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InternalMed_Harrison. rift valley fever The natural range of Rift Valley fever virus was previously confined to sub-Saharan Africa, with circulation of the virus markedly enhanced by substantial rainfall. The El Niño Southern Oscillation phenomenon of 1997 facilitated subsequent spread of Rift 1322 Valley fever to the Arabian Peninsula, with epidemic disease in 2000. The virus has also been found in Madagascar and has been introduced into Egypt, where it caused major epidemics in 1977–1979, 1993, and thereafter. Rift Valley fever virus is maintained in nature by transovarial transmission in floodwater Aedes mosquitoes and presumably also has a vertebrate amplifier. Increased transmission during particularly heavy rains leads to epizootics characterized by high-level viremia in cattle, goats, or sheep. Numerous types of mosquitoes then feed on these animals and become infected, thereby increasing the possibility of human infections. Remote sensing via satellite can detect the ecologic changes associated


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InternalMed_Harrison. types of mosquitoes then feed on these animals and become infected, thereby increasing the possibility of human infections. Remote sensing via satellite can detect the ecologic changes associated with high rainfall that predict the likelihood of Rift Valley fever virus transmission. High-resolution satellites can also detect the special depressions in floodwaters from which the mosquitoes emerge. In addition, the virus can be transmitted by contact with blood or aerosols from domestic animals. Transmission risk is therefore high during birthing, and both abortuses and placentas need to be handled with caution. Slaughtered animals are not infectious because anaerobic glycolysis in postmortem tissues results in an acidic environment that rapidly inactivates bunyaviruses. Neither person-to-person nor nosocomial transmission of Rift Valley fever has been documented. Rift Valley fever virus is unusual in that it causes several clinical syndromes. Most infections are manifested as the


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InternalMed_Harrison. nor nosocomial transmission of Rift Valley fever has been documented. Rift Valley fever virus is unusual in that it causes several clinical syndromes. Most infections are manifested as the fever–myalgia syndrome. A small proportion of infections result in VHF with especially prominent liver involvement. Renal failure and DIC are also common features. Perhaps 10% of otherwise mild infections lead to retinal vasculitis, and some patients have permanently impaired vision. Funduscopic examination reveals edema, hemorrhages, and infarction of the retina as well as optic nerve degeneration. In a small proportion of patients (<1 in 200), retinal vasculitis is followed by viral encephalitis. No proven therapy exists for Rift Valley fever. Both retinal disease and encephalitis occur after the acute febrile syndrome has resolved and serum neutralizing antibody has developed—events suggesting that only supportive care need be given. Epidemic disease is best prevented by vaccination of livestock.


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InternalMed_Harrison. febrile syndrome has resolved and serum neutralizing antibody has developed—events suggesting that only supportive care need be given. Epidemic disease is best prevented by vaccination of livestock. The ability of this virus to propagate after introduction into Egypt suggests that other potentially receptive areas, including the United States, should develop response plans. Rift Valley fever, like Venezuelan equine encephalitis, is likely to be controlled only with adequate stocks of an effective live attenuated vaccine, but such global stocks are unavailable. A formalin-inactivated vaccine confers immunity in humans, but quantities are limited and three injections are required; this vaccine is recommended for potentially exposed laboratory workers and for veterinarians working in sub-Saharan Africa. A new live attenuated vaccine, MP-12, is being tested in humans and may soon become available for general use. The vaccine is safe and licensed for use in sheep and cattle.


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InternalMed_Harrison. severe fever witH tHrombocytopenia syndrome This is a recently described tick-borne disease caused by a previously unknown and still-unclassified phlebovirus. Numerous human infections have been reported during the past few years from China, and several cases have also been detected in Japan and South Korea. The clinical presentation ranges from mild nonspecific fever to severe VHF with a high (>12%) lethality rate.


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InternalMed_Harrison. Flaviviruses The most important flaviviruses that cause VHF are the mosquito-borne dengue viruses 1–4 and yellow fever viruses. These viruses are widely distributed and cause tens to hundreds of thousands of infections each year. Kyasanur Forest disease virus and Omsk hemorrhagic fever virus are geographically very restricted but important tick-borne flaviviruses that cause VHF, sometimes with subsequent viral encephalitis. Tick-borne encephalitis virus has caused VHF in a few patients. There is currently no therapy for these VHFs, but an inactivated vaccine has been used in India to prevent Kyasanur Forest disease.


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InternalMed_Harrison. severe dengUe Several weeks after convalescence from infection with dengue virus 1, 2, 3, or 4, the transient protection conferred by that infection against reinfection with a heterotypic dengue virus usually wanes. Heterotypic reinfection may result in classic dengue or, less commonly, in severe dengue. In the past 20 years, A. aegypti has progressively reinvaded Latin America and other areas, and frequent travel by infected individuals has introduced multiple variants of dengue viruses 1–4 from many geographic areas. Thus the pattern of hyperendemic transmission of multiple dengue virus serotypes established in the Americas and the Caribbean has led to the emergence of severe dengue as a major problem. Among the millions of dengue virus 1–4 infections, ~500,000 cases of severe dengue occur annually, with a lethality rate of ~2.5%. The induction of vascular permeability and shock depends on multiple factors, such as the presence or absence of enhancing and nonneutralizing antibodies,


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InternalMed_Harrison. annually, with a lethality rate of ~2.5%. The induction of vascular permeability and shock depends on multiple factors, such as the presence or absence of enhancing and nonneutralizing antibodies, age (susceptibility to severe dengue drops considerably after 12 years of age), sex (females are more often affected than males), race (whites are more often affected than blacks), nutritional status (malnutrition is protective), or sequence of infections (e.g., dengue virus 1 infection followed by dengue virus 2 infection seems to be more dangerous than dengue virus 4 infection followed by dengue virus 2 infection). In addition, considerable heterogeneity exists among each dengue virus population. For instance, Southeast Asian dengue virus 2 variants have more potential to cause severe dengue than do other variants.


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InternalMed_Harrison. Severe dengue is identified by the detection of bleeding tendencies (tourniquet test, petechiae) or overt bleeding in the absence of underlying causes, such as preexisting gastrointestinal lesions. Shock may result from increased vascular permeability. In milder cases of severe dengue, restlessness, lethargy, thrombocytopenia (<100,000/μL), and hemoconcentration are detected 2–5 days after the onset of typical dengue, usually at the time of defervescence. The maculopapular rash that often develops in dengue may also appear in severe dengue. In more severe cases, frank shock is apparent, with low pulse pressure, cyanosis, hepatomegaly, pleural effusions, and ascites; in some patients, severe ecchymoses and gastrointestinal bleeding develop. The period of shock lasts only 1 or 2 days.


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InternalMed_Harrison. A virologic diagnosis of severe dengue can be made by the usual means. However, multiple flavivirus infections result in broad immune responses to several members of the genus, and this situation may result in a lack of virus specificity of the IgM and IgG immune responses. A secondary antibody response can be sought with tests against several flavivirus antigens to demonstrate the characteristic wide spectrum of reactivity. Most patients with shock respond promptly to close monitoring, oxygen administration, and infusion of crystalloid or—in severe cases— colloid. The case–fatality rates reported vary greatly with case ascertainment and quality of treatment; however, most patients with severe dengue respond well to supportive therapy, and the overall lethality rate at an experienced center in the tropics is probably as low as 1%.


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InternalMed_Harrison. The key to control of both dengue and severe dengue is the control of A. aegypti, which also reduces the risk of urban yellow fever and chikungunya virus circulation. Control efforts have been handicapped by the presence of nondegradable tires and long-lived plastic containers in trash repositories (perfect mosquito breeding grounds when filled with water during rainfall) and by insecticide resistance. Urban poverty and an inability of the public health community to mobilize the populace to respond to the need to eliminate mosquito breeding sites are also factors in lack of mosquito control. A tetravalent live attenuated dengue vaccine based on the attenuated yellow fever virus 17D platform is currently being evaluated in phase 3 clinical trials in Latin America, Asia, and Australia. At least two other live attenuated candidate vaccines based on modified recombinant dengue viruses have been evaluated in phase 1 clinical studies, but the results have not been promising.


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InternalMed_Harrison. yellow fever Yellow fever virus had caused major epidemics in Africa and Europe before its transmission by A. aegypti mosquitoes was discovered in 1900. Urban yellow fever became established in the New World as a result of colonization with A. aegypti, originally an African mosquito. Subsequently, different types of mosquitoes and nonhuman primates were found to maintain yellow fever virus in Africa and also in Central and South American jungles. Transmission to humans


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InternalMed_Harrison. Ebolavirus and Marburgvirus Infections Jens H. Kuhn Several viruses of the family Filoviridae cause severe and frequently fatal viral hemorrhagic fevers in humans. Introduction of filoviruses 234 is incidental, occurring via bites from mosquitoes that have fed on viremic monkeys. After the identification of A. aegypti mosquitoes as vectors of yellow fever, containment strategies were aimed at increased mosquito control. Today, urban yellow fever transmission occurs only in some African cities, but the threat exists in the great cities of South America, where reinfestation by A. aegypti has taken place and dengue virus 1–4 transmission by the same mosquito is common. Despite the existence of a highly effective and safe vaccine, several hundred jungle yellow fever cases occur annually in South America, and thousands of jungle and urban cases occur each year in Africa (29,000–60,000 estimated for 2013).


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InternalMed_Harrison. Yellow fever is a typical VHF accompanied by prominent hepatic necrosis. A period of viremia, typically lasting 3 or 4 days, is followed by a period of “intoxication.” During the latter phase in severe cases, characteristic jaundice, hemorrhages, black vomit, anuria, and terminal delirium occur, perhaps related in part to extensive hepatic involvement. Blood leukocyte counts may be normal or reduced and are often high in terminal stages. Albuminuria is usually noted and may be marked. As renal function fails in terminal or severe cases, the concentration of blood urea nitrogen rises proportionately. Abnormalities detected in liver function tests range from modest elevations of AST concentrations in mild cases to severe derangement.


