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Fungal lnfections species (lS%) followed by Aspergillus species (t+.g%), other microbiologically, is often resistant to azoles and polyenes and yeast (such as Cryptococcus species; 6.2%), and mucormycetes occasionally to echinocandins, and has been associated with (including Rhizopus and Mucor species; t.7"/.). numerous health care outbreaks. Initial treatment of candidemia and invasive candidia- sis should include an echinocandin (caspofungin, Systemic Candidiasis micafungin, or anidulafungin) and intravascular device Candida species are the fourth most commonly isolated removal (if present/possible). However, because echinocan- organisms in bloodstream infections and are associated with a dins have poor penetration into the central nervous system mortality rate of 30% lo 4O%. (CNS) and the eye, patients with CNS and eye infections Candidemia can present as an isolated fever or septic should be treated with amphotericin B or an azole; treat- shock. Signs and symptoms of focal infection depend on the ment may also require additional agents depending on host site involved. Meningitis, septic arthritis, and endocarditis are factors and disease extent. For all invasive candidal infec- other forms of invasive infection. The presence of yeast in the tions, prompt treatment initiation is critical, and follow-up respiratory or urinary tract (often in the presence of an blood cultures are required to document clearance. A indwelling catheter) generally represents colonization, not dilated funduscopic examination is also necessary to infection; whereas Candida isolated in blood cultures should exclude endophthalmitis. Speciation, sensitivities, and never be considered a contaminant. follow-up blood culture results guide de-escalation therapy. Diagnosing invasive candidiasis is challenging because Antifungal therapy duration for candidemia should be only 40'2, to 60% of patients with infection have positive blood 14 days from the first negative blood culture result in cultures. Recognizing risk factors (Table 25) for candidiasis is patients with uncomplicated candidemia or 74 to 42 days in essential to avoid delays in initiating antifungal therapy and patients with invasive candidal infections. increased mortality. Nonculture methods, such as the T2mag- KEY POITTS netic resonance assay of blood, provide rapid (within hours) diagnosis of invasive candidal infections and can be performed . Only 40"/,, to 60% of patients with invasive candidal infection have positive blood culture results, so recog- after antifungal therapy initiation. The B-o-glucan assay may nizing risk factors of candidiasis is essential to avoid also be used to support the diagnosis of invasive fungal infec delays in initiating effective antifungal therapy. tions, including candidiasis, particularly among patients with negative blood cultures; however, false-positive results may . Nonculture methods (T2 magnetic resonance and occur. These assays are particularly useful in patients at high B-o-glucan assays) may provide a rapid diagnosis of risk who are receiving antimicrobial agents and are not invasive candidal infections, particularly in patients responding to therapy. with negative blood cultures. When Candidais identified from a sterile site, identifying o Candidaspecies obtained from the respiratory or uri- HVC species and susceptibilities are necessary. Fewer than 15 of nary tract usually represents colonization; treatment is more than 160 known Candida species commonly produce not indicated unless clinical infection is suspected. disease. Additionally, several Candidaspecies (e.g., C. glabrata, . Initial management of candidemia and invasive candi- C. krusei, and C. ouris) have low susceptibility or intrinsic diasis should include an echinocandin and intravascular resistance to antifungal agents. C. ouris is an emerging species device removal (if possible); central nervous system and that presents a serious global threat. It is difficult to identify ocular infections require amphotericin B or an azole and potentially additional agents depending on host TABLE 25. Risk Factors for Systemic Candidiasis factors and disease extent. Centra I venous catheters Broad-spectru m antimicrobial agents Neutropenia Aspergillosis ICU stay for more than 3 days Aspergillus fumigatus is the most common species causing disease in humans, followed by A. flauus, A. niger, and