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InternalMed_Harrison. A commercially available test for coccidioidal antigenuria and antigenemia has been developed and appears to be particularly useful in immunosuppressed patients with severe or disseminated disease. False-positive results may occur in cases of histoplasmosis or blastomycosis. Some laboratories offer genomic detection by polymerase chain reaction. Currently, two main classes of antifungal agents are useful for the treatment of coccidioidomycosis (Table 237-1). While once prescribed routinely, amphotericin B in all its formulations is now reserved for only the most severe cases of dissemination and for intrathecal or intraventricular administration to patients with coccidioidal meningitis in whom triazole antifungal therapy has failed. The original formulation of amphotericin B, which is dispersed with deoxycholate, is usually administered intravenously in doses


InternalMed_Harrison

InternalMed_Harrison. TABLE 237-1 CLInICAL PREsEnTATIOns OF COCCIdIOIdOMyCOsIs, THEIR FREquEnCy, And RECOMMEndEd InITIAL THERAPy FOR THE IMMunOCOMPETEnT HOsT Clinical Presentation Frequency, % Recommended Therapy Primary pneumonia 40 In most cases, nonea (focal) Cavity — In most cases, noneb Skin, bone, joint, soft — Prolonged triazole therapyc aTreatment is indicated for hosts with depressed cellular immunity as well as for those with prolonged symptoms and signs of increased severity, including night sweats for >3 weeks, weight loss of >10%, a complement-fixation titer of >1:16, and extensive pulmonary involvement on chest radiography. bTreatment (usually with the oral triazoles fluconazole and itraconazole) is recommended for persistent symptoms. cIn severe cases, some clinicians would use amphotericin B as initial therapy. dIntraventricular or intrathecal amphotericin B is recommended in cases of triazole failure. Hydrocephalus may occur, requiring a CSF shunt.


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InternalMed_Harrison. Note: See text for dosages and durations. of 0.7–1.0 mg/kg either daily or three times per week. The newer lipid-based formulations—amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and amphotericin B liposomal complex (L-AmB)—are associated with less renal toxicity. The lipid dispersions are administered intravenously at doses of 5 mg/kg daily or three times per week.


InternalMed_Harrison

InternalMed_Harrison. Triazole antifungals are the principal drugs now used to treat most cases of coccidioidomycosis. Clinical trials have demonstrated the usefulness of both fluconazole and itraconazole. Evidence indicates that itraconazole may be more efficacious against bone and joint disease. Because of its demonstrated penetration into CSF, fluconazole is the azole of choice for the treatment of coccidioidal meningitis, but itraconazole also is effective. For both drugs, a minimal oral adult dosage of 400 mg/d should be used. The maximal dose of itraconazole is 200 mg three times daily, but higher doses of fluconazole may be given. Two newer triazole antifungals, posaconazole and voriconazole, are now available. Data suggest that both drugs may be useful against infections, including meningitis, in which prior fluconazole therapy has failed. High-dose triazole therapy may be teratogenic during the first trimester of pregnancy; thus, amphotericin B should be considered as therapy for


InternalMed_Harrison

InternalMed_Harrison. in which prior fluconazole therapy has failed. High-dose triazole therapy may be teratogenic during the first trimester of pregnancy; thus, amphotericin B should be considered as therapy for coccidioidomycosis in pregnant women during this period.


InternalMed_Harrison

InternalMed_Harrison. Most patients with focal primary pulmonary coccidioidomycosis require no therapy. Patients for whom antifungal therapy should be considered include those with underlying cellular immunodeficiencies and those with prolonged symptoms and signs of extensive disease. Specific criteria include symptoms persisting for ≥2 months, night sweats occurring for >3 weeks, weight loss of >10%, a serum CF antibody titer of >1:16, and extensive pulmonary involvement apparent on chest radiography. Diffuse pulmonary coccidioidomycosis represents a special situation. Because most patients with this form of disease are profoundly hypoxemic and critically ill, many clinicians favor beginning therapy with amphotericin B and switching to an oral triazole antifungal once clinical improvement occurs.


InternalMed_Harrison

InternalMed_Harrison. The nodules that may follow primary pulmonary coccidioidomycosis do not require treatment. As noted above, these nodules are not easily distinguished from pulmonary malignancies by means of radiographic imaging. Close clinical follow-up and biopsy may be required to distinguish between these two entities. Most pulmonary cavities do not require therapy. Antifungal treatment should be considered in patients with persistent cough, pleuritic chest pain, and hemoptysis. Occasionally, pulmonary coccidioidal cavities become secondarily infected. This development is usually manifested by an air-fluid level within the cavity. Bacterial flora or Aspergillus species are commonly involved, and therapy directed at these organisms should be considered. Surgery is rarely required except in cases of persistent hemoptysis or pyopneumothorax. For chronic pulmonary coccidioidomycosis, prolonged antifungal therapy—lasting for at least 1 year—is usually required, with monitoring of symptoms, radiographic


InternalMed_Harrison

InternalMed_Harrison. hemoptysis or pyopneumothorax. For chronic pulmonary coccidioidomycosis, prolonged antifungal therapy—lasting for at least 1 year—is usually required, with monitoring of symptoms, radiographic changes, sputum cultures, and serologic titers.


InternalMed_Harrison

InternalMed_Harrison. Most cases of disseminated coccidioidomycosis require prolonged antifungal therapy. Duration of treatment is based on resolution of the signs and symptoms of the lesions in conjunction with a significant decline in serum CF antibody titer. Such therapy routinely is continued for at least several years. Relapse occurs in 15–30% of individuals once therapy is discontinued.


InternalMed_Harrison

InternalMed_Harrison. Coccidioidal meningitis poses a special challenge. While most patients with this form of disease respond to treatment with oral triazoles, 80% experience relapse when therapy is stopped. Thus, lifelong therapy is recommended. In cases of triazole failure, intrathecal or intraventricular amphotericin B may be used. Installation requires considerable expertise and should be undertaken only by an experienced health care provider. Shunting of CSF in addition to appropriate antifungal therapy is required in cases of meningitis complicated by hydrocephalus. It is prudent to obtain expert consultation in all cases of coccidioidal meningitis.


InternalMed_Harrison

InternalMed_Harrison. There are no proven methods to reduce the risk of acquiring coccidioidomycosis among residents of an endemic region, but avoidance of direct contact with uncultivated soil or with visible dust containing soil is reasonable. For individuals with suppressed cellular immunity, the risk of developing symptomatic coccidioidomycosis is greater than that in the general population. Among those about to undergo allogeneic solid-organ transplantation, antifungal therapy is appropriate when there is evidence of active or recent coccidioidomycosis. Several cases of donor-transmitted coccidioidomycosis have occurred during transplantation. If possible, donors from an endemic region should be screened for coccidioidomycosis before transplantation. Data on the use of antifungal agents for prophylaxis in other situations are limited. The administration of an antifungal drug to prevent symptomatic coccidioidomycosis is not recommended for HIV-1-infected patients who live in an endemic region. Most


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InternalMed_Harrison. in other situations are limited. The administration of an antifungal drug to prevent symptomatic coccidioidomycosis is not recommended for HIV-1-infected patients who live in an endemic region. Most experts would administer a triazole to patients with a history of active coccidioidomycosis or a positive coccidioidal serology in whom therapy with tumor necrosis factor α antagonists is being initiated.


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InternalMed_Harrison. Blastomycosis Donna C. Sullivan, Rathel L. Nolan, III Blastomycosis is a systemic pyogranulomatous infection, involving pri-marily the lungs, that follows inhalation of the conidia of Blastomyces dermatitidis. Pulmonary blastomycosis varies from an asymptomatic infection to acute or chronic pneumonia. Hematogenous dissemina-238 tion to skin, bones, and the genitourinary system is common; however, almost any organ can be involved. B. dermatitidis is the asexual state of Ajellomyces dermatitidis. Two serotypes have been identified on the basis of the presence or absence of the A antigen. Distinct genotypic groups have been differentiated by rDNA polymerase chain reaction restriction fragment length FIGuRE 238-1 Blastomyces dermatitidis broad-based budding yeast in the aspirate of a chest wall abscess. Note the presence of multiple nuclei, the thickened cell wall, and the broad-based bud.


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InternalMed_Harrison. FIGuRE 238-1 Blastomyces dermatitidis broad-based budding yeast in the aspirate of a chest wall abscess. Note the presence of multiple nuclei, the thickened cell wall, and the broad-based bud. polymorphisms and microsatellite markers. B. dermatitidis exhibits thermal dimorphism, growing as the mycelial phase at room temperature and as the yeast phase at 37°C. Primary isolation in the laboratory is most dependable for the mycelial phase incubated at 30°C. Definitive identification usually requires conversion to the yeast phase at 37°C or— now more commonly—the use of nucleic acid amplification techniques that detect mycelial-phase growth. Under the microscope, the yeast cells are usually 8–15 μm in diameter, have thick refractile cell walls, are multinucleate, and exhibit a single, large, broad-based bud (Fig. 238-1).


InternalMed_Harrison

InternalMed_Harrison. Most cases of blastomycosis have been reported in North America. Endemic areas include the southeastern and south-central states bordering the Mississippi and Ohio river basins, the midwestern states, and the Canadian provinces bordering the Great Lakes. A small endemic area exists in New York and Canada along the St. Lawrence River. Acute blastomycosis is typically found only in North America, and the clinical presentation of blastomycosis in nonendemic areas is as a chronic disease. Outside North America, blastomycosis occurs sporadically in Nigeria, Zimbabwe, Tunisia, Saudi Arabia, Israel, Lebanon, and India. The disease has been reported most frequently in Africa.


InternalMed_Harrison

InternalMed_Harrison. Outside North America, blastomycosis occurs sporadically in Nigeria, Zimbabwe, Tunisia, Saudi Arabia, Israel, Lebanon, and India. The disease has been reported most frequently in Africa. Early studies indicated that middle-aged men with outdoor occupations were at greatest risk. Reported outbreaks, however, do not suggest a predilection according to sex, age, race, occupation, or season. The specific niche in nature in which the organism resides remains uncertain; B. dermatitidis probably grows as microfoci in the warm, moist soil of wooded areas rich in organic debris. Inhalation of conidia following exposure to soil, whether related to work or recreation, appears to be the common factor associated with infection. Outbreaks of human disease may be preceded by the occurrence of disease in simultaneously exposed dogs. Zoonotic transmission is rare but has been reported in association with dog bites, pet kinkajou bites, cat scratches, and animal necropsies.