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InternalMed_Harrison. Urban yellow fever can be prevented by the control of A. aegypti. The continuing sylvatic cycles require vaccination of all visitors to areas of potential transmission with live attenuated variant 17D vaccine virus, which cannot be transmitted by mosquitoes. With few exceptions, reactions to the vaccine are minimal; immunity is provided within 10 days and lasts for at least 25–35 years. An egg allergy mandates caution in vaccine administration. Although there are no documented harmful effects of the vaccine on fetuses, pregnant women should be immunized only if they are definitely at risk of exposure to yellow fever virus. Because vaccination has been associated with several cases of encephalitis in children <6 months of age, it is contraindicated in this age group, nor is it recommended for infants 6–8 months of age unless the risk of exposure is very high. Rare, serious, multisystemic adverse reactions (occasionally fatal) have been reported, particularly affecting the elderly, and


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InternalMed_Harrison. for infants 6–8 months of age unless the risk of exposure is very high. Rare, serious, multisystemic adverse reactions (occasionally fatal) have been reported, particularly affecting the elderly, and risk-to-benefit should be weighed prior to vaccine administration to individuals ≥60 years of age. Nevertheless, the number of deaths of unvaccinated travelers with yellow fever exceeds the number of deaths from vaccination, and a liberal vaccination policy for travelers to involved areas should be pursued. Timely information on changes in yellow fever distribution and yellow fever vaccine requirements can be obtained from the


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InternalMed_Harrison. U.S. Centers for Disease Control and Prevention (http://www.cdc.gov/ vaccines/vpd-vac/yf/default.htm). into human populations is an extremely rare event that most likely occurs by direct or indirect contact with healthy mammalian filovirus hosts or by contact with infected, sick, or deceased nonhuman primates. Filoviruses are highly infectious but not very contagious. Natural human-to-human transmission takes place through direct person-to-person (usually skin-to-skin) contact or exposure to infected bodily fluids and tissues; there is no evidence of such transmission by aerosol or respiratory droplets. Infections progress rapidly from influenza-like to hemorrhagic manifestations and typically culminate in multiple-organ dysfunction syndrome and shock. Treatment of filovirus infections is of necessity entirely supportive because no spe-1323 cific efficacious antiviral agents or vaccines are yet available.


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InternalMed_Harrison. Filoviruses are categorized as World Health Organization (WHO) Risk Group 4 Pathogens. Consequently, all work with material suspected of containing filoviruses should be conducted only in maximal containment (biosafety level 4) laboratories. Experienced personnel handling these viruses must wear appropriate personal protective gear (see “Prevention,” below) and follow rigorous standard operating procedures. The proper authorities and WHO reference laboratories should be contacted immediately when filovirus infections are suspected.


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InternalMed_Harrison. The family Filoviridae includes three genera: Cuevavirus, Ebolavirus, and Marburgvirus (Table 234-1 and Fig. 234-1). The available data suggest that the only known cuevavirus, Lloviu virus (LLOV), and one ebolavirus, Reston virus (RESTV), are not pathogenic for humans. The remaining four ebolaviruses—Bundibugyo virus (BDBV), Ebola virus (EBOV), Sudan virus (SUDV), and Taï Forest virus (TAFV)—cause Ebola virus disease (EVD; International Classification of Disease, Tenth Revision [ICD-10], code A98.4). The two marburgviruses, Marburg virus (MARV) and Ravn virus (RAVV), are the etiologic agents of Marburg virus disease (MVD; ICD-10 code A98.3).


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InternalMed_Harrison. Filoviruses have linear, nonsegmented, single-stranded, nega tive-sense RNA genomes that are ~19 kb in length. These genomes contain six or seven genes that encode the following seven structural proteins: nucleoprotein, polymerase cofactor (VP35), matrix protein (VP40), glycoprotein (GP1,2), transcriptional cofactor (VP30), secondary matrix protein (VP24), and RNA-dependent RNA polymerase (L protein). Cuevaviruses and ebolaviruses, but not marburgviruses, also encode three nonstructural proteins of unknown function (sGP, ssGP, and Δ-peptide). Filovirions are unique among human virus particles in that they are predominantly pleomorphic filaments but also assume torusor 6-like shapes (width, ~80 nm; average length, ≥790 nm). These enveloped virions contain helical ribonucleocapsids and are covered with GP1,2 spikes (Fig. 234-2). Virus 1: Marburg virus Virus: Lake Victoria (MARV) marburgvirus (MARV) Virus 2: Ravn virus (RAVV)


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InternalMed_Harrison. Virus 1: Marburg virus Virus: Lake Victoria (MARV) marburgvirus (MARV) Virus 2: Ravn virus (RAVV) Genus Ebolavirus Genus Ebolavirus Species Taï Forest ebolavirus Species Cote d’Ivoire ebolavirus [sica] Virus: Taï Forest virus Virus: Cote d’Ivoire ebolavirus (TAFV) [sic] (CIEBOV) Species Reston ebolavirus Species Reston ebolavirus Virus: Reston virus (RESTV) Virus: Reston ebolavirus (REBOV) Species Sudan ebolavirus Species Sudan ebolavirus Virus: Sudan virus (SUDV) Virus: Sudan ebolavirus (SEBOV) Species Zaire ebolavirus Species Zaire ebolavirus Virus: Ebola virus (EBOV) Virus: Zaire ebolavirus (ZEBOV) Species Bundibugyo ebolavirus Virus: Bundibugyo virus (BDBV) Genus Cuevavirus Species Lloviu cuevavirus Virus: Lloviu virus (LLOV) aThe correct spelling of the country for which this virus is named is Côte d’Ivoire. The lack of a circumflex in “Cote” in the virus designation produced a false country name. This fact is denoted by “[sic].” DQ447652 marburgviruses 1,100 DQ447650


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InternalMed_Harrison. DQ447652 marburgviruses 1,100 DQ447650 DQ447653 filovirus 10,436 7,583 3,210 2,128 ebolaviruses 4,364 3,807 0.2 1 FIGuRE 234-1 Filovirus phylogeny/evolution. Bayesian coalescent analysis of representative variants of all known filovirus clades (represented by underlined GenBank accession numbers). The maximal clade credibility tree is shown with the most recent common ancestor (MRCA) at each node. Posterior probability values are shown beneath MRCA estimates in years. Scale is in substitutions/site based on an analysis performed by Dr. Serena Carroll, Centers for Disease Control and Prevention. BDBV, Bundibugyo virus; EBOV, Ebola virus; LLOV, Lloviu virus; MARV, Marburg virus; RAVV, Ravn virus; RESTV, Reston virus; SUDV, Sudan virus; TAFV, Taï Forest virus.


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InternalMed_Harrison. To date (i.e., as of December 3, 2014), a total of 20,012 human filovirus infections and 8058 fatalities have been recorded (Fig. 234-3). These numbers emphasize both the high degree of lethality (number of deaths per number of sick people; 40.3%) and the overall low mortality (impact on healthy population) of filovirus infections. At least for the moment, natural filovirus infections do not FIGuRE 234-2 Ebola virus particle: the first transmission electron micrograph of an Ebola virion in a culture of Vero cells inoculated with a blood sample from a patient from the 1976 Zaire outbreak of Ebola virus disease. Shown is the typical and unique filamentous and pleomorphic structure of filovirions. (PHIL ID#1833, taken by Dr. Fredrick


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InternalMed_Harrison. A. Murphy, Centers for Disease Control and Prevention.) pose a global threat. Filoviruses pathogenic for humans appear to be exclusively endemic to Equatorial Africa, although this distribution may change if natural or artificial environmental alterations lead to filovirus host migration and increased contacts between nonhuman hosts and humans (Fig. 234-4). The majority of recorded EVD and MVD outbreaks can be traced back to single index cases who transmitted the infection to others. These chains of contacts suggest that only around 50 natural host-to-human spillover events have occurred since the discovery of filoviruses in 1967. Outbreak frequency, case numbers, and overall lethality probably depend on the particular etiologic agent, the geographic location and socioeconomic conditions of the affected country, and local customs. In particular, the availability of personal protective gear and reusable medical equipment, such as syringes and needles, has affected overall case numbers


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InternalMed_Harrison. of the affected country, and local customs. In particular, the availability of personal protective gear and reusable medical equipment, such as syringes and needles, has affected overall case numbers in the past, and outbreaks have been contained when local burial practices, such as ritual washing, have been either prevented or altered by the use of gloves. The incidence of EVD and MVD may have increased over the past two decades (Figs. 234-3 and 234-4), but researchers debate whether the observed change is due to increased filovirus activity, more frequent contact between filovirus hosts and humans, or continuous improvement in surveillance capabilities.


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InternalMed_Harrison. EVD and MVD outbreaks are associated with distinct meteorologic and geographic conditions and are probably associated with distinct hosts or reservoirs. The four ebolaviruses that cause disease in humans are endemic in humid rainforests. EVD outbreaks have often been linked to hunting or contact with bush meat (i.e., meat from apes, other nonhuman primates, duikers, or bush pigs) in forests. Ecologic studies indicate that EBOV may be the etiologic agent of extensive and frequently fatal epizootics among wild chimpanzee and gorilla populations. However, replicating isolates of ebolaviruses from wild nonhuman primates have thus far been obtained only in the case of TAFV, which was isolated from a succumbed western chimpanzee in Côte d’Ivoire in 1994. The marburgviruses MARV and RAVV, on the other hand, seem to infect hosts inhabiting arid woodlands. MVD outbreaks have almost always been epidemiologically linked to visits to or work in natural or artificial caves or mines. A pteropid


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InternalMed_Harrison. the other hand, seem to infect hosts inhabiting arid woodlands. MVD outbreaks have almost always been epidemiologically linked to visits to or work in natural or artificial caves or mines. A pteropid (fruit) bat, the cave-dwelling Egyptian rousette (Rousettus aegyptiacus), serves as a natural and subclinically infected reservoir for both MARV and RAVV. Although bats are suspected to be the hosts for ebolaviruses as


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InternalMed_Harrison. FIGuRE 234-3 Characteristics of outbreaks of human filovirus disease. Six of eight known filoviruses have caused disease in humans in the past. Outbreaks are listed by virus in chronological order. Laboratory infections are shaded gray and italicized. Arrows indicate international case exportation. Total number of cases and total number of lethal cases are summarized in the middle column (2014 EBOV infections as of December 3). The lethality/case–fatality rate (black dots) for each outbreak is plotted on a 0–100% scale along with 99% confidence intervals (black horizontal lines). The overall case–fatality rate for disease caused by a particular virus is delineated by vertical bold-colored lines, with vertical bold-colored dashed lines indicating the corresponding 99% confidence intervals; the overall case–fatality rate for all ebolavirus infections, all marburgvirus infections, and all filovirus infections are shown by vertical gray bars. BDBV, Bundibugyo virus; COD, Democratic


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InternalMed_Harrison. the overall case–fatality rate for all ebolavirus infections, all marburgvirus infections, and all filovirus infections are shown by vertical gray bars. BDBV, Bundibugyo virus; COD, Democratic Republic of the Congo (formerly Zaire); COG, Republic of the Congo; EBOV, Ebola virus; MARV, Marburg virus; RAVV, Ravn virus; SUDV, Sudan virus; TAFV, Taï Forest virus; UK, United Kingdom; USSR, Union of Soviet Socialist Republics (today Russia).