the Tota I parenteral nutrition amphotericin-resistant A. terreus. Aspergillus produces dis Genera I su rgery (especia I ly of the gastroi ntesti na I tract) ease after inhalation of airborne spores (qoZ,) and occasionally Burns by traumatic skin inoculation. Trauma Invasive aspergillosis most often occurs in immunosup- Mechanical ventilation for more than 3 days pressed patients with neutropenia or who are hematopoietic Tra nspla ntation ( hematopoietic ste m cel l/sol id orga n ) stem cell transplant recipients (Table 26). This type of asper gillosis usually begins in the respiratory tract and then Hemodia lysis-associated catheters enters the circulatory system (angioinvasion) (Figure 18). Severe acute pa ncreatitis The most common manifestation is pulmonary (60'1,), but

species (lS%) followed by Aspergillus species (t+.g%), other microbiologically, is often resistant to azoles and polyenes and yeast (such as Cryptococcus species; 6.2%), and mucormycetes occasionally to echinocandins, and has been associated with (including Rhizopus and Mucor species; t.7"/.). numerous health care outbreaks. Initial treatment of candidemia and invasive candidia- sis should include an echinocandin (caspofungin, Systemic Candidiasis micafungin, or anidulafungin) and intravascular device Candida species are the fourth most commonly isolated removal (if present/possible). However, because echinocan- organisms in bloodstream infections and are associated with a dins have poor penetration into the central nervous system mortality rate of 30% lo 4O%. (CNS) and the eye, patients with CNS and eye infections Candidemia can present as an isolated fever or septic should be treated with amphotericin B or an azole; treat- shock. Signs and symptoms of focal infection depend on the ment may also require additional agents depending on host site involved. Meningitis, septic arthritis, and endocarditis are factors and disease extent. For all invasive candidal infec- other forms of invasive infection. The presence of yeast in the tions, prompt treatment initiation is critical, and follow-up respiratory or urinary tract (often in the presence of an blood cultures are required to document clearance. A indwelling catheter) generally represents colonization, not dilated funduscopic examination is also necessary to infection; whereas Candida isolated in blood cultures should exclude endophthalmitis. Speciation, sensitivities, and never be considered a contaminant. follow-up blood culture results guide de-escalation therapy. Diagnosing invasive candidiasis is challenging because Antifungal therapy duration for candidemia should be only 40'2, to 60% of patients with infection have positive blood 14 days from the first negative blood culture result in cultures. Recognizing risk factors (Table 25) for candidiasis is patients with uncomplicated candidemia or 74 to 42 days in essential to avoid delays in initiating antifungal therapy and patients with invasive candidal infections. increased mortality. Nonculture methods, such as the T2mag- KEY POITTS netic resonance assay of blood, provide rapid (within hours) diagnosis of invasive candidal infections and can be performed . Only 40"/,, to 60% of patients with invasive candidal infection have positive blood culture results, so recog- after antifungal therapy initiation. The B-o-glucan assay may nizing risk factors of candidiasis is essential to avoid also be used to support the diagnosis of invasive fungal infec delays in initiating effective antifungal therapy. tions, including candidiasis, particularly among patients with negative blood cultures; however, false-positive results may . Nonculture methods (T2 magnetic resonance and occur. These assays are particularly useful in patients at high B-o-glucan assays) may provide a rapid diagnosis of risk who are receiving antimicrobial agents and are not invasive candidal infections, particularly in patients responding to therapy. with negative blood cultures. When Candidais identified from a sterile site, identifying o Candidaspecies obtained from the respiratory or uri- HVC species and susceptibilities are necessary. Fewer than 15 of nary tract usually represents colonization; treatment is more than 160 known Candida species commonly produce not indicated unless clinical infection is suspected. disease. Additionally, several Candidaspecies (e.g., C. glabrata, . Initial management of candidemia and invasive candi- C. krusei, and