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InternalMed_Harrison. If tularemia goes untreated, symptoms usually last 1–4 weeks but may continue for months. The mortality rate from severe untreated infection (including all cases of untreated pulmonary and typhoidal tularemia) can be as high as 30%. However, the overall mortality rate for untreated tularemia is <8%. With appropriate treatment, the mortality rate is <1%. Poor outcomes are often associated with long delays in diagnosis and treatment. Lifelong immunity usually follows tularemia.


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InternalMed_Harrison. The prevention of tularemia is based on avoidance of exposure to biting and blood-sucking insects, especially ticks and deerflies. A wide range of approaches to vaccine development are being evaluated, but no vaccine against tularemia is yet licensed. Prophylaxis of tularemia has not proved effective in patients with embedded ticks or insect bites. However, in patients who are known to have been exposed to large quantities of organisms (e.g., in the laboratory) and who have incubating infection with F. tularensis, early treatment can prevent the development of significant clinical disease. Michael B. Prentice


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InternalMed_Harrison. Plague is a systemic zoonosis caused by Yersinia pestis. It predominantly affects small rodents in rural areas of Africa, Asia, and the Americas and is usually transmitted to humans by an arthropod vector (the flea). Less often, infection follows contact with animal tissues or respiratory droplets. Plague is an acute febrile illness that is treatable with antimicrobial agents, but mortality rates among untreated patients are high. Ancient DNA studies have confirmed that the fourteenth-century “Black Death” in Europe was Y. pestis infection. Patients can present with the bubonic, septicemic, or pneumonic form of the disease. Although there is concern among the general public about epidemic spread of plague by the respiratory route, this is not the usual route of plague transmission, and established infection-control measures for respiratory plague exist. However, the fatalities associated with plague and the capacity for infection via the respiratory tract mean that Y. pestis fits the


InternalMed_Harrison

InternalMed_Harrison. infection-control measures for respiratory plague exist. However, the fatalities associated with plague and the capacity for infection via the respiratory tract mean that Y. pestis fits the profile of a potential agent of bioterrorism. Consequently, measures have been taken to restrict access to the organism, including legislation affecting diagnostic and research procedures in some countries (e.g., the United States).


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InternalMed_Harrison. The genus Yersinia comprises gram-negative bacteria of the family Enterobacteriaceae (gamma proteobacteria). Overwhelming taxonomic evidence showing Y. pestis strains as a clonal group within Yersinia pseudotuberculosis suggests recent evolution from the latter organism—an enteric pathogen of mammals that is spread by the fecal-oral route and thus has a phenotype distinctly different from that of Y. pestis. When grown in vivo or at 37°C, Y. pestis forms an amorphous capsule made from a plasmid-specified fimbrial protein, Caf or fraction 1 (F1) antigen, which is an immunodiagnostic marker of infection.


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InternalMed_Harrison. Human plague generally follows an outbreak in a host rodent population (epizootic). Mass deaths among the rodent primary hosts lead to a search by fleas for new hosts, with consequent incidental infection of other mammals. The precipitating cause for an epizootic may ultimately be related to climate or other environmental factors. The reservoir for Y. pestis causing enzootic plague in natural endemic foci between epizootics (i.e., when the organism may be difficult to detect in rodents or fleas) is a topic of ongoing research and may not be the same in all regions. The enzootic/epizootic pattern may be the result of complex dynamic interactions of host rodents that have different plague susceptibilities and different flea vectors; alternatively, an environmental reservoir may be important. In general, the enzootic areas for plague are lightly populated regions of Africa, Asia, and the Americas (Fig. 196-1).


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InternalMed_Harrison. Between 2004 and 2009, 12,503 cases of plague, with a global case-fatality rate of 6.7%, were recorded by the World Health Organization (WHO); these figures were obtained by combining cases notified under the International Health Regulations with data from national surveillance programs and publications. More than 97% of these cases were in Africa; the majority of cases were reported from the Democratic Republic of the Congo and the island of Madagascar. The period covered spans a change in the International Health Regulations from a requirement for nations to notify the WHO of all cases of plague to a requirement to report pneumonic plague or any suspected case of plague in an area not known to be endemic for plague. In the past decade, outbreaks of pneumonic plague have been recorded in the Democratic Republic of the Congo, Uganda, Algeria, Madagascar, China, and Peru. Countries reporting human plague cases, 1970−2005 Probable sylvatic foci


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InternalMed_Harrison. Countries reporting human plague cases, 1970−2005 Probable sylvatic foci FIGuRE 196-1 Approximate global distribution of Yersinia pestis.(Compiled from WHO, CDC, and country sources. Reprinted with permission from DT Dennis, GL Campbell: Plague and other Yersinia infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.)


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InternalMed_Harrison. Plague was introduced into North America via the port of San Francisco in 1900 as part of the Third Pandemic, which spread around the world from Hong Kong. The disease is presently enzootic on the western side of the continent from southwestern Canada to Mexico. Most human cases in the United States occur in two regions: “Four Corners” (the junction point of New Mexico, Arizona, Colorado, and Utah), especially northern New Mexico, northern Arizona, and southern Colorado; and further west in California, southern Oregon, and western Nevada (http://www.cdc.gov/plague/maps/index.html). From 1990 to 2011, 151 cases of plague were reported in the United States, a mean of seven cases per year. Most cases occurred from May to October—the time of year when people are outdoors and rodents and their fleas are most plentiful. The infection is most often acquired by fleabite in peridomestic environments; it can also be acquired through the handling of living or dead small mammals (e.g., rabbits,


InternalMed_Harrison

InternalMed_Harrison. fleas are most plentiful. The infection is most often acquired by fleabite in peridomestic environments; it can also be acquired through the handling of living or dead small mammals (e.g., rabbits, hares, and prairie dogs) or wild carnivores (e.g., wildcats, coyotes, or mountain lions). Dogs and cats may bring plague-infected fleas into the home, and infected cats may transmit plague directly to humans by the respiratory route. The last recorded case of person-to-person transmission in the United States occurred in 1925.


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InternalMed_Harrison. Plague most often develops in areas with poor sanitary conditions and infestations of rats—in particular, the widely distributed roof rat Rattus rattus and the brown rat Rattus norvegicus (which serves as a laboratory model of plague). Rat control in warehouses and shipping facilities has been recognized as important in preventing the spread of plague since the early twentieth century and features in the current WHO International Health Regulations. Urban rodents acquire infection from wild rodents, and the proximity of the former to humans increases the risk of transmission. The oriental rat flea Xenopsylla cheopis is the most efficient vector for transmission of plague among rats and onward to humans in Asia, Africa, and South America.


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InternalMed_Harrison. Worldwide, bubonic plague is the predominant form reported (80–95% of suspected cases), with mortality rates of 10–20%. The mortality rate is higher (22%) in the small proportion of patients (10–20%) with primary septicemic plague (i.e., systemic Y. pestis sepsis with no bubo; see “Clinical Manifestations,” below) and is highest with primary pulmonary plague; in this, the least common of the main plague presentations, the mortality rate approaches 100% without antimicrobial treatment and is >50% even with such treatment. Rare outbreaks of pharyngeal plague following consumption of raw or undercooked camel or goat meat have been reported. A total of 81 (76%) of the 107 plague cases reported in the United States from 1990 to 2005 were primary bubonic disease, 19 (18%) were primary septicemic disease, and 5 (5%) were primary pneumonic disease; 2 cases (2%) were not classified. Eleven cases (10%) were fatal.


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InternalMed_Harrison. As mentioned earlier, genetic evidence suggests that Y. pestis is a clone derived from the enteric pathogen Y. pseudotuberculosis in the recent evolutionary past (9000–40,000 years ago). The change from infection by the fecal-oral route to a two-stage life cycle, with alternate parasitization of arthropod and mammalian hosts, followed the acquisition of two plasmids (pFra and pPst) and the inactivation of remarkably few Y. pseudotuberculosis genes in conjunction with preexisting properties of the Y. pseudotuberculosis ancestor (e.g., the presence of a third plasmid, pYV, and the capacity to cause septicemia). In the arthropod-parasitizing portion of its life cycle, Y. pestis multiplies and forms biofilm-embedded aggregates in the flea midgut after ingestion of a blood meal containing bacteria. In some fleas, biofilm-embedded bacteria eventually fill the proventriculus (a valve connecting the esophagus to the midgut) and block normal blood feeding. Both “blocked” fleas and those


InternalMed_Harrison

InternalMed_Harrison. bacteria. In some fleas, biofilm-embedded bacteria eventually fill the proventriculus (a valve connecting the esophagus to the midgut) and block normal blood feeding. Both “blocked” fleas and those containing masses of biofilm-embedded Y. pestis without complete blockage inoculate Y. pestis into each bite site. The ability of Y. pestis to colonize and multiply in the flea requires phospholipase D encoded by the ymt gene on the pFra plasmid, and biofilm synthesis requires the chromosomal hms locus shared with Y. pseudotuberculosis. However, three Y. pseudotuberculosis genes inhibiting biofilm formation or promoting its degradation are inactivated in Y. pestis, together with urease, which causes acute flea gastrointestinal toxicity. Blockage takes days or weeks to come about after initial infection of the flea and is followed by the flea’s death. In addition, many flea vectors (including X. cheopis) are able to transmit plague in an early-phase unblocked state for up to 1 week after


InternalMed_Harrison

InternalMed_Harrison. infection of the flea and is followed by the flea’s death. In addition, many flea vectors (including X. cheopis) are able to transmit plague in an early-phase unblocked state for up to 1 week after feeding, but 10 fleas in this state are required to infect a mammalian host (mass transmission).


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InternalMed_Harrison. Y. pestis disseminates from the site of inoculation in the mammalian host in a process initially dependent on plasminogen activator Pla, which is encoded by the small pPst plasmid. This surface protease activates mammalian plasminogen, degrades complement, and adheres to the extracellular matrix component laminin. Pla is essential for the high-level virulence of Y. pestis in mice by subcutaneous or intradermal injection (laboratory proxies for fleabites) and for the development of primary pneumonic plague. When actual fleabite inoculation is used in mouse models, the fimbrial capsule-forming protein (Ca1 or fraction 1; F1 antigen) encoded on pFra increases the efficiency of transmission, and plasminogen activator is required for the formation 1072 of buboes. Because the antiphagocytic systems in Y. pestis are not fully operational at the time of inoculation into the mammalian host, the organism is taken up by macrophages from the inoculation site and transported to regional lymph


InternalMed_Harrison

InternalMed_Harrison. systems in Y. pestis are not fully operational at the time of inoculation into the mammalian host, the organism is taken up by macrophages from the inoculation site and transported to regional lymph nodes. After intracellular replication,


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InternalMed_Harrison. Y. pestis switches to extracellular replication with full expression of its antiphagocytic systems: the type III secretion machines and their effectors encoded by pYV as well as the F1 capsule. Overproduction of the type III secretion substrate and translocation protein LcrV exerts an anti-inflammatory effect, reducing host immune responses. Likewise, Y. pestis lipopolysaccharide is modified to minimize stimulation of host Toll-like receptor 4, thereby reducing protective host inflammatory responses during peripheral infection and prolonging host survival with high-grade bacteremia—an effect that probably enhances the pathogen’s subsequent transmission by fleabite.