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InternalMed_Harrison. FIGuRE 234-4 Geographic distribution of human filovirus disease outbreaks and years of occurrence. Arrows indicate international case exportation. BDBV, Bundibugyo virus; COD, Democratic Republic of the Congo (formerly Zaire); COG, Republic of the Congo; EBOV, Ebola virus; MARV, Marburg virus; RAVV, Ravn virus; SUDV, Sudan virus; TAFV, Taï Forest virus. well, definitive proof is still lacking. In fact, thus far, only EBOV and RESTV have been loosely connected to frugivorous and insectivorous bats by means of antibody or genome fragment detection, whereas the hosts of BDBV, SUDV, and TAFV remain unclear.


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InternalMed_Harrison. Human infections typically occur through direct exposure of skin lesions or mucosal surfaces to contaminated bodily fluids or material or by parenteral inoculation (e.g., via accidental needlesticks or reuse of needles in poorly equipped hospitals). Numerous studies, both in vitro and in vivo (in several animal models of human disease), have shed light on key pathogenetic events that evolve subsequent to filovirion exposure. The GP1,2 spikes on the surface of filovirions determine their cell and tissue tropism by engaging yet-unidentified cell-surface molecules and the intracellular receptor Niemann-Pick C1. One of the pathogenetic hallmarks of filovirus infection is a pronounced suppression of the immune system. The first targets of filovirions are local macrophages, monocytes, and dendritic cells.


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InternalMed_Harrison. Several structural proteins of filovirions, in particular VP35, VP40, and VP24, then suppress cellular innate immune responses by, for instance, inhibiting the interferon pathway and thereby enabling a productive filovirus infection. The result is the secretion of copious numbers of progeny virions, as evidenced by high titers in the bloodstream (>106 plaque-forming units [pfu]/mL of serum in humans) and the lymphatics, and dissemination to most tissues. Filovirions then infect additional phagocytic cells, such as other macrophages (alveolar, peritoneal, pleural), Kupffer cells in the liver, and microglia, as well as other targets, such as adrenal cortical cells, fibroblasts, hepatocytes, endothelial cells, and a variety of epithelial cells. Infection leads to the secretion of soluble signaling molecules (varying with the cell type) that most likely are crucial factors in immune response modulation and development of multiorgan dysfunction syndrome. For instance, infected macrophages


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InternalMed_Harrison. molecules (varying with the cell type) that most likely are crucial factors in immune response modulation and development of multiorgan dysfunction syndrome. For instance, infected macrophages react by secreting proinflammatory cytokines, a response that leads to further recruitment of macrophages to the site of infection. In contrast, infected dendritic cells are not activated to secrete cytokines, and expression of major histocompatibility class II antigens is partially suppressed. Immunosuppression occurs in part by massive lymphoid depletion in lymph nodes, spleen, and thymus in the absence of reactive inflammatory cellular responses. Results from animal studies suggest that depletion is a direct consequence of considerable bystander apoptosis of lymphocytes; this explanation would also account for the severe lymphopenia that develops in patients. The consequence of these events is not only florid filovirus dissemination but also a proclivity of the patient for secondary bacterial


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InternalMed_Harrison. account for the severe lymphopenia that develops in patients. The consequence of these events is not only florid filovirus dissemination but also a proclivity of the patient for secondary bacterial and fungal infections.


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InternalMed_Harrison. Other pathogenetic hallmarks of filovirus infections are a severe disturbance of the clotting system and the impairment of vascular integrity. Disseminated intravascular coagulation is the cause of the severe imbalance in the clotting system of filovirus-infected patients. Thrombocytopenia, increased concentrations of tissue factor, consumption of clotting factors, increased concentrations of fibrin degradation products (d-dimers), and declining concentrations of protein C are typical features of infection. Consequently, the occlusion of small vessels by widely distributed microthrombi leads to extensive necroses/hypoxic infarcts in target tissues (particularly the gonads, kidneys, liver, and spleen) in the absence of marked inflammatory 1327 responses. In addition, petechiae, ecchymoses, extensive visceral effusions, and other hemorrhagic signs are observed in internal organs, mucous membranes, and skin. Actual severe blood loss, however, is a rare event. Aberrance in cytokines or


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InternalMed_Harrison. extensive visceral effusions, and other hemorrhagic signs are observed in internal organs, mucous membranes, and skin. Actual severe blood loss, however, is a rare event. Aberrance in cytokines or other factors such as nitric oxide and direct infection and activation of endothelial cells most likely are responsible for upregulated permeability of the endothelia of blood vessels. This upregulation leads to fluid redistribution (third spacing); interstitial and myocardial edema and hypovolemic shock are common developments. Clinical improvement is rare and is usually characterized by falling viral titers during the development of a virus-specific immune response.


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InternalMed_Harrison. MVD and EVD cannot be differentiated by mere observation of clinical manifestations. The incidence of clinical signs does not differ significantly among infections caused by disparate filoviruses (Table 234-2). The incubation period ranges from 3 to 25 days, after which infected people develop a biphasic syndrome with a 1to 2-day Abbreviations: BDBV, Bundibugyo virus; EBOV, Ebola virus; MARV, Marburg virus; NR, not reported.


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InternalMed_Harrison. 1328 relative remission separating the two phases. The first phase (disease onset until around day 5–7) resembles influenza and is characterized by sudden onset of fever and chills, severe headaches, cough, myalgia, pharyngitis, arthralgia of the larger joints, development of a maculopapular rash, and other signs/symptoms (Table 234-2). The second phase (approximately 5–7 days after disease onset and thereafter) involves the gastrointestinal tract (abdominal pain with vomiting and/ or diarrhea), respiratory tract (chest pain, cough), vascular system (postural hypotension, edema), and central nervous system (confusion, coma, headache). Hemorrhagic manifestations such as subconjunctival injection, nosebleeds, hematemesis, hematuria, and melena are typical (Table 234-2). Typical laboratory findings are leukopenia (with cell counts as low as 1000/μL) with a left shift prior to leukocytosis, thrombocytopenia (with counts as low as 50,000/μL), increased concentrations of liver and


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InternalMed_Harrison. findings are leukopenia (with cell counts as low as 1000/μL) with a left shift prior to leukocytosis, thrombocytopenia (with counts as low as 50,000/μL), increased concentrations of liver and pancreatic enzymes (aspartate aminotransferase > alanine aminotransferase, γ-glutamyltransferase, serum amylase), hypokalemia, hypoproteinemia, increased creatinine and urea concentrations with proteinuria, and prolonged prothrombin and partial thromboplastin times. Patients usually succumb to disease 4–14 days after infection. Patients who survive experience prolonged and sometimes incapacitating sequelae such as arthralgia, asthenia, iridocyclitis, hearing loss, myalgia, orchitis, parotitis, psychosis, recurrent hepatitis, transverse myelitis, or uveitis. Temporary hair loss and desquamation of skin areas previously affected by a typical maculopapular rash are visible consequences of the disease. Rarely, filoviruses can persist in the liver, eyes, or testicles of survivors and may cause


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InternalMed_Harrison. of skin areas previously affected by a typical maculopapular rash are visible consequences of the disease. Rarely, filoviruses can persist in the liver, eyes, or testicles of survivors and may cause recurrent disease months after convalescence.


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InternalMed_Harrison. Filovirus infections cannot be diagnosed on the basis of clinical presentation alone. Numerous diseases typical for Equatorial Africa need to be considered in the differential diagnosis of a febrile patient. Almost all of these diseases occur at a much higher incidence than filovirus infections and are therefore the more likely candidates during differential diagnostic deliberations. The most important of the infectious diseases that closely mimic EVD and MVD are falciparum malaria and typhoid fever; also important are enterohemorrhagic Escherichia coli enteritis, gram-negative septicemia (including shigellosis), meningococcal septicemia, rickettsial infections, fulminant viral hepatitis, leptospirosis, measles, and all other viral hemorrhagic fevers (in particular, yellow fever). Other ailments, such as venomous snakebites, warfarin intoxication, and the many transient or inherited platelet and vascular disorders, also must be considered. Visits to caves or mines and direct contact


InternalMed_Harrison

InternalMed_Harrison. ailments, such as venomous snakebites, warfarin intoxication, and the many transient or inherited platelet and vascular disorders, also must be considered. Visits to caves or mines and direct contact with bats, nonhuman primates (especially apes), or bush meat should raise suspicion of filovirus infection, as should admission to or treatment in rural hospitals or direct contact with severely ill local residents.


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InternalMed_Harrison. If EVD or MVD is suspected on the basis of epidemiologic history, exposure history, and/or clinical manifestations, infectious disease specialists and the proper public health authorities, including the WHO, should be notified immediately. Laboratory diagnosis of EVD and MVD is relatively straightforward but requires maximal containment (biosafety level 4), which usually is not available in filovirus-endemic countries, or the involvement of on-site personnel trained in the use of diagnostic assays adapted for field use. Consequently, diagnostic samples should be collected with great caution and with use of proper personal protective equipment and strict barrier nursing techniques. With adherence to established biosafety precautionary measures, samples should be sent in suitable transport media to national or international WHO reference laboratories. Acute-phase blood/serum is the preferred diagnostic specimen because it usually contains high titers of filovirions and


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InternalMed_Harrison. transport media to national or international WHO reference laboratories. Acute-phase blood/serum is the preferred diagnostic specimen because it usually contains high titers of filovirions and filovirion-specific antibodies.


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InternalMed_Harrison. The current methods of choice for the diagnosis of filovirus infection are reverse-transcription polymerase chain reaction (detection limit, 1000–2000 virus genome copies per milliliter of serum) and antigen capture enzyme-linked immunosorbent assay (ELISA) for the detection of filovirus genomes and filovirion components, respectively. Direct IgM and IgG or IgM capture ELISA is used for the detection of filovirion-targeting antibodies from patients in later stages of disease—i.e., those who have been able to mount a detectable immune response, including survivors. All these assays can be conducted on samples treated with guanidinium isothiocyanate (for polymerase chain reaction) or cobalt-60 irradiation (for ELISA) or subjected to other effective measures that render filoviruses noninfectious. Virus isolation in cell culture and plaque assays for quantification or diagnostic confirmation is relatively easy but must be performed in maximal-containment laboratories. If available,


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InternalMed_Harrison. Virus isolation in cell culture and plaque assays for quantification or diagnostic confirmation is relatively easy but must be performed in maximal-containment laboratories. If available, electron microscopic examination of properly inactivated samples or cultures can confirm the diagnosis because filovirions have unique filamentous shapes (Fig. 234-2). Formalin-fixed skin biopsies can be useful for safe postmortem diagnoses.