C. ouris) have low susceptibility or intrinsic diasis should include an echinocandin and intravascular resistance to antifungal agents. C. ouris is an emerging species device removal (if possible); central nervous system and that presents a serious global threat. It is difficult to identify ocular infections require amphotericin B or an azole and potentially additional agents depending on host TABLE 25. Risk Factors for Systemic Candidiasis factors and disease extent. Centra I venous catheters Broad-spectru m antimicrobial agents Neutropenia Aspergillosis ICU stay for more than 3 days Aspergillus fumigatus is the most common species causing disease in humans, followed by A. flauus, A. niger, and the Tota I parenteral nutrition amphotericin-resistant A. terreus. Aspergillus produces dis Genera I su rgery (especia I ly of the gastroi ntesti na I tract) ease after inhalation of airborne spores (qoZ,) and occasionally Burns by traumatic skin inoculation. Trauma Invasive aspergillosis most often occurs in immunosup- Mechanical ventilation for more than 3 days pressed patients with neutropenia or who are hematopoietic Tra nspla ntation ( hematopoietic ste m cel l/sol id orga n ) stem cell transplant recipients (Table 26). This type of asper gillosis usually begins in the respiratory tract and then Hemodia lysis-associated catheters enters the circulatory system (angioinvasion) (Figure 18). Severe acute pa ncreatitis The most common manifestation is pulmonary (60'1,), but 40

Fungal lnfections ClinicalDisease Microbe Risk Factors Comments Pulmonary MAC Older persons with or without All organisms ubiquitous in the underlying lung disease; cystic fibrosis environment M. kansasii MAC most common cause of Possible person-to-person transmission of M. abscessus pulmonary NTM infection in U.S., M. abscessus among patients with cystic M. fortuitum followed by M. kansasii and M. fibrosis has been reported, but mechanism abscessus of transmission is unclear; otherwise, no M. xenopi evidence of human-to-human transmission Municipal water sources (M. kansasii, M. malmoense M. xenopi) M. szulgai Aspiration (M. foftuitu m) M. simiae M. asiaticum Lymphadenitis MAC More commonly seen in children MAC most common: surgical excision results in>907" cure rate M. abscessus M.fortuitum M. scrofulaceum M. malmoense Skin and soft tissue M. marinum Exposure to fish tanks (M. marinum) Results from direct inoculation

Pulmonary MAC Older persons with or without All organisms ubiquitous in the underlying lung disease; cystic fibrosis environment M. kansasii MAC most common cause of Possible person-to-person transmission of M. abscessus pulmonary NTM infection in U.S., M. abscessus among patients with cystic M. fortuitum followed by M. kansasii and M. fibrosis has been reported, but mechanism abscessus of transmission is unclear; otherwise, no M. xenopi evidence of human-to-human transmission Municipal water sources (M. kansasii, M. malmoense M. xenopi) M. szulgai Aspiration (M. foftuitu m) M. simiae M. asiaticum Lymphadenitis MAC More commonly seen in children MAC most common: surgical excision results in>907" cure rate M. abscessus M.fortuitum M. scrofulaceum M. malmoense Skin and soft tissue M. marinum Exposure to fish tanks (M. marinum) Results from direct inoculation M. ulcerans Surgical-site infections (RGM) M. abscessus Whirlpool footbaths, tattoo ink (RGM) RGM Buruliu ulcer, an extensive disabling ulcer with central necrosis; tropics, not U.S. (M. ulcerans)

M. ulcerans Surgical-site infections (RGM) M. abscessus Whirlpool footbaths, tattoo ink (RGM) RGM Buruliu ulcer, an extensive disabling ulcer with central necrosis; tropics, not U.S. (M. ulcerans) Catheter-related RGM Lon g-te rm catheterizatio n ; bloodstream i nfections immunocompromise Disseminated MAC (in persons lmmunocompromise, especially Clinical presentation: fever, night sweats, with AIDS and CD4 persons with AIDS or those taking weight loss cell count <50/pL) tumor necrosis factor-a inhi bitors (MAC, M. kansasii) Prosthetic valve endocarditis months to M. kansasii years after surgery (M. chimaera); diagnosis Heater-cooler devices in cardiac requires multiple mycobacterial blood M. chimaera surgery(M. chimaera) cultures RGM MAC= Mycobacterium avium complex; NTM = nontuberculous mycobacteria; RGM = rapidly growing mycobacteria; U.S. = United States. "Named for the Buruli district in Uganda, where initial cases were described.

