patients who have many recurrent seizures. For the treatment of patients with brain parenchymal cysticerci, most authorities favor antiparasitic drugs, including albendazole (15 mg/kg per day for 8–28 days) or praziquantel (50–100 mg/kg daily in three divided doses for


InternalMed_Harrison

InternalMed_Harrison. with brain parenchymal cysticerci, most authorities favor antiparasitic drugs, including albendazole (15 mg/kg per day for 8–28 days) or praziquantel (50–100 mg/kg daily in three divided doses for 15–30 days). A combination of albendazole and praziquantel (50 mg/kg per day) may be more effective in patients with multiple lesions. A longer course or combination therapy is often needed in patients with multiple subarachnoid cysticerci. Both agents may exacerbate the inflammatory response around the dying parasite, thereby exacerbating seizures or hydrocephalus as well. Thus, patients receiving these drugs should be carefully monitored. High-dose glucocorticoids should be used during treatment. Because glucocorticoids induce first-pass metabolism of praziquantel and may decrease its antiparasitic effect, cimetidine should be co-administered to inhibit praziquantel metabolism.


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InternalMed_Harrison. For patients with hydrocephalus, the emergent reduction of intra-cranial pressure is the mainstay of therapy. In the case of obstructive hydrocephalus, the preferred approach is removal of the cysticercus via endoscopic surgery. However, this intervention is not always possible. An alternative approach is initially to perform a diverting procedure, such as ventriculoperitoneal shunting. Historically, shunts have usually failed, but low failure rates have been attained with administration of antiparasitic drugs and glucocorticoids. Open craniotomy to remove cysticerci is now required only infrequently but is an alternative for fourth-ventricular cysticerci. For patients with subarachnoid cysts or giant cysticerci, anti-inflammatory medications such as glucocorticoids are needed to reduce arachnoiditis and accompanying vasculitis. Most authorities recommend prolonged courses of antiparasitic drugs as well as shunting when hydrocephalus is present. Methotrexate should be used as a


InternalMed_Harrison

InternalMed_Harrison. arachnoiditis and accompanying vasculitis. Most authorities recommend prolonged courses of antiparasitic drugs as well as shunting when hydrocephalus is present. Methotrexate should be used as a steroid-sparing agent in patients requiring prolonged therapy. In patients with diffuse cerebral edema and elevated intracranial pressure due to multiple inflamed lesions, glucocorticoids are the mainstay of therapy, and antiparasitic drugs should be avoided. For ocular and spinal medullary lesions, drug-induced inflammation may cause irreversible damage. Ocular disease should be managed surgically. Recent data suggest that either medical or surgical therapy can be used for spinal disease.


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InternalMed_Harrison. Prevention Measures for the prevention of intestinal T. solium infection consist of the application to pork of precautions similar to those described above for beef with regard to T. saginata infection. The prevention of cysticercosis involves minimizing the opportunities for ingestion of fecally derived eggs by means of good personal hygiene, effective fecal disposal, and treatment and prevention of human intestinal infections. Mass chemotherapy has been administered to human and porcine populations in efforts at disease eradication. Finally, vaccines to prevent porcine cysticercosis have shown promise in studies and are under development.


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InternalMed_Harrison. Echinococcosis is an infection caused in humans by the larval stage of the Echinococcus granulosus complex, E. multilocu laris, or E. vogeli. E. granulosus complex parasites produce cystic hydatid disease, with unilocular cystic lesions. These infections are prevalent in most areas where livestock is raised in association with dogs. Molecular evidence suggests that E. granulosus strains may actually belong to more than one species; specifically, strains from sheep, cattle, pigs, horses, and camels probably represent separate species. These parasites are found on all continents, with areas of high prevalence in China, central Asia, the Middle East, the Mediterranean region, eastern Africa, and parts of South America. E. multilocularis, which causes multilocular alveolar lesions that are locally invasive, is found in Alpine, sub-Arctic, or Arctic regions, including Canada, the United States, and central and northern Europe; China; and central Asia. E. vogeli causes polycystic hydatid


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InternalMed_Harrison. locally invasive, is found in Alpine, sub-Arctic, or Arctic regions, including Canada, the United States, and central and northern Europe; China; and central Asia. E. vogeli causes polycystic hydatid disease and is found only in Central and South America.


InternalMed_Harrison

InternalMed_Harrison. Like other cestodes, echinococcal species have both intermediate and definitive hosts. The definitive hosts are canines that pass eggs in their feces. After the ingestion of eggs, cysts develop in the intermediate hosts—sheep, cattle, humans, goats, camels, and horses for the E. granulosus complex and mice and other rodents for E. multilocularis. When a dog (E. granulosus) or fox (E. multilocularis) ingests infected meat containing cysts, the life cycle is completed.


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InternalMed_Harrison. Etiology The small (5-mm-long) adult E. granulosus complex worms, which live for 5–20 months in the jejunum of dogs, have only three proglottids: one immature, one mature, and one gravid. The gravid segment splits to release eggs that are morphologically similar to Taenia eggs and are extremely hardy. After humans ingest the eggs, embryos escape from the eggs, penetrate the intestinal mucosa, enter the portal circulation, and are carried to various organs, most commonly the liver and lungs. Larvae develop into fluid-filled unilocular hydatid cysts that consist of an external membrane and an inner germinal layer. Daughter cysts develop from the inner aspect of the germinal layer, as do germinating cystic structures called brood capsules. New larvae, called protoscolices, develop in large numbers within the brood capsule. The cysts expand slowly over a period of years.


InternalMed_Harrison

InternalMed_Harrison. The life cycle of E. multilocularis is similar except that wild canines, such as foxes, serve as the definitive hosts and small rodents serve as the intermediate hosts. The larval form of E. multilocularis, however, is quite different in that it remains in the proliferative phase, the parasite is always multilocular, and vesicles without brood capsule or protoscolices progressively invade the host tissue by peripheral extension of processes from the germinal layer.


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InternalMed_Harrison. Clinical Manifestations Slowly enlarging echinococcal cysts generally remain asymptomatic until their expanding size or their space-occupying effect in an involved organ elicits symptoms. The liver and the lungs are the most common sites of these cysts. The liver is involved in about two-thirds of E. granulosus infections and in nearly all E. multilocularis infections. Because a period of years elapses before cysts enlarge sufficiently to cause symptoms, they may be discovered incidentally on a routine x-ray or ultrasound study.


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InternalMed_Harrison. Patients with hepatic echinococcosis who are symptomatic most often present with abdominal pain or a palpable mass in the right upper quadrant. Compression of a bile duct or leakage of cyst fluid into the biliary tree may mimic recurrent cholelithiasis, and biliary obstruction can result in jaundice. Rupture of or episodic leakage from a hydatid cyst may produce fever, pruritus, urticaria, eosinophilia, or anaphylaxis. Pulmonary hydatid cysts may rupture into the bronchial tree or pleural cavity and produce cough, salty phlegm, dyspnea, chest pain, or hemoptysis. Rupture of hydatid cysts, which can occur spontaneously or at surgery, may lead to multifocal dissemination of protoscolices, which can form additional cysts. Other presentations are due to the involvement of bone (invasion of the medullary cavity with slow bone erosion producing pathologic fractures), the CNS (spaceoccupying lesions), the heart (conduction defects, pericarditis), and the pelvis (pelvic mass).


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InternalMed_Harrison. The larval forms of E. multilocularis characteristically present as a slowly growing hepatic tumor, with progressive destruction of the liver and extension into vital structures. Patients commonly report upper-quadrant and epigastric pain. Liver enlargement and obstructive jaundice may be apparent. The lesions may infiltrate adjoining organs (e.g., diaphragm, kidneys, or lungs) or may metastasize to the spleen, lungs, or brain.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis Radiographic and related imaging studies are important in detecting and evaluating echinococcal cysts. Plain x-rays will define pulmonary cysts of E. granulosus—usually as rounded masses of uniform density—but may miss cysts in other organs unless there is cyst wall calcification (as occurs in the liver). MRI, CT, and ultrasound reveal well-defined cysts with thick or thin walls. When older cysts contain a layer of hydatid sand that is rich in accumulated protoscolices, these imaging methods may detect this fluid layer of different density. However, the most pathognomonic finding, if demonstrable, is that of daughter cysts within the larger cyst. This finding, like eggshell or mural calcification on CT, is indicative of E. granulosus infection and helps to distinguish the cyst from carcinomas, bacterial or amebic liver abscesses, or hemangiomas. In contrast, ultrasound or CT of alveolar hydatid cysts reveals indistinct solid masses with central necrosis and plaquelike


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InternalMed_Harrison. cyst from carcinomas, bacterial or amebic liver abscesses, or hemangiomas. In contrast, ultrasound or CT of alveolar hydatid cysts reveals indistinct solid masses with central necrosis and plaquelike calcifications.