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InternalMed_Harrison. Any treatment of patients with suspected or confirmed filovirus infection must be administered under increased safety precautions by experienced specialists using appropriate personal protective equipment (see “Prevention,” below). Treatment of EVD and MVD is entirely supportive because no accepted/approved, efficacious, specific antiviral agents or vaccines are yet available. The one exception is hyperimmune equine immunoglobulin, which has been approved in Russia—in the absence of convincing efficacy data—for emergency treatment of laboratory infections. Given the extraordinarily high lethality of filoviruses, special protocols may be established by ad hoc expert groups to outline treatment of exposed individuals with one of several regimens that have shown promise in experimental nonhuman primates. Current options include postexposure vaccination with filovirus GP1,2-expressing recombinant replicating vesicular stomatitis Indiana virus; administration of specific filovirus genomeor


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InternalMed_Harrison. primates. Current options include postexposure vaccination with filovirus GP1,2-expressing recombinant replicating vesicular stomatitis Indiana virus; administration of specific filovirus genomeor transcript-targeting small interfering RNAs or phosphorodiamidate morpholino oligomers; administration of filovirusspecific antibodies or antibody cocktails (convalescent sera have not yet been proven effective); and use of a synthetic adenosine analog (BCX4430) that acts as a non-obligate RNA chain terminator. In the absence of these candidate treatments, measures to stabilize patients include those generally recommended for severe septicemia/sepsis/shock. Countermeasures should address hypotension and hypoperfusion, vascular leakage in the systemic and pulmonary circulatory system, disseminated intravascular coagulation and overt hemorrhaging, acute kidney failure, and electrolyte (especially potassium) imbalances. Pain management and administration of antipyretics and antiemetics should


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InternalMed_Harrison. intravascular coagulation and overt hemorrhaging, acute kidney failure, and electrolyte (especially potassium) imbalances. Pain management and administration of antipyretics and antiemetics should always be considered.


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InternalMed_Harrison. Given the severe immunosuppression induced by filovirus infection, secondary infections should be kept in mind and appropriately treated as early as possible. Pregnancy and labor cause severe and frequently fatal complications in filovirus infections due to clotting factor consumption, fetal loss, and/or severe blood loss during birth. The prognosis of filovirus infections is generally poor, although outcome probably depends somewhat on which particular virus causes the infection (Fig. 234-3). Convalescence may take months, with skin peeling, alopecia, prostration, weight loss, orchitis, amnesia, confusion, and anxiety as typical sequelae. Rarely, filoviruses persist in apparently healthy survivors and are either reactivated by unknown means at a later point or transmitted sexually. Condom use or abstinence from sexual activity for at least 3 months after disappearance of clinical signs is therefore recommended for survivors.


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InternalMed_Harrison. Currently, filovirus vaccines are not available. Prevention of filovirus infection in nature is difficult because the ecology of the viruses is not completely understood. As stated above, frugivorous cave-dwelling diagnosis and Treatment of Fungal Infections John E. Edwards, Jr. TERMINOLOGY AND MICROBIOLOGY Traditionally, fungal infections have been classified into specific cat-235 sECTIOn 16 FungAL InFECTIOns


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InternalMed_Harrison. Diagnosis and Treatment of Fungal Infections pteropid bats (Egyptian rousettes) have been identified as healthy carriers of MARV and RAVV. Avoidance of direct or indirect contact with these bats is therefore useful advice to people entering or living in areas where the animals can be found. Prevention seems to be more difficult in the case of ebolaviruses, for which definite reservoirs have not yet been pinpointed. EVD outbreaks have been associated not with bats but rather with hunting or consumption of nonhuman primates. The mechanism of introduction of ebolaviruses into nonhuman primate populations is unclear. Therefore, the best advice to locals and travelers is to avoid contact with bush meat, nonhuman primates, and bats.


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InternalMed_Harrison. Relatively simple barrier nursing techniques, vigilant use of proper personal protective equipment, and quarantine measures usually suffice to terminate or at least contain filovirus disease outbreaks. Isolation of filovirus-infected people and avoidance of direct person-to-person contact without proper personal protective equipment usually suffice to prevent further spread as the pathogens are not 1329 transmitted through droplets or aerosols under natural conditions. Typical protective gear sufficient to prevent filovirus infections consists of disposable gloves, gowns, and shoe covers and a face shield and/or goggles. If available, N-95/N-100 respirators may be used to further limit infection risk. Positive air pressure respirators should be considered for high-risk medical procedures such as intubation or suctioning. Medical equipment used in the care of a filovirus-infected patient, such as gloves or syringes, should never be reused unless safety-tested sterilization or


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InternalMed_Harrison. such as intubation or suctioning. Medical equipment used in the care of a filovirus-infected patient, such as gloves or syringes, should never be reused unless safety-tested sterilization or disinfection methods are properly applied. Because filovirions are enveloped, disinfection with detergents, such as 1% sodium deoxycholate, diethyl ether, or phenolic compounds, is relatively straightforward. Bleach solutions of 1:100 and 1:10 are recommended for surface disinfection and application to excreta/corpses, respectively. Whenever possible, potentially contaminated materials should be autoclaved, irradiated, or destroyed.


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InternalMed_Harrison. egories based on both anatomic location and epidemiology. The most common general anatomic categories are mucocutaneous and deep organ infection; the most common general epidemiologic categories are endemic and opportunistic infection. Although mucocutaneous infections can cause serious morbidity, they are rarely fatal. Deep organ infections also cause severe illness in many cases and, in contrast to mucocutaneous infections, are often fatal. The endemic mycoses (e.g., coccidioidomycosis) are caused by fungal organisms that are not part of the normal human microbiota but rather are acquired from environmental sources. In contrast, opportunistic mycoses are caused by organisms (e.g., Candida and Aspergillus) that commonly are components of the normal human microbiota and whose ubiquity in nature renders them easily acquired by the immunocompromised host (Table 235-1). Opportunistic fungi cause serious infections when the immunologic response of the host becomes ineffective, allowing


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InternalMed_Harrison. nature renders them easily acquired by the immunocompromised host (Table 235-1). Opportunistic fungi cause serious infections when the immunologic response of the host becomes ineffective, allowing the organisms to transition from harmless commensals to invasive pathogens. Frequently, the diminished effectiveness of the immune system is a result of advanced modern therapies that coincidentally either cause an imbalance in the host’s microbiota or directly interfere with immunologic responses. Endemic mycoses cause more severe


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InternalMed_Harrison. Pneumocystosis aThe endemic mycoses can also occur as opportunistic infections. illness in immunocompromised patients than in immunocompetent individuals.


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InternalMed_Harrison. illness in immunocompromised patients than in immunocompetent individuals. Patients acquire deep organ infection with endemic fungi almost exclusively by inhalation. Cutaneous infections result either from hematogenous dissemination or, more often, from direct contact with soil—the natural reservoir for the vast majority of endemic mycoses. The dermatophytic fungi may be acquired by human-to-human transmission, but the majority of infections result from environmental contact. In contrast, the opportunistic fungus Candida invades the host from normal sites of colonization, usually the mucous membranes of the gastrointestinal tract. In general, innate immunity is the primary defense mechanism against fungi. Although antibodies are formed during many fungal infections (and even during commensalism), they generally do not constitute the primary mode of host defense. Nevertheless, in selected infections, as discussed below, measurement of antibody titers may be a useful diagnostic test.


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InternalMed_Harrison. Three other terms frequently used in clinical discussions of fungal infections are yeast, mold, and dimorphic fungus. Yeasts are seen as rounded single cells or as budding organisms. Candida and Cryptococcus are traditionally classified as yeasts. Molds grow as filamentous forms called hyphae both at room temperature and in invaded tissue. Aspergillus, Rhizopus (the genus that causes mucormycosis, also known as zygomycosis), and fungi commonly infecting the skin to cause ringworm and related cutaneous conditions are classified as molds. Variations occur within this classification of yeasts and molds. For instance, when Candida infects tissue, both yeasts and filamentous forms may be present (except with C. glabrata, which forms only yeasts in tissue); in contrast, Cryptococcus exists only in yeast form. Dimorphic is the term used to describe fungi that grow as yeasts or large spherical structures in tissue but as filamentous forms at room temperature in the environment. Classified in


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InternalMed_Harrison. in yeast form. Dimorphic is the term used to describe fungi that grow as yeasts or large spherical structures in tissue but as filamentous forms at room temperature in the environment. Classified in this group are the organisms causing blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, and sporotrichosis.


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InternalMed_Harrison. The incidence of nearly all fungal infections has risen substantially. Opportunistic infections have increased in frequency as a consequence of intentional immunosuppression in organ and stem cell transplantation and other disorders, the administration of cytotoxic chemotherapy for cancers, the liberal use of antibacterial agents, and, more recently, the increasing use of monoclonal antibodies. Within a global context, the incidence of endemic mycoses has stantial population growth. When advances in medical care (e.g., more aggressive treatment of cancer or organ transplantation) are introduced into a given area, the opportunistic mycoses increase in incidence.