Catheter-related RGM Lon g-te rm catheterizatio n ; bloodstream i nfections immunocompromise Disseminated MAC (in persons lmmunocompromise, especially Clinical presentation: fever, night sweats, with AIDS and CD4 persons with AIDS or those taking weight loss cell count <50/pL) tumor necrosis factor-a inhi bitors (MAC, M. kansasii) Prosthetic valve endocarditis months to M. kansasii years after surgery (M. chimaera); diagnosis Heater-cooler devices in cardiac requires multiple mycobacterial blood M. chimaera surgery(M. chimaera) cultures RGM MAC= Mycobacterium avium complex; NTM = nontuberculous mycobacteria; RGM = rapidly growing mycobacteria; U.S. = United States. "Named for the Buruli district in Uganda, where initial cases were described. Mycoba cte ri u m ka nsasii M. konsasii infection mimics pulmonary tuberculosis with . MAcobacteriumauiumcomplex is a common cause of cavitary lung disease. Predisposing conditions include under- chronic lung infection worldwide, causing cavitary lung lying lung disease, alcoholism, and immunocompromised disease. status. . MAcobactenum obscessus, Mgcobacterium chelonae, and Mycobocterium fortuitum can produce lung disease, adenitis, skin and soft tissue infections, surgical site Rapidly Growing Mycobacteria infections, and catheter-related bloodstream infections. Rapidly growing NTM have been implicated in NTM outbreaks. The most common rapidly growing mycobacterial species include M. abscessus, M. chelonae, and M. fortuitum. M. obscessus is the most common. Considering its intrin- Fungal lnfections sic drug resistance and increased prevalence, it is one of the The incidence of fungal infections is increasing because of the most difficult to treat. Most of these mycobacteria are associ- increased recognition of these infections and an increase in ated with chronic pulmonary infections and nonhealing the population at risk worldwide. Most commonly encoun- ulcers unresponsive to appropriate antibiotic therapy. tered infections in North America are caused by Candida

Mycoba cte ri u m ka nsasii M. konsasii infection mimics pulmonary tuberculosis with . MAcobacteriumauiumcomplex is a common cause of cavitary lung disease. Predisposing conditions include under- chronic lung infection worldwide, causing cavitary lung lying lung disease, alcoholism, and immunocompromised disease. status. . MAcobactenum obscessus, Mgcobacterium chelonae, and Mycobocterium fortuitum can produce lung disease, adenitis, skin and soft tissue infections, surgical site Rapidly Growing Mycobacteria infections, and catheter-related bloodstream infections. Rapidly growing NTM have been implicated in NTM outbreaks. The most common rapidly growing mycobacterial species include M. abscessus, M. chelonae, and M. fortuitum. M. obscessus is the most common. Considering its intrin- Fungal lnfections sic drug resistance and increased prevalence, it is one of the The incidence of fungal infections is increasing because of the most difficult to treat. Most of these mycobacteria are associ- increased recognition of these infections and an increase in ated with chronic pulmonary infections and nonhealing the population at risk worldwide. Most commonly encoun- ulcers unresponsive to appropriate antibiotic therapy. tered infections in North America are caused by Candida 39

Fungal lnfections I(EY POIffTS TABLE 2?. lndicators of Poor Prognosis in Cryptococcal o Aspergillus infection can manifest in various ways, Meningitis including invasive pulmonary aspergillosis, chronic Altered mentalstate necrotizing pulmonary aspergillosis, and allergic bron Visualabnormalities chopulmonary aspergillosis. CSF leukocyte count less than 20/ttL(20 x 106/L) o Tissue biopsy is frequently necessary to establish a defini- CSF cryptococcal antigen assay greater than 1 :1 0,000 tive diagnosis of invasive aspergillosis; however, early No previous antiretroviral therapy in those with HIV infection chest CT, the serum or bronchoalveolar lavage, and galac, CSF = cerebrospinal fluid tomannan assay results are typically used to establish a presumptive diagnosis in patients at high risk of infection. . Voriconazole is first-line treatment for invasive or patients. Occasionally, blood culture results are positive, indi- chronic pulmonary Aspergillus infection. cating disseminated disease. Symptoms of increased ICP may be improved by cerebro- spinal fluid removal through sequential lumbar punctures or Cryptococcosis insertion of a shunt. Aggressive ICP reduction decreases early morbidity and mortality. Amphotericin B plus flucytosine is the Cryptococcus is an encapsulated yeast that is ubiquitous in the