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InternalMed_Harrison. A specific diagnosis of E. granulosus infection can be made by the examination of aspirated fluids for protoscolices or hooklets, but diagnostic aspiration is not usually recommended because of the risk of fluid leakage resulting in either dissemination of infection or anaphy-1433 lactic reactions. Serodiagnostic assays can be useful, although a negative test does not exclude the diagnosis of echinococcosis. Cysts in the liver elicit positive antibody responses in ~90% of cases, whereas up to 50% of individuals with cysts in the lungs are seronegative. Detection of antibody to specific echinococcal antigens by immunoblotting has the highest degree of specificity.


InternalMed_Harrison

InternalMed_Harrison. Therapy for cystic echinococcosis is based on considerations of the size, location, and manifestations of cysts and the overall health of the patient. Surgery has traditionally been the principal definitive method of treatment. Currently, ultrasound staging is recommended for E. granulosus infections (Fig. 260-2). Small CL, CE1, and CE3 lesions may respond to chemotherapy with albendazole. For CE1 lesions and uncomplicated CE3 lesions, PAIR (percutaneous aspiration, infusion of scolicidal agents, and reaspiration) is now recommended instead of surgery. PAIR is contraindicated for superficially located cysts (because of the risk of rupture), for cysts with multiple thick internal septal divisions (honeycombing pattern), and for cysts communicating with the biliary tree. For prophylaxis of secondary peritoneal echinococcosis due to inadvertent spillage of fluid during PAIR, the administration of albendazole (15 mg/kg daily in two divided doses) should be initiated at least 2 days before


InternalMed_Harrison

InternalMed_Harrison. peritoneal echinococcosis due to inadvertent spillage of fluid during PAIR, the administration of albendazole (15 mg/kg daily in two divided doses) should be initiated at least 2 days before the procedure and continued for at least 4 weeks afterward. Ultrasound-or CT-guided aspiration allows confirmation of the diagnosis by demonstration of protoscolices in the aspirate. After aspiration, contrast material should be injected to detect occult communications with the biliary tract. Alternatively, the fluid should be checked for bile staining visually and by dipstick. If no bile is found and no communication is visualized, the contrast material is reaspirated, with subsequent infusion of scolicidal agents (usually 95% ethanol; alternatively, hypertonic saline). This approach, when implemented by a skilled practitioner, yields rates of cure and relapse equivalent to those following surgery, with less perioperative morbidity and shorter hospitalization. In experienced hands, some CE2


InternalMed_Harrison

InternalMed_Harrison. by a skilled practitioner, yields rates of cure and relapse equivalent to those following surgery, with less perioperative morbidity and shorter hospitalization. In experienced hands, some CE2 lesions can be treated by aspiration with a trocar. Daughter cysts within the primary cyst may need to be punctured separately, and catheter drainage may be required.


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InternalMed_Harrison. FIGuRE 260-2 Management of cystic hydatid disease caused by Echinococcus granulosus should be based on viability of the parasite, which can be estimated from radiographic appearance. The ultrasound appearance includes lesions classified as active, transitional, and inactive. Active cysts include types CL (with a cystic lesion and no visible cyst wall), CE1 (with a visible cyst wall and internal echoes [snowflake sign]), and CE2 (with a visible cyst wall and internal septation). Transitional cysts (CE3) may have detached laminar membranes or may be partially collapsed. Inactive cysts include types CE4 (a nonhomogeneous mass) and CE5 (a cyst with a thick calcified wall). (Adapted from RL Guerrant et al [eds]: Tropical Infectious Diseases: Principles, Pathogens and Practice, 2nd ed, p 1312. © 2005, with permission from Elsevier Science.) 1434 Surgery remains the treatment of choice for complicated


InternalMed_Harrison

InternalMed_Harrison. E. granulosus cysts (e.g., those communicating with the biliary tract), for most thoracic and intracranial cysts, and for areas where PAIR is not possible. For E. granulosus of the liver, the preferred surgical approach is pericystectomy, in which the entire cyst and the surrounding fibrous tissue are removed. The risks posed by leakage of fluid during surgery or PAIR include anaphylaxis and dissemination of infectious protoscolices. The latter complication has been minimized by careful attention to the prevention of spillage of the cyst and by soaking of the drapes with hypertonic saline. Infusion of scolicidal agents is no longer recommended because of problems with hypernatremia, intoxication, or sclerosing cholangitis. Albendazole, which is active against Echinococcus, should be administered adjunctively, beginning several days before resection of the liver and continuing for several weeks for E. granulosus. Praziquantel (50 mg/kg daily for 2 weeks) may hasten the death of the


InternalMed_Harrison

InternalMed_Harrison. adjunctively, beginning several days before resection of the liver and continuing for several weeks for E. granulosus. Praziquantel (50 mg/kg daily for 2 weeks) may hasten the death of the protoscolices. Medical therapy with albendazole alone for 12 weeks to 6 months results in cure in ~30% of cases and in improvement in another 50%. In many instances of treatment failure, E. granulosus infections are subsequently treated successfully with PAIR or additional courses of medical therapy. Response to treatment is best assessed by serial imaging studies, with attention to cyst size and consistency. Some cysts may not demonstrate complete radiologic resolution even though no viable protoscolices are present. Some of these cysts with partial radiologic resolution (e.g., CE4 or CE5) can be managed with observation only.


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InternalMed_Harrison. Surgical resection remains the treatment of choice for E. multilocularis infection. Complete removal of the parasite continues to offer the best chance for cure. Ongoing therapy with albendazole for at least 2 years after presumptively curative surgery is recommended. Positron emission tomography can be used to follow disease activity. Most cases are diagnosed at a stage at which complete resection is not possible; in these cases, albendazole treatment should be continued indefinitely, with careful monitoring. In some cases, liver transplantation has been used because of the size of the necessary liver resection. However, continuous immunosuppression favors the proliferation of E. multilocularis larvae and reinfection of the transplant. Thus, indefinite treatment with albendazole is required.


InternalMed_Harrison

InternalMed_Harrison. Prevention In endemic areas, echinococcosis can be pre vented by administering praziquantel to infected dogs, by denying dogs access to infected animals, or by vaccinating sheep. Limitation of the number of stray dogs is helpful in reducing the prevalence of infection among humans. In Europe, E. multilocularis infection has been associated with gardening; gloves should be used when working with soil. Infection with Hymenolepis nana, the dwarf tapeworm, is the most common of all the cestode infections. H. nana is endemic in both temperate and tropical regions of the world. Infection is spread by fecal/oral contamination and is common among institutionalized children.


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InternalMed_Harrison. Etiology and Pathogenesis H. nana is the only cestode of humans that does not require an intermediate host. Both the larval and adult phases of the life cycle take place in the human. The adult—the smallest tapeworm parasitizing humans—is ~2 cm long and dwells in the proximal ileum. Proglottids, which are small and rarely seen in the stool, release spherical eggs 30–44 μm in diameter, each of which contains an oncosphere with six hooklets. The eggs are immediately infective and are unable to survive for >10 days in the external environment. When the egg is ingested by a new host, the oncosphere is freed and penetrates the intestinal villi, becoming a cysticercoid larva. Larvae migrate back into the intestinal lumen, attach to the mucosa, and mature into adult worms over 10–12 days. Eggs may also hatch before passing into the stool, causing internal autoinfection with increasing numbers of intestinal worms. Although the life span of adult H. nana worms is only ~4–10 weeks, the


InternalMed_Harrison

InternalMed_Harrison. Eggs may also hatch before passing into the stool, causing internal autoinfection with increasing numbers of intestinal worms. Although the life span of adult H. nana worms is only ~4–10 weeks, the autoinfection cycle perpetuates the infection.