InternalMed_Harrison

InternalMed_Harrison. Alveolar macrophages and polymorphonuclear leukocytes are critical for phagocytosis and killing of the inhaled conidia of B. dermatitidis. The interaction of these mediators of the innate immune response with local host factors, such as lung surfactant, plays a significant role in inhibiting conversion to the pathogenic yeast form. This inhibition prevents the establishment of symptomatic disease and may account for the high frequency of asymptomatic infections in outbreaks. Once conversion to the thick-walled yeast form has occurred, phagocytosis and killing are much more difficult, and the development of clinically 1338 apparent infection is much more likely. Ultimately, the T lymphocyte response—specifically, a TH1 response—is the primary factor in limiting infection and dissemination. Moreover, yeast-phase conversion results in the expression of yeast phase–specific proteins such as the 120-kDa glycoprotein adhesin BAD-1 and the Blastomyces yeast phase–specific protein 1 (BYS1).


InternalMed_Harrison

InternalMed_Harrison. Moreover, yeast-phase conversion results in the expression of yeast phase–specific proteins such as the 120-kDa glycoprotein adhesin BAD-1 and the Blastomyces yeast phase–specific protein 1 (BYS1). BAD-1 has been well characterized as a virulence factor and is the major epitope for humoral and cellular immunity. The role of BYS1, putatively identified as a signal peptide, has not been determined.


InternalMed_Harrison

APPROACH TO THE PATIENT:

InternalMed_Harrison. APPROACH TO THE PATIENT:


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InternalMed_Harrison. Blastomycosis most commonly presents as acute or chronic pneumonia that has been refractory to therapy with antibacterial drugs. Whether acute or chronic, blastomycosis may mimic many other disease processes. For example, acute pulmonary blastomycosis may present with signs and symptoms indistinguishable from those of bacterial pneumonia or influenza, and chronic pulmonary blastomycosis may mimic malignancy or tuberculosis. Skin lesions are often misdiagnosed as basal cell or squamous cell carcinoma, pyoderma gangrenosum, or keratoacanthoma. Laryngeal lesions are frequently mistaken for squamous cell carcinoma. Thus, the clinician must maintain a high index of suspicion and ensure that secretions or biopsy materials from patients who live in or have visited regions endemic for blastomycosis are subjected to careful histologic evaluation. This diligence is especially important in caring for individuals with pneumonia who fail to respond to treatment with antibacterial agents.


InternalMed_Harrison

InternalMed_Harrison. Acute pulmonary infection is often diagnosed in association with point-source outbreaks. Typical symptoms include the abrupt onset of fever, chills, pleuritic chest pain, arthralgias, and myalgias. Cough is initially nonproductive but frequently becomes purulent as disease progresses. Chest radiographs usually reveal alveolar infiltrates with consolidation. Pleural effusions and hilar adenopathy are uncommon. Most patients diagnosed with pulmonary blastomycosis have chronic indolent pneumonia with signs and symptoms of fever, weight loss, productive cough, and hemoptysis. The most common radiologic findings are alveolar infiltrates with or without cavitation, mass lesions that mimic bronchogenic carcinoma, and fibronodular infiltrates. Hematogenous dissemination to the skin, bones, and genitourinary tract occurs most often in association with chronic pulmonary disease. Although blastomycosis is not considered an opportunistic infection, immunosuppression has been recognized as a risk


InternalMed_Harrison

InternalMed_Harrison. tract occurs most often in association with chronic pulmonary disease. Although blastomycosis is not considered an opportunistic infection, immunosuppression has been recognized as a risk factor for more serious pulmonary involvement, including respiratory failure (adult respiratory distress syndrome) associated with miliary disease or diffuse pulmonary infiltrates. In the late stages of AIDS, mortality rates of ≥50% have been documented. Most deaths occur within the first few days of therapy. Solid-organ transplant recipients with endemic fungal infections, including both histoplasmosis and blastomycosis, frequently have more severe pulmonary disease as well as dissemination. Blastomycosis has been associated with a mortality rate of 36% in these patients.


InternalMed_Harrison

InternalMed_Harrison. In Africa, pulmonary cases typically include bony involvement (frequently of the vertebrae), with subcutaneous abscesses of the chest wall or legs. All of the manifestations seen in African patients fall within the spectrum of blastomycosis observed in North America. The increased prevalence of chronic and disseminated bone disease in these patients may reflect a delay in diagnosis in regions where spinal disease is often treated empirically as tuberculosis. Skin disease is the most common extrapulmonary manifestation of blastomycosis. Two types of skin lesions occur: verrucous (more common) and ulcerative. Osteomyelitis occurs in as many as one-fourth of B. dermatitidis infections. The vertebrae, pelvis, sacrum, skull, ribs, and long bones are most frequently involved. Patients with


InternalMed_Harrison

InternalMed_Harrison. B. dermatitidis osteomyelitis often present with contiguous soft-tissue abscesses or chronic draining sinuses. In men, blastomycosis may involve the prostate and epididymis. Central nervous system (CNS) disease occurs in fewer than 5% of immunocompetent patients with blastomycosis. A recent multicenter review identified 22 patients with CNS disease, of whom 12 (54%) met at least one criterion for immunosuppression; although most cases of CNS blastomycosis are associated with infection at other sites, 22.7% of the reviewed cases had only CNS involvement. CNS disease, usually presenting as a brain abscess, has been reported in ~40% of cases in patients with AIDS. Less common forms of CNS disease are cranial or spinal epidural abscess and meningitis.


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InternalMed_Harrison. Definitive diagnosis of blastomycosis requires growth of the organism from sputum, bronchial washings, pus, or biopsy material. Specimens should be inoculated onto a fungal medium such as Sabouraud dextrose agar, with or without chloramphenicol. B. dermatitidis is generally visible in 5–10 days but may require incubation for up to 30 days if only a few organisms are present in the specimen. A presumptive diagnosis may be based on demonstration of the characteristic broad-based budding yeast by microscopic examination of wet preps of sputum in pneumonia or of skin-lesion scrapings. Serologic testing for antibodies to B. dermatitidis by complement fixation, immunodiffusion, or enzyme immunoassay is of little value for diagnosis because of limited sensitivity and specificity as well as cross-reactivity with other fungal antigens.


InternalMed_Harrison

InternalMed_Harrison. A Blastomyces antigen assay that detects antigen in urine and serum is commercially available and is reasonably sensitive and specific (MiraVista Diagnostics, Indianapolis, IN). Antigen detection appears to be more sensitive in urine than in serum. This antigen test may be useful for monitoring of patients during therapy or for early detection of relapse. Chemiluminescent DNA probes (AccuProbe; GenProbe Inc., San Diego, CA) are commonly used to confirm identification of B. dermatitidis once growth has been detected in culture. Repetitive sequence–based PCR is available (DiversiLab System; bioMérieux, Durham, NC). Molecular identification techniques are currently used only to supplement traditional diagnostic methods.


InternalMed_Harrison

InternalMed_Harrison. The Infectious Diseases Society of America has published guidelines for the treatment of blastomycosis. Selection of an appropriate therapeutic regimen must be based on the clinical form and severity of the disease, the immune status of the patient, and the toxicity of the antifungal agent (Table 238-1). Although spontaneous cures of acute pulmonary infection are well documented, there are no criteria by which to distinguish patients whose disease will progress or resolve without treatment. Thus all patients with blastomycosis should be treated.


InternalMed_Harrison

InternalMed_Harrison. Itraconazole is the agent of choice for immunocompetent patients with mild to moderate pulmonary or non-CNS extrapulmonary disease. Therapy is continued for 6–12 months. Amphotericin B (AmB) is the preferred initial treatment for patients who are severely immunocompromised, who have life-threatening disease or CNS disease, or whose disease progresses during treatment with itraconazole. Although not rigorously studied, lipid formulations of AmB provide an alternative for patients who cannot tolerate AmB deoxycholate. Most patients with non-CNS disease whose clinical condition improves after an initial course of AmB (usually 2 weeks in duration) can be switched to itraconazole to complete 6–12 months of therapy. Fluconazole, because of its excellent penetration of the CNS, is useful in the treatment of patients with brain abscess or meningitis after an initial course of AmB.


InternalMed_Harrison

InternalMed_Harrison. Voriconazole has been used successfully to treat refractory blastomycosis, blastomycosis in immunosuppressed patients, and—given 1339TABLE 238-1 TREATMEnT OF BLAsTOMyCOsIsa Disease Primary Therapy Alternative Therapy Immunocompetent Patient/Life-Threatening Disease Pulmonary Lipid AmB, 3–5 mg/ kg qd, or AmB deoxycholate, 0.7–1.0 mg/kg qd (total dose: 1.5–2.5 g) Itraconazole, 200–400 mg/d (once patient's condition has stabilized) Cryptococcosis Arturo Casadevall DEFINITION AND ETIOLOGY Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of cryptococcosis. Both species, C. neoformans and C. gattii, can cause cryptococcosis in humans. The two varieties of C. neoformans—grubii 239 dose: 1.5–2.5 g) aTherapy is generally given for 6–12 months. For bone and joint disease, a 12-month course is usually necessary. bSuppressive therapy with itraconazole may be considered for patients whose immunocompromised state continues. Fluconazole (800 mg/d) may be useful for patients who have


InternalMed_Harrison

InternalMed_Harrison. course is usually necessary. bSuppressive therapy with itraconazole may be considered for patients whose immunocompromised state continues. Fluconazole (800 mg/d) may be useful for patients who have CNS disease or cannot tolerate itraconazole.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: AmB, amphotericin B; CNS, central nervous system. its good penetration of cerebrospinal fluid—CNS disease. Posaconazole has also been used for refractory pulmonary disease. The echinocandins have variable activity against B. dermatitidis and therefore are not used in the treatment of blastomycosis. Cure rates are 90–95% among compliant immunocompetent patients given itraconazole for mild to moderate pulmonary and extrapulmonary disease without CNS involvement. Bone and joint disease usually requires 12 months of therapy. The fewer than 5% of infections that relapse after an initial course of itraconazole usually respond well to a second treatment course. The authors thank Dr. Stanley W. Chapman, Professor Emeritus, University of Mississippi, for his continued help and support and for his contributions to this chapter in an earlier edition. and neoformans—correlate with serotypes A and D, respectively.