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InternalMed_Harrison. Replication of Y. pestis in a regional lymph node results in the local swelling of the lymph node and periglandular region known as a bubo. On histology, the node is found to be hemorrhagic or necrotic, with thrombosed blood vessels, and the lymphoid cells and normal architecture are replaced by large numbers of bacteria and fibrin. Periglandular tissues are inflamed and also contain large numbers of bacteria in a serosanguineous, gelatinous exudate.


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InternalMed_Harrison. Continued spread through the lymphatic vessels to contiguous lymph nodes produces second-order primary buboes. Infection is initially contained in the infected regional lymph nodes, although transient bacteremia can be detected. As the infection progresses, spread via efferent lymphatics to the thoracic duct produces high-grade bacteremia. Hematogenous spread to the spleen, liver, and secondary buboes follows, with subsequent uncontrolled septicemia, endotoxic shock, and disseminated intravascular coagulation leading to death. In some patients, this septicemic phase occurs without obvious prior bubo development or lung disease (septicemic plague). Hematogenous spread to the lungs results in secondary plague pneumonia, with bacteria initially more prominent in the interstitium than in the air spaces (the reverse being the case in primary plague pneumonia). Hematogenous spread to other organs, including the meninges, can occur.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Bubonic Plague After an incubation period of 2–6 days, the onset of bubonic plague is sudden and is characterized by fever (>38°C), malaise, myalgia, dizziness, and increasing pain due to progressive lymphadenitis in the regional lymph nodes near the fleabite or other inoculation site. Lymphadenitis manifests as a tense, tender swelling (bubo) that, when palpated, has a boggy consistency with an underlying hard core. Generally, there is one painful and erythematous bubo with surrounding periganglionic edema. The bubo is most commonly inguinal but can also be crural, axillary (Fig. 196-2), cervical, or submaxillary, depending on the site of the bite. Abdominal pain from intraabdominal node involvement can occur without other visible signs. Children are most likely to present with cervical or axillary buboes.


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InternalMed_Harrison. The differential diagnosis includes acute focal lymphadenopathy of other etiologies, such as streptococcal or staphylococcal infection, tularemia, cat-scratch disease, tick typhus, infectious mononucleosis, or lymphatic filariasis. These infections do not progress as rapidly, are not as painful, and are associated with visible cellulitis or ascending lymphangitis—both of which are absent in plague. Without treatment, Y. pestis dissemination occurs and causes serious illness, including pneumonia (secondary pneumonic plague) and meningitis. Secondary pneumonic plague can be the source of person-to-person transmission of respiratory infection by productive cough (droplet infection), with the consequent development of primary plague pneumonia. Appropriate treatment of bubonic plague results in fever resolution within 2–5 days, but buboes may remain enlarged for >1 week after initial treatment and can become fluctuant. Primary Septicemic Plague A minority (10–25%) of infections with


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InternalMed_Harrison. Primary Septicemic Plague A minority (10–25%) of infections with Y. pestis present as gram-negative septicemia (hypotension, shock) without preceding lymphadenopathy. Septicemic plague occurs in all age groups, but persons older than age 40 years are at elevated risk. Some chronic conditions may predispose to septicemic plague: in 2009 in the United States, a fatal laboratory-acquired infection with an attenuated Y. pestis strain manifested as septicemic plague in a 60-yearold researcher with diabetes mellitus and undiagnosed hemochromatosis. These conditions also carry an increased risk of septicemia with other pathogenic Yersinia species. The term septicemic plague can be confusing since most patients with buboes have detectable bacteremia at some stage, with or without systemic signs of sepsis. In laboratory experiments, however, septicemic disease without histologic changes in lymph nodes is seen in a minority of mice infected via fleabites.


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InternalMed_Harrison. FIGuRE 196-2 Plague patient in the southwestern United States with a left axillary bubo and an unusual plague ulcer and eschar at the site of the infective flea bite. (Reprinted with permission from DT Dennis, GL Campbell: Plague and other Yersinia infections, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.)


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InternalMed_Harrison. Pneumonic Plague Primary pneumonic plague results from inhalation of infectious bacteria in droplets expelled from another person or an animal with primary or secondary plague pneumonia. This syndrome has a short incubation period, averaging from a few hours to 2–3 days (range, 1–7 days), and is characterized by a sudden onset of fever, headache, myalgia, weakness, nausea, vomiting, and dizziness. Respiratory signs—cough, dyspnea, chest pain, and sputum production with hemoptysis—typically arise after 24 h. Progression of initial segmental pneumonitis to lobar pneumonia and then to bilateral lung involvement may occur (Fig. 196-3). The possible release of aerosolized Y. pestis bacteria in a bioterrorist attack, manifesting as an outbreak of primary pneumonic plague in nonendemic regions or in an urban setting where plague is rarely seen, has been a source of public health concern. Secondary pneumonic plague is a consequence of bacteremia occurring in ~10–15% of patients with bubonic


InternalMed_Harrison

InternalMed_Harrison. or in an urban setting where plague is rarely seen, has been a source of public health concern. Secondary pneumonic plague is a consequence of bacteremia occurring in ~10–15% of patients with bubonic plague. Bilateral alveolar infiltrates are seen on chest x-ray, and diffuse interstitial pneumonitis with scanty sputum production is typical.


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InternalMed_Harrison. Meningitis Meningeal plague is uncommon, occurring in ≤6% of plague cases reported in the United States. Presentation with headache and fever typically occurs >1 week after the onset of bubonic or septicemic plague and may be associated with suboptimal antimicrobial therapy (delayed therapy, penicillin administration, or low-dose tetracycline treatment) and cervical or axillary buboes. Pharyngitis Symptomatic plague pharyngitis can follow the consumption of contaminated meat from an animal dying of plague or contact with persons or animals with pneumonic plague. This condition can resemble tonsillitis, with peritonsillar abscess and cervical


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InternalMed_Harrison. FIGuRE 196-3 Sequential chest radiographs of a patient with fatal primary plague pneumonia. Left: Upright posteroanterior film taken at admission to the hospital emergency department on the third day of illness, showing segmental consolidation of the right upper lobe. Center: Portable anteroposterior film taken 8 h after admission, showing extension of pneumonia to the right middle and right lower lobes. Right: Portable anteroposterior film taken 13 h after admission (when the patient had clinical adult respiratory distress syndrome), showing diffuse infiltration throughout the right lung and patchy infiltration of the left lower lung. A cavity later developed at the site of the initial rightupper-lobe consolidation. (Reprinted with permission from DT Dennis, GL Campbell: Plague and other Yersinia infections, in Harrison’s Principles of Internal Medicine, 17th ed., AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.) lymphadenopathy. Asymptomatic pharyngeal carriage of Y.


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InternalMed_Harrison. Yersinia infections, in Harrison’s Principles of Internal Medicine, 17th ed., AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.) lymphadenopathy. Asymptomatic pharyngeal carriage of Y. pestis can also occur in close contacts of patients with pneumonic plague.


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InternalMed_Harrison. Because of the scarcity of laboratory facilities in regions where human Y. pestis infection is most common, and because of the potential significance of Y. pestis isolation in a nonendemic area or an area from which human plague has been absent for many years, the WHO recommends an initial presumptive diagnosis followed by reference laboratory confirmation (Table 196-1). In the United States, comprehensive national diagnostic facilities for plague have been in place since a federal Laboratory Response Network (LRN; www.bt.cdc.gov/lrn/) was set up in 1999 to detect possible use of biological terrorism agents, including Y. pestis. Routine diagnostic clinical microbiology laboratories that are included in this network as sentinel-level laboratories use joint protocols from the Centers for Disease Control and Prevention (CDC) and the American Society for Microbiology to identify suspected Y. pestis isolates and to refer these specimens to LRN reference laboratories for confirmatory tests


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InternalMed_Harrison. Control and Prevention (CDC) and the American Society for Microbiology to identify suspected Y. pestis isolates and to refer these specimens to LRN reference laboratories for confirmatory tests (http:// www.asm.org/index.php/issues/sentinel-laboratory-guidelines). Y. pestis is designated a “Tier 1 select agent” under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 and subsequent executive orders; the provisions of this act, the Patriot Act of 2001, and related executive orders apply to all U.S. laboratories and individuals working with Y. pestis. Details of the applicable regulations are available from the CDC.


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InternalMed_Harrison. Yersinia species are gram-negative coccobacilli (short rods with rounded ends) 1–3 μm in length and 0.5–0.8 μm in diameter. Y. pestis in particular appears bipolar (with a “closed safety pin” appearance) and pleomorphic when stained with a polychromatic stain (Wayson or Wright-Giemsa; Fig. 196–4). Its lack of motility distinguishes Y. pestis from other Yersinia species, which are motile at 25°C and nonmotile at 37°C. Transport medium (e.g., Cary-Blair medium) preserves the viability of Y. pestis if transport is delayed. Consistent epidemiologic features, such as exposure to infected animals or humans and/or evidence of fleabites and/or residence in or travel to a known endemic focus within the previous 10 days Presumptive case Meeting the definition of a suspected case


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InternalMed_Harrison. Presumptive case Meeting the definition of a suspected case Putative new or reemerging focus: ≥2 of the following tests positive • Microscopy: gram-negative coccobacilli in material from bubo, blood, or sputum; bipolar appearance on Wayson or Wright-Giemsa antigen detected in bubo aspirate, blood, or sputum single anti-F1 serology without evidence of previous Y. pestis infection or immunization chain reaction (PCR) detection of Y. pestis in bubo aspirate, blood, or sputum Known endemic focus: ≥1 of the following tests positive evidence of gram-negative or bipolar (Wayson, Wright-Giemsa) coccobacilli from bubo, blood, or sputum sample single anti-F1 serology without evidence of previous plague infection or immunization antigen detected in bubo aspirate, blood, or sputum


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InternalMed_Harrison. Confirmed case Meeting the definition of a suspected case • Identification of an isolate from a clinical sample as Y. pestis (colonial morphology and 2 of the 4 following tests positive: phage lysis of cultures at 20–25°C and 37°C; F1 antigen detection; PCR; Y. pestis biochemical profile) • In endemic areas when no other confirmatory test can be performed, a positive rapid diagnostic test with immunochromatography Source: Interregional Meeting on Prevention and Control of Plague, Antananarivo, Madagascar, 7–11 April 2006 (www.who.int/entity/csr/resources/publications/WHO_HSE_EPR_2008_3w .pdf ).