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InternalMed_Harrison. Clinical Manifestations H. nana infection, even with many intestinal worms, is usually asymptomatic. When infection is intense, anorexia, abdominal pain, and diarrhea develop. Diagnosis Infection is diagnosed by the finding of eggs in the stool. Praziquantel (25 mg/kg once) is the treatment of choice, because it acts against both the adult worms and the cysticercoids in the intestinal villi. Nitazoxanide (500 mg bid for 3 days) may be used as an alternative. Prevention Good personal hygiene and improved sanitation can eradicate the disease. Epidemics have been controlled by mass chemotherapy coupled with improved hygiene. Hymenolepis diminuta, a cestode of rodents, occasionally infects small children, who ingest the larvae in uncooked cereal foods contaminated by fleas and other insects in which larvae develop. Infection is usually asymptomatic and is diagnosed by the detection of eggs in the stool. Treatment with praziquantel results in cure in most cases.


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InternalMed_Harrison. Diphyllobothrium latum and other Diphyllobothrium species are found in the lakes, rivers, and deltas of the Northern Hemisphere, central Africa, and South America. Etiology and Pathogenesis The adult worm—the longest tapeworm (up to 25 m)—attaches to the ileal and occasionally to the jejunal mucosa by its suckers, which are located on its elongated scolex. The adult worm has 3000–4000 proglottids, which release ~1 million eggs daily into the feces. If an egg reaches water, it hatches and releases a free-swimming embryo that can be eaten by small freshwater crustaceans (Cyclops or Diaptomus species). After an infected crustacean containing a developed procercoid is swallowed by a fish, the larva migrates into the fish’s flesh and grows into a plerocercoid, or sparganum larva. Humans acquire the infection by ingesting infected raw or smoked fish. Within 3–5 weeks, the tapeworm matures into an adult in the human intestine.


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InternalMed_Harrison. Clinical Manifestations Most D. latum infections are asymptomatic, although manifestations may include transient abdominal discomfort, diarrhea, vomiting, weakness, and weight loss. Occasionally, infection can cause acute abdominal pain and intestinal obstruction; in rare cases, cholangitis or cholecystitis may be produced by migrating proglottids. Because the tapeworm absorbs large quantities of vitamin B12 and interferes with ileal B12 absorption, vitamin B12 deficiency can develop, but this effect has been noted only in Scandinavia, where up to 2% of infected patients, especially the elderly, have megaloblastic anemia resembling pernicious anemia and may exhibit neurologic sequelae of B12 deficiency. Diagnosis The diagnosis is made readily by the detection of the characteristic eggs in the stool. The eggs possess a single shell with an operculum at one end and a knob at the other. Mild to moderate eosinophilia may be detected.


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InternalMed_Harrison. Praziquantel (5–10 mg/kg once) is highly effective. Parenteral vitamin B12 should be given if B12 deficiency is manifest. Prevention Infection can be prevented by heating fish to 54°C for 5 min or by freezing it at −18°C for 24 h. Placing fish in brine with a high salt concentration for long periods kills the eggs. Dipylidium caninum, a common tapeworm of dogs and cats, may accidentally infect humans. Dogs, cats, and occasionally humans become infected by ingesting fleas harboring cysticercoids. Children are more likely to become infected than adults. Most infections are asymptomatic, but abdominal pain, diarrhea, anal pruritus, urticaria, eosinophilia, or passage of segments in the stool may occur. The diagnosis is made by the detection of proglottids or ova in the stool. As in D. latum infection, therapy consists of praziquantel. Prevention requires anthelmintic treatment and flea control for pet dogs or cats.


InternalMed_Harrison

InternalMed_Harrison. Humans can be infected by the sparganum, or plerocercoid larva, of a diphyllobothrid tapeworm of the genus Spirometra. Infection can be acquired by the consumption of water containing infected Cyclops; 1435 by the ingestion of infected snakes, birds, or mammals; or by the application of infected flesh as poultices. The worm migrates slowly in tissues, and infection commonly presents as a subcutaneous swelling. Periorbital tissues can be involved, and ocular sparganosis may destroy the eye. Surgical excision is used to treat localized sparganosis. This rare infection of humans by the larval stage (coenurus) of the dog tapeworm Taenia multiceps or T. serialis results in a space-occupying cystic lesion. As in cysticercosis, involvement of the CNS and subcutaneous tissue is most common. Both definitive diagnosis and treatment require surgical excision of the lesion. Chemotherapeutic agents generally are not effective.


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InternalMed_Harrison. the genetic modification of microbes for the purposes of antimicrobial resistance or evasion by the immune system, creation of fine-particle aerosols, chemical treatment to stabilize and prolong infectivity, and H. Clifford Lane, Anthony S. Fauci alteration of host range through changes in surface proteins. Certain


InternalMed_Harrison

InternalMed_Harrison. Descriptions of the use of microbial pathogens as potential weapons of war or terrorism date from ancient times. Among the most frequently cited of such episodes are the poisoning of water supplies in the sixth century b.c. with the fungus Claviceps purpurea (rye ergot) by the Assyrians, the hurling of the dead bodies of plague victims over the walls of the city of Kaffa by the Tartar army in 1346, and the efforts by the British to spread smallpox to the Native American population loyal to the French via contaminated blankets in 1763. The tragic attacks on the World Trade Center and the Pentagon on September 11, 2001, followed closely by the mailing of letters containing anthrax spores to media and congressional offices through the U.S. Postal Service, dramatically changed the mindset of the American public regarding both our vulnerability to microbial bioterrorist attacks and the seriousness and intent of the federal government to protect its citizens against future attacks. Modern


InternalMed_Harrison

InternalMed_Harrison. the American public regarding both our vulnerability to microbial bioterrorist attacks and the seriousness and intent of the federal government to protect its citizens against future attacks. Modern science has revealed methods of deliberately spreading or enhancing disease in ways not appreciated by our ancestors. The combination of basic research, good medical practice, and constant vigilance will be needed to defend against such attacks.


InternalMed_Harrison

InternalMed_Harrison. Although the potential impact of a bioterrorist attack could be enormous, leading to thousands of deaths and high morbidity rates, acts of bioterrorism would be expected to produce their greatest impact through the fear and terror they generate. In contrast to biowarfare, where the primary goal is destruction of the enemy through mass casualties, an important goal of bioterrorism is to destroy the morale of a society through fear and uncertainty. Although the actual biologic impact of a single act may be small, the degree of disruption created by the realization that such an attack is possible may be enormous. This was readily apparent with the impact on the U.S. Postal Service and the functional interruption of the activities of the legislative branch of the U.S. government following the anthrax attacks noted above. Thus, the key to the defense against these attacks is a highly functioning system of public health surveillance and education so that attacks can be quickly recognized


InternalMed_Harrison

InternalMed_Harrison. anthrax attacks noted above. Thus, the key to the defense against these attacks is a highly functioning system of public health surveillance and education so that attacks can be quickly recognized and effectively contained. This is complemented by the availability of appropriate countermeasures in the form of diagnostics, therapeutics, and vaccines, both in response to and in anticipation of bioterrorist attacks.


InternalMed_Harrison

InternalMed_Harrison. The Working Group for Civilian Biodefense created a list of key features that characterize the elements of biologic agents that make them particularly effective as weapons (Table 261e-1). Included among these are the ease of spread and transmission of the agent and the presence of an adequate database to allow newcomers to the field to quickly apply the good science of others to bad intentions of their own. Agents of bioterrorism may be used in their naturally occurring forms, or they can be deliberately modified to deliver greater impact. Among the approaches to maximizing the deleterious effects of biologic agents are Key Features oF BioLogiC agents used as Bioweapons 1. 2. 3. 4. Lack of rapid diagnostic capability 5. Lack of universally available effective vaccine 6. Potential to cause anxiety 7. Availability of pathogen and feasibility of production 8. 9. Database of prior research and development 10. Potential to be “weaponized”


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InternalMed_Harrison. Potential to cause anxiety 7. Availability of pathogen and feasibility of production 8. 9. Database of prior research and development 10. Potential to be “weaponized” Source: From L Borio et al: JAMA 287:2391, 2002; with permission. of these approaches fall under the category of weaponization, which is a term generally used to describe the processing of microbes or toxins in a manner that would ensure a devastating effect following release. For example, weaponization of anthrax by the Soviets involved the production of vast numbers of spores of appropriate size to reach the lower respiratory tract easily in a form that maintained aerosolization for prolonged periods of time and that could be delivered in a massive release, such as via widely dispersed bomblets.