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InternalMed_Harrison. 1330 DIAGNOSIS The definitive diagnosis of any fungal infection requires histopathologic identification of the fungus invading tissue and accompanying evidence of an inflammatory response. The identification of an inflammatory response has been especially important with regard to Aspergillus infection. Aspergillus is ubiquitous and can float in the air onto biopsy material. Therefore, in rare but important instances, this fungus is an ex vivo contaminant during processing of a specimen for microscopy, with a consequent incorrect diagnosis. The stains most commonly used to identify fungi are periodic acid–Schiff and Gomori methenamine silver. Candida, unlike other fungi, is visible on gram-stained tissue smears. Hematoxylin and eosin stain is not sufficient to identify Candida in tissue specimens. When positive, an india ink preparation of cerebrospinal fluid (CSF) is diagnostic for cryptococcosis. Most laboratories now use calcofluor white staining coupled with fluorescent microscopy


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InternalMed_Harrison. When positive, an india ink preparation of cerebrospinal fluid (CSF) is diagnostic for cryptococcosis. Most laboratories now use calcofluor white staining coupled with fluorescent microscopy to identify fungi in fluid specimens. Extensive investigations of the diagnosis of deep organ fungal infections have yielded a variety of tests with different degrees of specificity and sensitivity. The most reliable tests are the detection of antibody to Coccidioides immitis in serum and CSF; of Histoplasma capsulatum antigen in urine, serum, and CSF; and of cryptococcal polysaccharide antigen in serum and CSF. These tests have a general sensitivity and specificity of 90%; however, because of variability among laboratories, testing on multiple occasions is advisable. The test for galactomannan has been used extensively in Europe and is now approved in the United States for diagnosis of aspergillosis. Sources of concern regarding galactomannan are the incidence of false-negative results and the


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InternalMed_Harrison. been used extensively in Europe and is now approved in the United States for diagnosis of aspergillosis. Sources of concern regarding galactomannan are the incidence of false-negative results and the need for multiple serial tests to reduce this incidence. The β-glucan test for Candida is also under evaluation but, like the galactomannan test, still requires additional validation; this test has a negative predictive value of ~90%. Both of these tests are being used with increasing frequency, especially for guiding the timing of initiation and duration of therapy. The galactomannan test is being evaluated in both serum and bronchoalveolar lavage fluid. Numerous polymerase chain reaction assays to detect antigens are in the developmental stages, as are nucleic acid hybridization techniques; currently, these tests are not widely available. Of the fungal organisms, Candida is by far the most frequently recovered from blood. Although Candida species can be detected with any of the


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InternalMed_Harrison. currently, these tests are not widely available. Of the fungal organisms, Candida is by far the most frequently recovered from blood. Although Candida species can be detected with any of the automated blood culture systems widely used at present, the lysis-centrifugation technique increases the sensitivity of blood cultures for Candida and for less common organisms (e.g., H. capsulatum). Lysis-centrifugation should be used when disseminated fungal infection is suspected. Except in the cases of coccidioidomycosis, cryptococcosis, and histoplasmosis, there are no fully validated and widely used tests for serodiagnosis of disseminated fungal infection. Skin tests for the endemic mycoses are no longer available.


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InternalMed_Harrison. This discussion is intended as a brief overview of general strategies for the use of antifungal agents in the treatment of fungal infections. Regimens, schedules, and strategies are detailed in the chapters on specific mycoses that follow in this section. The doses cited here are standard doses for adults with invasive infection. Since fungal organisms are eukaryotic cells that contain most of the same organelles (with many of the same physiologic functions) as human cells, the identification of drugs that selectively kill or inhibit fungi but are not toxic to human cells has been highly problematic. Far fewer antifungal than antibacterial agents have been introduced into clinical medicine.


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InternalMed_Harrison. The introduction of amphotericin B (AmB) in the late 1950s revolutionized the treatment of fungal infections in deep organs. Before AmB became available, cryptococcal meningitis and other disseminated fungal infections were nearly always fatal. For nearly a decade after AmB was introduced, it was the only effective agent for the treatment of life-threatening fungal infections. AmB remains the broadest-spectrum antifungal agent but carries several disadvantages, including significant nephrotoxicity, lack of an oral preparation, and unpleasant side effects (fever, chills, and nausea) during treatment. To circumvent nephrotoxicity and infusion side effects, lipid formulations of AmB were developed and have virtually replaced the original colloidal deoxycholate formulation in clinical use (although the older formulation is still available). The lipid formulations include liposomal AmB (L-AmB; 3–5 mg/kg per day) and AmB lipid complex (ABLC; 5 mg/kg per day). A third preparation, AmB


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InternalMed_Harrison. (although the older formulation is still available). The lipid formulations include liposomal AmB (L-AmB; 3–5 mg/kg per day) and AmB lipid complex (ABLC; 5 mg/kg per day). A third preparation, AmB colloidal dispersion (ABCD; 3–4 mg/kg per day), is rarely used because of the high incidence of side effects associated with infusion.


InternalMed_Harrison

InternalMed_Harrison. The lipid formulations of AmB have the disadvantage of being considerably more expensive than the deoxycholate formulation. Experience is still accumulating on the comparative efficacy, toxicity, and advantages of the different formulations for specific clinical fungal infections, including central nervous system (CNS) infection. Whether there is a clinically significant difference in these drugs with respect to CNS penetration or nephrotoxicity remains controversial. Despite these issues and despite the expense, the lipid formulations are now much more commonly used than AmB deoxycholate in developed countries. In developing countries, AmB deoxycholate is still preferred because of the expense of the lipid formulations.


InternalMed_Harrison

InternalMed_Harrison. This class of antifungal drugs offers important advantages over AmB: the azoles cause little or no nephrotoxicity and are available in oral formulations. Early azoles included ketoconazole and miconazole, which have been replaced by newer agents for the treatment of deep organ fungal infections. The azoles’ mechanism of action is inhibition of ergosterol synthesis in the fungal cell wall. Unlike AmB, these drugs are considered fungistatic, not fungicidal.


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InternalMed_Harrison. Fluconazole Since its introduction, fluconazole has played an extremely important role in the treatment of a wide variety of serious fungal infections. Its major advantages are the availability of both oral and IV formulations, a long half-life, satisfactory penetration of most body fluids (including ocular fluid and CSF), and minimal toxicity (especially relative to that of AmB). Its disadvantages include (usually reversible) hepatotoxicity and—at high doses—alopecia, muscle weakness, and dry mouth with a metallic taste. Fluconazole is not effective for the treatment of aspergillosis, mucormycosis, or Scedosporium apiospermum infections. It is less effective than the newer azoles against Candida glabrata and Candida krusei.


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InternalMed_Harrison. Fluconazole has become the agent of choice for the treatment of coccidioidal meningitis, although relapses have followed therapy with this drug. In addition, fluconazole is useful as both consolidation and maintenance therapy for cryptococcal meningitis. This agent has been shown to be as efficacious as AmB in the treatment of candidemia. The effectiveness of fluconazole in candidemia and the drug’s relatively minimal toxicity, in conjunction with the inadequacy of diagnostic tests for widespread hematogenously disseminated candidiasis, have led to a change in the paradigm for candidemia management. The standard of care is now to treat all candidemic patients with an antifungal agent and to change all their intravascular lines, if feasible, rather than merely removing a singular suspect intravascular line and then observing the patient. The usual fluconazole regimen for treatment of candidemia is 400 mg/d given until 2 weeks after the last positive blood culture.


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InternalMed_Harrison. Fluconazole is considered effective as fungal prophylaxis in bone marrow transplant recipients and high-risk liver transplant patients. Its general use for prophylaxis in patients with leukemia, in AIDS patients with low CD4+ T cell counts, and in patients on surgical intensive care units remains controversial. Because of concerns about the possibility of infection due to resistant Candida species and of infection with Aspergillus species, many clinicians are initiating therapy with an echinocandin, which is then replaced by fluconazole once a susceptible Candida species is recovered and concern about Aspergillus is diminished.


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InternalMed_Harrison. Voriconazole Voriconazole, which is available in both oral and IV formulations, has a broader spectrum than fluconazole against Candida species (including C. glabrata and C. krusei) and is active against Aspergillus, Scedosporium, and Fusarium. It is generally considered the first-line drug of choice for treatment of aspergillosis. A few case reports have shown voriconazole to be effective in individual patients with coccidioidomycosis, blastomycosis, and histoplasmosis, but because of limited data this agent is not recommended for primary treatment of the endemic mycoses. Among the disadvantages of voriconazole (compared with fluconazole) are its more numerous interactions with many of the drugs used in patients predisposed to fungal infections. Hepatotoxicity, skin rashes (including photosensitivity), and visual disturbances are relatively common. Skin cancer surveillance is now recommended for patients taking voriconazole. In addition, voriconazole is considerably more expensive


InternalMed_Harrison

InternalMed_Harrison. and visual disturbances are relatively common. Skin cancer surveillance is now recommended for patients taking voriconazole. In addition, voriconazole is considerably more expensive than fluconazole. Moreover, it is advisable to monitor voriconazole levels in certain patients since (1) this drug is completely metabolized in the liver by CYP2C9, CYP3A4, and CYP2C19; and (2) human genetic variability in CYP2C19 activity exists. Dosages should be reduced accordingly in patients with liver failure. Dose adjustments for renal insufficiency are not necessary; however, because the IV formulation is prepared in cyclodextrin, it should not be given to patients with severe renal insufficiency.


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InternalMed_Harrison. Itraconazole Itraconazole is available in IV and oral (capsule and suspension) formulations. Varying blood levels among patients taking oral itraconazole reflect a disadvantage compared with the other azoles. Itraconazole is the drug of choice for mild to moderate histoplasmosis and blastomycosis and has often been used for chronic mucocutaneous candidiasis. It has been approved by the


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InternalMed_Harrison. U.S. Food and Drug Administration (FDA) for use in febrile neutropenic patients. Itraconazole has also proved useful for the treatment of chronic coccidioidomycosis, sporotrichosis, and S. apiospermum infection. The mucocutaneous and cutaneous fungal infections that have been treated successfully with itraconazole include oropharyngeal candidiasis (especially in AIDS patients), tinea versicolor, tinea capitis, and onychomycosis. Disadvantages of itraconazole include its poor penetration into CSF, the use of cyclodextrin in both the oral suspension and the IV formulation, the variable absorption of the drug in capsule form, and the need for monitoring of blood levels in patients taking capsules for disseminated mycoses. Reported cases of severe congestive heart failure in patients taking itraconazole have been a source of concern. Like the other azoles, itraconazole can cause hepatic toxicity.


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InternalMed_Harrison. Posaconazole Posaconazole is approved by the FDA for prophylaxis of aspergillosis and candidiasis in patients at high risk for developing these infections because of severe immunocompromise. It has also been approved for the treatment of oropharyngeal candidiasis and has been evaluated as therapy for zygomycosis, fusariosis, aspergillosis, cryptococcosis, and various other forms of candidal infection. The relevant studies of posaconazole in zygomycosis, fusariosis, and aspergillosis have examined salvage therapy. A study of more than 90 patients whose zygomycosis was refractory to other therapy yielded encouraging results. No trials of posaconazole for the treatment of candidemia have yet been reported. Case reports have described the drug’s efficacy in coccidioidomycosis and histoplasmosis. Controlled trials have shown its effectiveness as a prophylactic agent in patients with acute leukemia and in bone marrow transplant recipients. In addition, posaconazole has been found to be


InternalMed_Harrison

InternalMed_Harrison. Controlled trials have shown its effectiveness as a prophylactic agent in patients with acute leukemia and in bone marrow transplant recipients. In addition, posaconazole has been found to be effective against fluconazole-resistant Candida species. The results of a large-scale study of the use of posaconazole as salvage therapy for aspergillosis indicated that it is an alternative to other agents for salvage therapy; however, that study predated the use of voriconazole and the echinocandins.