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InternalMed_Harrison. Source: Interregional Meeting on Prevention and Control of Plague, Antananarivo, Madagascar, 7–11 April 2006 (www.who.int/entity/csr/resources/publications/WHO_HSE_EPR_2008_3w .pdf ). FIGuRE 196-4 Peripheral blood smear from a patient with fatal plague septicemia and shock, showing characteristic bipolar-stain-ing Yersinia pestis bacilli (Wright’s stain, oil immersion). (Reprinted with permission from DT Dennis, GL Campbell: Plague and other Yersinia infec-tions, in Harrison’s Principles of Internal Medicine, 17th ed, AS Fauci et al [eds]. New York, McGraw-Hill, Chap. 152, 2008.)


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InternalMed_Harrison. The appropriate specimens for diagnosis of bubonic, pneumonic, and septicemic plague are bubo aspirate, bronchoalveolar lavage fluid or sputum, and blood, respectively. Culture of postmortem organ biopsy samples can also be diagnostic. A bubo aspirate is obtained by injection of 1 mL of sterile normal saline into a bubo under local anesthetic and aspiration of a small amount of (usually blood-stained) fluid. Gram’s staining of these specimens may reveal gram-negative rods, which are shown by Wayson or Wright-Giemsa staining to be bipolar. These bacteria may even be visible in direct blood smears in septicemic plague (Fig. 196-4); this finding indicates very high numbers of circulating bacteria and a poor prognosis.


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InternalMed_Harrison. Y. pestis grows on nutrient agar and other standard laboratory media but forms smaller colonies than do other Enterobacteriaceae. Specimens should be inoculated onto nutrient-rich media such as sheep blood agar (SBA), into nutrient-rich broth such as brain-heart infusion broth, and onto selective agar such as MacConkey or eosin methylene blue (EMB) agar. Yersinia-specific CIN (cefsulodin, triclosan [Irgasan], novobiocin) agar can be useful for culture of contaminated specimens, such as sputum. Blood should be cultured in a standard blood culture system. The optimal growth temperature is <37°C (25–29°C), with pinpoint colonies only on SBA at 24 h. Slower growth occurs at 37°C. Y. pestis is oxidase-negative, catalase-positive, urea-negative, indole-negative, and lactose-negative. Automated biochemical identification systems can misidentify Y. pestis as Y. pseudo-tuberculosis or other bacterial species.


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InternalMed_Harrison. Reference laboratory tests for definitive identification of isolates include direct immunofluorescence for F1 antigen; specific polymerase chain reaction (PCR) for targets such as F1 antigen, the pesticin gene, and the plasminogen activator gene; and specific bacteriophage lysis. PCR can also be applied to diagnostic specimens, as can direct immunofluorescence for F1 antigen (produced in large amounts by Y. pestis) by slide microscopy. An immunochromatographic test strip for F1 antigen detection by monoclonal antibodies in clinical specimens has been devised in Madagascar. This method is effective for both laboratory and near-patient use and is now widely used in endemic countries. A similar test strip for Pla antigen has recently been developed and could be used to detect wild-type or engineered F1-negative virulent strains. Many other rapid diagnostic kits for possible bioterrorism pathogens, including Y. pestis, have been described in recent years, but none is widely used for


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InternalMed_Harrison. or engineered F1-negative virulent strains. Many other rapid diagnostic kits for possible bioterrorism pathogens, including Y. pestis, have been described in recent years, but none is widely used for primary or reference laboratory identification, and only one (a field real-time PCR for a range of potential bioterrorism agents) is approved by the U.S. Food and Drug Administration (FDA). Detailed phylogeographic DNA sequence data based on culture collections have been accumulated to trace plague evolution, and this system could be adapted in the future to determine real-time clinical plague epidemiology.


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InternalMed_Harrison. In the absence of other positive laboratory diagnostic tests, a retrospective serologic diagnosis may be made on the basis of rising titers of hemagglutinating antibody to F1 antigen. Enzyme-linked immunosorbent assays (ELISAs) for IgG and IgM antibodies to F1 antigen are also available. The white blood cell (WBC) count is generally raised (to 10,000– 20,000/μL) in plague, with neutrophilic leukocytosis and a left shift (numerous immature neutrophils); in some cases, however, the WBC count is normal or leukopenia develops. WBC counts are occasionally very high, especially in children (>100,000/μL). Levels of fibrinogen degradation products are elevated in a majority of patients, but platelet counts are usually normal or low-normal. However, disseminated intravascular coagulation, with low platelet counts, prolonged prothrombin times, reduced fibrinogen, and elevated fibrinogen degradation product levels, occurs in a significant minority of patients.


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InternalMed_Harrison. Guidelines for the treatment of plague are given in Table 196-2. A 10-day course of antimicrobial therapy is recommended. Streptomycin has historically been the parenteral treatment of choice for plague and is approved for this indication by the FDA. Although not yet approved by the FDA for plague, gentamicin has proven safe and effective in clinical trials in Tanzania and Madagascar Drug Daily Dose Interval, h Route aAminoglycoside dose should be adjusted in light of renal function. There are no published trial data for once-daily gentamicin as plague therapy in adults or children, but this regimen is efficacious in gram-negative sepsis of other causes and was successful in a recent outbreak of pneumonic plague in the Democratic Republic of the Congo. Neonates up to 1 week of age and premature infants should receive gentamicin (2.5 mg/kg IV bid).


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InternalMed_Harrison. Source: Dennis DT, Campbell GL: Plague and other Yersinia infections, in AS Fauci et al (eds): Harrison’s Principles of Internal Medicine, 17th ed. 2008, p. 980; Inglesby TV et al: Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 283:2281, 2000; and FDA Product Label Reference ID 3123374 (www.accessdata.fda.gov/drugsatfda_docs/label/2012/020634s061,020635s067,021721s028l bl.pdf ).


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InternalMed_Harrison. and in retrospectively reviewed cases in the United States. In view of streptomycin’s adverse-reaction profile and limited availability, some experts now recommend gentamicin over streptomycin. In 2012, the FDA approved levofloxacin for prophylaxis and treatment of plague (including septicemic and pneumonic disease), making it the first antibiotic approved for a new indication under a regulatory approach based on animal studies alone, known as the Animal Rule. An FDA decision on ciprofloxacin is pending. Levofloxacin is more efficacious than ciprofloxacin for postexposure prophylaxis of inhalational anthrax in animal models and also received FDA approval for this indication (Chap. 261e); thus it is approved for multiagent prophylaxis in possible bioterrorism exposures.


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InternalMed_Harrison. While systemic chloramphenicol therapy is available in the resource-poor countries primarily affected by plague, it is less likely to be available or used in high-income countries because of its adverse effect profile. Tetracyclines are also effective and can be given by mouth but are not recommended for children under the age of 7 years because of tooth discoloration. Doxycycline is the tetracycline of choice; at an oral dosage of 100 mg twice daily, this drug was as effective as IM gentamicin (2.5 mg/kg twice daily) in a trial in Tanzania.


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InternalMed_Harrison. Although Y. pestis is sensitive to β-lactam drugs in vitro and these drugs have been efficacious against plague in some animal models, the response to penicillins has been poor in some clinical cases; thus β-lactams and macrolides are not generally recommended as first-line therapy. Chloramphenicol, alone or in combination, is recommended for some focal complications of plague (e.g., meningitis, endophthalmitis, myocarditis) because of its tissue penetration properties. Fluoroquinolones, effective in vitro and in animal models, are recommended in guidelines for possible bioterrorism-associated pneumonic plague and are increasingly used in therapy, although the only human efficacy data available so far are from a case report. Animal and in vitro studies suggest that fluoroquinolones other than levofloxacin, at doses used in systemic gram-negative sepsis, should be effective as therapy for plague: e.g., ciprofloxacin (400 mg twice daily IV, 500 mg twice daily by mouth), ofloxacin (400


InternalMed_Harrison

InternalMed_Harrison. than levofloxacin, at doses used in systemic gram-negative sepsis, should be effective as therapy for plague: e.g., ciprofloxacin (400 mg twice daily IV, 500 mg twice daily by mouth), ofloxacin (400 mg twice daily IV or by mouth), or moxifloxacin (400 mg/d IV or by mouth).


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InternalMed_Harrison. In endemic areas, the control of plague in humans is based on reduction of the likelihood of being bitten by infected fleas or exposed to infected droplets from either humans or animals with plague pneumonia. In the United States, residence and outdoor activity in rural areas of western states where epizootics occur are the main risk factors for infection. To assess potential risks to humans in specific areas, surveillance for Y. pestis infection among animal plague hosts and vectors is carried out regularly as well as in response to observed animal die-offs. Personal protective measures include avoidance of areas where a plague epizootic has been identified and publicized (e.g., by warning signs or closure of campsites). Sick or dead animals should not be handled by the general public. Hunters and zoologists should wear gloves when handling wild-animal carcasses in endemic areas. General measures to avoid rodent fleabite during outdoor activity are appropriate and include the use of


InternalMed_Harrison

InternalMed_Harrison. and zoologists should wear gloves when handling wild-animal carcasses in endemic areas. General measures to avoid rodent fleabite during outdoor activity are appropriate and include the use of insect repellant, insecticide, and protective clothing. General measures to reduce peridomestic and occupational human contact with rodents are advised and include rodent-proofing of buildings and food-waste stores and removal of potential rodent habitats (e.g., woodpiles and junk heaps). Flea control by insecticide treatment of wild rodents is an effective means of minimizing human contact with plague if an epizootic is identified in an area close to human habitation. Any attempt to reduce rodent numbers must be preceded by flea suppression to reduce the migration of infected fleas to human hosts. An oral F1-V subunit vaccine using raccoon poxvirus (RCN) as a vector protects prairie dogs against Y. pestis injections and is being investigated for efficacy in preventing disease in wild animals,


InternalMed_Harrison

InternalMed_Harrison. An oral F1-V subunit vaccine using raccoon poxvirus (RCN) as a vector protects prairie dogs against Y. pestis injections and is being investigated for efficacy in preventing disease in wild animals, thus potentially reducing human exposure.


InternalMed_Harrison

InternalMed_Harrison. Patients in whom pneumonic plague is suspected should be man-1075 aged in isolation, with droplet precautions observed until pneumonia is excluded or effective antimicrobial therapy has been given for 48 h. Review of the literature published before the advent of antimicrobial agents suggests that the main infective risk is posed by patients in the final stages of disease who are coughing up sputum with plentiful visible blood and/or pus. Cotton and gauze masks were protective in these circumstances. Current surgical masks capable of barrier protection against droplets, including large respiratory particles, are considered protective; a particulate respirator (e.g., N95 or greater) is not required.