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InternalMed_Harrison. The U.S. Centers for Disease Control and Prevention (CDC) classifies potential biologic threats into three categories: A, B, and C (Table 261e-2). Category A agents are the highest-priority pathogens. They pose the greatest risk to national security because they (1) can be easily disseminated or transmitted from person to person, (2) result in high mortality rates and have the potential for major public health impact, (3) might cause public panic and social disruption, and (4) require special action for public health preparedness. Category B agents are the second highest priority pathogens and include those that are moderately easy to disseminate, result in moderate morbidity rates and low mortality rates, and require specifically enhanced diagnostic capacity. Category C agents are the third highest priority. These include certain emerging pathogens to which the general population lacks immunity; that could be engineered for mass dissemination in the future because of availability,


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InternalMed_Harrison. third highest priority. These include certain emerging pathogens to which the general population lacks immunity; that could be engineered for mass dissemination in the future because of availability, ease of production, and ease of dissemination; and that have a major public health impact and the potential for high morbidity and mortality rates. It should be pointed out, however, that these A, taBLe 261e-2 CdC Category a, B, and C agents


InternalMed_Harrison

InternalMed_Harrison. Arenaviruses: Lassa, New World (Machupo, Junin, Guanarito, and Sabia) Bunyaviridae: Crimean-Congo, Rift Valley Filoviridae: Ebola, Marburg Brucellosis (Brucella spp.) Epsilon toxin of Clostridium perfringens Food safety threats (e.g., Salmonella spp., Escherichia coli 0157:H7, Shigella) Glanders (Burkholderia mallei) Melioidosis (Burkholderia pseudomallei) Psittacosis (Chlamydophila psittaci) Q fever (Coxiella burnetii) Ricin toxin from Ricinus communis (castor beans) Staphylococcal enterotoxin B Typhus fever (Rickettsia prowazekii) Viral encephalitis (alphaviruses [e.g., Venezuelan, eastern, and western equine encephalitis]) Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum) Emerging infectious diseases threats such as Nipah, hantavirus, SARS or MERS coronavirus, and pandemic influenza Abbreviations: MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome. Source: Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases. B, and C designations are empirical and, depending on evolving circumstances such as intelligence-based threat assessments, the priority rating of any given microbe or toxin could change. The CDC classification system also largely reflects the severity of illness produced by a given agent, rather than its accessibility to potential terrorists. See also Chap. 175.


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InternalMed_Harrison. Bacillus anthracis as a Bioweapon Anthrax may be the prototypic disease of bioterrorism. Although rarely, if ever, spread from person to person, the illness embodies the other major features of a disease introduced through terrorism, as outlined in Table 261e-1. U.S. and British government scientists studied anthrax as a potential biologic weapon beginning approximately at the time of World War II (WWII). Offensive bioweapons activity including bioweapons research on microbes and toxins in the United States ceased in 1969 as a result of two executive orders by President Richard M. Nixon. Although the 1972 Biological and Toxin Weapons Convention Treaty outlawed research of this type worldwide, the Soviet Union produced and stored tons of anthrax spores for potential use as a bioweapon until at least the late 1980s. At present, there is suspicion that research on anthrax as an agent of bioterrorism is ongoing by several nations and extremist groups. One example of this was the release


InternalMed_Harrison

InternalMed_Harrison. at least the late 1980s. At present, there is suspicion that research on anthrax as an agent of bioterrorism is ongoing by several nations and extremist groups. One example of this was the release of anthrax spores by the Aum Shinrikyo cult in Tokyo in 1993. Fortunately, there were no casualties associated with that episode because of the inadvertent use of a nonpathogenic strain of anthrax by the terrorists.


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InternalMed_Harrison. The potential impact of anthrax spores as a bioweapon was clearly demonstrated in 1979 following the accidental release of spores into the atmosphere from a Soviet Union bioweapons facility in Sverdlovsk, Russia. Although total figures are not known, at least 77 cases of anthrax were diagnosed with certainty, of which 66 were fatal. These victims were exposed in an area within 4 km downwind of the facility, and deaths due to anthrax were also noted in livestock up to 50 km further downwind. Based on recorded wind patterns, the interval between the time of exposure and development of clinical illness ranged from 2 to 43 days. The majority of cases were within the first 2 weeks. Death typically occurred within 1–4 days following the onset of symptoms. It is likely that the widespread use of postexposure penicillin prophylaxis limited the total number of cases. The extended period of time between exposure and disease in some individuals supports the data from nonhuman primate studies,


InternalMed_Harrison

InternalMed_Harrison. of postexposure penicillin prophylaxis limited the total number of cases. The extended period of time between exposure and disease in some individuals supports the data from nonhuman primate studies, suggesting that anthrax spores can lie dormant in the respiratory tract for at least 4–6 weeks without evoking an immune response. This extended period of microbiologic latency following exposure poses a significant challenge for management of victims in the postexposure period.


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InternalMed_Harrison. In September 2001, the American public was exposed to anthrax spores as a bioweapon delivered through the U.S. Postal Service by an employee of the United States Army Medical Research Institute for Infectious Diseases (USAMRIID) who had access to such materials and who committed suicide prior to being indicted for this crime. The CDC identified 22 confirmed or suspected cases of anthrax as a consequence of this attack. These included 11 patients with inhalational anthrax, of whom 5 died, and 11 patients with cutaneous anthrax (7 confirmed), all of whom survived (Fig. 261e-1). Cases occurred in individuals who opened contaminated letters as well as in postal workers involved in the processing of mail. A minimum of five letters mailed from Trenton, NJ, served as the vehicles for these attacks. One of these letters was reported to contain 2 g of material, equivalent to 100 billion to 1 trillion weapon-grade spores. Based on studies performed in the 1950s using monkeys exposed to


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InternalMed_Harrison. attacks. One of these letters was reported to contain 2 g of material, equivalent to 100 billion to 1 trillion weapon-grade spores. Based on studies performed in the 1950s using monkeys exposed to aerosolized anthrax demonstrating that ~10,000 spores were required to produce lethal disease in 50% of animals exposed to this dose (the LD50), the contents of one letter had the theoretical potential, under optimal conditions, of causing illness or death in up to 50 million individuals. The strain used in this attack was the Ames strain. Although it was noted to have an inducible β-lactamase and to constitutively express a cephalosporinase, it was susceptible to all antibiotics standard for B. anthracis.


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InternalMed_Harrison. Envelopes mailed to news media companies, Sept. 18 Envelopes mailed to government leaders, Oct. 9 Anthrax first confirmed 0 2Numberof cases4 6 Symptom onset dates, September–November 2001 Dist. of Columbia* = inhalation anthrax cases. * = Metropolitan District of Columbia Area, cases were residents of Maryland (3) and Virginia (2). Figure 261e-1 Confirmed anthrax cases associated with bioterrorism: United States, 2001. A. Geographic location, clinical manifestation, and outcome of the 11 cases of confirmed inhalational and 11 cases of confirmed cutaneous anthrax. B. Epidemic curve for 22 cases of anthrax. (From DB Jernigan et al: Emerg Infect Dis 8:1019, 2002; with permission.)


InternalMed_Harrison

InternalMed_Harrison. Microbiology and Clinical Features Anthrax is caused by B. anthracis, a gram-positive, nonmotile, spore-forming rod that is found in soil and predominantly causes disease in herbivores such as cattle, goats, and sheep. Anthrax spores can remain viable for decades. The remarkable stability of these spores makes them an ideal bioweapon, and their destruction in decontamination activities can be a challenge. Naturally occurring human infection is generally the result of contact with anthrax-infected animals or animal products such as goat hair in textile mills or animal skins used in making drums. While an LD50 of 10,000 spores is a generally accepted number, it has also been suggested that as few as one to three spores may be adequate to cause disease in some settings. Advanced technology is likely to be necessary to generate a bioweapon containing spores of the optimal size (1–5 μm) to travel to the alveolar spaces.