InternalMed_Harrison

InternalMed_Harrison. and neoformans—correlate with serotypes A and D, respectively. C. gattii, although not divided into varieties, also is antigenically diverse, encompassing serotypes B and C. Most clinical microbiology laboratories do not routinely distinguish between C. neoformans and C. gattii, or among varieties, but rather identify and report all isolates simply as C. neoformans.


InternalMed_Harrison

InternalMed_Harrison. Cryptococcosis was first described in the 1890s but remained relatively rare until the mid-twentieth century, when advances in diagnosis and increases in the number of immunosuppressed individuals markedly raised its reported prevalence. Although serologic evidence of cryptococcal infection is common among immunocompetent individuals, cryptococcal disease (cryptococcosis) is relatively rare in the absence of impaired immunity. Individuals at high risk for disease due to C. neoformans include patients with hematologic malignancies, recipients of solid organ transplants who require ongoing immunosuppressive therapy, persons whose medical conditions necessitate glucocorticoid therapy, and patients with advanced HIV infection and CD4+ T lymphocyte counts of <200/μL. In contrast, C. gattii–related disease is not associated with specific immune deficits and often occurs in immunocompetent individuals. Cryptococcal infection is acquired from the environment.


InternalMed_Harrison

InternalMed_Harrison. Cryptococcal infection is acquired from the environment. C. neoformans and C. gattii inhabit different ecologic niches. C. neoformans is frequently found in soils contaminated with avian excreta and can easily be recovered from shaded and humid soils contaminated with pigeon droppings. In contrast, C. gattii is not found in bird feces. Instead, it inhabits a variety of arboreal species, including several types of eucalyptus tree. C. neoformans strains are found throughout the world; however, var. grubii (serotype A) strains are far more common than var. neoformans (serotype D) strains among both clinical and environmental isolates. The geographic distribution of C. gattii was thought to be largely limited to tropical regions until an outbreak of cryptococcosis caused by a new serotype B strain began in Vancouver in 1999. This outbreak has extended into the United States, and C. gattii infections are being encountered increasingly in several states in the Pacific Northwest.


InternalMed_Harrison

InternalMed_Harrison. The global burden of cryptococcosis was recently estimated at ~1 million cases, with >600,000 deaths annually. Thus cryptococci are important human pathogens. Since the onset of the HIV pandemic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS (Chap. 226). To comprehend the impact of HIV infection on the epidemiology of cryptococcosis, it is instructive to note that in the early 1990s there were >1000 cases of cryptococcal meningitis each year in New York City—a figure far exceeding that for all cases of bacterial meningitis. With the advent of effective antiretroviral therapy, the incidence of AIDS-related cryptococcosis has been sharply reduced among treated individuals. Thus most cases of cryptococcosis now occur in resource-limited regions of the world. The disease remains distressingly common in regions where antiretroviral therapy is not readily available (e.g., parts of Africa and Asia); in these regions, up to one-third


InternalMed_Harrison

InternalMed_Harrison. regions of the world. The disease remains distressingly common in regions where antiretroviral therapy is not readily available (e.g., parts of Africa and Asia); in these regions, up to one-third of patients with AIDS have cryptococcosis. Among HIV-infected persons, those with a decreased percentage of memory B cells expressing IgM may be at greater risk for cryptococcosis.


InternalMed_Harrison

InternalMed_Harrison. 1340 PATHOGENESIS Cryptococcal infection is acquired by inhalation of aerosolized infectious particles. The exact nature of these particles is not known; the two leading candidate forms are small desiccated yeast cells and basidiospores. Little is known about the pathogenesis of initial infection. Serologic studies have shown that cryptococcal infection is acquired in childhood, but it is not known whether the initial infection is symptomatic. Given that cryptococcal infection is common while disease is rare, the consensus is that pulmonary defense mechanisms in immunologically intact individuals are highly effective at containing this fungus. It is not clear whether initial infection leads to a state of immunity or whether most individuals are subject throughout life to frequent and recurrent infections that resolve without clinical disease. However, evidence indicates that some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for


InternalMed_Harrison

InternalMed_Harrison. recurrent infections that resolve without clinical disease. However, evidence indicates that some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for prolonged periods, possibly in granulomas. Thus the inhalation of cryptococcal cells and/or spores can be followed by either clearance or establishment of the latent state. The consequences of prolonged harboring of cryptococcal cells in the lung are not known, but evidence from animal studies indicates that the organisms’ prolonged presence could alter the immunologic milieu in the lung and predispose to allergic airway disease. Cryptococcosis usually presents clinically as chronic meningoencephalitis. The mechanisms by which the fungus undergoes extrapulmonary dissemination and enters the central nervous system (CNS) remain poorly understood. The mechanism by which cryptococcal cells cross the blood–brain barrier is a subject of intensive study. Current evidence suggests that both direct


InternalMed_Harrison

InternalMed_Harrison. nervous system (CNS) remain poorly understood. The mechanism by which cryptococcal cells cross the blood–brain barrier is a subject of intensive study. Current evidence suggests that both direct fungal-cell migration across the endothelium and fungal-cell carriage inside macrophages as “Trojan horse” invaders can occur. Cryptococcus species have well-defined virulence factors that include the expression of the polysaccharide capsule, the ability to make melanin, and the elaboration of enzymes (e.g., phospholipase and urease) that enhance the survival of fungal cells in tissue. Among these virulence factors, the capsule and melanin production have been most extensively studied. The cryptococcal capsule is antiphagocytic, and the capsular polysaccharide has been associated with numerous deleterious effects on host immune function. Cryptococcal infections can elicit little or no tissue inflammatory response. The immune dysfunction seen in cryptococcosis has been attributed to the release


InternalMed_Harrison

InternalMed_Harrison. effects on host immune function. Cryptococcal infections can elicit little or no tissue inflammatory response. The immune dysfunction seen in cryptococcosis has been attributed to the release of copious amounts of capsular polysaccharide into tissues, where it probably interferes with local immune responses (Fig. 239-1). In clinical practice, the capsular polysaccharide is the antigen that is measured as a diagnostic marker of cryptococcal infection.


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InternalMed_Harrison. FIGuRE 239-1 Cryptococcal antigen in human brain tissue, as revealed by immunohistochemical staining. Brown areas show polysaccharide deposits in the midbrain of a patient who died of cryptococcal meningitis. (Reprinted with permission from SC Lee et al: Hum Pathol 27:839, 1996.) APPROACH TO THE PATIENT: Cryptococcosis should be included in the differential diagnosis when any patient presents with findings suggestive of chronic meningitis. Concern about cryptococcosis is heightened by a history of headache and neurologic symptoms in a patient with an underlying immunosuppressive disorder or state that is associated with an increased incidence of cryptococcosis, such as advanced HIV infection or solid organ transplantation.


InternalMed_Harrison

InternalMed_Harrison. The clinical manifestations of cryptococcosis reflect the site of fungal infection. The spectrum of disease caused by Cryptococcus species consists predominantly of meningoencephalitis and pneumonia, but skin and soft tissue infections also occur; in fact, cryptococcosis can affect any tissue or organ. CNS involvement usually presents as signs and symptoms of chronic meningitis, such as headache, fever, lethargy, sensory deficits, memory deficits, cranial nerve paresis, vision deficits, and meningismus. Cryptococcal meningitis differs from bacterial meningitis in that many Cryptococcus-infected patients present with symptoms of several weeks’ duration. In addition, classic characteristics of meningeal irritation, such as meningismus, may be absent in cryptococcal meningitis. Indolent cases can present as subacute dementia. Meningeal cryptococcosis can lead to sudden catastrophic vision loss.


InternalMed_Harrison

InternalMed_Harrison. Pulmonary cryptococcosis usually presents as cough, increased sputum production, and chest pain. Patients infected with C. gattii can present with granulomatous pulmonary masses known as cryptococcomas. Fever develops in a minority of cases. Like CNS disease, pulmonary cryptococcosis can follow an indolent course, and the majority of cases probably do not come to clinical attention. In fact, many cases are discovered incidentally during the workup of an abnormal chest radio-graph obtained for other diagnostic purposes. Pulmonary cryptococcosis can be associated with antecedent diseases such as malignancy, diabetes, and tuberculosis.


InternalMed_Harrison

InternalMed_Harrison. Skin lesions are common in patients with disseminated cryptococcosis and can be highly variable, including papules, plaques, purpura, vesicles, tumor-like lesions, and rashes. The spectrum of cryptococcosis in HIV-infected patients is so varied and has changed so much since the advent of antiretroviral therapy that a distinction between HIV-related and HIV-unrelated cryptococcosis is no longer pertinent. In patients with AIDS and solid organ transplant recipients, the lesions of cutaneous cryptococcosis often resemble those of molluscum contagiosum (Fig. 239-2; Chap. 220e).


InternalMed_Harrison

InternalMed_Harrison. A diagnosis of cryptococcosis requires the demonstration of yeast cells in normally sterile tissues. Visualization of the capsule of fungal cells in cerebrospinal fluid (CSF) mixed with India ink is a useful rapid diagnostic technique. Cryptococcal cells in India ink have a distinctive appearance because their capsules exclude ink particles. However, the CSF India ink examination may yield negative results in patients with a low fungal burden. This examination should be performed by a trained individual, since leukocytes and fat globules can sometimes be mistaken for fungal cells. Cultures of CSF and blood that are positive for cryptococcal cells are diagnostic for cryptococcosis. In cryptococcal meningitis, CSF examination usually reveals evidence of chronic meningitis with mononuclear cell pleocytosis and increased protein levels. A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood. The assay is based on serologic detection of cryptococcal


InternalMed_Harrison

InternalMed_Harrison. cell pleocytosis and increased protein levels. A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood. The assay is based on serologic detection of cryptococcal polysaccharide and is both sensitive and specific. A positive CRAg test provides strong presumptive evidence for cryptococcosis; however, because the result is often negative in pulmonary cryptococcosis, the test is less useful in the diagnosis of pulmonary disease and is of only limited usefulness in monitoring the response to therapy.