InternalMed_Harrison

InternalMed_Harrison. Antimicrobial Prophylaxis Postexposure antimicrobial prophylaxis lasting 7 days is recommended following household, hospital, or other close contact with persons with untreated pneumonic plague. (Close contact is defined as contact with a patient at <2 m.) In animal aerosol-infection studies, levofloxacin and ciprofloxacin are associated with higher survival rates than doxycycline (Table 196-3).


InternalMed_Harrison

InternalMed_Harrison. Immunization Studies with candidate plague vaccines in animal models show that neutralizing antibody provides protection against exposure but that cell-mediated immunity is critical for protection and clearance of Y. pestis from the host. A killed whole-cell vaccine used in humans required multiple doses, caused significant local and systemic reactions, and was not protective against pneumonic plague; this vaccine is not currently available in the United States. A live attenuated vaccine based on strain EV76 is still used in countries of the former Soviet Union but has significant side effects. The vaccines closest to licensure are subunit vaccines comprising recombinant F1 (rF1) and various recombinant V (rV) proteins produced in Escherichia coli, which are combined either as a fusion protein or as a mixture, purified, and adsorbed to aluminum hydroxide for injection. This combination protects mice and various nonhuman primates in laboratory models of bubonic and pneumonic plague and


InternalMed_Harrison

InternalMed_Harrison. or as a mixture, purified, and adsorbed to aluminum hydroxide for injection. This combination protects mice and various nonhuman primates in laboratory models of bubonic and pneumonic plague and has been evaluated in phase 2 clinical trials. Special ethical considerations with controlled clinical studies involving plague in humans make prelicensure field efficacy studies unlikely. In the United States, the FDA is therefore prepared to assess plague vaccines for human use under the Animal Rule, using efficacy data and other results from animal studies as well as antibodies and other correlates of immunity from human vaccine recipients (www.fda.gov/BiologicsBloodVaccines/ScienceRe search/BiologicsResearchAreas/ucm127288.htm). Live attenuated


InternalMed_Harrison

InternalMed_Harrison. Drug Daily Dose Interval, h Route Source: Dennis DT, Campbell GL: Plague and other Yersinia infections, in AS Fauci et al (eds): Harrison’s Principles of Internal Medicine. 2008, p. 980; Inglesby TV et al: Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 283:2281, 2000; and FDA Drug Product Label Reference ID 3123374 (www .accessdata.fda.gov/drugsatfda_docs/label/2012/020634s061,020635s067,021721s028lbl.pdf ).


InternalMed_Harrison

InternalMed_Harrison. 1076 Y. pseudotuberculosis and Salmonella strains expressing Y. pestis–specific antigens have been shown to be protective in laboratory animal models of bubonic and pneumonic plague and could be delivered by the oral route. A wide variety of other delivery mechanisms for Y. pestis antigens are being explored. Antigens other than F1 and V that could be added to subunit vaccines are being investigated. Advances providing impetus for exploration of these antigens are (1) the recovery of F1-negative Y. pestis strains from natural sources and (2) the observation that F1 antigen is not required for virulence in primate models of pneumonic plague.


InternalMed_Harrison

InternalMed_Harrison. Yersiniosis is a zoonotic infection with an enteropathogenic Yersinia species, usually Yersinia enterocolitica or Y. pseudotuberculosis. The usual hosts for these organisms are pigs and other wild and domestic animals; humans are usually infected by the oral route, and outbreaks from contaminated food occur. Yersiniosis is most common in childhood and in colder climates. Patients present with abdominal pain and sometimes with diarrhea (which may not occur in up to 50% of cases). Y. enterocolitica is more closely associated with terminal ileitis and Y. pseudotuberculosis with mesenteric adenitis, but both organisms may cause mesenteric adenitis and symptoms of abdominal pain and tenderness that result in pseudoappendicitis, with the surgical removal of a normal appendix. Diagnosis is based on culture of the organism or convalescent serology. Y. pseudotuberculosis and some rarer strains of


InternalMed_Harrison

InternalMed_Harrison. Y. enterocolitica are especially likely to cause systemic infection, which is also particularly common among patients with diabetes or iron overload. Systemic sepsis is treatable with antimicrobial agents, but postinfective arthropathy responds poorly to such therapy. Fourteen other Yersinia species are now recognized, but all lack the virulence plasmid pYV common to Y. pestis, Y. pseudotuberculosis, and Y. enterocolitica and are generally considered to be, at most, opportunistic pathogens of humans (Y. aldovae, Y. aleksiciae, Y. bercovieri, Y. entomophaga, Y. frederiksenii, Y. intermedia, Y. kristensenii, Y. massiliensis, Y. mollaretii, Y. nurmii, Y. pekkanenii, Y. rohdei, Y. similis, and Y. ruckeri). Molecular phylogeny shows that Y. enterocolitica is more distantly related to Y. pseudotuberculosis than these other Yersinia species, and the similar virulence plasmid they share has probably been acquired independently by at least one of the two since the species diverged.


InternalMed_Harrison

InternalMed_Harrison. Y. enterocolitica Y. enterocolitica is found worldwide and has been isolated from a wide variety of wild and domestic animals and environmental samples, including samples of food and water. In vitro, Y. enterocolitica is resistant to predation by the protozoon Acanthamoeba castellanii and can survive inside it, suggesting a possible mode of environmental persistence. Strains are differentiated by combined biochemical reactions (biovar) and serogroup. Most clinical infections are associated with serogroups O:3, O:9, and O:5,27, with a declining number of O:8 infections in North America. Some O:8 infections, previously confined to North America, have been reported from Europe and Japan in recent years, and serogroup O:8 now causes a high percentage of yersiniosis cases in Poland. Yersiniosis, mostly due to Y. enterocolitica, is the third commonest zoonosis reported in Europe; most reports come from northern Europe, especially Germany and Scandinavia. The incidence is highest among


InternalMed_Harrison

InternalMed_Harrison. mostly due to Y. enterocolitica, is the third commonest zoonosis reported in Europe; most reports come from northern Europe, especially Germany and Scandinavia. The incidence is highest among children; children under the age of 4 years are more likely to present with diarrhea than are older children. Abdominal pain with mesenteric adenitis and terminal ileitis is more prominent among older children and adults. Septicemia is more likely in patients with preexisting conditions such as diabetes mellitus, liver disease, any condition involving iron overload (including thalassemia and hemochromatosis), advanced age, malignancy, or HIV/AIDS. As in enteritis of other bacterial etiologies, postinfective complications such as reactive arthritis occur mainly in individuals who are HLA-B27 positive. Erythema nodosum (see Fig. 25e-40) following Yersinia infection is not associated with HLAB27 and is more common among women than among men.


InternalMed_Harrison

InternalMed_Harrison. Consumption or preparation of raw pork products (such as chitterlings) and some processed pork products is strongly linked with infection because a high percentage of pigs carry pathogenic Y. enterocolitica strains. Outbreaks of Y. enterocolitica infection have been associated with consumption of milk (pasteurized, unpasteurized, and chocolate-flavored) and various foods contaminated with springwater. Person-to-person transmission is suspected in a few cases (e.g., in nosocomial and familial outbreaks) but is much less likely with Y. enterocolitica than with other causes of gastrointestinal infection, such as Salmonella. A multivariate analysis indicates that contact with companion animals is a risk factor for Y. enterocolitica infection among children in Sweden, and low-level colonization of dogs and cats with Y. enterocolitica has been reported. Transfusion-associated septicemia due to Y. enterocolitica, while recognized as a very rare but frequently fatal event for over 30 years,


InternalMed_Harrison

InternalMed_Harrison. of dogs and cats with Y. enterocolitica has been reported. Transfusion-associated septicemia due to Y. enterocolitica, while recognized as a very rare but frequently fatal event for over 30 years, has been difficult to eradicate.


InternalMed_Harrison

InternalMed_Harrison. Y. pseudotuberculosis Y. pseudotuberculosis is less frequently reported as a cause of human disease than Y. enterocolitica, and infection with Y. pseudotuberculosis is more likely to pres ent as fever and abdominal pain due to mesenteric lymphadenitis. This organism is associated with wild mammals (rodents, rabbits, and deer), birds, and domestic pigs. Strains are differentiated by combined biochemical reactions (biovar) and serogroup. Although outbreaks are generally rare, several have recently occurred in Finland in association with consumption of lettuce and raw carrots.


InternalMed_Harrison

InternalMed_Harrison. The usual route of infection is oral. Studies with both Y. enterocolitica and Y. pseudotuberculosis in animal models suggest that initial replication in the small intestine is followed by invasion of Peyer’s patches of the distal ileum via M cells, with onward spread to mesenteric lymph nodes. The liver and spleen can also be involved after oral infection. The characteristic histologic appearance of enteropathogenic yersiniae after invasion of host tissues is as extracellular microabscesses surrounded by an epithelioid granulomatous lesion.


InternalMed_Harrison

InternalMed_Harrison. Experiments involving oral infection of mice with tagged Y. enterocolitica show that only a very small proportion of bacteria in the gut invade tissues. Individual bacterial clones from an orally inoculated pool give rise to each microabscess in a Peyer’s patch, and the host restricts the invasion of previously infected Peyer’s patches. A prior model positing progressive bacterial spread from Peyer’s patches and mesenteric lymph nodes to the liver and spleen appears to be inaccurate: spread of individually tagged clones of Y. pseudotuberculosis to the liver and spleen of mice occurs independently of regional lymph node colonization and in mice lacking Peyer’s patches.


InternalMed_Harrison

InternalMed_Harrison. Invasion requires the expression of several nonfimbrial adhesins, such as invasin (Inv) and—in Y. pseudotuberculosis—Yersinia adhesin A (YadA). Inv interacts directly with β1 integrins, which are expressed on the apical surfaces of M cells but not enterocytes. YadA of Y. pseudotuberculosis interacts with extracellular matrix proteins such as collagen and fibronectin to facilitate host cell integrin association and invasion. YadA of Y. enterocolitica lacks a crucial N-terminal region and binds collagen and laminin but not fibronectin and does not cause invasion. Inv is chromosomally encoded, whereas YadA is encoded on the virulence plasmid pYV. YadA helps to confer serum resistance by binding host complement regulators such as factor H and C4-binding protein. Another chromosomal gene, ail (attachment and invasion locus), encodes the extracellular protein Ail, which also confers serum resistance by binding these complement regulators. By binding to host cell surfaces, YadA allows


InternalMed_Harrison

InternalMed_Harrison. ail (attachment and invasion locus), encodes the extracellular protein Ail, which also confers serum resistance by binding these complement regulators. By binding to host cell surfaces, YadA allows targeting of immune effector cells by the pYV plasmid–encoded type III secretion system (injectisome). As a consequence, the host’s innate immune response is altered; toxins (Yersinia outer proteins, or Yops) are injected into host macrophages, neutrophils, and dendritic cells, affecting signal transduction pathways, resulting in reduced phagocytosis and inhibited production of reactive oxygen species by neutrophils, and triggering apoptosis of macrophages. Other factors functional in invasive disease include yersiniabactin (Ybt), a siderophore produced by some strains of Y. pseudotuberculosis and Y. enterocolitica as well as other Enterobacteriaceae. Yersiniabactin allows bacteria to access iron from saturated lactoferrin during infection and reduces the production of reactive oxygen


InternalMed_Harrison

InternalMed_Harrison. and Y. enterocolitica as well as other Enterobacteriaceae. Yersiniabactin allows bacteria to access iron from saturated lactoferrin during infection and reduces the production of reactive oxygen species by innate immune effector cells, thereby decreasing bacterial killing. Y. pseudotuberculosis and Y. pestis make other siderophores in addition to yersiniabactin.