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InternalMed_Harrison. The three major clinical forms of anthrax are gastrointestinal, cutaneous, and inhalational. Gastrointestinal anthrax typically results from the ingestion of contaminated meat; the condition is rarely seen and is unlikely to be the result of a bioterrorism event. The lesion of cutaneous anthrax typically begins as a papule following the introduction of spores through an opening in the skin. This papule then evolves to a painless vesicle followed by the development of a coal-black, necrotic eschar (Fig. 261e-2). It is the Greek word for coal (anthrax) that gives the organism and the disease its name. Cutaneous anthrax was ~20% fatal prior to the availability of antibiotics. Inhalational anthrax is the Figure 261e-2 Clinical manifestations of a pediatric case of cutaneous anthrax associated with the bioterrorism attack of 2001. The lesion progresses from vesicular on day 5 (A) to necrotic with the classic black eschar on day 12 (B) to a healed scar 2 months later (C).


InternalMed_Harrison

InternalMed_Harrison. (Photographs provided by Dr. Mary Wu Chang. Part A reproduced with permission from KJ Roche et al: N Engl J Med 345:1611, 2001 and Parts B and C reproduced with permission from A Freedman et al: JAMA 287:869, 2002.) form most likely to be responsible for death in the setting of a bioterrorist attack. It occurs following the inhalation of spores that become deposited in the alveolar spaces. These spores are phagocytized by macrophages and transported to the mediastinal and peribronchial lymph nodes where they germinate, leading to active bacterial growth and elaboration of the bacterial products edema toxin and lethal toxin. Subsequent hematogenous spread of bacteria is accompanied by cardiovascular collapse and death. The earliest symptoms are typically a viral-like prodrome with fever, malaise, and abdominal and/or chest symptoms that progress over the course of a few days to a moribund state. Characteristic findings on chest x-ray include mediastinal widening and pleural effusions


InternalMed_Harrison

InternalMed_Harrison. malaise, and abdominal and/or chest symptoms that progress over the course of a few days to a moribund state. Characteristic findings on chest x-ray include mediastinal widening and pleural effusions (Fig. 261e-3). Although initially thought to be 100% fatal, the experiences at Sverdlovsk in 1979 and in the United States in 2001 (see below) indicate that with prompt initiation of antibiotic therapy, survival is possible. The characteristics of the 11 cases of inhalational anthrax diagnosed in the United States in 2001 following exposure to contaminated letters postmarked September 18 or October 9, 2001, followed the classic pattern established for this illness, with patients presenting with a rapidly progressive course characterized by fever, fatigue or malaise, nausea or vomiting, cough, and shortness of breath. At presentation, the total white blood cell counts were ~10,000 cells/μL; transaminases tended to be elevated, and all 11 had abnormal findings on chest x-ray and computed


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InternalMed_Harrison. and shortness of breath. At presentation, the total white blood cell counts were ~10,000 cells/μL; transaminases tended to be elevated, and all 11 had abnormal findings on chest x-ray and computed tomography (CT). Radiologic findings included infiltrates, mediastinal widening, and hemorrhagic pleural effusions. For cases in which the dates of exposure were known, symptoms appeared within 4–6 days. Death occurred within 7 days of diagnosis in the five fatal cases (overall mortality rate 55%). Rapid diagnosis and prompt initiation of antibiotic therapy were key to survival.


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InternalMed_Harrison. Anthrax can be successfully treated if the disease is promptly recognized and appropriate therapy with antibiotics and antitoxin is initiated early. Although penicillin, ciprofloxacin, and doxycycline are the currently licensed antibiotics for this indication, clindamycin and rifampin also have in vitro activity against the organism and have been used as part of treatment regimens. Until sensitivity results are known, suspected cases are best managed with a combination of broadly active agents (Table 261e-3). The B. anthracis toxins lethal factor and edema factor share a component known as protective antigen. Raxibacumab, a monoclonal antibody directed toward protective antigen, was licensed in 2012 under the animal rule (see below) for treatment of adult and pediatric patients with inhalational anthrax in combination with appropriate antibacterial drugs. Patients with inhalational anthrax are not contagious and do not require special isolation procedures.


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InternalMed_Harrison. Vaccination and Prevention The first successful vaccine for anthrax was developed for animals by Louis Pasteur in 1881. At present, the single vaccine licensed for human use is a product produced from the cell-free culture supernatant of an attenuated, nonencapsulated strain of B. anthracis (Stern strain), referred to as anthrax vaccine adsorbed (AVA). Clinical trials for safety in humans and efficacy in animals are currently under way to evaluate the role of recombinant protective antigen as an alternative to AVA. In a postexposure setting in nonhuman primates, a 2-week course of AVA plus ciprofloxacin was found to be superior to ciprofloxacin alone in preventing the development of clinical disease and death. Although the current recommendation for postexposure prophylaxis is 60 days of antibiotics, it would seem prudent to include immunization with anthrax vaccine if available. Given the potential for


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InternalMed_Harrison. B. anthracis to be engineered to express penicillin resistance, the empirical regimen of choice in this setting is either ciprofloxacin or doxycycline. In settings where these approaches are not available or appropriate, one can administer the antitoxin monoclonal antibody raxibacumab. See also Chap. 196.


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InternalMed_Harrison. Yersinia pestis as a Bioweapon Although it lacks the environmental stability of anthrax, the highly contagious nature and high mortality rate of plague make it a close to ideal agent of bioterrorism, particularly if delivered in a weaponized form. Occupying a unique place in history, plague has been alleged to have been used as a biologic weapon for centuries. The catapulting of plague-infected corpses into besieged fortresses is a practice that was first noted in 1346 during the assault of the Crimean city of Kaffa by the Mongolian Tartars. Although unlikely to have resulted in disease transmission, some believe that this event may have played a role in the start of the Black Death pandemic of the fourteenth and fifteenth centuries in Europe. Given that plague was already moving across Asia toward Europe at this time, it is unclear whether such an allegation is accurate. During WWII, the infamous Unit 731 of the Japanese army was reported to have repeatedly dropped plague-infested


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InternalMed_Harrison. Asia toward Europe at this time, it is unclear whether such an allegation is accurate. During WWII, the infamous Unit 731 of the Japanese army was reported to have repeatedly dropped plague-infested fleas over parts of China, including Manchuria. These drops were associated with subsequent outbreaks of plague in the targeted areas. Following WWII, the United States and the Soviet Union conducted programs of research on how to create aerosolized Y. pestis that could be used as a bioweapon to cause primary pneumonic plague. As mentioned above, plague was thought to be an excellent bioweapon due to the fact that in addition to causing infection in those inhaling the aerosol, significant numbers of secondary cases of primary pneumonic plague would also likely occur due to the contagious nature of the disease and person-to-person transmission via respiratory aerosol. Secondary reports of research conducted during that time suggest that organisms remain viable for up to 1 h and can be


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InternalMed_Harrison. nature of the disease and person-to-person transmission via respiratory aerosol. Secondary reports of research conducted during that time suggest that organisms remain viable for up to 1 h and can be dispersed for


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InternalMed_Harrison. Figure 261e-3 Progression of chest x-ray findings in a patient with inhalational anthrax. Findings evolved from subtle hilar prominence and right perihilar infiltrate to a progressively widened mediastinum, marked perihilar infiltrates, peribronchial cuffing, and air bronchograms.


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InternalMed_Harrison. (From L Borio et al: JAMA 286:2554, 2001; with permission.) distances up to 10 km. Although the offensive bioweapons program in the United States was terminated prior to production of sufficient quantities of plague organisms for use as a weapon, it is believed that Soviet scientists did manufacture quantities sufficient for such a purpose. It has also been reported that more than 10 Soviet institutes and >1000 scientists were working with plague as a biologic weapon. Of concern is the fact that in 1995 a microbiologist in Ohio was arrested for having obtained Y. pestis in the mail from the American Type Culture Collection, using a credit card and a false letterhead. In the wake of this incident, the U.S. Congress passed a law in 1997 requiring that anyone intending to send or receive any of 42 different agents that could potentially be used as bioweapons first register with the CDC.