treatment of choice for induction therapy and is effective in environment. Patients with immune suppression, such as more than 90% of patients. After at least 2 weeks of successful AIDS, neutropenia, cirrhosis, or organ transplantation are induction therapy, consolidation therapy with fluconazole may most commonly infected, but it can occur in healthy persons. be initiated, continuing for at least 8 weeks. HlV-infected C. neoformons is the most commonly identified species, but C. patients require maintenance (suppressive) therapy with flu- gottii is seen with increasing frequency in the Pacific Northwest conazole for at least l year after successful treatment and until region of North America and appears to be spreading south- they have maintained their CD4 cell counts greater than 100/pL ward. Pathogenesis of cryptococcosis involves inhalation of for a minimum of 3 months and have an undetectable viral load. spores into the respiratory tract, followed by dissemination into susceptible tissues, especially the CNS. KEY POIl{TS Cryptococcal infection most commonly manifests in the o In patients with suspected cryptococcal infection, cerebro- CNS, and cryptococcosis is the most common cause of fungal spinal fluid (CSF) analysis and documentation of the CSF meningitis worldwide. Clinical manifestations are listed in opening pressure are necessary; CSF and serum cryptococ- Table 28, and indicators of poor prognosis are provided in cal antigen are highly sensitive for identi$ring infection. Table 29. Because patients with cryptococcosis-related . Amphotericin B plus flucytosine is effective in more increased intracranial pressure (lCP) may develop sudden than 90% of patients; for those with elevated intracra- blindness, deafness, or coma, opening pressure should always nial pressure (lCP), cerebrospinal fluid removal through be documented during initial lumbar puncture. Cerebrospinal sequential lumbar punctures or shunt insertion can fluid analysis is essential to diagnose CNS involvement; classic reduce ICB thus reducing morbidi$ and mortaiity. findings include an increased leukocyte count (mainly lym- phocytes), an increased protein level, a low to normal glucose level, and the presence of cryptococcal antigen. Serum crypto- Histoplasmosis coccal antigen is positive in greater than 95% of infected Histoplasma capsulatum is one of the most common endemic mycoses in the world. Acquired by inhalation of conidia, this TABLE 28. Clinical Features of Cryptococcosis organism primarily produces asymptomatic pulmonary infec Signs and Symptoms of Meningeal lnfection (% Affected) tion. It is distributed along the Mississippi River Valley (Ohio, Fever (607"-90%) Missouri, Indiana, Mississippi) in the United States, in Central Headache (80%-90%) and South America, the Caribbean, and in regions of Africa, Nausea/vomiting ( - 50%) Australia, and India. Histoplasmosis most commonly presents with acute res- Meningism (30%) piratory symptoms. Other presentations include disseminated Altered mental status (207"-30%) infections (immunosuppressed host), chronic pulmonary Extrameningeal I nfection Sites symptoms, rheumatologic symptoms, pericarditis, and scle- Lung rosing mediastinitis. The Histoplasma urinary antigen assay has a sensitivity Bone marrow and specificity of greater than 85% in acute and disseminated Skin infection but less than 50% in chronic infection. Identification Prostate (can be a cryptic reservoir of infection) by tissue culture can be a lengthy process but is indicated for

I(EY POIffTS TABLE 2?. lndicators of Poor Prognosis in Cryptococcal o Aspergillus infection can manifest in various ways, Meningitis including invasive pulmonary aspergillosis, chronic Altered mentalstate necrotizing pulmonary aspergillosis, and allergic bron Visualabnormalities chopulmonary aspergillosis. CSF leukocyte count less than 20/ttL(20 x 106/L) o Tissue biopsy is frequently necessary to establish a defini- CSF cryptococcal antigen assay greater than 1 :1 0,000 tive diagnosis of invasive aspergillosis; however, early No previous antiretroviral therapy in those with HIV infection chest CT, the serum or bronchoalveolar lavage, and galac, CSF = cerebrospinal fluid tomannan assay results are typically used to establish a presumptive diagnosis in patients at high risk of infection. . Voriconazole is first-line treatment for invasive or patients. Occasionally, blood culture results are positive, indi- chronic pulmonary Aspergillus infection. cating disseminated disease. Symptoms of increased ICP may be improved by cerebro- spinal fluid removal through sequential lumbar punctures or Cryptococcosis