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InternalMed_Harrison. FIGuRE 239-2 Disseminated fungal infection. A liver transplant recipient developed six cutaneous lesions similar to the one shown. Biopsy and serum antigen testing demonstrated Cryptococcus. Important features of the lesion include a benign-appearing fleshy papule with central umbilication resembling molluscum contagio-sum. (Photo courtesy of Dr. Lindsey Baden; with permission.) In areas of Africa where there is a high prevalence of HIV infection, routine screening of blood for CRAg in HIV-infected patients with low CD4+ T lymphocyte counts may identify individuals at high risk of cryptococcal disease who are candidates for antifungal therapy. Similarly, CRAg screening has shown that a significant proportion of HIV-infected patients hospitalized with pneumonia in Thailand harbor cryptococcal infection. Inexpensive point-of-care CRAg tests that are under development could be of great diagnostic benefit in resource-limited regions.


InternalMed_Harrison

InternalMed_Harrison. Both the site of infection and the immune status of the host must be considered in the selection of therapy for cryptococcosis. The disease has two general patterns of manifestation: (1) pulmonary cryptococcosis, with no evidence of extrapulmonary dissemination; and (2) extrapulmonary (systemic) cryptococcosis, with or without meningoencephalitis. Pulmonary cryptococcosis in an immunocompetent host sometimes resolves without therapy. However, given the propensity of Cryptococcus species to disseminate from the lung, the inability to gauge the host’s immune status precisely, and the availability of low-toxicity therapy in the form of fluconazole, the current recommendation is for pulmonary cryptococcosis in an immunocompetent individual to be treated with fluconazole (200– 400 mg/d for 3–6 months). Extrapulmonary cryptococcosis without CNS involvement in an immunocompetent host can be treated with the same regimen, although amphotericin B (AmB; 0.5–1 mg/ kg daily for 4–6 weeks) may be


InternalMed_Harrison

InternalMed_Harrison. months). Extrapulmonary cryptococcosis without CNS involvement in an immunocompetent host can be treated with the same regimen, although amphotericin B (AmB; 0.5–1 mg/ kg daily for 4–6 weeks) may be required for more severe cases. In general, extrapulmonary cryptococcosis without CNS involvement requires less intensive therapy, with the caveat that morbidity and death in cryptococcosis are associated with meningeal involvement. Thus the decision to categorize cryptococcosis as “extrapulmonary without CNS involvement” should be made only after careful evaluation of the CSF reveals no evidence of cryptococcal infection. For CNS involvement in a host without AIDS or obvious immune impairment, most authorities recommend initial therapy with AmB (0.5–1 mg/kg daily) during an induction phase, which is followed by prolonged therapy with fluconazole (400 mg/d) during a consolidation phase. For cryptococcal meningoencephalitis without a concomitant immunosuppressive condition, the recommended


InternalMed_Harrison

InternalMed_Harrison. is followed by prolonged therapy with fluconazole (400 mg/d) during a consolidation phase. For cryptococcal meningoencephalitis without a concomitant immunosuppressive condition, the recommended regimen is AmB (0.5–1 mg/kg) plus flucytosine (100 mg/kg) daily for 6–10 weeks. Alternatively, patients can be treated with AmB (0.5–1 1341 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks and then with fluconazole (400 mg/d) for at least 10 weeks. Patients with immunosuppression are treated with the same initial regimens except that consolidation therapy with fluconazole is given for a prolonged period to prevent relapse.


InternalMed_Harrison

InternalMed_Harrison. Cryptococcosis in patients with HIV infection always requires aggressive therapy and is considered incurable unless immune function improves. Consequently, therapy for cryptococcosis in the setting of AIDS has two phases: induction therapy (intended to reduce the fungal burden and alleviate symptoms) and lifelong maintenance therapy (to prevent a symptomatic clinical relapse). Pulmonary and extrapulmonary cryptococcosis without evidence of CNS involvement can be treated with fluconazole (200–400 mg/d). In patients who have more extensive disease, flucytosine (100 mg/kg per day) may be added to the fluconazole regimen for 10 weeks, with lifelong fluconazole maintenance therapy thereafter. For HIV-infected patients with evidence of CNS involvement, most authorities recommend induction therapy with AmB. An acceptable regimen is AmB (0.7–1 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks followed by fluconazole (400 mg/d) for at least 10 weeks and then by lifelong maintenance therapy


InternalMed_Harrison

InternalMed_Harrison. with AmB. An acceptable regimen is AmB (0.7–1 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks followed by fluconazole (400 mg/d) for at least 10 weeks and then by lifelong maintenance therapy with fluconazole (200 mg/d). Fluconazole (400–800 mg/d) plus flucytosine (100 mg/kg per day) for 6–10 weeks followed by fluconazole (200 mg/d) as maintenance therapy is an alternative. Newer triazoles like voriconazole and posaconazole are highly active against cryptococcal strains and appear effective clinically, but clinical experience with these agents in the treatment of cryptococcosis is limited. Lipid formulations of AmB can be substituted for AmB deoxycholate in patients with renal impairment. Neither caspofungin nor micafungin is effective against Cryptococcus species; consequently, neither drug has a role in the treatment of cryptococcosis. Cryptococcal meningoencephalitis is often associated with increased intracranial pressure, which is believed to be responsible for damage to


InternalMed_Harrison

InternalMed_Harrison. drug has a role in the treatment of cryptococcosis. Cryptococcal meningoencephalitis is often associated with increased intracranial pressure, which is believed to be responsible for damage to the brain and cranial nerves. Appropriate management of CNS cryptococcosis requires careful attention to the management of intracranial pressure, including the reduction of pressure by repeated therapeutic lumbar puncture and the placement of shunts. Recent studies suggest that the addition of a short course of interferon γ to antifungal therapy in patients with HIV infection increases clearance of cryptococci from the CSF.


InternalMed_Harrison

InternalMed_Harrison. In HIV-infected patients with previously treated cryptococcosis who are receiving fluconazole maintenance therapy, it may be possible to discontinue antifungal drug treatment if antiretroviral therapy results in immunologic improvement. However, certain recipients of maintenance therapy who have a history of successfully treated cryptococcosis can develop a troublesome immune reconstitution syndrome when antiretroviral therapy produces a rebound in immunologic function.


InternalMed_Harrison

InternalMed_Harrison. Even with antifungal therapy, cryptococcosis is associated with high rates of morbidity and death. For the majority of patients with cryptococcosis, the most important prognostic factors are the extent and the duration of the underlying immunologic deficits that predisposed them to develop the disease. Therefore, cryptococcosis is often curable with antifungal therapy in individuals with no apparent immunologic dysfunction, but, in patients with severe immunosuppression (e.g., those with AIDS), the best that can be hoped for is that antifungal therapy will induce remission, which can then be maintained with lifelong suppressive therapy. Before the advent of antiretroviral therapy, the median overall survival period for AIDS patients with cryptococcosis was <1 year. Cryptococcosis in patients with underlying neoplastic disease has a particularly poor prognosis. For CNS cryptococcosis, poor prognostic markers are a CSF assay positive for yeast cells on initial India ink examination


InternalMed_Harrison

InternalMed_Harrison. with underlying neoplastic disease has a particularly poor prognosis. For CNS cryptococcosis, poor prognostic markers are a CSF assay positive for yeast cells on initial India ink examination (evidence of a heavy fungal burden), high CSF pressure, low CSF glucose levels, low CSF pleocytosis (<2/μL), recovery of yeast cells from extraneural sites, absence of antibody to capsular 1342 polysaccharide, a CSF or serum cryptococcal antigen level of ≥1:32, and concomitant glucocorticoid therapy or hematologic malignancy. A response to treatment does not guarantee cure since relapse of cryptococcosis is common even among patients with relatively intact immune systems. Complications of CNS cryptococcosis include cranial nerve deficits, vision loss, and cognitive impairment.


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InternalMed_Harrison. No vaccine is available for cryptococcosis. In patients at high risk (e.g., those with advanced HIV infection and CD4+ T lymphocyte counts of <200/μL), primary prophylaxis with fluconazole (200 mg/d) is effective in reducing the prevalence of disease. Since antiretroviral therapy raises the CD4+ T lymphocyte count, it constitutes an immunologic form of prophylaxis. However, cryptococcosis in the setting of immune reconstitution has been reported in patients with HIV infection and in recipients of solid organ transplants. Candidiasis John E. Edwards, Jr. The genus Candida encompasses more than 150 species, only a few of which cause disease in humans. With rare exceptions (although the exceptions are increasing in number), the human pathogens are C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, 240


InternalMed_Harrison

InternalMed_Harrison. C. kefyr, C. lusitaniae, C. dubliniensis, and C. glabrata. Ubiquitous in nature, they inhabit the gastrointestinal tract (including the mouth and oropharynx), the female genital tract, and the skin. Although cases of candidiasis have been described since antiquity in debilitated patients, the advent of Candida species as common human pathogens dates to the introduction of modern therapeutic approaches that suppress normal host defense mechanisms. Of these relatively recent advances, the most important is the use of antibacterial agents that alter the normal human microbiota and allow nonbacterial species to become more prevalent in the commensal flora. With the introduction of anti-fungal agents, the causes of Candida infections shifted from an almost complete dominance of C. albicans to the common involvement of


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InternalMed_Harrison. C. glabrata and the other species listed above. The non-albicans species now account for approximately half of all cases of candidemia and hematogenously disseminated candidiasis. Recognition of this change is clinically important, since the various species differ in susceptibility to the newer antifungal agents. In developed countries, where medical therapeutics are commonly used, Candida species are now among the most common nosocomial pathogens. Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm in diameter and reproduces by budding. Organisms of this genus occur in three forms in tissue: blastospores, pseudohyphae, and hyphae. Candida grows readily on simple medium; lysis centrifugation enhances its recovery from blood. Species are identified by biochemical testing (currently with automated devices) or on special agar (e.g., CHROMagar).


InternalMed_Harrison

InternalMed_Harrison. Candida organisms are ubiquitous in nature; worldwide, these fungi are present in humans as commensals, in animals, in foods, and on inanimate objects. In developed countries, where advanced medical therapeutics are commonly used (see “Treatment,” below), Candida species are now among the most common health care–associated pathogens. In the United States, these species are the fourth most common isolates from the blood of hospitalized patients. In countries where advanced medical care is rarely available, mucocutaneous Candida infections, such as thrush, are more common than deep organ infections, which rarely occur; however, the incidence of deep organ candidiasis increases steadily as advances in health care—such as therapy with broad-spectrum antibiotics, more aggressive treatment of cancer, and the use of immunosuppression for sustaining organ transplants—are introduced and implemented. In recent decades, as a result of the HIV epidemic, the incidence of thrush and Candida


InternalMed_Harrison

InternalMed_Harrison. of cancer, and the use of immunosuppression for sustaining organ transplants—are introduced and implemented. In recent decades, as a result of the HIV epidemic, the incidence of thrush and Candida esophagitis has increased substantially. In aggregate, the global incidence of infections due to Candida species has risen steadily over the past few decades.