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InternalMed_Harrison. Microbiology and Clinical Features Plague is caused by Y. pestis, a non-motile, gram-negative bacillus that exhibits bipolar, or “safety pin,” staining with Wright, Giemsa, or Wayson stains. It has had a major impact on the course of history, thus adding to the element of fear evoked by its mention. The earliest reported plague epidemic was in 224 b.c. in China. The most infamous pandemic began in Europe in the fourteenth century, during which time one-third to one-half of the entire population of Europe was killed. During a plague outbreak in India in 1994, even though the number of confirmed cases was relatively small, it is estimated that 500,000 individuals fled their homes in fear of this disease. In the first decade of the twenty-first century, 21,725 cases of plague were reported to the World Health Organization (WHO). Over 90% of these cases were from Africa, and the overall case fatality rate was 7.4%.


InternalMed_Harrison

InternalMed_Harrison. The clinical syndromes of plague generally reflect the mode of infection. Bubonic plague is the consequence of an insect bite; primary pneumonic plague arises through the inhalation of bacteria. Most of the plague seen in the world today is bubonic plague and is the result of a bite by a plague-infected flea. In part as a consequence of past pandemics, plague infection of rodents exists widely in nature, including in the southwestern United States, and each year thousands of cases of plague occur worldwide through contact with infected animals or fleas. Following inoculation of regurgitated bacteria into the skin by a flea bite, organisms travel through the lymphatics to regional lymph nodes, where they are phagocytized but not destroyed. Inside the cell, they multiply rapidly leading to inflammation, painful lymphadenopathy with necrosis, fever, bacteremia, septicemia, and death. The characteristic enlarged, inflamed lymph nodes, or buboes, give this form of plague its name. In some


InternalMed_Harrison

InternalMed_Harrison. inflammation, painful lymphadenopathy with necrosis, fever, bacteremia, septicemia, and death. The characteristic enlarged, inflamed lymph nodes, or buboes, give this form of plague its name. In some instances, patients may develop bacteremia without lymphadenopathy following infection, a condition referred to as primary septicemic plague. Extensive ecchymoses may develop due 261e-5 taBLe 261e-3 CLiniCaL syndroMes, prevention, and treatMent strategies For diseases Caused By Category a agents


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InternalMed_Harrison. Cutaneous lesion: Papule to eschar Inhalational disease: Fever, malaise, chest and abdominal discomfort Pleural effusion, widened mediastinum on chest x-ray Fever, cough, dyspnea, hemoptysis Fever, malaise, headache, backache, emesis Maculopapular to vesicular to pustular skin lesions Fever, chills, malaise, myalgia, chest discomfort, dyspnea, headache, skin rash, pharyngitis, conjunctivitis Fever, myalgia, rash, encephalitis, prostration Dry mouth, blurred vision, ptosis, weakness, dysarthria, dysphagia, dizziness, respiratory failure, progressive paralysis, dilated pupils 1–12 days Culture, Gram stain, PCR, Wright stain of peripheral smear 1–60 days Postexposure: Ciprofloxacin, 500 mg, PO bid × 60 d or Doxycycline, 100 mg PO bid × 60 d or Amoxicillin, 500 mg PO q8h × 60 d, likely to be effective if strain is penicillin sensitive Active disease: Ciprofloxacin, 400 mg IV q12h or doxycycline, 100 mg IV q12h plus


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InternalMed_Harrison. Amoxicillin, 500 mg PO q8h × 60 d, likely to be effective if strain is penicillin sensitive Active disease: Ciprofloxacin, 400 mg IV q12h or doxycycline, 100 mg IV q12h plus Clindamycin, 900 mg IV q8h and/or rifampin, 300 mg IV q12h; switch to PO when stable × 60 d total plus Raxibacumab, 40 mg/kg IV over 2.25 h; diphenhydramine to reduce reaction Gentamicin, 2.0 mg/kg IV loading then 1.7 mg/kg q8h IV or Streptomycin, 1.0 g q12h IM or IV Alternatives include doxycycline, 100 mg bid PO or IV; chloramphenicol, 500 mg qid PO or IV Supportive measures; consideration for cidofovir, tecovirimat, antivaccinia immunoglobulin Streptomycin, 1 g IM bid or Gentamicin, 5 mg/kg per day div q8h IV for 14 days or Doxycycline, 100 mg IV bid or Chloramphenicol, 15 mg/kg up to 1 g IV qid or Ciprofloxacin, 400 mg IV bid Ribavirin 30 mg/kg up to 2 g × 1, followed by 16 mg/kg IV up to 1 g q6h for 4 days, followed by 8 mg/ kg IV up to 0.5 g q8h × 6 days


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InternalMed_Harrison. Ciprofloxacin, 400 mg IV bid Ribavirin 30 mg/kg up to 2 g × 1, followed by 16 mg/kg IV up to 1 g q6h for 4 days, followed by 8 mg/ kg IV up to 0.5 g q8h × 6 days Supportive measures including ventilation, HBAT equine antitoxin from the CDC Emergency Operations Center, 770-488-7100 Anthrax vaccine adsorbed Recombinant protective antigen vaccines are under study Raxibacumab when alternative therapies are not available or appropriate Doxycycline, 100 mg PO bid or Levofloxacin, 500 mg PO daily Doxycycline, 100 mg PO bid × 14 days or Ciprofloxacin, 500 mg PO bid × 14 days Administration of antitoxin Abbreviations: CDC, U.S. Centers for Disease Control and Prevention; FDA, U.S. Food and Drug Administration; HBAT, heptavalent botulinum antitoxin; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction.


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InternalMed_Harrison. to disseminated intravascular coagulation, and gangrene of the digits infiltrates and consolidation on chest x-ray. In the absence of antibiotand/or nose may develop in patients with advanced septicemic plague. ics, the mortality rate of this form of plague is on the order of 85%, and It is thought that this appearance of some patients gave rise to the term death usually occurs within 2–6 days. Black Death in reference to the plague epidemic of the fourteenth and fifteenth centuries. Some patients may develop pneumonia (secondary pneumonic plague) as a complication of bubonic or septicemic plague. These patients may then transmit the agent to others via the respira-Streptomycin, tetracycline, doxycycline, and levofloxacin are tory route, causing cases of primary pneumonic plague. Primary pneu-licensed by the U.S. Food and Drug Administration (FDA) for the monic plague is the manifestation most likely to occur as the result of a treatment of plague. Levofloxacin was approved for this


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InternalMed_Harrison. pneu-licensed by the U.S. Food and Drug Administration (FDA) for the monic plague is the manifestation most likely to occur as the result of a treatment of plague. Levofloxacin was approved for this indication bioterrorist attack, with an aerosol of bacteria spread over a wide area in 2012 via the animal rule (see below). Multiple additional antibiotor a particular environment that is densely populated. In this setting, ics licensed for other infections are commonly used and are likely patients would be expected to develop fever, cough with hemoptysis, effective. Among these are aminoglycosides such as gentamicin, dyspnea, and gastrointestinal symptoms 1–6 days following exposure. cephalosporins, trimethoprim/sulfamethoxazole, chloramphenicol, Clinical features of pneumonia would be accompanied by pulmonary and ciprofloxacin (Table 261e-3). A multidrug-resistant strain of


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InternalMed_Harrison. Y. pestis was identified in 1995 from a patient with bubonic plague in Madagascar. Although this organism was resistant to streptomycin, ampicillin, chloramphenicol, sulfonamides, and tetracycline, it retained its susceptibility to other aminoglycosides and cephalosporins. Given the subsequent identification of a similar organism in 1997 coupled with the fact that this resistance is plasmid-mediated, it seems likely that genetically modifying Y. pestis to a multidrugresistant form is possible. Unlike patients with inhalational anthrax (see above), patients with pulmonary plague should be cared for under conditions of strict respiratory isolation comparable to that used for multidrug-resistant tuberculosis.


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InternalMed_Harrison. Vaccination and Prevention A formalin-fixed, whole-organism vaccine was licensed by the FDA for the prevention of plague. That vaccine is no longer being manufactured, but its potential value as a current countermeasure against bioterrorism would likely have been modest at best as it was ineffective against animal models of primary pneumonic plague. Efforts are under way to develop a second generation of vaccines that will protect against aerosol challenge. Among the candidates being tested are recombinant forms of the fraction 1 capsular (F1) antigen and the virulence component of the type III secretion apparatus (V) antigen of Y. pestis. It is likely that doxycycline or levofloxacin would provide coverage in a chemoprophylaxis setting. Unlike the case with anthrax, in which one has to be concerned about the persistence of ungerminated spores in the respiratory tract, the duration of prophylaxis against plague need only extend to 7 days following exposure. See also Chap. 220e.