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InternalMed_Harrison. The echinocandins, including the FDA-approved drugs caspofungin, anidulafungin, and micafungin, have added considerably to the antifungal armamentarium. All three of these agents inhibit β-1,3-glucan synthase, which is necessary for cell wall synthesis in 1331 fungi and is not a component of human cells. None of these agents is currently available in an oral formulation. The echinocandins are considered fungicidal for Candida and fungistatic for Aspergillus. Their greatest use to date is against candidal infections. They offer two advantages: broad-spectrum activity against all Candida species and relatively low toxicity. The minimal inhibitory concentrations (MICs) of all the echinocandins are highest against Candida parapsilosis; it is not clear whether these higher MIC values represent less clinical effectiveness against this species. The echinocandins are among the safest antifungal agents.


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InternalMed_Harrison. In controlled trials, caspofungin has been at least as efficacious as AmB for the treatment of candidemia and invasive candidiasis and as efficacious as fluconazole for the treatment of candidal esophagi-tis. In addition, caspofungin has been efficacious as salvage therapy for aspergillosis. Anidulafungin has been approved by the FDA as therapy for candidemia in nonneutropenic patients and for Candida esophagitis, intraabdominal infection, and peritonitis. In controlled trials, anidulafungin has been shown to be noninferior and possibly superior to fluconazole against candidemia and invasive candidiasis. It is as efficacious as fluconazole against candidal esophagitis. When anidulafungin is used with cyclosporine, tacrolimus, or voriconazole, no dosage adjustment is required for either drug in the combination. Micafungin has been approved for the treatment of esophageal candidiasis and candidemia and for prophylaxis in patients receiving stem cell transplants. In a head-to-head trial,


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InternalMed_Harrison. in the combination. Micafungin has been approved for the treatment of esophageal candidiasis and candidemia and for prophylaxis in patients receiving stem cell transplants. In a head-to-head trial, micafungin was noninferior to caspofungin for the treatment of candidemia. Studies thus far have shown that coadministration of micafungin and cyclosporine does not require dose adjustments for either drug. When micafungin is given with sirolimus, the area under the plasma drug concentration–time curve rises for sirolimus, usually necessitating a reduction in its dose. In open-label trials, favorable results have been obtained with micafungin for the treatment of deep-seated Aspergillus and Candida infections.


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InternalMed_Harrison. The use of flucytosine has diminished as newer antifungal drugs have been developed. This agent is now used most commonly in combination with AmB (deoxycholate or lipid formulations) for the initial treatment of cryptococcal meningitis. Flucytosine has a unique mechanism of action based on intrafungal conversion to 5-fluorouracil, which is toxic to the fungal cell. Development of resistance to the compound has limited its use as a single agent. Flucytosine is nearly always used in combination with AmB. Its good penetration into the CSF makes it attractive for use with AmB for treatment of cryptococcal meningitis. Flucytosine has also been recommended for the treatment of candidal meningitis in combination with AmB; comparative trials with AmB alone have not been done. Significant and frequent bone marrow depression is seen with flucytosine when this drug is used with AmB.


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InternalMed_Harrison. Historically, griseofulvin has been useful primarily for ringworm infection. This agent is usually given for relatively long periods. Terbinafine has been used primarily for onychomycosis but also for ringworm. In comparative studies, terbinafine has been as effective as itraconazole and more effective than griseofulvin for both conditions.


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InternalMed_Harrison. A detailed discussion of the agents used for the treatment of cutaneous fungal infections and onychomycosis is beyond the scope of this chapter; the reader is referred to the dermatology literature. Many classes of compounds have been used to treat the common fungal infections of the skin. Among the azoles used are clotrimazole, econazole, miconazole, oxiconazole, sulconazole, ketoconazole, tioconazole, butoconazole, and terconazole. In general, topical treatment of vaginal candidiasis has been successful. Since little difference is thought to exist in the efficacy of the various vaginal preparations, the choice of agent is made by the physician and/or


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InternalMed_Harrison. Diagnosis and Treatment of Fungal Infections 1332 the patient on the basis of preference and availability. Fluconazole given orally at 150 mg has the advantage of not requiring repeated intravaginal application. Nystatin is a polyene that has been used for both oropharyngeal thrush and vaginal candidiasis. Useful agents in other classes include ciclopirox olamine, haloprogin, terbinafine, naftifine, tolnaftate, and undecylenic acid. Histoplasmosis Chadi A. Hage, L. Joseph Wheat ETIOLOGY Histoplasma capsulatum, a thermal dimorphic fungus, is the etiologic agent of histoplasmosis. In most endemic areas, H. capsulatum var. capsulatum is the causative agent. In 236 Africa, H. capsulatum var. duboisii also is found; var. duboisii can be differentiated from var. capsulatum as the duboisii yeasts are larger. In Central and South America, histoplasmosis is common and is caused by clades of H. capsulatum var. capsulatum that differ genetically from those involved elsewhere.


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InternalMed_Harrison. Mycelia—the naturally infectious form of Histoplasma—have a characteristic appearance, with microconidial and macroconidial forms. Microconidia are oval and are small enough (2–4 μm) to reach the terminal bronchioles and alveoli. Shortly after infecting the host, mycelia transform into the yeasts that are found inside macrophages and other phagocytes. The yeast forms are characteristically small (2–5 μm), with occasional narrow budding. In the laboratory, mycelia are best grown at room temperature, whereas yeasts are grown at 37°C on enriched media. Histoplasmosis is the most prevalent endemic mycosis in


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InternalMed_Harrison. North America. Although this fungal disease has been reported throughout the world, its endemicity is particularly notable in certain parts of North, Central, and South America; Africa; and Asia. In Europe, histoplasmosis is diagnosed fairly often, mostly in emigrants from or travelers to endemic areas on other continents. In the United States, the endemic areas spread over the Ohio and Mississippi river valleys. This pattern is related to the humid and acidic nature of the soil in these areas. Soil enriched with bird or bat droppings promotes the growth and sporulation of Histoplasma. Disruption of soil containing the organism leads to aerosolization of the microconidia and exposure of humans nearby. Activities associated with high-level exposure include spelunking, excavation, cleaning of chicken coops, demolition and remodeling of old buildings, and cutting of dead trees. Most cases seen outside of highly endemic areas represent imported disease—e.g., cases reported in Europe after


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InternalMed_Harrison. chicken coops, demolition and remodeling of old buildings, and cutting of dead trees. Most cases seen outside of highly endemic areas represent imported disease—e.g., cases reported in Europe after travel to the Americas, Africa, or Asia.


InternalMed_Harrison

InternalMed_Harrison. Infection follows inhalation of microconidia (Fig. 236-1). Once they reach the alveolar spaces, microconidia are rapidly recognized and engulfed by alveolar macrophages. At this point, the microconidia transform into budding yeasts (Fig. 236-2), a process that is integral to the pathogenesis of histoplasmosis and is dependent on the availability of calcium and iron inside the phagocytes. The yeasts are capable of growing and multiplying inside resting macrophages. Neutrophils and then lymphocytes are attracted to the site of infection. Before the development of cellular immunity, yeasts use the phagosomes as a vehicle for translocation to local draining lymph nodes, whence they spread hematogenously throughout the reticuloendothelial system. Adequate cellular immunity develops ~2 weeks after infection. T cells produce interferon γ to assist the macrophages in killing the organism and controlling the progression of disease. Interleukin 12 and tumor necrosis factor α (TNF-α) play an


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InternalMed_Harrison. after infection. T cells produce interferon γ to assist the macrophages in killing the organism and controlling the progression of disease. Interleukin 12 and tumor necrosis factor α (TNF-α) play an essential role in cellular immunity to H. capsulatum. In the immunocompetent host, macrophages, lymphocytes, and epithelial cells eventually organize and form granulomas that contain the organisms. These granulomas typically fibrose and calcify; calcified mediastinal lymph nodes and hepatosplenic calcifications are frequently found in healthy individuals from endemic areas. In immunocompetent hosts, infection with H. capsulatum confers some immunity to reinfection. In patients with impaired cellular immunity, the infection is not contained and can disseminate. Progressive disseminated histoplasmosis (PDH) can involve multiple organs, most commonly the bone marrow, spleen, liver (Fig. 236-3), adrenal glands, and mucocutaneous membranes. Unlike latent tuberculosis, latent histoplasmosis


InternalMed_Harrison

InternalMed_Harrison. (PDH) can involve multiple organs, most commonly the bone marrow, spleen, liver (Fig. 236-3), adrenal glands, and mucocutaneous membranes. Unlike latent tuberculosis, latent histoplasmosis rarely reactivates.


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InternalMed_Harrison. FIGuRE 236-1 Spiked spherical conidia of H. capsulatum (lacto- phenol cotton blue stain). Structural lung disease (e.g., emphysema) impairs the clearance of pulmonary histoplasmosis, and chronic pulmonary disease can result. This chronic process is characterized by progressive inflammation, tissue necrosis, and fibrosis mimicking cavitary tuberculosis. FIGuRE 236-2 Small (2–5 μm) narrow budding yeasts of H. capsulatum from bronchoalveolar lavage fluid (Grocott’s methena-mine silver stain). FIGuRE 236-3 Intracellular yeasts (arrows) of H. capsulatum in a liver biopsy specimen (hematoxylin and eosin stain). The clinical spectrum of histoplasmosis ranges from asymptomatic infection to life-threatening illness. The attack rate and the extent and severity of the disease depend on the intensity of exposure, the immune status of the exposed individual, and the underlying lung architecture of the host.