InternalMed_Harrison

InternalMed_Harrison. Self-limiting diarrhea is the most common reported presentation in infection with pathogenic Y. enterocolitica, especially in children under the age of 4, who form the single largest group in most case series. Blood may be detected in diarrheal stool. Older children and adults are more likely than younger children to present with abdominal pain, which can be localized to the right iliac fossa—a situation that often leads to laparotomy for presumed appendicitis (pseudoappendicitis). Appendectomy is not indicated for Yersinia infection causing pseudoappendicitis. Thickening of the terminal ileum and cecum is seen on endoscopy and ultrasound, with elevated round or oval lesions that may overlie Peyer’s patches. Mesenteric lymph nodes are enlarged. Ulcerations of the mucosa are noted on endoscopy. Gastrointestinal complications include granulomatous appendicitis, a chronic inflammatory condition affecting the appendix that is responsible for ≤2% of cases of appendicitis; Yersinia is


InternalMed_Harrison

InternalMed_Harrison. endoscopy. Gastrointestinal complications include granulomatous appendicitis, a chronic inflammatory condition affecting the appendix that is responsible for ≤2% of cases of appendicitis; Yersinia is involved in a minority of cases.


InternalMed_Harrison

InternalMed_Harrison. Y. enterocolitica infection can present as acute pharyngitis with or without other gastrointestinal symptoms. Fatal Y. enterocolitica pharyngitis has been recorded. Mycotic aneurysm can follow Y. enterocolitica bacteremia, as can focal infection (abscess) in many other sites and body compartments (liver, spleen, kidney, bone, meninges, endocardium).


InternalMed_Harrison

InternalMed_Harrison. In all age groups, Y. pseudotuberculosis infection is more likely to present as abdominal pain and fever than as diarrhea. A superantigenic toxin—Y. pseudotuberculosis mitogen (YPM)—is produced by strains seen in eastern Russia in association with Far Eastern scarlet-like fever, a childhood illness with desquamating rash, arthralgia, and toxic shock. A similar illness is recognized in Japan (Izumi fever) and Korea. Similarities have been noted with Kawasaki disease, the idiopathic acute systematic vasculitis of childhood. There is an epidemiologic link between exposure of populations to superantigen-positive Y. pseudotuberculosis and an elevated incidence of Kawasaki disease.


InternalMed_Harrison

InternalMed_Harrison. Y. enterocolitica or Y. pseudotuberculosis septicemia presents as a severe illness with fever and leukocytosis, often without localizing features, and is significantly associated with predisposing conditions such as diabetes mellitus, liver disease, and iron overload. Hemochromatosis combines several of these risk factors. Administration of iron chelators like desferrioxamine, which provide iron accessible to Yersinia (and have an inhibitory effect on neutrophil function), may result in Yersinia septicemia in patients with iron overload who presumably have an otherwise mild gastrointestinal infection. HIV/AIDS has been associated with Y. pseudotuberculosis septicemia. The unusual phenomenon of transfusion-associated septicemia is linked to the ability of Y. enterocolitica to multiply at refrigerator temperature (psychrotrophy). Typically, the transfused unit has been stored for >20 days, and it is believed that small numbers of yersiniae from an apparently healthy donor with


InternalMed_Harrison

InternalMed_Harrison. at refrigerator temperature (psychrotrophy). Typically, the transfused unit has been stored for >20 days, and it is believed that small numbers of yersiniae from an apparently healthy donor with subclinical bacteremia are amplified to very high numbers by growth inside the bag at ≤4°C, with consequent septic shock after transfusion. A method for preventing this very rare event (i.e., a range of 1 case in 500,000 to 1 case in several million transfused units in countries such as the United States and France) without unacceptable restriction in the blood supply has not yet been devised.


InternalMed_Harrison

InternalMed_Harrison. Like other invasive infections of intestinal origin (salmonello sis, shigellosis), reactive arthritis (articular arthritis of multiple joints developing within 2–4 weeks of a preceding infection) results from autoimmune activity initiated by the deposition of bacterial components (not viable bacteria) in joints in combination with the immune response to invading bacteria. The majority of individuals affected by reactive arthritis due to Yersinia are HLA-B27 positive. Myocarditis with electrocardiographic ST-segment abnormalities may occur with Yersinia-associated reactive arthritis. Most Yersiniaassociated cases follow Y. enterocolitica infection (presumably because it is more common than infection with other species), but Y. pseudotuberculosis–associated reactive arthritis is also well documented in Finland, where sporadic and outbreak infections with 1077


InternalMed_Harrison

InternalMed_Harrison. Y. pseudotuberculosis are more common than in other countries. Of infected individuals identified in a recent Y. pseudotuberculosis serotype O:3 outbreak in Finland, 12% developed reactive arthritis affecting the small joints of the hands and feet, knees, ankles, and shoulders and lasting >6 months in most cases. Erythema nodosum (see Fig. 25e-40) occurs after Yersinia infection (more commonly in women) with no evidence of HLA-B27 linkage.


InternalMed_Harrison

InternalMed_Harrison. There is a long-standing association between antithyroid and anti-Yersinia antibodies. Antibody evidence of prior Y. enterocolitica infection in Graves’ disease and increased levels of antithyroid antibody in patients with Y. enterocolitica antibodies were first noted in the 1970s. Y. enterocolitica contains a thyroid-stimulating hormone (TSH)–binding site that is recognized by anti-TSH antibodies from Graves’ disease patients. Raised titers of antibodies to Y. enterocolitica whole cells and Yops have been found in some series of Graves’ disease patients but not in others. One Danish study of twins found no evidence of an association between asymptomatic Yersinia infection (as evidenced by anti-Yop antibody titers) and antithyroid antibodies in euthyroid individuals, while another Danish study of twins with and without Graves’ disease found that increased anti-Yop antibody titers were associated with Graves’ disease. It remains unclear whether this cross-reactivity is significant in


InternalMed_Harrison

InternalMed_Harrison. study of twins with and without Graves’ disease found that increased anti-Yop antibody titers were associated with Graves’ disease. It remains unclear whether this cross-reactivity is significant in the etiology of Graves’ disease.


InternalMed_Harrison

InternalMed_Harrison. Standard laboratory culture methods can be used to isolate enteropathogenic Yersinia species from sterile samples, including blood and cerebrospinal fluid. Culture on specific selective media (CIN agar), with or without pre-enrichment in broth or phosphate-buffered saline at either 4°C or 16°C, is the basis of most schema for isolation of yersiniae from stool or other nonsterile samples. Outside known high-incidence areas, specific culture may be carried out by laboratories only upon request. Virulence plasmid–negative strains of Y. enterocolitica can be isolated from cultures of stool from asymptomatic individuals, especially after cold enrichment. These strains usually differ in biotype (typically biovar 1a) from virulence plasmid–possessing strains; although some display apparent pathogenicity in a mouse model, virulence plasmid–negative strains are not commonly accepted as human pathogens. Because of the frequency with which the virulence plasmid is lost on laboratory subculture,


InternalMed_Harrison

InternalMed_Harrison. in a mouse model, virulence plasmid–negative strains are not commonly accepted as human pathogens. Because of the frequency with which the virulence plasmid is lost on laboratory subculture, combined biochemical identification (with biotyping according to a standard schema) and serologic identification are usually required to interpret the significance of an isolate of Y. enterocolitica from a nonsterile site. Most pathogenic


InternalMed_Harrison

InternalMed_Harrison. Y. enterocolitica strains currently isolated from humans are of serogroup O:3/biovar 4 or serogroup O:9/biovar 2; this pattern holds even in the United States, where serogroup O:8/biovar 1B strains were previously predominant. Many self-validated multiplex PCR screens for detection of Y. enterocolitica in clinical samples—and rather more for its detection in food—have been described, but none of these assays is widely used outside its originating laboratory. Some CE-marked real-time PCR kits are now available in Europe for the diagnosis of yersiniosis in animals; as molecular diagnosis of enteric infection becomes more routine in human disease, it is likely that Y. enterocolitica will be included in diagnostic multiplex PCR screens of feces. Because of the presence of Ail in biovar 1a strains, this antigen cannot be used alone in diagnostic assays. A standard for PCR detection in food samples is being prepared by the International Organization for Standardization.


InternalMed_Harrison

InternalMed_Harrison. Agglutinating or ELISA antibody titers to specific O-antigen types are used in the retrospective diagnosis of both Y. enterocolitica and Y. pseudotuberculosis infections. IgA and IgG antibodies persist in patients with reactive arthritis. Serologic cross-reactions between Y. enterocolitica serogroup O:9 and Brucella are due to the similarity of their lipopolysaccharide structures. Multiple assays are required to cover even the predominant serogroups (Y. enterocolitica O:3, O:5,27, and O:9; Y. pseudotuberculosis O:1a, O:1b, and O:3), and these assays are generally available only in reference laboratories. ELISA and western blot tests for antibodies to Yops, which are expressed by all pathogenic strains of Y. enterocolitica and Y. pseudotuberculosis, are 1078 also available; most of the positivity in these assays probably relates to previous infection with Y. enterocolitica.