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InternalMed_Harrison. Variola Virus as a Bioweapon Given that most of the world’s population was once vaccinated against smallpox, variola virus would not have been considered a good candidate as a bioweapon 30 years ago. However, with the cessation of immunization programs in the United States in 1972 and throughout the world in 1980 due to the successful global eradication of smallpox, close to 50% of the U.S. population is fully susceptible to smallpox today. Given its infectious nature and the 10–30% mortality rate in unimmunized individuals, the deliberate spread of this virus could have a devastating effect on our society and unleash a previously conquered deadly disease. It is estimated that an initial infection of 50–100 persons in a first generation of cases could expand by a factor of 10–20 with each succeeding generation in the absence of any effective containment measures. Although the likely implementation of an effective public health response makes this scenario unlikely, it does illustrate


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InternalMed_Harrison. succeeding generation in the absence of any effective containment measures. Although the likely implementation of an effective public health response makes this scenario unlikely, it does illustrate the potential damage and disruption that can result from a smallpox outbreak.


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InternalMed_Harrison. In 1980, the WHO recommended that all immunization programs be terminated; that representative samples of variola virus be transferred to two locations, one at the CDC in Atlanta, GA, in the United States and the other at the Institute of Virus Preparations in the Soviet Union; and that all other stocks of smallpox be destroyed. Several years later, it was recommended that these two authorized collections be destroyed. However, these latter recommendations were placed on hold in the wake of increased concerns on the use of variola virus as a biologic weapon and thus the need to maintain an active program of defensive research. Many of these concerns were based on allegations made by former Soviet officials that extensive programs had been in place in that country for the production and weaponization of large quantities of smallpox virus. The dismantling of these programs with the fall of the Soviet Union and the subsequent weakening of security measures led to fears that stocks of


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InternalMed_Harrison. weaponization of large quantities of smallpox virus. The dismantling of these programs with the fall of the Soviet Union and the subsequent weakening of security measures led to fears that stocks of Variola major may have made their way to other countries or terrorist organizations. In addition, accounts that efforts had been taken to produce recombinant strains of Variola that would be more virulent and more contagious than the wild-type virus have led to an increase in the need to be vigilant for the reemergence of this often fatal infectious disease.


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InternalMed_Harrison. Microbiology and Clinical Features Smallpox is caused by one of two variants of variola virus, V. major and V. minor. Variola is a double-strand DNA virus and member of the Orthopoxvirus genus of the Poxviridae family. Infections with V. minor are generally less severe than those of V. major, with milder constitutional symptoms and lower mortality rates; thus V. major is the only one considered to be a viable bioweapon. Infection with V. major typically occurs following contact with an infected person. Patients are infectious from the time that a maculopapular rash appears on the skin and oropharynx through the resolution and scabbing of the pustular lesions. Infection occurs principally during close contact, through the inhalation of saliva droplets containing virus from the oropharyngeal exanthem. Aerosolized material from contaminated clothing or linen can also spread infection. Several days after exposure, a primary viremia is believed to occur that results in dissemination of


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InternalMed_Harrison. exanthem. Aerosolized material from contaminated clothing or linen can also spread infection. Several days after exposure, a primary viremia is believed to occur that results in dissemination of virus to lymphoid tissues. A secondary viremia occurs ~4 days later that leads to localization of infection in the dermis. Approximately 12–14 days following the initial exposure, the patient develops high fever, malaise, vomiting, headache, backache, and a maculopapular rash that begins on the face and extremities and spreads to the trunk (centripetal) with lesions in the same developmental stage in any given location. This is in contrast to the rash of varicella (chickenpox) that begins on the trunk and face and spreads to the extremities (centrifugal) with lesions at all stages of development. The lesions are initially maculopapular and evolve to vesicles that eventually become pustules and then scabs. The oral mucosa also develops maculopapular lesions that evolve to ulcers. The lesions


InternalMed_Harrison

InternalMed_Harrison. The lesions are initially maculopapular and evolve to vesicles that eventually become pustules and then scabs. The oral mucosa also develops maculopapular lesions that evolve to ulcers. The lesions appear over a period of 1–2 days and evolve at the same rate. Although virus can be isolated from the scabs on the skin, the conventional thinking is that once the scabs have formed the patient is no longer contagious. Smallpox is associated with 10–30% mortality rates, with patients typically dying of severe systemic illness during the second week of symptoms. Historically, ~5–10% of naturally occurring smallpox cases take either of two highly virulent atypical forms, classified as hemorrhagic and malignant. These are difficult to diagnose because of their atypical presentations. The hemorrhagic form is uniformly fatal and begins with the relatively abrupt onset of a severely prostrating illness characterized by high fevers and severe headache and back and abdominal pain. This form of the


InternalMed_Harrison

InternalMed_Harrison. form is uniformly fatal and begins with the relatively abrupt onset of a severely prostrating illness characterized by high fevers and severe headache and back and abdominal pain. This form of the illness resembles a severe systemic inflammatory syndrome, in which patients have a high viremia but die without developing the characteristic rash. Cutaneous erythema develops accompanied by petechiae and hemorrhages into the skin and mucous membranes. Death usually occurs within 5–6 days. The malignant, or “flat,” form of smallpox is frequently fatal and has an onset similar to the hemorrhagic form, but with confluent skin lesions developing more slowly and never progressing to the pustular stage.


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InternalMed_Harrison. Given the infectious nature of smallpox and the extreme vulnerability of contemporary society, patients who are suspected cases should be handled with strict isolation procedures. Although laboratory confirmation of a suspected case by culture, polymerase chain reaction (PCR), and electron microscopy is essential, it is equally important that appropriate precautions be used when obtaining samples for culture and laboratory testing. All health care and laboratory workers caring for patients should have been recently immunized with vaccinia, and all samples should be transported in doubly sealed containers. Patients should be cared for in negative-pressure rooms with strict isolation precautions.


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InternalMed_Harrison. There is no licensed specific therapy for smallpox, and historic treatments have focused solely on supportive care. Although several antiviral agents, including cidofovir, that are licensed for other diseases have in vitro activity against V. major, they have never been tested in the setting of human disease. For this reason, it is difficult to predict whether or not they would be effective in cases of smallpox and, if effective, whether or not they would be of value in patients with advanced disease. Agents currently being studied as possible antiviral compounds against V.�major include a viral egress inhibitor (tecovirimat, ST-246, or Arestvyr) and a lipid-conjugated form of cidofovir (brincidofovir, CMX001). preparations were made for mass production of 261e-7


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InternalMed_Harrison. preparations were made for mass production of 261e-7 CoMpLiCations FroM 438,134 adMinistrations oF vaCCinia during the u.s. departMent oF deFense (dod) sMaLLpox iMMunization CaMpaign initiated in F. tularensis by the United States, but no stockdeCeMBer 2002 piling of any agent took place. Stocks of F. tula rensis were reportedly generated by the Soviet DoD Rate per Million Number of Vaccinees (95% Historic Rate Per Union in the mid-1950s. It has also been sug-Complication Cases Confidence Interval) Million Vaccinees gested that the Soviet program extended into the era of molecular biology and that some strains were engineered to be resistant to common anti biotics. F. tularensis is an extremely infectious606a organism, and human infections have occurred streaked with colonies. Given these facts, it is 2.6–8.7a reasonable to conclude that this organism might 100b be used as a bioweapon through either an aero2–35a sol or contamination of food or drinking water.