insertion of a shunt. Aggressive ICP reduction decreases early morbidity and mortality. Amphotericin B plus flucytosine is the Cryptococcus is an encapsulated yeast that is ubiquitous in the treatment of choice for induction therapy and is effective in environment. Patients with immune suppression, such as more than 90% of patients. After at least 2 weeks of successful AIDS, neutropenia, cirrhosis, or organ transplantation are induction therapy, consolidation therapy with fluconazole may most commonly infected, but it can occur in healthy persons. be initiated, continuing for at least 8 weeks. HlV-infected C. neoformons is the most commonly identified species, but C. patients require maintenance (suppressive) therapy with flu- gottii is seen with increasing frequency in the Pacific Northwest conazole for at least l year after successful treatment and until region of North America and appears to be spreading south- they have maintained their CD4 cell counts greater than 100/pL ward. Pathogenesis of cryptococcosis involves inhalation of for a minimum of 3 months and have an undetectable viral load. spores into the respiratory tract, followed by dissemination into susceptible tissues, especially the CNS. KEY POIl{TS Cryptococcal infection most commonly manifests in the o In patients with suspected cryptococcal infection, cerebro- CNS, and cryptococcosis is the most common cause of fungal spinal fluid (CSF) analysis and documentation of the CSF meningitis worldwide. Clinical manifestations are listed in opening pressure are necessary; CSF and serum cryptococ- Table 28, and indicators of poor prognosis are provided in cal antigen are highly sensitive for identi$ring infection. Table 29. Because patients with cryptococcosis-related . Amphotericin B plus flucytosine is effective in more increased intracranial pressure (lCP) may develop sudden than 90% of patients; for those with elevated intracra- blindness, deafness, or coma, opening pressure should always nial pressure (lCP), cerebrospinal fluid removal through be documented during initial lumbar puncture. Cerebrospinal sequential lumbar punctures or shunt insertion can fluid analysis is essential to diagnose CNS involvement; classic reduce ICB thus reducing morbidi$ and mortaiity. findings include an increased leukocyte count (mainly lym- phocytes), an increased protein level, a low to normal glucose level, and the presence of cryptococcal antigen. Serum crypto- Histoplasmosis coccal antigen is positive in greater than 95% of infected Histoplasma capsulatum is one of the most common endemic mycoses in the world. Acquired by inhalation of conidia, this TABLE 28. Clinical Features of Cryptococcosis organism primarily produces asymptomatic pulmonary infec Signs and Symptoms of Meningeal lnfection (% Affected) tion. It is distributed along the Mississippi River Valley (Ohio, Fever (607"-90%) Missouri, Indiana, Mississippi) in the United States, in Central Headache (80%-90%) and South America, the Caribbean, and in regions of Africa, Nausea/vomiting ( - 50%) Australia, and India. Histoplasmosis most commonly presents with acute res- Meningism (30%) piratory symptoms. Other presentations include disseminated Altered mental status (207"-30%) infections (immunosuppressed host), chronic pulmonary Extrameningeal I nfection Sites symptoms, rheumatologic symptoms, pericarditis, and scle- Lung rosing mediastinitis. The Histoplasma urinary antigen assay has a sensitivity Bone marrow and specificity of greater than 85% in acute and disseminated Skin infection but less than 50% in chronic infection. Identification Prostate (can be a cryptic reservoir of infection) by tissue culture can be a lengthy process but is indicated for 42

Fungal lnfections TABLE 26. Risk Factors for lnvasive Aspergillosis TAELE 27. Clinical Features of lnvasive Aspergillosis Major Minor Feveru Neutropenia COPD treated with Pulmonary findings glucocorticoids Pleuritic chest pain, pleural rub G raft-versus-host d isease Cirrhosis Dry cough Cytomega lovi rus i nfection/ reactivation Following influenza Dyspnea Hematopoietic stem cel I Burns Hemoptysis: usually minor but occasionally catastrophic transplantation Solid organ malignancies Chest radiograph: potentially normal in early disease; Solid organ transplantation infiltrates, infarction, nodules, and cavitation in late disease lmmunosuppressants System ic g ucocorticoids I Focal neurologic deficits (>1 m g/kg/d) or inhaled Cyclosporine steroi ds Methotrexate M ultiorgan dysfunction Hematologic malignancies Cyclophosphamide Hemorrhagic skin lesions Advanced HIV with CD4 cell uFrequently the only feature present.