InternalMed_Harrison

InternalMed_Harrison. Most cases of diarrhea caused by enteropathogenic Yersinia are self-limiting. Data from clinical trials do not support antimicrobial treatment for adults or children with Y. enterocolitica diarrhea. Systemic infections with bacteremia or focal infections outside the gastrointestinal tract generally require antimicrobial therapy. Infants <3 months of age with documented Y. enterocolitica infection may require antimicrobial treatment because of the increased likelihood of bacteremia in this age group. Y. enterocolitica strains nearly always express β-lactamases. Because of the relative rarity of systemic Y. enterocolitica infection, there are no clinical trial data to guide antimicrobial choice or to suggest the optimal dose and duration of therapy. On the basis of retrospective case series and in vitro sensitivity data, fluoroquinolone therapy is effective for bacteremia in adults; for example, ciprofloxacin is given at a typical dose of 500 mg twice daily by mouth or 400 mg twice


InternalMed_Harrison

InternalMed_Harrison. and in vitro sensitivity data, fluoroquinolone therapy is effective for bacteremia in adults; for example, ciprofloxacin is given at a typical dose of 500 mg twice daily by mouth or 400 mg twice daily IV for at least 2 weeks (longer if positive blood cultures persist). A third-generation cephalosporin is an alternative—e.g., cefotaxime (typical dose, 6–8 g/d in three or four divided doses). In children, third-generation cephalosporins are effective; for example, cefotaxime is given to children ≥1 month of age at a typical dose of 75–100 mg/kg per day in three or four divided doses, with an increase to 150–200 mg/ kg per day in severe cases (maximal daily dose, 8–10 g). Amoxicillin and amoxicillin/clavulanate have shown poor efficacy in case series. Trimethoprim-sulfamethoxazole, gentamicin, and imipenem are all active in vitro. Y. pseudotuberculosis strains do not express β-lactamase but are intrinsically resistant to polymyxin. Because human infection with Y. pseudotuberculosis is


InternalMed_Harrison

InternalMed_Harrison. and imipenem are all active in vitro. Y. pseudotuberculosis strains do not express β-lactamase but are intrinsically resistant to polymyxin. Because human infection with Y. pseudotuberculosis is less common than that with Y. enterocolitica, less case information is available; however, studies in mice suggest that ampicillin is ineffective. Drugs similar to those used against Y. enterocolitica should be used. The best results have been obtained with a quinolone.


InternalMed_Harrison

InternalMed_Harrison. Some trials of treatment for reactive arthritis (with a large proportion of cases due to Yersinia) found that 3 months of oral ciprofloxacin therapy did not affect outcome. One trial in which the same therapy was given specifically for Y. enterocolitica–reactive arthritis found that, while outcome indeed was not affected, there was a trend toward faster remission of symptoms in the treated group. Follow-up 4–7 years after initial antibiotic treatment of reactive arthritis (predominantly following Salmonella and Yersinia infections) demonstrated apparent efficacy in the prevention of chronic arthritis in HLA-B27-positive individuals. A trial showing that azithromycin therapy did not affect outcome in reactive arthritis included cases believed to follow yersiniosis, although no breakdown of cases was provided. A Cochrane review evaluating the use of antibiotics for reactive arthritis is in progress.


InternalMed_Harrison

InternalMed_Harrison. Current control measures are similar to those used against other enteric pathogens like Salmonella and Campylobacter, which colonize the intestine of food animals. The focus is on safe handling and processing of food. No vaccine is effective in preventing intestinal colonization of food animals by enteropathogenic Yersinia. Consumption of food made from raw pork (which is popular in Germany and Belgium) should be discouraged at present because it is not possible to eliminate contamination with the enteropathogenic Yersinia strains found worldwide in pigs. Exposure of infants to raw pig intestine during domestic preparation of chitterlings is inadvisable. Modification of abattoir technique in Scandinavian countries from the 1990s onward included the removal of pig intestines in a closed plastic bag; levels of carcass contamination with Y. enterocolitica were reduced, but such contamination was not eliminated. Experimental pig herds free of pathogenic Y. enterocolitica O:3 (and also of


InternalMed_Harrison

InternalMed_Harrison. bag; levels of carcass contamination with Y. enterocolitica were reduced, but such contamination was not eliminated. Experimental pig herds free of pathogenic Y. enterocolitica O:3 (and also of Salmonella, Toxoplasma, and Trichinella) have been established in Norway and may be commercialized in the future because of their enhanced safety. In the food industry, vigilance is required because of the potential for large outbreaks if small numbers of enteropathogenic yersiniae contaminate any ready-to-eat food whose safe preservation is based on refrigeration before consumption.


InternalMed_Harrison

InternalMed_Harrison. The rare phenomenon of contamination of blood for transfusion has proved impossible to eradicate. However, leukodepletion is now practiced in most blood transfusion centers, primarily to prevent non-hemolytic febrile transfusion reactions and alloimmunization against HLA antigens. This measure reduces but does not eliminate the risk of Yersinia blood contamination. Notification of yersiniosis is now obligatory in some countries. Bartonella Infections, Including Michael Giladi, Moshe Ephros


InternalMed_Harrison

InternalMed_Harrison. Bartonella species are fastidious, facultative intracellular, slow-growing, gram-negative bacteria that cause a broad spectrum of diseases in humans. This genus includes more than 30 distinct species or subspecies, of which at least 16 have been recognized as confirmed or potential human pathogens; Bartonella bacilliformis, Bartonella quintana, and Bartonella henselae are most commonly identified (Table 197-1). Most Bartonella species have successfully adapted to survival in specific domestic or wild mammals. Prolonged intraerythrocytic infection in these animals creates a niche where the bacteria are protected from both innate and adaptive immunity and which serves as a reservoir for human infections. Bartonella characteristically evades the host immune system by modification of its virulence factors (e.g., lipopolysaccharides or flagella) and by attenuation of the immune response. B. bacilliformis and B. quintana, which are not zoonotic, are exceptions. Arthropod vectors are often


InternalMed_Harrison

InternalMed_Harrison. factors (e.g., lipopolysaccharides or flagella) and by attenuation of the immune response. B. bacilliformis and B. quintana, which are not zoonotic, are exceptions. Arthropod vectors are often involved. Isolation and characterization of Bartonella species are difficult and require special techniques. Clinical presentation generally depends on both the infecting Bartonella species and the immune status of the infected individual. Bartonella species are susceptible to many antibiotics in vitro; however, clinical responses to therapy and studies in animal models suggest that the minimal inhibitory concentrations of many antimicrobial agents correlate poorly with the drugs’ in vivo efficacies in patients with Bartonella infections.


InternalMed_Harrison

InternalMed_Harrison. Usually a self-limited illness, cat-scratch disease (CSD) has two general clinical presentations. Typical CSD, the more common, is characterized by subacute regional lymphadenopathy; atypical CSD is the collective designation for numerous extranodal manifestations involving various organs. B. henselae is the principal etiologic agent of CSD. Rare cases have been associated with Afipia felis and other Bartonella species.


InternalMed_Harrison

InternalMed_Harrison. CSD occurs worldwide, favoring warm and humid climates. In temperate climates, incidence peaks during fall and winter; in the tropics, disease occurs year-round. Adults are affected nearly as frequently as children. Intrafamilial clustering is rare, and person-to-person transmission does not occur. Apparently healthy cats constitute the major reservoir of B. henselae, and cat fleas (Ctenocephalides felis) may be responsible for cat-to-cat transmission. CSD usually follows contact with cats (especially kittens), but other animals (e.g., dogs) have been implicated as possible reservoirs in rare instances. In the United States, the estimated disease incidence is ~10 cases per 100,000 population. About 10% of patients are hospitalized.


InternalMed_Harrison

InternalMed_Harrison. aMany other Bartonella species exist but are not recognized as human pathogens. bB. henselae, B. vinsonii subsp. berkhoffii, B. koehlerae, Candidatus B. melophagi, or more than one Bartonella spp. (co-infection) were detected in blood samples from patients with extensive arthropod and other animal exposure who presented with various chronic neurologic or neurocognitive syndromes. The role of these pathogens in these patients needs further study. cAnimals are implicated when existing evidence supports their infection with Bartonella species. Data supporting animal-to-human transmission may be lacking. dRetinitis may also be associated with B. grahamii. eCandidatus is a taxonomic status for bacteria that cannot be described in sufficient detail to warrant establishment of a novel taxon or cannot be cultured or propagated in culture media. The phylogenetic relatedness of these bacteria has been determined by gene amplification and sequence analysis.


InternalMed_Harrison

InternalMed_Harrison. Inoculation of B. henselae, possibly via contaminated flea feces, usually results from a cat scratch or bite. Infection of mucous membranes or conjunctivae via droplets or licking may occur as well. With lymphatic drainage to one or more regional lymph nodes in immunocompetent hosts, a TH1 response can result in necrotizing granulomatous lymphadenitis. Dendritic cells, along with their associated chemokines, play a role in the host inflammatory response and granuloma formation.


InternalMed_Harrison

InternalMed_Harrison. Of patients with CSD, 85–90% have typical disease. The primary lesion, a small (0.3to 1-cm) painless erythematous papule or pustule, develops at the inoculation site (usually the site of a scratch or a bite) within days to 2 weeks in about one-third to two-thirds of patients (Fig. 197–1A, B). Lymphadenopathy develops 1–3 weeks or longer after cat contact. The affected lymph node(s) are enlarged and usually painful, sometimes have overlying erythema, and suppurate in 10–15% of cases (Fig. 197–1C, D, and E). Axillary/epitrochlear nodes are most commonly involved; next in frequency are head/neck nodes and then inguinal/femoral nodes. Approximately 50% of patients have fever, malaise, and anorexia. A smaller proportion experience weight loss and night sweats mimicking the presentation of lymphoma. Fever is usually low-grade but infrequently rises to ≥39°C. Resolution is slow, requiring weeks (for fever, pain, and accompanying signs and symptoms) to months (for node shrinkage).


InternalMed_Harrison

InternalMed_Harrison. Atypical CSD occurs in 10–15% of patients as extranodal or complicated disease in the absence or presence of lymphadenopathy. Atypical disease includes Parinaud’s oculoglandular syndrome (granulomatous conjunctivitis with ipsilateral preauricular lymphadenitis; Fig. 197–1E), granulomatous hepatitis/splenitis, neuroretinitis (often presenting as unilateral deterioration of vision; Fig. 197–1F), and other ophthalmologic manifestations. In addition, neurologic involvement (encephalopathy, seizures, myelitis, radiculitis, cerebellitis, facial and other cranial or peripheral palsies), fever of unknown origin, debilitating myalgia, arthritis or arthralgia (affecting mostly women >20 years old), osteomyelitis (including multifocal disease), tendinitis, neuralgia, and dermatologic manifestations (including erythema nodosum [see Fig. 25e-40], sometimes accompanying arthropathy) occur. Other manifestations and syndromes (pneumonitis, pleural effusion, idiopathic thrombocytopenic purpura,


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InternalMed_Harrison. (including erythema nodosum [see Fig. 25e-40], sometimes accompanying arthropathy) occur. Other manifestations and syndromes (pneumonitis, pleural effusion, idiopathic thrombocytopenic purpura, Henoch-Schönlein purpura, erythema multiforme [see Fig. 25e-25], hypercalcemia, glomerulonephritis, myocarditis) have also been associated with CSD. In elderly patients (>60 years old), lymphadenopathy is more often absent but encephalitis and fever of unknown origin are more common than in younger patients. In immunocompetent individuals, CSD—whether typical or atypical—usually resolves without treatment and without sequelae. Lifelong immunity is the rule.