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InternalMed_Harrison. 1–7a Microbiology and Clinical Features Although 1–2a similar in many ways to anthrax and plague, aBased on adolescent and adult smallpox vaccinations from 1968 studies, both primary and revaccinations. bBased on tularemia, also referred to as rabbit fever or deer case series in Finnish military recruits given the Finnish strain of smallpox vaccine. cPotentially attributable to vaccina-fly fever, is neither as lethal nor as fulminant astion; after lupus-like illness. either of these other two category A bacterial Source: From JD Grabenstein and W Winkenwerder: http://www.smallpox.mil/event/SPSafetySum.asp. infections. It is, however, extremely infectious,


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InternalMed_Harrison. Vaccination and Prevention In 1796, Edward Jenner demonstrated that deliberate infection with cowpox virus could prevent illness on subsequent exposure to smallpox. Today, smallpox is a preventable disease following immunization with vaccinia. The current dilemma facing our society regarding assessment of the risk and benefit of smallpox vaccination is that the degree of risk that someone will deliberately and effectively release smallpox into our society is unknown. Given that there are well-described risks associated with vaccination, the degree of risk/benefit for the general population does not favor immunization. As a prudent first step in preparedness for a smallpox attack, however, members of the U.S. armed services received primary or booster immunizations with vaccinia before 1990 and after 2002. In addition, a number of civilian health care workers who comprise smallpox-response teams at the state and local public health level have been vaccinated.


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InternalMed_Harrison. Initial fears regarding the immunization of a segment of the American population with vaccinia when there are more individuals receiving immunosuppressive drugs and other immunocompromised patients than ever before were dispelled by the data generated from the military and civilian immunization campaigns of 2002–2004. Adverse event rates for the first 450,000 immunizations were similar to and, in certain categories of adverse events, even lower than those from prior historic data, in which most severe sequelae of vaccination occurred in young infants (Table 261e-4). In addition, 11 patients with early-stage HIV infection were inadvertently immunized without problem. One significant concern during that immunization campaign, however, was the description of a syndrome of myopericarditis, which had not been appreciated during prior immunization campaigns with vaccinia. In an effort to provide a safer vaccine to protect against smallpox, ACAM 2000, a cloned virus propagated in tissue


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InternalMed_Harrison. which had not been appreciated during prior immunization campaigns with vaccinia. In an effort to provide a safer vaccine to protect against smallpox, ACAM 2000, a cloned virus propagated in tissue culture, was developed and became the first second-generation smallpox vaccine to be licensed. This vaccine is now the only vaccinia product currently licensed in the United States and has been used by the U.S. military since 2008. It is part of the U.S. government stockpile. Research continues on attenuated forms of vaccinia such as modified vaccinia Ankara (MVA). Vaccinia immune globulin is available to treat those who experience a severe reaction to immunization with vaccinia.


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See also Chap. 195.

InternalMed_Harrison. See also Chap. 195.


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InternalMed_Harrison. Francisella tularensis as a Bioweapon Tularemia has been studied as an agent of bioterrorism since the mid-twentieth century. It has been speculated by some that the outbreak of tularemia among German and Soviet soldiers during fighting on the Eastern Front during WWII was the consequence of a deliberate release. Unit 731 of the Japanese army studied the use of tularemia as a bioweapon during WWII. Large and as few as 10 organisms can lead to establishment of infection. Despite this fact, it is not spread from person to person. Tularemia is caused by F. tularensis, a small, nonmotile, gram-negative coccobacillus. Although it is not a spore-forming organism, it is a hardy bacterium that can survive for weeks in the environment. Infection typically comes from insect bites or contact with organisms in the environment. Infections have occurred in laboratory workers studying the agent. Large waterborne outbreaks have been recorded. It is most likely that the outbreak among German and


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InternalMed_Harrison. organisms in the environment. Infections have occurred in laboratory workers studying the agent. Large waterborne outbreaks have been recorded. It is most likely that the outbreak among German and Russian soldiers and Russian civilians noted above during WWII represented a large waterborne tularemia outbreak in a Tularensis-enzootic area devastated by warfare.


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InternalMed_Harrison. Humans can become infected through a variety of environmental sources. Infection is most common in rural areas where a variety of small mammals may serve as reservoirs. Human infections in the summer are often the result of insect bites from ticks, flies, or mosquitoes that have bitten infected animals. In colder months, infections are most likely the result of direct contact with infected mammals and are most common in hunters. In these settings, infection typically presents as a systemic illness with an area of inflammation and necrosis at the site of tissue entry. Drinking of contaminated water may lead to an oropharyngeal form of tularemia characterized by pharyngitis with cervical and/or retropharyngeal lymphadenopathy (Chap. 195). The most likely mode of dissemination of tularemia as a biologic weapon would be as an aerosol, as has occurred in a number of natural outbreaks in rural areas, including Martha’s Vineyard in the United States. Approximately 1–14 days following


InternalMed_Harrison

InternalMed_Harrison. as a biologic weapon would be as an aerosol, as has occurred in a number of natural outbreaks in rural areas, including Martha’s Vineyard in the United States. Approximately 1–14 days following exposure by this route, one would expect to see inflammation of the airways with pharyngitis, pleuritis, and bronchopneumonia. Typical symptoms would include the abrupt onset of fever, fatigue, chills, headache, and malaise (Table 261e-3). Some patients might experience conjunctivitis with ulceration, pharyngitis, and/or cutaneous exanthems. A pulse-temperature dissociation might be present. Approximately 50% of patients would show a pulmonary infiltrate on chest x-ray. Hilar adenopathy might also be present, and a small percentage of patients could have adenopathy without infiltrates. The highly variable presentation makes acute recognition of aerosol-disseminated tularemia very difficult. The diagnosis would likely be made by immunohistochemistry, molecular techniques, or culture of infected


InternalMed_Harrison

InternalMed_Harrison. presentation makes acute recognition of aerosol-disseminated tularemia very difficult. The diagnosis would likely be made by immunohistochemistry, molecular techniques, or culture of infected tissues or blood. Untreated, mortality rates range from 5 to 15% for cutaneous routes of infection and from 30 to 60% for infection by inhalation. Since the advent of antibiotic therapy, these rates have dropped to <2%.


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InternalMed_Harrison. Both streptomycin and doxycycline are licensed for treatment of tularemia. Other agents likely to be effective include gentamicin, chloramphenicol, and ciprofloxacin (Table 261e-3). Given the potential for genetic modification of this organism to yield antibiotic-resistant strains, broad-spectrum coverage should be the rule until sensitivities have been determined. As mentioned above, special isolation procedures for patients are not required. Vaccination and Prevention There are no vaccines currently licensed for the prevention of tularemia. Although a live, attenuated strain of the organism has been used in the past with some reported success, there are inadequate data to support its widespread use at this time. Development of a vaccine for this agent is an important part of the current biodefense research agenda. In the absence of an effective vaccine, postexposure chemoprophylaxis with either doxycycline or ciprofloxacin appears to be a reasonable approach (Table 261e-3).


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InternalMed_Harrison. See also Chaps. 233 and 234. Hemorrhagic Fever Viruses as Bioweapons Several of the hemorrhagic fever viruses have been reported to have been weaponized by the Soviet Union and the United States. Nonhuman primate studies indicate that infection can be established with very few virions and that infectious aerosol preparations can be produced. Under the guise of wanting to aid victims of an Ebola outbreak, members of the Aum Shinrikyo cult in Japan were reported to have traveled to central Africa in 1992 in an attempt to obtain Ebola virus for use in a bioterrorist attack. Thus, although there has been no evidence that these agents have ever been used in a biologic attack, there is clear interest in their potential for this purpose.


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InternalMed_Harrison. Microbiology and Clinical Features The viral hemorrhagic fevers are a group of illnesses caused by any one of a number of similar viruses (Table 261e-2). These viruses are all enveloped, single-strand RNA viruses that are thought to depend on a host reservoir for long-term survival. Although rodents or insects have been identified as the hosts for some of these viruses, for others the hosts are unknown. These viruses tend to be geographically restricted according to the migration patterns of their hosts. Great apes are not a natural reservoir for Ebola virus, but large numbers of these animals in sub-Saharan Africa have died from Ebola infection over the past decade. Humans can become infected with hemorrhagic fever viruses if they come into contact with an infected host or other infected animals. Person-to-person transmission, largely through direct contact with virus-containing body fluids, has been documented for Ebola, Marburg, and Lassa viruses and rarely for the New World


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InternalMed_Harrison. animals. Person-to-person transmission, largely through direct contact with virus-containing body fluids, has been documented for Ebola, Marburg, and Lassa viruses and rarely for the New World arenaviruses. Although there is no clear evidence of respiratory spread among humans, these viruses have been shown in animal models to be highly infectious by the aerosol route. This, coupled with mortality rates as high as 90%, makes them excellent candidate agents of bioterrorism.