InternalMed_Harrison

InternalMed_Harrison. In the most serious form of Candida infection, the organisms disseminate hematogenously and form microabscesses and small macroabscesses in major organs. Although the exact mechanism is not known, Candida probably enters the bloodstream from mucosal surfaces after growing to large numbers as a consequence of bacterial suppression by antibacterial drugs; alternatively, in some instances, the organism may enter from the skin. A change from the blastospore stage to the pseudohyphal and hyphal stages is generally considered integral to the organism’s penetration into tissue. However, C. glabrata can cause extensive infection even though it does not transform into pseudohyphae or hyphae. Adherence to both epithelial and endothelial cells, thought to be the first step in invasion and infection, has been studied extensively, and several adhesins have been identified. Biofilm formation also is considered important in pathogenesis. Numerous reviews of cases of hematogenously disseminated


InternalMed_Harrison

InternalMed_Harrison. has been studied extensively, and several adhesins have been identified. Biofilm formation also is considered important in pathogenesis. Numerous reviews of cases of hematogenously disseminated candidiasis have identified the predisposing factors or conditions associated with disseminated disease (Table 240-1). Women who receive antibacterial agents may develop vaginal candidiasis.


InternalMed_Harrison

InternalMed_Harrison. Innate immunity is the most important defense mechanism against hematogenously disseminated candidiasis, and the neutrophil is the most important component of this defense. Macrophages also play an important defensive role. STAT1, Dectin-1, CARD9, and TH1 and TH17 lymphocytes contribute significantly to innate defense (see “Clinical Manifestations,” below). Although many immunocompetent individuals have antibodies to Candida, the role of these antibodies in defense against the organism is not clear. Multiple genetic polymorphisms that predispose to disseminated candidiasis will most likely be identified in future studies.


InternalMed_Harrison

InternalMed_Harrison. CLINICAL MANIFESTATIONS Mucocutaneous Candidiasis Thrush is characterized by white, adherent, painless, discrete or confluent patches in the mouth, on the tongue, or in the esophagus, occasionally with fissuring at the corners of the mouth. This form of disease caused by Candida can also occur at points of contact with dentures. Organisms are identifiable in gram-stained scrapings from lesions. The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection. More commonly, thrush is seen as a nonspecific manifestation of severe debilitating illness. Vulvovaginal candidiasis is accompanied by pruritus, pain, and vaginal discharge which is usually thin but may contain whitish “curds” in severe cases. A subset of patients with recurrent vulvovaginitis have a deficiency in the surface expression of Dectin-1, a major recognition factor for β-glucan on Candida. This deficiency leads to suboptimal functioning of the CARD9


InternalMed_Harrison

InternalMed_Harrison. with recurrent vulvovaginitis have a deficiency in the surface expression of Dectin-1, a major recognition factor for β-glucan on Candida. This deficiency leads to suboptimal functioning of the CARD9 pathway, which ultimately increases the propensity for recurrent vaginal infections.


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InternalMed_Harrison. FIGuRE 240-1 Macronodular skin lesions associated with hematogenously disseminated candidiasis. Candida organisms are usually but not always visible on histopathologic examination. The fungi grow when a portion of the biopsied specimen is cultured. Therefore, for optimal identification, both histopathology and culture should be performed. (Image courtesy of Dr. Noah Craft and the Victor Newcomer collection at UCLA, archived by Logical Images, Inc.; with permission.)


InternalMed_Harrison

InternalMed_Harrison. Other Candida skin infections include paronychia, a painful swelling at the nail-skin interface; onychomycosis, a fungal nail infection rarely caused by this genus; intertrigo, an erythematous irritation with redness and pustules in the skin folds; balanitis, an erythematouspustular infection of the glans penis; erosio interdigitalis blastomycetica, an infection between the digits of the hands or toes; folliculitis, with pustules developing most frequently in the area of the beard; perianal candidiasis, a pruritic, erythematous, pustular infection surrounding the anus; and diaper rash, a common erythematous-pustular perineal infection in infants. Generalized disseminated cutaneous candidiasis, another form of infection that occurs primarily in infants, is characterized by widespread eruptions over the trunk, thorax, and extremities. The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 240-1) indicate a high probability of dissemination to multiple


InternalMed_Harrison

InternalMed_Harrison. eruptions over the trunk, thorax, and extremities. The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 240-1) indicate a high probability of dissemination to multiple organs as well as the skin. While the lesions are seen predominantly in immunocompromised patients treated with cytotoxic drugs, they may also develop in patients without neutropenia.


InternalMed_Harrison

InternalMed_Harrison. Chronic mucocutaneous candidiasis is a heterogeneous infection of the hair, nails, skin, and mucous membranes that persists despite intermittent therapy. The onset of disease usually comes in infancy or within the first two decades of life but in rare cases comes in later life. The condition may be mild and limited to a specific area of the skin or nails, or it may take a severely disfiguring form (Candida granuloma) characterized by exophytic outgrowths on the skin. Chronic mucocutaneous candidiasis is usually associated with specific immunologic dysfunction; most frequently reported is a failure of T lymphocytes to proliferate or to excrete cytokines in response to stimulation by Candida antigens in vitro. A subset of the affected patients have mutations in the STAT1 gene resulting in an insufficiency of interferon γ, interleukin 17, and interleukin 22.


InternalMed_Harrison

InternalMed_Harrison. Approximately half of patients with chronic mucocutaneous candidiasis have associated endocrine abnormalities that together are designated the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. This syndrome is due to mutations in the autoimmune regulator (AIRE) gene and is most prevalent among Finns, Iranian Jews, Sardinians, northern Italians, and Swedes. Conditions that usually follow the onset of the disease include hypoparathyroidism, adrenal insufficiency, autoimmune thyroiditis, Graves’ disease, chronic active hepatitis, alopecia, juvenile-onset pernicious anemia, malabsorption, and primary hypogonadism. In addition, dental enamel dysplasia, vitiligo, pitted nail dystrophy, and calcification of the tympanic membranes may occur. Patients with chronic mucocutaneous candidiasis rarely develop hematogenously 1343 disseminated candidiasis, probably because their neutrophil function remains intact.


InternalMed_Harrison

InternalMed_Harrison. Deeply Invasive Candidiasis Deeply invasive Candida infections may or may not be due to hematogenous seeding. Deep esophageal infection may result from penetration by organisms from superficial esophageal erosions; joint or deep wound infection from contiguous spread of organisms from the skin; kidney infection from catheter-initiated spread of organisms through the urinary tract; infection of intraabdominal organs and the peritoneum from perforation of the gastrointestinal tract; and gallbladder infection from retrograde migration of organisms from the gastrointestinal tract into the biliary drainage system.


InternalMed_Harrison

InternalMed_Harrison. However, far more commonly, deeply invasive candidiasis results from hematogenous seeding of various organs as a complication of candidemia. Once the organism gains access to the intravascular compartment (either from the gastrointestinal tract or, less often, from the skin through the site of an indwelling intravascular catheter), it may spread hematogenously to a variety of deep organs. The brain, chorioretina (Fig. 240-2), heart, and kidneys are most commonly infected and the liver and spleen less commonly so (most often in neutropenic patients). In fact, nearly any organ can become involved, including the endocrine glands, pancreas, heart valves (native or prosthetic), skeletal muscle, joints (native or prosthetic), bone, and meninges. Candida organisms can also spread hematogenously to the skin and cause classic macronodular lesions (Fig. 240-1). Frequently, painful muscular involvement also is evident beneath the area of affected skin. Chorioretinal involvement and skin


InternalMed_Harrison

InternalMed_Harrison. to the skin and cause classic macronodular lesions (Fig. 240-1). Frequently, painful muscular involvement also is evident beneath the area of affected skin. Chorioretinal involvement and skin involvement are highly significant, since both findings are associated with a very high probability of abscess formation in multiple deep organs as a result of generalized hematogenous seeding. Ocular involvement (Fig. 240-2) may require specific treatment (e.g., partial vitrectomy or intraocular injection of antifungal agents) to prevent permanent blindness. An ocular examination is indicated for all patients with candidemia, whether or not they have ocular manifestations.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of Candida infection is established by visualization of pseudohyphae or hyphae on wet mount (saline and 10% KOH), tissue Gram’s stain, periodic acid–Schiff stain, or methenamine silver stain in the presence of inflammation. Absence of organisms on hematoxylineosin staining does not reliably exclude Candida infection. The most


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 240-2 Hematogenous Candida endophthalmitis. A classic off-white lesion projecting from the chorioretina into the vitreous causes the surrounding haze. The lesion is composed primarily of inflammatory cells rather than organisms. Lesions of this type may progress to cause extensive vitreal inflammation and eventual loss of the eye. Partial vitrectomy, combined with IV and possibly intravitreal antifungal therapy, may be helpful in controlling the lesions. (Image courtesy of Dr. Gary Holland; with permission.) challenging aspect of diagnosis is determining which patients with Candida isolates have hematogenously disseminated candidiasis. For instance, recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection, and Candida isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter. Despite extensive


InternalMed_Harrison

InternalMed_Harrison. isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter. Despite extensive research into both antigen and antibody detection systems, there is currently no widely available and validated diagnostic test to distinguish patients with inconsequential seeding of the blood from those whose positive blood cultures represent hematogenous dissemination to multiple organs. Many studies are under way to establish the utility of the β-glucan test; at present, its greatest utility is its negative predictive value (∼90%). Meanwhile, the presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs. Although extensive research is being conducted on other tests for infection, such as PCR, none of these tests is fully validated or widely available at present.