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InternalMed_Harrison. Routine laboratory tests usually yield normal or nonspecific results. Histopathology initially shows lymphoid hyperplasia and later demonstrates stellate granulomata with necrosis, coalescing microabscesses, and occasional multinucleated giant cells—findings that, although nonspecific, may narrow the differential diagnosis. Serologic testing (immunofluorescence or enzyme immunoassay) is the most commonly used laboratory diagnostic approach, with variable sensitivity and specificity. Seroconversion may take a few weeks. Other tests are of low sensitivity (culture, Warthin-Starry silver staining), of low specificity (cytology, histopathology), or of limited availability in routine diagnostic laboratories (polymerase chain reaction [PCR], immunohistochemistry). PCR of lymph node tissue, pus, or the primary inoculation lesion is highly sensitive and specific and is particularly useful for definitive and rapid diagnosis in seronegative patients. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: A history of cat contact, a primary inoculation lesion, and regional lymphadenopathy are highly suggestive of CSD. A characteristic clinical course and corroborative laboratory tests make the diagnosis very likely. Conversely, when acuteand convalescent-phase sera are negative (as is the case in 10–20% of CSD patients), when spontaneous regression of lymph node size does not occur, and particularly when constitutional symptoms persist, malignancy must be ruled out. Pyogenic lymphadenitis, mycobacterial infection, brucellosis, syphilis, tularemia, plague, toxoplasmosis, sporotrichosis, and histoplasmosis should also be considered. In clinically suspected CSD in a seronegative individual, fine-needle aspiration may be adequate and PCR can confirm the diagnosis. When data are


InternalMed_Harrison

InternalMed_Harrison. Bartonella Infections, Including Cat-Scratch Disease less supportive of CSD, lymph node biopsy rather than fine-needle aspiration is preferred. In seronegative CSD patients with lymphadenopathy and severe complications (e.g., encephalitis or neuroretinitis), early biopsy is important to establish a specific diagnosis. (Table 197-2) Treatment regimens are based on only minimal data. Suppurative nodes should be drained by large-bore needle aspiration and not by incision and drainage in order to avoid chronic draining tracts. Immunocompromised patients must always be treated with systemic antimicrobials. Avoiding cats (especially kittens) and instituting flea control are options for immunocompromised patients and for patients with valvular heart disease.


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InternalMed_Harrison. Avoiding cats (especially kittens) and instituting flea control are options for immunocompromised patients and for patients with valvular heart disease. Trench fever, also known as 5-day fever or quintan fever, is a febrile illness caused by B. quintana. It was first described as an epidemic in the trenches of World War I and recently reemerged as chronic bacteremia seen most often in homeless people (also referred to in the latter setting as urban or contemporary trench fever).


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InternalMed_Harrison. FIGuRE 197-1 Manifestations of cat-scratch disease. A. Primary inoculation lesion. Axillary and epitrochlear lymphadenitis appeared 2 weeks later. B. Primary inoculation lesion. Submental lymphadenitis appeared 10 days later. C. Axillary lymphadenopathy of 2 weeks’ duration. The overlying skin appears normal. D. Cervical lymphadenopathy of 6 weeks’ duration. The overlying skin is red. Thick, odorless pus (12 mL) was aspirated. E. Preauricular lymphadenopathy. F. Left-eye neuroretinitis. Note papilledema and stellate macular exudates (“macular star”).


InternalMed_Harrison

InternalMed_Harrison. In addition to epidemics during World Wars I and II, sporadic outbreaks of trench fever have been reported in many regions of the world. The human body louse has been identified as the vector and humans as the only known reservoir. After a hiatus of several decades during which trench fever was almost forgotten, small clusters of cases of B. quintana chronic bacteremia were reported sporadically, primarily from the United States and France, in HIV-uninfected homeless people. Alcoholism and louse infestation were identified as risk factors.


InternalMed_Harrison

InternalMed_Harrison. The typical incubation period is 15–25 days (range, 3–38 days). “Classical” trench fever, as described in 1919, ranges from a mild febrile illness to a recurrent or protracted and debilitating disease. Onset may be abrupt or preceded by a prodrome of several days. Fever is often periodic, lasting 4–5 days with 5-day (range, 3to 8-day) intervals between episodes. Other symptoms and signs include headache, back and limb pain, profuse sweating, shivering, myalgia, arthralgia, splenomegaly, a maculopapular rash in occasional cases, and nuchal rigidity in some cases. Untreated, the disease usually lasts Typical cat-scratch disease Not routinely indicated; for patients with extensive lymphadenopathy, consider azithromycin (500 mg PO on day 1, then 250 mg PO qd for 4 days)


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InternalMed_Harrison. Typical cat-scratch disease Not routinely indicated; for patients with extensive lymphadenopathy, consider azithromycin (500 mg PO on day 1, then 250 mg PO qd for 4 days) Trench fever or chronic bacteremia Gentamicin (3 mg/kg IV qd for 14 days) plus doxycycline (200 mg PO qd or 100 mg PO bid for 6 weeks) with B. quintana Suspected Bartonella endocarditis Gentamicinb (1 mg/kg IV q8h for ≥14 days) plus doxycycline (100 mg PO/IV bid for 6 weeksc) plus ceftriaxone (2 g IV qd for 6 weeks) Confirmed Bartonella endocarditis As for suspected Bartonella endocarditis minus ceftriaxone Bacillary angiomatosis Erythromycind (500 mg PO qid for 3 months)


InternalMed_Harrison

InternalMed_Harrison. Ciprofloxacin (500 mg PO bid for 10 days) Verruga peruana Rifampin (10 mg/kg PO qd, to a maximum of 600 mg, for 14 days) aData on treatment efficacy for encephalitis and hepatosplenic CSD are lacking. Therapy similar to that given for retinitis is reasonable. bSome experts recommend gentamicin at 3 mg/ kg IV qd. If gentamicin is contraindicated, rifampin (300 mg PO bid) can be added to doxycycline for documented Bartonella endocarditis. cSome experts recommend extending oral doxycycline therapy for 3–6 months. dOther macrolides are probably effective and may be substituted for erythromycin or doxycycline. Source: Recommendations are modified from JM Rolain et al: Antimicrob Agents Chemother 48:1921, 2004.


InternalMed_Harrison

InternalMed_Harrison. Source: Recommendations are modified from JM Rolain et al: Antimicrob Agents Chemother 48:1921, 2004. Bartonella Infections, Including Cat-Scratch Disease 1082 4–6 weeks. Death is rare. The clinical spectrum of B. quintana bacteremia in homeless people ranges from asymptomatic infection to a febrile illness with headache, severe leg pain, and thrombocytopenia. Endocarditis sometimes develops. Definitive diagnosis requires isolation of B. quintana by blood culture. Some patients have positive blood cultures for several weeks. Patients with acute trench fever typically develop significant titers of antibody to Bartonella, whereas those with chronic B. quintana bacteremia may be seronegative. Patients with high titers of IgG antibodies should be evaluated for endocarditis. In epidemics, trench fever should be differentiated from epidemic louse-borne typhus and relapsing fever, which occur under similar conditions and share many features.


InternalMed_Harrison

InternalMed_Harrison. TREATMEnT b. QUintana bacteremia (Table 197–2) In a small, randomized, placebo-controlled trial involving homeless people with B. quintana bacteremia, therapy with gentamicin and doxycycline was superior to administration of placebo in eradicating bacteremia. Treatment of bacteremia is important even in clinically mild cases to prevent endocarditis. Optimal therapy for trench fever without documented bacteremia is uncertain. Coxiella burnetii (Chap. 211) and Bartonella species are the (Chap. 155). In France, for example, Bartonella species were identified as the etiologic agents in 28% of 348 cases of culture-negative endocarditis. Prevalence, however, varies by geographic location and epidemiologic setting. In addition to B. quintana and B. henselae (the most common Bartonella species implicated in endocarditis, the former more commonly than the latter), other Bartonella species have reportedly caused rare cases (Table 197-1).


InternalMed_Harrison

InternalMed_Harrison. B. henselae (the most common Bartonella species implicated in endocarditis, the former more commonly than the latter), other Bartonella species have reportedly caused rare cases (Table 197-1). Bartonella endocarditis has been reported worldwide. Most patients are adults; more are male than female. Risk factors associated with B. quintana endocarditis include homelessness, alcoholism, and body louse infestation; however, individuals with no risk factors have had Bartonella endocarditis diagnosed as well. B. henselae endocarditis is associated with exposure to cats. Most cases involve native rather than prosthetic valves; the aortic valve accounts for ~60% of cases. Patients with B. henselae endocarditis usually have preexisting valvulopathy, whereas B. quintana often infects normal valves.


InternalMed_Harrison

InternalMed_Harrison. Clinical manifestations are usually characteristic of subacute endocarditis of any etiology. However, a substantial number of patients have a prolonged, minimally febrile or even afebrile indolent illness, with mild nonspecific symptoms lasting weeks or months before the diagnosis is made. Initial echocardiography may not show vegetations. Acute, aggressive disease is rare. Blood cultures, even with use of special techniques (lysis centrifugation or EDTA-containing tubes), are positive in only ~25% of cases— mostly those caused by B. quintana and only rarely those caused by


InternalMed_Harrison

InternalMed_Harrison. B. henselae. Prolonged incubation of cultures (up to 6 weeks) is required. Serologic tests—either immunofluorescence or enzyme immunoassay—usually demonstrate high-titer IgG antibodies to Bartonella. Because of cross-antigenicity, serology does not distinguish between B. quintana and B. henselae and may also be low-titer cross-reactive with other pathogens, such as C. burnetii and Chlamydia species. Identification of Bartonella to the species level is usually accomplished by application of PCR-based methods to valve tissue.


InternalMed_Harrison

InternalMed_Harrison. (Table 197-2) For patients with culture-negative endocarditis suspected to be due to Bartonella species, empirical treatment consists of gentamicin, doxycycline, and ceftriaxone; the major role of ceftriaxone in this regimen is to adequately treat other potential causes of culture-negative endocarditis, including members of the HACEK group (Chap. 183e). Once a diagnosis of Bartonella endocarditis has been established, ceftriaxone is discontinued. Aminoglycosides, the only antibiotics known to be bactericidal against Bartonella, should be included in the regimen for ≥2 weeks. Indications for valvular surgery are the same as in subacute endocarditis due to other pathogens; however, the proportion of patients who undergo surgery (~60%) is high, probably as a consequence of delayed diagnosis.