InternalMed_Harrison

InternalMed_Harrison. In immunocompetent individuals with low-level exposure, most Histoplasma infections are either asymptomatic or mild and self-limited. Of adults residing in endemic areas, 50–80% have skin-test and/or radiographic evidence of previous infection without clinical manifestations. When symptoms do develop, they usually appear 1–4 weeks after exposure. Heavy exposure leads to a flulike illness with fever, chills, sweats, headache, myalgia, anorexia, cough, dyspnea, and chest pain. Chest radiographs usually show signs of pneumonitis with prominent hilar or mediastinal adenopathy. Pulmonary infiltrates may be focal with light exposure or diffuse with heavy exposure. Rheumatologic symptoms of arthralgia or arthritis, often associated with erythema nodosum, occur in 5–10% of patients with acute histoplasmosis. Pericarditis may also develop. These manifestations represent inflammatory responses to the acute infection rather than its direct effects. Hilar or mediastinal lymph nodes may undergo


InternalMed_Harrison

InternalMed_Harrison. Pericarditis may also develop. These manifestations represent inflammatory responses to the acute infection rather than its direct effects. Hilar or mediastinal lymph nodes may undergo necrosis and coalesce to form large mediastinal masses that can cause compression of great vessels, proximal airways, and the esophagus. These necrotic lymph nodes may also rupture and create fistulas between mediastinal structures (e.g., bronchoesophageal fistulas).


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InternalMed_Harrison. PDH is typically seen in immunocompromised individuals, who account for ~70% of cases. Common risk factors include AIDS (CD4+ T cell count, <200/μL), extremes of age, immunosuppressive medications administered for prevention or treatment of rejection following transplantation (e.g., prednisone, mycophenolate, calcineurin inhibitors, and biologic response modifiers), and methotrexate, anti-TNF-α agents, or other biologic response modifiers given for inflammatory arthritis or Crohn’s disease.


InternalMed_Harrison

InternalMed_Harrison. The spectrum of PDH ranges from an acute, rapidly fatal course— with diffuse interstitial or reticulonodular lung infiltrates causing respiratory failure, shock, coagulopathy, and multiorgan failure—to a more subacute course with a focal organ distribution. Common manifestations include fever and weight loss. Hepatosplenomegaly also is common. Other findings may include meningitis or focal brain lesions, ulcerations of the oral mucosa, gastrointestinal ulcerations, and adrenal insufficiency. Prompt recognition of this devastating illness is of paramount importance in patients with more severe manifestations or with underlying immunosuppression, especially AIDS (Chap. 226).


InternalMed_Harrison

InternalMed_Harrison. Chronic cavitary histoplasmosis is seen in smokers who have structural lung disease (e.g., bullous emphysema). This chronic illness is characterized by productive cough, dyspnea, low-grade fever, night sweats, and weight loss. Chest radiographs usually show upper-lobe infiltrates, cavitation, and pleural thickening—findings resembling those of tuber-1333 culosis. Without treatment, the course is slowly progressive. Fibrosing mediastinitis is an uncommon and serious complication of histoplasmosis. In certain patients, acute infection is followed for unknown reasons by progressive fibrosis around the hilar and mediastinal lymph nodes. Involvement may be unilateral or bilateral; bilateral involvement carries a worse prognosis. Major manifestations include superior vena cava syndrome, obstruction of pulmonary vessels, and airway obstruction. Patients may experience recurrent pneumonia, hemoptysis, or respiratory failure. Fibrosing mediastinitis is fatal in up to one-third of cases.


InternalMed_Harrison

InternalMed_Harrison. In healed histoplasmosis, calcified mediastinal nodes or lung parenchyma may erode through the walls of the airways and cause hemoptysis. This condition is called broncholithiasis. The clinical features and management of histoplasmosis caused by the genetically different clades in Central and South America are similar to those of the disease in North America. African histoplasmosis caused by var. duboisii is clinically distinct and is characterized by frequent skin and bone involvement.


InternalMed_Harrison

InternalMed_Harrison. America are similar to those of the disease in North America. African histoplasmosis caused by var. duboisii is clinically distinct and is characterized by frequent skin and bone involvement. Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, culture results may not be known for up to 1 month, and cultures are often negative in less severe cases. Cultures are positive in ~75% of cases of PDH and chronic pulmonary histoplasmosis. Cultures of bronchoalveolar lavage (BAL) fluid are positive in about half of cases that include acute pulmonary histoplasmosis causing diffuse infiltrates with hypoxemia. In PDH, the culture yield is highest for BAL fluid, bone marrow aspirate, and blood. Cultures of sputum or bronchial washings are usually positive in chronic pulmonary histoplasmosis. Cultures are typically negative, however, in other forms of histoplasmosis.


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InternalMed_Harrison. Fungal stains of cytopathology or biopsy materials showing structures resembling Histoplasma yeasts are helpful in the diagnosis of PDH, yielding positive results in about half of cases. Yeasts can be seen in BAL fluid (Fig. 236-2) from patients with diffuse pulmonary infiltrates, in bone marrow biopsy samples, and in biopsy specimens of other involved organs (e.g., the adrenal glands). Occasionally, yeasts are seen in blood smears from patients with severe PDH. However, artifacts and other fungal elements sometimes stain positive and may be misidentified as Histoplasma yeasts.


InternalMed_Harrison

InternalMed_Harrison. The detection of Histoplasma antigen in body fluids is extremely useful in the diagnosis of PDH and acute diffuse pulmonary histoplasmosis. The sensitivity of this technique is >95% in patients with PDH and >80% in patients with acute pulmonary histoplasmosis if both urine and serum are tested. Antigen level correlates with severity of illness in PDH and can be used to follow disease progression as levels predictably decrease with effective therapy. An increase in antigen levels also predicts relapse. Antigen can be detected in cerebrospinal fluid from patients with meningitis and in BAL fluid from those with pneumonia. Cross-reactivity occurs with African histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and Penicillium marneffei infection.


InternalMed_Harrison

InternalMed_Harrison. Serologic tests, including immunodiffusion and complement fixation, are useful for the diagnosis of histoplasmosis in immunocompetent patients. Serum antibody titers may rise fourfold in patients with acute histoplasmosis. Serologic tests are especially useful for the diagnosis of chronic pulmonary histoplasmosis. The limitations of serology, however, include insensitivity early in the course of infection (at least 1 month is required for the production of antibodies), insensitivity in immunosuppressed patients, and persistence of detectable antibody for several years after infection. Positive results from past infection may lead to a misdiagnosis of active histoplasmosis in a patient with another disease process. Treatment recommendations for histoplasmosis are summarized in Table 236-1. Treatment is indicated for all patients with PDH or chronic pulmonary histoplasmosis as well as for symptomatic Type of Treatment Histoplasmosis Recommendations Comments


InternalMed_Harrison

InternalMed_Harrison. Type of Treatment Histoplasmosis Recommendations Comments Abbreviation: AmB, amphotericin B. patients with acute pulmonary histoplasmosis causing diffuse infiltrates, especially with hypoxemia. In most cases of pulmonary histoplasmosis, treatment is not recommended because the degree of exposure is not heavy; the infection is asymptomatic or symptoms are mild, subacute, and not progressive; and the illness resolves without therapy. The preferred treatments for histoplasmosis include the lipid formulations of amphotericin B (AmB) in more severe cases and itraconazole in others. Liposomal AmB has been more effective than the deoxycholate formulation for treatment of PDH in patients with AIDS. The deoxycholate formulation is an alternative to lipid formulations for patients at low risk for nephrotoxicity. Posaconazole, voriconazole, and fluconazole are alternatives for patients who cannot take itraconazole.


InternalMed_Harrison

InternalMed_Harrison. In severe cases requiring hospitalization, a lipid formulation of AmB is followed by itraconazole. In patients with meningitis, a lipid formulation of AmB should be given for 4–6 weeks before the switch to itraconazole. In immunosuppressed patients, the degree of immunosuppression should be reduced if possible, although immune reconstitution inflammatory syndrome (IRIS) may ensue. Antiretroviral treatment improves the outcome of PDH in patients with AIDS and is recommended; however, whether antiretroviral treatment should be delayed to avoid IRIS is unknown.


InternalMed_Harrison

InternalMed_Harrison. Blood levels of itraconazole should be monitored to ensure adequate drug exposure, with target concentrations of the parent drug and its hydroxy metabolites of 1–5 μg/mL as measured by high-performance liquid chromatography and 2–10 μg/mL as measured by microbiologic assay. Drug interactions should be carefully assessed: itraconazole not only is cleared by cytochrome P450 metabolism but also inhibits cytochrome P450. This profile causes interactions with many other medications. The duration of treatment for acute pulmonary histoplasmosis is 6–12 weeks, while that for PDH and chronic pulmonary histoplasmosis is ≥1 year. Antigen levels in urine and serum should be monitored during and for at least 1 year after therapy for PDH. Stable or rising antigen levels suggest treatment failure or relapse.


InternalMed_Harrison

InternalMed_Harrison. Previously, lifelong itraconazole maintenance therapy was recommended for patients with AIDS once histoplasmosis was diagnosed. Today, however, maintenance therapy is not required for patients who respond well to antiretroviral therapy, with CD4+ T cell counts of at least 150/μL (preferably >250/μL); who complete at least 1 year of itraconazole therapy; and who exhibit neither clinical evidence of active histoplasmosis nor an antigenuria level of >4 ng/ mL. Maintenance therapy also appears to be unnecessary in patients receiving immunosuppressive treatment if the degree of immunosuppression can be reduced through an approach similar to that used for patients with AIDS.


InternalMed_Harrison

InternalMed_Harrison. Fibrosing mediastinitis, which represents a chronic fibrotic reaction to past mediastinal histoplasmosis rather than an active infection, does not respond to antifungal therapy. While treatment is often prescribed for patients with pulmonary histoplasmosis who have not recovered within 1 month and for those with persistent mediastinal lymphadenopathy, the effectiveness of antifungal therapy in these situations is unknown. Neil M. Ampel Coccidioidomycosis, commonly known as Valley fever (see “Epidemiology,” below), is caused by dimorphic soil-dwelling fungi of the genus Coccidioides. Genetic analysis has demonstrated the existence of two species, C. immitis and C. posadasii. These species are indistinguishable with regard to the clinical disease they cause and their appearance on routine laboratory media. Thus, the organisms will be referred to simply as Coccidioides for the remainder of this chapter.


InternalMed_Harrison

InternalMed_Harrison. Coccidioidomycosis is confined to the Western Hemisphere between the latitudes of 40°N and 40°S. In the United States, areas of high endemicity include the southern portion of the San Joaquin Valley of California and the south-central region of Arizona. However, infection may be acquired in other areas of the southwestern United States, including the southern coastal counties in California, southern Nevada, southwestern Utah, southern New Mexico, and western Texas, including the Rio Grande Valley. Outside the United States, coccidioidomycosis is endemic to northern Mexico as well as to localized regions of Central America. In South America, there are endemic foci in Colombia, Venezuela, northeastern Brazil, Paraguay, Bolivia, and north-central Argentina.