InternalMed_Harrison

InternalMed_Harrison. The treatment of mucocutaneous candidiasis is summarized in Table 240-2. All patients with candidemia are treated with a systemic antifungal agent. A certain percentage of patients, including many of those who have candidemia associated with an indwelling intravascular catheter, probably have “benign” candidemia rather than deep-organ seeding. However, because there is no reliable way to distinguish benign candidemia from deep-organ infection, and because antifungal drugs less toxic than amphotericin B are available, anti-fungal treatment for candidemia—with or without clinical evidence of deep-organ involvement—has become the standard of practice. In addition, if an indwelling intravascular catheter is present, it is best to remove or replace the device whenever feasible.


InternalMed_Harrison

InternalMed_Harrison. The drugs used for the treatment of candidemia and suspected disseminated candidiasis are listed in Table 240-3. Various lipid formulations of amphotericin B, three echinocandins, and the azoles fluconazole and voriconazole are used; no agent within a given class has been clearly identified as superior to the others. Most institutions choose an agent from each class on the basis of their own specific microbial epidemiology, strategies to minimize toxicities, and cost considerations. Unless azole resistance is considered likely, fluconazole is the agent of choice for the treatment of candidemia and suspected disseminated candidiasis in nonneutropenic, hemodynamically stable patients. Initial treatment in the context of likely azole resistance depends, as mentioned above, on the epidemiology of the individual hospital. For example, certain hospitals have a high rate of recovery of C. glabrata, while others do not. At institutions where non-albicans Candida species are frequently


InternalMed_Harrison

InternalMed_Harrison. of the individual hospital. For example, certain hospitals have a high rate of recovery of C. glabrata, while others do not. At institutions where non-albicans Candida species are frequently recovered, therapy with an echinocandin is typically started while the results of sensitivity testing are awaited. For hemodynamically unstable or neutropenic patients, initial treatment with broader-spectrum agents is desirable; these drugs include polyenes, echinocandins, or later-generation azoles such as voriconazole. Once the clinical response has been assessed and the pathogen specifically identified, the regimen can be altered accordingly. At present, the vast majority of C. albicans isolates are sensitive to fluconazole. Isolates of C. glabrata and C. krusei are less sensitive to fluconazole and more sensitive to polyenes and echinocandins. C. parapsilosis is less sensitive to echinocandins in vitro; however, this lesser sensitivity is considered nonsignificant.


InternalMed_Harrison

InternalMed_Harrison. Some generalizations exist regarding the management of specific Candida infections. Recovery of Candida from sputum is almost never indicative of underlying pulmonary candidiasis and does not by itself warrant antifungal treatment. Similarly, Candida in the urine of a patient with an indwelling bladder catheter may represent colonization only rather than bladder or kidney infection; however, the threshold for systemic treatment is lower in severely ill patients in


InternalMed_Harrison

InternalMed_Harrison. Agent Route of Administration Dosea Comment aFor loading doses and adjustments in renal failure, see Pappas PG et al: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503, 2009. The recommended duration of therapy is 2 weeks beyond the last positive blood culture and the resolution of signs and symptoms of infection. bAlthough ketoconazole is approved for the treatment of disseminated candidiasis, it has been replaced by the newer agents listed in this table. Posaconazole has been approved for prophylaxis in neutropenic patients and for oropharyngeal candidiasis. FDA, U.S. Food and Drug Administration.


InternalMed_Harrison

InternalMed_Harrison. this category since it is impossible to distinguish colonization from 1345 lower or upper urinary tract infection. If the isolate is C. albicans, Aspergillosis most clinicians use oral fluconazole rather than a bladder washout with amphotericin B, which was more commonly used in the past. David W. Denning Caspofungin has been used with success; although echinocandins are poorly excreted into the urine, they may be an option, especially for non-albicans isolates. The doses and duration are the same as for disseminated candidiasis. The significance of the recovery of Candida from abdominal drains in postoperative patients is unclear, but again the threshold for treatment is generally low because most of the affected patients have been subjected to factors predisposing to disseminated candidiasis.


InternalMed_Harrison

InternalMed_Harrison. Removal of the infected valve and long-term antifungal therapy constitute appropriate treatment for Candida endocarditis. Although definitive studies are not available, patients usually are treated for weeks with a systemic antifungal agent (Table 240-2) and then given chronic suppressive therapy for months or years (sometimes indefinitely) with an oral azole (usually fluconazole at 400–800 mg/d).


InternalMed_Harrison

InternalMed_Harrison. Hematogenous Candida endophthalmitis is a special problem requiring ophthalmologic consultation. When lesions are expanding or are threatening the macula, an IV polyene combined with flucytosine (25 mg/kg four times daily) has been the regimen of choice, although comparative studies with other regimens have not yet been reported. As more data on the azoles and echinocandins become available, new strategies involving these agents are developing. Of paramount importance is the decision to perform a partial vitrectomy. This procedure debulks the infection and can preserve sight, which may otherwise be lost as a result of vitreal scarring. All patients with candidemia should undergo ophthalmologic examination because of the relatively high frequency of this ocular complication. Not only can this examination detect a developing eye lesion early in its course; in addition, identification of a lesion signifies a probability of ~90% of deep-organ abscesses and may prompt prolongation of


InternalMed_Harrison

InternalMed_Harrison. can this examination detect a developing eye lesion early in its course; in addition, identification of a lesion signifies a probability of ~90% of deep-organ abscesses and may prompt prolongation of therapy for candidemia beyond the recommended 2 weeks after the last positive blood culture. Although the basis for the consensus is a very small data set, the recommended treatment for Candida meningitis is a polyene (Table 240-3) plus flucytosine (25 mg/kg four times daily). Successful treatment of Candida-infected prosthetic material (e.g., an artificial joint) nearly always requires removal of the infected material followed by long-term administration of an antifungal agent selected on the basis of the isolate’s sensitivity and the logistics of administration.


InternalMed_Harrison

InternalMed_Harrison. The use of antifungal agents to prevent Candida infections has been controversial, but some general principles have emerged. Most centers administer prophylactic fluconazole (400 mg/d) to recipients of allogeneic stem cell transplants. High-risk liver transplant recipients also are given fluconazole prophylaxis in most centers. The use of prophylaxis for neutropenic patients has varied considerably from center to center; many centers that elect to give prophylaxis to this population use either fluconazole (200–400 mg/d) or a lipid formulation of amphotericin B (AmBiSome, 1–2 mg/d). Caspofungin (50 mg/d) also has been recommended. Some centers have used itraconazole suspension (200 mg/d). Posaconazole (200 mg three times daily) also has been approved by the FDA for prophylaxis in neutropenic patients and is gaining in popularity.


InternalMed_Harrison

InternalMed_Harrison. Prophylaxis is sometimes given to surgical patients at very high risk. The widespread use of prophylaxis for nearly all patients in general surgical or medical intensive care units is not—and should not be—a common practice for three reasons: (1) the incidence of disseminated candidiasis is relatively low, (2) the cost-benefit ratio is suboptimal, and (3) increased resistance with widespread prophylaxis is a valid concern. Prophylaxis for oropharyngeal or esophageal candidiasis in HIV-infected patients is not recommended unless there are frequent recurrences.


InternalMed_Harrison

InternalMed_Harrison. Aspergillosis is the collective term used to describe all disease entities caused by any one of ~50 pathogenic and allergenic species of Aspergillus. Only those species that grow at 37°C can cause invasive infection, although some species without this ability can cause allergic syndromes. A. fumigatus is responsible for most cases of invasive aspergillosis, almost all cases of chronic aspergillosis, and most allergic syndromes. A. flavus is more prevalent in some hospitals and causes a higher proportion of cases of sinus infections, cutaneous infections, and keratitis than A. fumigatus. A. niger can cause invasive infection but more commonly colonizes the respiratory tract and causes external otitis. A. terreus causes only invasive disease, usually with a poor prognosis. A. nidulans occasionally causes invasive infection, primarily in patients with chronic granulomatous disease.


InternalMed_Harrison

InternalMed_Harrison. Aspergillus has a worldwide distribution, most commonly growing in decomposing plant materials (i.e., compost) and in bedding. This hyaline (nonpigmented), septate, branching mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth. Aspergilli are found in indoor and outdoor air, on surfaces, and in water from surface reservoirs. Daily exposures vary from a few to many millions of conidia; the latter high numbers of conidia are encountered in hay barns and other very dusty environments. The required size of the infecting inoculum is uncertain; however, only intense exposures (e.g., during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease in healthy immunocompetent individuals. Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection;


InternalMed_Harrison

InternalMed_Harrison. exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection; thus HEPA filters should be installed and monitored for efficiency in operating rooms and in areas of the hospital that house high-risk patients.


InternalMed_Harrison

InternalMed_Harrison. The incubation period of invasive aspergillosis after exposure is highly variable, extending in documented cases from 2 to 90 days. Thus community acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial acquisition is also common. Outbreaks usually are directly related to a contaminated air source in the hospital.


InternalMed_Harrison

InternalMed_Harrison. mated (Table 241-1). However, given the inadequate diagnos tic capability in almost all lowand middle-income countries, the accuracy of these estimates is uncertain. The frequency of different manifestations of aspergillosis varies considerably with geographic location; most notably, chronic granulomatous sinusitis is rare outside the Middle East and India, and fungal keratitis is particularly common in Nepal, Myanmar, Bhutan, and India (800 and 113 cases/100,000 population, respectively). The potential effects of chronic pulmonary aspergillosis after pulmonary tuberculosis have only recently been appreciated and include life-threatening hemoptysis, misdiagnosis of smear-negative tuberculosis, and general exacerbation of posttuberculosis morbidity.


InternalMed_Harrison

InternalMed_Harrison. The primary risk factors for invasive aspergillosis are profound neutropenia and glucocorticoid use; risk increases with longer duration of these conditions. Higher doses of glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte dysfunction also is an important risk factor, as evidenced by aspergillosis in chronic granulomatous disease, advanced HIV infection, and relapsed leukemia. An increasing incidence of invasive aspergillosis in medical intensive care units suggests that, in patients who are not immunocompromised, temporary abrogation of protective responses as a result of glucocorticoid use or a general anti-inflammatory state is a significant risk factor. Many Type of Disease Culture ✓ ✓✓ Microscopy ✓ ?? Antigen ✓✓✓ ? ✓✓✓ Real-time PCR ✓✓✓ ✓✓✓ ✓✓✓ β-D-glucan ✓✓ ✓ ? Real-time PCR ✓✓ ??