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InternalMed_Harrison. Bacillary angiomatosis (sometimes called bacillary epithelioid angiomatosis or epithelioid angiomatosis) is a disease of severely immunocompromised patients, is caused by B. henselae or B. quintana, and is characterized by neovascular proliferative lesions involving the skin and other organs. Both species cause cutaneous lesions; hepatosplenic lesions are caused only by B. henselae, whereas subcutaneous and lytic bone lesions are more frequently associated with B. quintana. Bacillary peliosis is a closely related angioproliferative disorder caused by B. henselae and involving primarily the liver (peliosis hepatis) but also the spleen and lymph nodes. Bacillary peliosis is characterized by blood-filled cystic structures whose size ranges from microscopic to several millimeters.


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InternalMed_Harrison. Bacillary angiomatosis and bacillary peliosis occur primarily in HIV-infected persons (Chap. 226) with CD4+ T cell counts <100/μL but also affect other immunosuppressed patients and, in rare instances, immunocompetent patients. The previously reported incidence of ~1 case per 1000 HIV-infected persons is now lower; the decrease is most likely attributable to effective antiretroviral therapy and the routine use of rifabutin and macrolides to prevent Mycobacterium avium complex infection in AIDS patients. Contact with cats or cat fleas increases the risk of B. henselae infection. Risk factors for B. quintana infection are low income, homelessness, and body louse infestation.


InternalMed_Harrison

InternalMed_Harrison. Bacillary angiomatosis presents most commonly as one or more cutaneous lesions that are not painful and that may be tan, red, or purple in color. Subcutaneous masses or nodules, superficial ulcerated plaques (Fig. 197-2), and verrucous growths are also seen. Nodular forms resemble those seen in fungal or mycobacterial infections. Subcutaneous nodules are often tender. Painful osseous lesions, most often involving long bones, may underlie cutaneous lesions and occasionally develop in their absence. In rare cases, other organs are involved in bacillary angiomatosis. Patients usually have constitutional symptoms, including fever, chills, malaise, headache, anorexia, weight loss, and night sweats. In osseous disease, lytic lesions are generally seen on radiography, and technetium scan shows focal uptake. The differential diagnosis of cutaneous bacillary angiomatosis includes Kaposi’s sarcoma, pyogenic granuloma, subcutaneous tumors, and verruga peruana. In bacillary peliosis, hypodense


InternalMed_Harrison

InternalMed_Harrison. focal uptake. The differential diagnosis of cutaneous bacillary angiomatosis includes Kaposi’s sarcoma, pyogenic granuloma, subcutaneous tumors, and verruga peruana. In bacillary peliosis, hypodense hepatic areas are usually evident on imaging. In patients with advanced immunodeficiency, B. henselae and B. quintana are important causes of fever of unknown origin. Intermittent bacteremia with positive blood cultures can occur with or without endocarditis.


InternalMed_Harrison

InternalMed_Harrison. Bacillary angiomatosis consists of lobular proliferations of small blood vessels lined by enlarged endothelial cells interspersed with mixed infiltrates of neutrophils and lymphocytes, with predominance of the former. Histologic examination of organs with bacillary peliosis reveals small blood-filled cystic lesions partially lined by endothelial Donovanosis Nigel O’Farrell Donovanosis is a chronic, progressive bacterial infection that usually involves the genital region. The condition is generally regarded as a sexually transmitted infection of low infectivity. This infection has been known by many other names, the most common being granu-198e loma inguinale.


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InternalMed_Harrison. The causative organism has been reclassified as Klebsiella granulomatis comb nov on the basis of phylogenetic analysis, although there is ongoing debate about this decision. Some authorities consider the original nomenclature (Calymmatobacterium granulomatis) to be more appropriate in light of analysis of 16S rRNA gene sequences. Donovanosis was first described in Calcutta in 1882, and the causative organism was recognized by Charles Donovan in Madras in 1905. He identified the characteristic Donovan bodies, measuring 1.5 × 0.7 μm, in macrophages and the stratum malpighii. The organism was not reproducibly cultured until the mid-1990s, when its isolation in peripheral-blood monocytes and human epithelial cell lines was reported.


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InternalMed_Harrison. includes Papua New Guinea, parts of southern Africa, India, the Caribbean, French Guyana, Brazil, and aboriginal communities in Australia. In Australia, donovanosis has been almost entirely eliminated through a sustained program backed by strong political commitment and resources at the primary health care level. Although few cases are now reported in the United States, donovanosis was once prevalent in this country, with 5000–10,000 cases recorded in 1947. The largest epidemic recorded was in Dutch South Guinea, where 10,000 cases were identified in a population of 15,000 (the Marind-anim people) between 1922 and 1952. Donovanosis is associated with poor hygiene and is more common in lower socioeconomic groups than in those who are better off and in men than in women. Infection in sexual partners of index cases occurs to a limited extent. Donovanosis is a risk factor for HIV infection (Chap. 226).


InternalMed_Harrison

InternalMed_Harrison. Globally, the incidence of donovanosis has decreased significantly in recent times. This decline probably reflects a greater focus on effective management of genital ulcers because of their role in facilitating HIV transmission. A lesion starts as a papule or subcutaneous nodule that later ulcerates after trauma. The incubation period is uncertain, but experimental infections in humans indicate a duration of ~50 days. Four types of lesions have been described: (1) the classic ulcerogranulomatous lesion (Fig. 198e-1), a beefy red ulcer that bleeds readily when touched; (2) a hypertrophic or verrucous ulcer with a raised irregular edge; (3) a necrotic, offensive-smelling ulcer causing tissue destruction; and (4) a sclerotic or cicatricial lesion with fibrous and scar tissue.


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InternalMed_Harrison. The genitals are affected in 90% of patients and the inguinal region in 10%. The most common sites of infection are the prepuce, coronal sulcus, frenum, and glans in men and the labia minora and fourchette in women. Cervical lesions may mimic cervical carcinoma. In men, lesions are associated with lack of circumcision. Lymphadenitis is uncommon. Extragenital lesions occur in 6% of cases and may involve the lip, gums, cheek, palate, pharynx, larynx, and chest. Hematogenous spread with involvement of liver and bone has been reported. During pregnancy, lesions tend to develop more quickly and respond more slowly to treatment. Polyarthritis and osteomyelitis are rare complications. In newborn infants, donovanosis may present with ear infection. Cases in children have been attributed to sitting on the laps of infected adults. FIGURE 198e-1 Ulcerogranulomatous penile lesion of donovanosis, with some hypertrophic features.


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InternalMed_Harrison. FIGURE 198e-1 Ulcerogranulomatous penile lesion of donovanosis, with some hypertrophic features. As the incidence of donovanosis has decreased, the number of unusual case reports has appeared to be increasing. Complications include neoplastic changes, pseudo-elephantiasis, and stenosis of the urethra, vagina, or anus.


InternalMed_Harrison

InternalMed_Harrison. A clinical diagnosis of donovanosis made by an experienced practitioner on the basis of the lesion’s appearance usually has a high positive predictive value. The diagnosis is confirmed by microscopic identification of Donovan bodies (Fig. 198e-2) in tissue smears. Preparation of a good-quality smear is important. If donovanosis is suspected on clinical grounds, the smear for Donovan bodies should be taken before swab samples are collected to be tested for other causes of genital ulceration so that enough material can be collected from the ulcer. A swab should be rolled firmly over an ulcer previously cleaned with a dry swab to remove debris. Smears can be examined in a clinical setting by direct microscopy with a rapid Giemsa or Wright’s stain. Alternatively, a piece of granulation tissue crushed and spread between two slides can be used. Donovan bodies can be seen in large, mononuclear (Pund) cells as gram-negative intracytoplasmic cysts filled with deeply staining bodies that may


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InternalMed_Harrison. crushed and spread between two slides can be used. Donovan bodies can be seen in large, mononuclear (Pund) cells as gram-negative intracytoplasmic cysts filled with deeply staining bodies that may have a safety-pin appearance. These cysts eventually rupture and release the infective organisms. Histologic changes


InternalMed_Harrison

InternalMed_Harrison. FIGURE 198e-2 Pund cell stained by rapid Giemsa (RapiDiff) technique. Numerous Donovan bodies are visible. include chronic inflammation with infiltration of plasma cells and neutrophils. Epithelial changes include ulceration, microabscesses, and elongation of rete ridges. A diagnostic polymerase chain reaction (PCR) test was based on the observation that two unique base changes in the phoE gene eliminate Hae111 restriction sites, enabling differentiation of K. granulomatis comb nov from related Klebsiella species. PCR analysis with a colorimetric detection system can now be used in routine diagnostic laboratories. A genital ulcer multiplex PCR that includes K. granulomatis has been developed. Serologic tests are only poorly specific and are not currently used.


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis of donovanosis includes primary syphilitic chancres, secondary syphilis (condylomata lata), chancroid, lymphogranuloma venereum, genital herpes, neoplasm, and amebiasis. Mixed infections are common. Histologic appearances should be distinguished from those of rhinoscleroma, leishmaniasis, and histoplasmosis. Many patients with donovanosis present quite late with extensive ulceration. They may be embarrassed and have low self-esteem related to their disease. Reassurance that they have a treatable condition is important, as is the need to administer antibiotics and monitor patients for an adequate interval (see below). Epidemiologic treatment of sexual partners and advice about how to improve genital hygiene are recommended. Azithromycin 1 g on day 1, then 500 mg daily for 7 days or 1 g weekly for 4 weeks


InternalMed_Harrison

InternalMed_Harrison. Azithromycin 1 g on day 1, then 500 mg daily for 7 days or 1 g weekly for 4 weeks The recommended drug regimens for donovanosis are shown in Table 198e-1. Gentamicin can be added if the response is slow. Ceftriaxone, chloramphenicol, and norfloxacin are also effective. Patients treated for 14 days should be monitored until lesions have healed completely. Those treated with azithromycin probably do not need such rigorous follow-up. Surgery may be indicated for very advanced lesions. Donovanosis is probably the cause of genital ulceration that is most readily recognizable clinically. Donovanosis is now limited to a few specific locations, and its global eradication is a distinct possibility.


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InternalMed_Harrison. FIGuRE 197-2 Nodular lesion of bacillary angiomatosis with superficial ulceration in an AIDS patient with advanced immuno-deficiency. (Reprinted with permission from DH Spach and E Darby: Bartonella Infections, Including Cat-Scratch Disease, in Harrison’s Principles of Internal Medicine, 17th ed, AF Fauci et al [eds]. New York, McGraw-Hill, 2008, p 989.) cells that can be several millimeters in size. Peliotic lesions are surrounded by fibromyxoid stroma containing inflammatory cells, dilated capillaries, and clumps of granular material. Warthin-Starry silver staining of bacillary angiomatosis and peliosis lesions reveals clusters of bacilli. Cultures are usually negative. Bacillary angiomatosis and bacillary peliosis are diagnosed on histologic grounds. Blood cultures may be positive. (Table 197-2) Prolonged therapy with a macrolide or doxycycline is recommended for both bacillary angiomatosis and bacillary peliosis.