InternalMed_Harrison

InternalMed_Harrison. The risk of infection is increased by direct exposure to soil harboring Coccidioides. Because of difficulty in isolating Coccidioides from the soil, the precise characteristics of potentially infectious soil are not known. In the United States, several outbreaks of coccidioidomycosis have been associated with soil from archaeologic excavations of Amerindian sites both within and outside of the recognized endemic region. These cases often involved alluvial soils in regions of relative aridity with moderate temperature ranges. Coccidioides was isolated at depths of 2–20 cm below the surface. The recent identification of three cases of coccidioidomycosis in eastern Washington State may suggest that the endemic region is expanding.


InternalMed_Harrison

InternalMed_Harrison. In endemic areas, many cases of Coccidioides infection occur without obvious soil or dust exposure. Climatic factors appear to increase the infection rate in these regions. In particular, periods of aridity following rainy seasons have been associated with marked increases in the number of symptomatic cases. Overall, the incidence within the United States has increased substantially over the past decade, with nearly 43 cases per 100,000 residents of the endemic region in 2011. Most of that increase has occurred in south-central Arizona, where most of that state’s population resides, and in the southern San Joaquin Valley of California, a much less populated region. The factors causing this increase have not been fully elucidated; however, an influx of older individuals without prior coccidioidal infection appears to be involved. Other variables, such as climate change, construction activity, and increased awareness and reporting, may also be factors. Health care providers should


InternalMed_Harrison

InternalMed_Harrison. coccidioidal infection appears to be involved. Other variables, such as climate change, construction activity, and increased awareness and reporting, may also be factors. Health care providers should consider coccidioidomycosis when evaluating persons with pneumonia who live in or have traveled to endemic areas.


InternalMed_Harrison

InternalMed_Harrison. PATHOGENESIS, PATHOLOGY, AND IMMuNE RESPONSE On agar media and in the soil, Coccidioides organisms exist as filamentous molds. Within this mycelial structure, individual filaments (hyphae) elongate and branch, some growing upward. Alternating cells within the hyphae degenerate, leaving barrel-shaped viable elements called arthroconidia. Measuring ∼2 by 5 μm, arthroconidia may become airborne for extended periods. Their small size allows them to evade initial mechanical mucosal defenses and reach deep into the bronchial tree, where infection is initiated in the nonimmune host.


InternalMed_Harrison

InternalMed_Harrison. Once in a susceptible host, the arthroconidia enlarge, become rounded, and develop internal septations. The resulting structures, called spherules(Fig. 237-1), may attain sizes of 200 μm and are unique to Coccidioides. The septations encompass uninuclear elements called endospores. Spherules may rupture and release packets of endospores that can themselves develop into spherules, thus propagating infection locally. If returned to artificial media or the soil, the fungus reverts to its mycelial stage. Clinical observations and data from studies of animals strongly support the critical role of a robust cellular immune response in the host’s control of coccidioidomycosis. Necrotizing granulomas containing


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 237-1 Life cycle of Coccidioides.(From TN Kirkland, J Fierer: Emerg Infect Dis 2:192, 1996.) spherules are typically identified in patients with resolved pulmonary 1335 infection. In disseminated disease, granulomas are generally poorly formed or do not develop at all, and a polymorphonuclear leukocyte response occurs frequently. In patients who are asymptomatic or in whom the initial pulmonary infection resolves, delayed-type hypersensitivity to coccidioidal antigens has been routinely documented. Of infected individuals, 60% are completely asymptomatic, and the remaining 40% have symptoms that are related principally to pulmonary infection, including fever, cough, and pleuritic chest pain. The risk of symptomatic illness increases with age. Coccidioidomycosis is commonly misdiagnosed as community-acquired bacterial pneumonia.


InternalMed_Harrison

InternalMed_Harrison. There are several cutaneous manifestations of primary pulmonary coccidioidomycosis. Toxic erythema consisting of a maculopapular rash has been noted in some cases. Erythema nodosum (see Fig. 25e-40)— typically over the lower extremities—or erythema multiforme (see Fig. 25e-25)—usually in a necklace distribution—may occur; these manifestations are seen particularly often in women. Arthralgias and arthritis may develop. The diagnosis of primary pulmonary coccidioidomycosis is suggested by a history of night sweats or profound fatigue as well as by peripheral-blood eosinophilia and hilar or mediastinal lymphadenopathy on chest radiography. While pleuritic chest pain is common, pleural effusions occur in fewer than 10% of cases. Such effusions are invariably associated with a pulmonary infiltrate on the same side. The cellular content of these effusions is mononuclear in nature; Coccidioides is rarely grown from effusions.


InternalMed_Harrison

InternalMed_Harrison. In most patients, primary pulmonary coccidioidomycosis usually resolves without sequelae in weeks. However, several pneumonic complications may arise. Pulmonary nodules are residua of primary pneumonia. Generally single, frequently located in the upper lobes, and ≤4 cm in diameter, nodules are often discovered on a routine chest radiograph in an asymptomatic patient. Calcification is uncommon. Coccidioidal pulmonary nodules can be difficult to distinguish radiographically from pulmonary malignancies. Like malignancies, coccidioidal nodules often enhance on positron emission tomography. However, routine CT often demonstrates multiple nodules in coccidioidomycosis. Biopsy is often required to distinguish between these two conditions.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary cavities occur when a nodule extrudes its contents into the bronchus, resulting in a thin-walled shell. These cavities can be associated with persistent cough, hemoptysis, and pleuritic chest pain. Rarely, a cavity may rupture into the pleural space, causing pyopneumothorax. In such cases, patients present with acute dyspnea, and the chest radiograph reveals a collapsed lung with a pleural air-fluid level. Chronic or persistent pulmonary coccidioidomycosis manifests with prolonged symptoms of fever, cough, and weight loss and is radio-graphically associated with pulmonary scarring, fibrosis, and cavities. It occurs most commonly in patients who already have chronic lung disease due to other etiologies.


InternalMed_Harrison

InternalMed_Harrison. In some cases, primary pneumonia presents as a diffuse reticulonodular pulmonary process (detected by plain chest radiography) in association with dyspnea and fever. Primary diffuse coccidioidal pneumonia may occur in settings of intense environmental exposure or profoundly suppressed cellular immunity (e.g., in patients with AIDS), with unrestrained fungal growth that is frequently associated with fungemia.


InternalMed_Harrison

InternalMed_Harrison. Clinical dissemination outside the thoracic cavity occurs in fewer than 1% of infected individuals. Dissemination is more likely to occur in male patients, particularly those of African-American or Filipino ancestry, and in persons with depressed cellular immunity, including patients with HIV infection and peripheral-blood CD4+ T cell counts of <250/μL; those receiving chronic glucocorticoid therapy; those with allogeneic solid-organ transplants; and those being treated with tumor necrosis factor α antagonists. Women who acquire infection during the second or third trimester of pregnancy also are at risk for disseminated disease. Common sites for dissemination include the skin, bone, joints, soft tissues, and meninges. Dissemination may follow symptomatic or asymptomatic pulmonary infection and may involve 1336 only one site or multiple anatomic foci. When it occurs, clinical dissemination is usually evident within the first few months after primary pulmonary infection. Coccidioidal


InternalMed_Harrison

InternalMed_Harrison. and may involve 1336 only one site or multiple anatomic foci. When it occurs, clinical dissemination is usually evident within the first few months after primary pulmonary infection. Coccidioidal meningitis, if untreated, is uniformly fatal. Patients usually present with a persistent headache, which is sometimes accompanied by lethargy and confusion. Nuchal rigidity, if present, is not severe. Examination of cerebrospinal fluid (CSF) demonstrates lymphocytic pleocytosis with profound hypoglycorrhachia and elevated protein levels. CSF eosinophilia is occasionally documented. With or without appropriate therapy, patients may develop hydrocephalus, which presents clinically as a marked decline in mental status, often with gait disturbances.


InternalMed_Harrison

InternalMed_Harrison. As mentioned above, coccidioidomycosis is often misdiagnosed as community-acquired bacterial pneumonia. Clues that suggest a diagnosis of coccidioidomycosis include peripheral-blood eosinophilia, hilar or mediastinal adenopathy on radiographic imaging, marked fatigue, and failure to improve with antibiotic therapy.


InternalMed_Harrison

InternalMed_Harrison. Serology plays an important role in establishing a diagnosis of coccidioidomycosis. Several techniques are available, including the traditional tube-precipitin (TP) and complement-fixation (CF) assays, immunodiffusion (IDTP and IDCF), and enzyme immunoassay (EIA) to detect IgM and IgG antibodies. TP and IgM antibodies are found in serum soon after infection and persist for weeks. They are not useful for gauging disease progression and are not found in the CSF. The CF and IgG antibodies occur later in the course of the disease and persist longer than TP and IgM antibodies. Rising CF titers are associated with clinical progression, and the presence of CF antibody in CSF is indicative of coccidioidal meningitis. Antibodies disappear over time in persons whose clinical illness resolves.


InternalMed_Harrison

InternalMed_Harrison. Because of its commercial availability, the coccidioidal EIA is frequently used as a screening tool for coccidioidal serology. There has been concern that the IgM EIA is occasionally falsely positive, particularly in asymptomatic individuals. In addition, while the sensitivity and specificity of the IgG EIA appear to be higher than those of the CF and IDCF assays, the optical density obtained in the EIA does not correlate with the serologic titer of either of the latter tests.


InternalMed_Harrison

InternalMed_Harrison. Coccidioides grows within 3–7 days at 37°C on a variety of artificial media, including blood agar. Therefore, it is always useful to obtain samples of sputum or other respiratory fluids and tissues for culture in suspected cases of coccidioidomycosis. The clinical laboratory should be alerted to the possibility of this diagnosis, since Coccidioides poses a significant laboratory hazard if it is inadvertently inhaled. The organism can also be identified directly. While treatment of samples with potassium hydroxide is rarely fruitful in establishing the diagnosis, examination of sputum or other respiratory fluids after Papanicolaou or Gomori methenamine silver staining reveals spherules in a significant proportion of patients with pulmonary coccidioidomycosis. For fixed tissues (e.g., those obtained from biopsy specimens), spherules with surrounding inflammation can be demonstrated with hematoxylineosin or Gomori methenamine silver staining.