Neutropenia COPD treated with Pulmonary findings glucocorticoids Pleuritic chest pain, pleural rub G raft-versus-host d isease Cirrhosis Dry cough Cytomega lovi rus i nfection/ reactivation Following influenza Dyspnea Hematopoietic stem cel I Burns Hemoptysis: usually minor but occasionally catastrophic transplantation Solid organ malignancies Chest radiograph: potentially normal in early disease; Solid organ transplantation infiltrates, infarction, nodules, and cavitation in late disease lmmunosuppressants System ic g ucocorticoids I Focal neurologic deficits (>1 m g/kg/d) or inhaled Cyclosporine steroi ds Methotrexate M ultiorgan dysfunction Hematologic malignancies Cyclophosphamide Hemorrhagic skin lesions Advanced HIV with CD4 cell uFrequently the only feature present. count <50/pL lnjection drug use (rare) First-line treatment of invasive aspergillosis is voricona- G ram-negative bacteria I pneumonia zole; alternative agents include liposomal amphotericin B, isavuconazole, or other lipid formulations of amphotericin B. When possible, reversing immunosuppression improves treat- sinusitis, brain abscess, and disseminated infection may ment response. also occur. Timely diagnosis is essential to decrease mor- Chronic necrotizing aspergillosis is a semi-invasive, indo- bidity and mortality. However, symptoms and signs are lent form of infection that does not typically disseminate and nonspecific (Table 27), and blood culture results are gener- may occur in patients who have lesser degrees of immunosup- ally negative. Therefore, when invasive pulmonary asper- pression (such as those who take chronic glucocorticoids) or gillosis is suspected, bronchoscopy, bronchoalveolar lavage, chronic pulmonary disease. Treatment is similar to that for and, if possible, tissue biopsy are recommended to estab- invasive pulmonary aspergillosis. lish the diagnosis. Early CT of the chest, along with the Allergic bronchopulmonary aspergillosis results from bronchoalveolar lavage and serum galactomannan assay hypersensitivity to Aspergillus species colonizing the respira- results, can be useful in establishing a diagnosis of invasive tory tract. This disorder is seen primarily in patients with infection; septic emboli (nodules, often with a "halo sign") cystic fibrosis and occasionally in those with asthma (see (Figure 19), thromboembolic pulmonary infarction (wedge- MKSAP 19 Pulmonary and Critical Care Medicine for more shaped peripheral densities), or necrosis with cavitation information) . Because allergic bronchopulmonary aspergillo- (air-crescent sign) are typical findings, especially in neu- sis represents a hypersensitivity response, systemic glucocor- tropenic patients and hematopoietic stem cell transplant ticoids are the mainstay oftreatment (sometimes supplemented recipients. by antifungal therapy with an azole).

count <50/pL lnjection drug use (rare) First-line treatment of invasive aspergillosis is voricona- G ram-negative bacteria I pneumonia zole; alternative agents include liposomal amphotericin B, isavuconazole, or other lipid formulations of amphotericin B. When possible, reversing immunosuppression improves treat- sinusitis, brain abscess, and disseminated infection may ment response. also occur. Timely diagnosis is essential to decrease mor- Chronic necrotizing aspergillosis is a semi-invasive, indo- bidity and mortality. However, symptoms and signs are lent form of infection that does not typically disseminate and nonspecific (Table 27), and blood culture results are gener- may occur in patients who have lesser degrees of immunosup- ally negative. Therefore, when invasive pulmonary asper- pression (such as those who take chronic glucocorticoids) or gillosis is suspected, bronchoscopy, bronchoalveolar lavage, chronic pulmonary disease. Treatment is similar to that for and, if possible, tissue biopsy are recommended to estab- invasive pulmonary aspergillosis. lish the diagnosis. Early CT of the chest, along with the Allergic bronchopulmonary aspergillosis results from bronchoalveolar lavage and serum galactomannan assay hypersensitivity to Aspergillus species colonizing the respira- results, can be useful in establishing a diagnosis of invasive tory tract. This disorder is seen primarily in patients with infection; septic emboli (nodules, often with a "halo sign") cystic fibrosis and occasionally in those with asthma (see (Figure 19), thromboembolic pulmonary infarction (wedge- MKSAP 19 Pulmonary and Critical Care Medicine for more shaped peripheral densities), or necrosis with cavitation information) . Because allergic bronchopulmonary aspergillo- (air-crescent sign) are typical findings, especially in neu- sis represents a hypersensitivity response, systemic glucocor- tropenic patients and hematopoietic stem cell transplant ticoids are the mainstay oftreatment (sometimes supplemented recipients. by antifungal therapy with an azole). r*. II DIIE: llav 2tl 1t]7"1 il,t ilz DFBT' Jls.rr Er.t]\t

r*. II DIIE: llav 2tl 1t]7"1 il,t ilz DFBT' Jls.rr Er.t]\t 1 ! k\' 1 FIGURE 1 9. CT scan showing typical findings suggesting aspergillosis with a F lG U R E 1 8. Aspergillus in lung tissue; methenamine silver stain. 0rganisms "halo sign," which is an area of low attenuation surrounding a pulmonary nodule appear as septate hyaline hyphae with dichotomous acute angle (45") branching that reflects hemorrhage into the adjacent tissues. 41