InternalMed_Harrison

InternalMed_Harrison. Type of Disease Culture ✓ ✓✓ Microscopy ✓ ?? Antigen ✓✓✓ ? ✓✓✓ Real-time PCR ✓✓✓ ✓✓✓ ✓✓✓ β-D-glucan ✓✓ ✓ ? Real-time PCR ✓✓ ?? aIncidence and prevalence figures are for Europe. From www.ecdc.europa.eu/en/publications/ publications/risk-assessment-impact-environmental-usage-of-triazoles-on-aspergillus-sppresistance-to-medical-triazoles.pdf. bPeople are not born with allergic fungal disease; the annual frequency with which it occurs is not known. cAllergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. dGD Brown et al: Human fungal infections: the hidden killers. Sci Transl Med 2012:4:165rv13. eKey for sensitivity: 1 check = limited (as the text indicates, 10–30% for culture); 2 checks = higher; 3 checks = >80%; and 4 checks = ~95%. Abbreviation: PCR, polymerase chain reaction.


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InternalMed_Harrison. Abbreviation: PCR, polymerase chain reaction. patients have some evidence of prior pulmonary disease—typically, a history of pneumonia or chronic obstructive pulmonary disease. Therapy with infliximab, adalimumab, alemtuzumab, daclizumab, rituximab, and possibly bevacizumab therapy also carries an increased risk of invasive aspergillosis, as do severe liver disease and high levels of stored iron in bone marrow. Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, including tuberculosis, prior pneumothorax, or chronic obstructive pulmonary disease. These patients are immunocompetent except for some cytokine regulation defects, most of which are consistent with an inability to mount an inflammatory immune (TH1-like) response or to control it adequately. Glucocorticoids accelerate disease progression.


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InternalMed_Harrison. Allergic bronchopulmonary aspergillosis (ABPA) is associated with polymorphisms of interleukin (IL) 4Ra, IL-10, and SPA2 genes (and others) and with heterozygosity of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These associations suggest a strong genetic basis for the development of a TH2-like and “allergic” response to A. fumigatus. CD4+CD25+ T (Treg) cells also appear to be pivotal in determining disease phenotype. Remarkably, high-dose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis.


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InternalMed_Harrison. Invasive Pulmonary Aspergillosis Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise. Invasive aspergillosis is arbitrarily classified as acute and subacute, with courses of ≤1 month and 1–3 months, respectively. More than 80% of cases of invasive aspergillosis involve the lungs. The most common clinical features are no symptoms at all, fever, cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis, and shortness of breath. Although the fever often responds to glucocorticoids, the disease progresses. The keys to early diagnosis in at-risk patients are a high index of suspicion, screening for circulating antigen (in leukemia), and urgent CT of the thorax. Invasive aspergillosis is one of the most common diagnostic errors revealed at autopsy.


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InternalMed_Harrison. Invasive Sinusitis The sinuses are involved in 5–10% of cases of invasive aspergillosis, especially affecting patients with leukemia and recipients of hematopoietic stem cell transplants. In addition to fever, the most common features are nasal or facial discomfort, blocked nose, and nasal discharge (sometimes bloody). Endoscopic examination of the nose reveals pale, dusky or necrotic-looking tissue in any location. CT or MRI of the sinuses is essential but does not distinguish invasive Aspergillus sinusitis from preexisting allergic or bacterial sinusitis early in the disease process.


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InternalMed_Harrison. Tracheobronchitis Occasionally, only the airways are infected by Aspergillus. The resulting manifestations range from acute or chronic bronchitis to ulcerative or pseudomembranous tracheobronchitis. These entities are particularly common among lung transplant recipients. Obstruction with mucous plugs occurs in normal individuals; in persons with ABPA, cystic fibrosis, and/or bronchiectasis; and in immunocompromised patients.


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InternalMed_Harrison. Disseminated Aspergillosis In the most severely immunocompromised patients, Aspergillus disseminates from the lungs to multiple organs— most often to the brain but also to the skin, thyroid, bone, kidney, liver, gastrointestinal tract, eye (endophthalmitis), and heart valve. Aside from cutaneous lesions, the most common features are gradual clinical deterioration over 1–3 days, with low-grade fever and features of mild sepsis, and nonspecific abnormalities in laboratory tests. In most cases, at least one localization becomes apparent before death. Blood cultures are almost always negative. Cerebral Aspergillosis Hematogenous dissemination to the brain is a devastating complication of invasive aspergillosis. Single or multiple lesions may develop. In acute disease, hemorrhagic infarction is most


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InternalMed_Harrison. Type of Disease typical, and cerebral abscess is common. Rarer manifestations include meningitis, mycotic aneurysm, and cerebral granuloma (mimicking a brain tumor). Local spread from cranial sinuses also occurs. Postoperative infection develops rarely and is exacerbated by glucocorticoids, often given after neurosurgery. The presentation can be either acute or subacute, with mood changes, focal signs, seizures, and decline in mental status. MRI is the most useful immediate investigation; unenhanced CT of the brain is usually nonspecific, and contrast is often contraindicated because of poor renal function.


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InternalMed_Harrison. Endocarditis Most cases of Aspergillus endocarditis are prosthetic valve infections resulting from contamination during surgery. Native valve disease is reported, especially as a feature of disseminated infection and in persons using illicit IV drugs. Culture-negative endocarditis with large vegetations is the most common presentation; embolectomy occasionally reveals the diagnosis. Cutaneous Aspergillosis Dissemination of Aspergillus occasionally results in cutaneous features, usually an erythematous or purplish nontender area that progresses to a necrotic eschar. Direct invasion of the skin occurs in neutropenic patients at the site of IV catheter insertion and in burn patients; such invasion may also follow trauma. Wounds may become infected with Aspergillus (especially A. flavus) after surgery.


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InternalMed_Harrison. Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 241-1) is one or more pulmonary cavities expanding over a period of months or years in association with pulmonary symptoms and systemic manifestations such as fatigue and weight loss. (Pulmonary aspergillosis developing over <3 months is better classified as subacute invasive aspergillosis.) Often mistaken initially for tuberculosis, almost all cases occur in patients with prior pulmonary disease (e.g., tuberculosis, atypical mycobacterial infection, sarcoidosis, rheumatoid lung disease, pneumothorax, bullae) or lung surgery. The onset is insidious, and systemic features may be more prominent than pulmonary symptoms. Cavities may have a fluid level or a well-formed fungal ball, but pericavitary infiltrates and multiple cavities—with or without pleural thickening—are typical. An irregular


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InternalMed_Harrison. than pulmonary symptoms. Cavities may have a fluid level or a well-formed fungal ball, but pericavitary infiltrates and multiple cavities—with or without pleural thickening—are typical. An irregular internal cavity surface and thickened cavity walls are indicative of disease activity.


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InternalMed_Harrison. FIGuRE 241-1 CT scan image of the chest in a patient with longstanding bilateral chronic cavitary pulmonary aspergillosis. This patient had a history of several bilateral pneumothoraces and had required bilateral pleurodesis in 1990. CT scan then demonstrated multiple bullae, and sputum cultures grew A. fumigatus. The patient had initially weakly and later strongly positive serum Aspergillus antibody tests (precipitins). This scan (2003) shows a mixture of thickand thin-walled cavities in both lungs (each marked with C), with a probable fungal ball (black arrow) protruding into the large cavity on the patient's right side (R). There is also considerable pleural thickening bilaterally.


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InternalMed_Harrison. IgG antibodies (usually precipitating) to Aspergillus are almost always 1347 detectable in blood, and levels fall slowly with successful therapy. Some patients have concurrent infections—even without a fungal ball—with atypical mycobacteria and/or other bacterial pathogens. One or more Aspergillus nodules that resemble early lung carcinoma and may cavitate have been recognized. If untreated, chronic pulmonary aspergillosis typically progresses (sometimes relatively rapidly) to unilateral or upper-lobe fibrosis. This end-stage entity is termed chronic fibrosing pulmonary aspergillosis.


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InternalMed_Harrison. Aspergilloma Aspergilloma (fungal ball) occurs in up to 20% of residual pulmonary cavities ≥2.5 cm in diameter. Signs and symptoms associated with single (simple) aspergillomas are minor, including cough (sometimes productive), hemoptysis, wheezing, and mild fatigue. More significant signs and symptoms are associated with chronic cavitary pulmonary aspergillosis and should be treated as such. The vast majority of fungal balls are caused by A. fumigatus, but A. niger has been implicated, particularly in diabetic patients; aspergillomas due to A. niger can lead to oxalosis with renal dysfunction. The most significant complication of aspergilloma is life-threatening hemoptysis, which may be the presenting manifestation. Some fungal balls resolve spontaneously, but the cavity may still be infected.


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InternalMed_Harrison. Chronic Aspergillus Sinusitis Three entities are subsumed under this broad designation: fungal ball of the sinus, chronic invasive sinusitis, and chronic granulomatous sinusitis. Fungal ball of the sinus is limited to the maxillary sinus (except in rare cases involving the sphenoid sinus) and consists of a chronic saprophytic entity in which the sinus cavity is filled with a fungal ball. Maxillary disease is associated with prior upper-jaw root canal work and chronic (bacterial) sinusitis. About 90% of CT scans show focal hyperattenuation related to concretions; on MRI scans, the T2-weighted signal is decreased, whereas it is increased in bacterial sinusitis. Removal of the fungal ball is curative. No tissue invasion is demonstrable histologically or radiologically.


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InternalMed_Harrison. In contrast, chronic invasive sinusitis is a slowly destructive process that most commonly affects the ethmoid and sphenoid sinuses but can involve any sinus. Patients are usually but not always immunocompromised to some degree (e.g., as a result of diabetes or HIV infection). Imaging of the cranial sinuses shows opacification of one or more sinuses, local bone destruction, and invasion of local structures. The differential diagnosis is wide, including infections caused by numerous other fungi; sphenoid sinusitis is often caused by bacteria. Apart from a history of chronic nasal discharge and blockage, loss of the sense of smell, and persistent headache, the usual presenting features are related to local involvement of critical structures. The orbital apex syndrome (blindness and proptosis) is characteristic. Facial swelling, cavernous sinus thrombosis, carotid artery occlusion, pituitary fossa, and brain and skull base invasion have been described.


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InternalMed_Harrison. Chronic granulomatous sinusitis due to Aspergillus is most commonly seen in the Middle East and India and is often caused by A. flavus. It typically presents late, with facial swelling and unilateral proptosis. The prominent granulomatous reaction histologically distinguishes this disease from chronic invasive sinusitis, in which tissue necrosis with a low-grade mixed-cell infiltrate is typical. IgG antibodies to A. flavus are usually detectable.


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InternalMed_Harrison. Allergic Bronchopulmonary Aspergillosis In almost all cases, ABPA represents a hypersensitivity reaction to A. fumigatus; rare cases are due to other aspergilli and other fungi. ABPA occurs in ~2.5% of patients with asthma who are referred to secondary care and in up to 15% of adults with cystic fibrosis. Episodes of bronchial obstruction with mucous plugs leading to coughing fits, “pneumonia,” consolidation, and breathlessness are typical. Many patients report coughing up thick sputum casts. Eosinophilia commonly develops before systemic glucocorticoids are given. The cardinal diagnostic tests include an elevated serum level of total IgE (usually >1000 IU/mL), a positive skin-prick test in response to A. fumigatus extract, or detection of Aspergillus-specific IgE and IgG antibodies. The presence of hyperattenuated mucus in airways is highly specific. Central bronchiectasis is characteristic, and some patients develop chronic cavitary pulmonary aspergillosis.


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InternalMed_Harrison. 1348 Severe Asthma with Fungal Sensitization Many adults with severe asthma do not fulfill the criteria for ABPA and yet are allergic to fungi. Although A. fumigatus is a common allergen, numerous other fungi (e.g., Cladosporium and Alternaria species) are implicated by skin-prick testing and/or specific IgE radioallergosorbent testing. Serum total IgE concentrations are <1000 IU/mL, and bronchiectasis is moderately common.


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InternalMed_Harrison. Allergic Sinusitis Like the lungs, the sinuses manifest allergic responses to Aspergillus and other fungi. The affected patients present with chronic (i.e., perennial) sinusitis that is relatively unresponsive to antibiotics. Many of these patients have nasal polyps, and all have congested nasal mucosae and sinuses full of mucoid material. The histologic hallmarks of allergic fungal sinusitis are local eosinophilia and Charcot-Leyden crystals. Removal of abnormal mucus and polyps, with local and occasionally systemic administration of glucocorticoids, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy. Recurrence is common, often after another bacterial or viral infection.


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InternalMed_Harrison. Superficial Aspergillosis Aspergillus can cause keratitis and otitis externa. The former may be difficult to diagnose early enough to save the patient’s sight. Treatment requires local surgical debridement as well as intensive topical antifungal therapy. Otitis externa usually resolves with debridement and local application of antifungal agents.


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InternalMed_Harrison. Several techniques are required to establish the diagnosis of any form of aspergillosis with confidence (Table 241-1). Patients with acute invasive aspergillosis have a relatively heavy load of fungus in the affected organ; thus culture, molecular diagnosis, antigen detection, and histopathology usually confirm the diagnosis. However, the pace of progression leaves only a narrow window for making the diagnosis without losing the patient, and some invasive procedures are not possible because of coagulopathy, respiratory compromise, and other factors. Currently, ~40% of cases of invasive aspergillosis are missed clinically and are diagnosed only at autopsy. Histologic examination of affected tissue reveals either infarction, with invasion of blood vessels by many fungal hyphae, or acute necrosis, with limited inflammation and fewer hyphae. Aspergillus hyphae are hyaline, narrow, and septate, with branching at 45°; no yeast forms are present in infected tissue. Hyphae can be seen in


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InternalMed_Harrison. necrosis, with limited inflammation and fewer hyphae. Aspergillus hyphae are hyaline, narrow, and septate, with branching at 45°; no yeast forms are present in infected tissue. Hyphae can be seen in cytology or microscopy preparations, which therefore provide a rapid means of presumptive diagnosis.


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InternalMed_Harrison. Culture is important in confirming the diagnosis, given that multiple other (rarer) fungi can mimic Aspergillus species histologically. Bacterial agar is less sensitive than fungal media for culture. Thus, if physicians do not request fungal culture, the diagnosis may be missed. Culture may be falsely positive (e.g., in patients whose airways are colonized by Aspergillus) or falsely negative. Only 10–30% of patients with invasive aspergillosis have a positive culture at any time. Both antigen detection and real-time polymerase chain reaction (PCR) are faster and much more sensitive than culture of respiratory samples and blood. The Aspergillus antigen test relies on detection of galactomannan release from Aspergillus organisms during growth. Positive serum antigen results usually precede clinical or radiologic features by several days. The sensitivity of antigen detection is reduced by antifungal prophylaxis and empirical therapy.


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InternalMed_Harrison. Definitive confirmation of the diagnosis requires (1) a positive culture of a sample taken directly from an ordinarily sterile site (e.g., a brain abscess) or (2) positive results of both histologic testing and culture of a sample taken from an affected organ (e.g., sinuses or skin). Most diagnoses of invasive aspergillosis are inferred from fewer data, including the presence of the halo sign on a high-resolution thoracic CT scan, in which a localized ground-glass appearance representing hemorrhagic infarction surrounds a nodule. While a halo sign may be produced by other fungi, Aspergillus species are by far the most common cause. Halo signs are present for ~7 days early in the course of infection in neutropenic patients and are a good prognostic feature, reflecting an early diagnosis. Thick CT sections can give the false appearance of a halo sign, as can other technical factors. Other common radiologic features of invasive pulmonary aspergillosis include nodules and pleural-based


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InternalMed_Harrison. Thick CT sections can give the false appearance of a halo sign, as can other technical factors. Other common radiologic features of invasive pulmonary aspergillosis include nodules and pleural-based infarction or cavitation, with pleural fluid apparent in 10% of patients.


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InternalMed_Harrison. For chronic invasive aspergillosis, Aspergillus antibody testing is invaluable although relatively imprecise. Biopsy of new nodules reveals hyphae surrounded by cells of chronic inflammation and sometimes granulomas. Antibody titers fall with successful therapy. Cultures are infrequently positive but are important in checking for azole resistance. Real-time PCR of sputum is often strongly positive. Some patients with chronic pulmonary aspergillosis also have elevated titers of total serum IgE and Aspergillus-specific IgE. ABPA and severe asthma with fungal sensitization are diagnosed serologically with elevated total and specific serum IgE levels and with skin-prick tests. Allergic Aspergillus sinusitis is usually diagnosed histologically, although precipitating antibodies in blood also may be useful.


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InternalMed_Harrison. Antifungal drugs active against Aspergillus include voriconazole, itraconazole, posaconazole, caspofungin, micafungin, and amphotericin B (AmB). Drug interactions with azoles must be considered before these agents are prescribed. In addition, plasma azole concentrations vary substantially from one patient to another, and many authorities recommend monitoring to ensure that drug concentrations are adequate but not excessive. Initial IV administration is preferred for acute invasive aspergillosis and oral administration for all other disease that requires antifungal therapy. Current recommendations are shown in Table 241-3.


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InternalMed_Harrison. Voriconazole is the preferred agent for invasive aspergillosis; caspofungin, posaconazole, and lipid-associated AmB are second-line agents. AmB is not active against A. terreus or A. nidulans. An infectious disease consultation is advised for patients with invasive disease, given the complexity of management. Combination therapy (voriconazole plus an echinocandin) for acute invasive aspergillosis may be beneficial for non-neutropenic patients. Immune reconstitution can complicate recovery. The duration of therapy for invasive aspergillosis varies from ~3 months to several years, depending on the patient’s immune status and response to therapy. Relapse occurs if the response is suboptimal and immune reconstitution is not complete.


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InternalMed_Harrison. Itraconazole is currently the preferred oral agent for chronic and allergic forms of aspergillosis. Voriconazole or posaconazole can be substituted when failure, emergence of resistance, or adverse events occur. An itraconazole dose of 200 mg twice daily is recommended, with monitoring of drug concentrations in the blood. Chronic cavitary pulmonary aspergillosis probably requires lifelong therapy, whereas the duration of treatment for other forms of chronic and allergic aspergillosis requires case-by-case evaluation.


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InternalMed_Harrison. Resistance to one or more azoles, although uncommon, is present in isolates from the environment in many regions, including northern Europe, India, China, and North America. Resistance may be derived from azole fungicide use for crops. In addition, resistance arising from multiple mechanisms may develop during long-term treatment, and a positive culture during antifungal therapy is an indication for susceptibility testing. Combined resistance to itraconazole and voriconazole is the most common type of cross-resistance. Glucocorticoids should be used in chronic cavitary pulmonary aspergillosis only if covered by adequate antifungal therapy. Surgical treatment is important in several forms of aspergillosis, including fungal ball of the sinus and single aspergillomas, in which surgery is curative; invasive aspergillosis involving bone, Prophylaxis Posaconazole, itracon-AI azole solution Chronic pulmonaryc Itraconazole, voricon-BII azole


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InternalMed_Harrison. Prophylaxis Posaconazole, itracon-AI azole solution Chronic pulmonaryc Itraconazole, voricon-BII azole ABPA/SAFS Itraconazole AI Drug interactions (especially with rifampin), renal failure (IV only) Diarrhea and vomiting with itraconazole, vincristine interaction Multicavity disease: poor outcome of surgery, medical therapy preferable Poor absorption of itraconazole capsules with proton pump inhibitors or H2 blockers Some glucocorticoid interactions, including with inhaled formulations AmB, caspofungin, posaconazole, micafungin Micafungin, aerosolized AmB Itraconazole, voriconazole, intracavity AmB Posaconazole, IV AmB, IV micafungin Voriconazole, posaconazole As primary therapy, voriconazole carries 20% more responses than AmB. Consider initial combination therapy with an echinocandin in nonneutropenic patients. Some centers monitor plasma levels of itraconazole and posaconazole. Single large cavities with an aspergilloma are best resected.


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InternalMed_Harrison. Some centers monitor plasma levels of itraconazole and posaconazole. Single large cavities with an aspergilloma are best resected. Resistance may emerge during treatment, especially if plasma drug levels are subtherapeutic. Long-term therapy is helpful in most cases. No evidence indicates whether therapy modifies progression to bronchiectasis/fibrosis. aFor information on duration of therapy, see text. bEvidence levels are those used in treatment guidelines (TJ Walsh et al: Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America [IDSA]. Clin Infect Dis 46:327, 2008). cAn infectious disease consultation is appropriate for these patients.