The epidemiology of opportunistic mycoses is evolving. In certain populations, the frequency of opportunistic mycoses is increasing due to use of immune-modulating therapies, a higher frequency of invasive procedures and devices, and changes in climate and regional environments. In other populations, the frequency of opportunistic mycoses is decreasing, due to antifungal prophylaxis in high-risk patients and reconstitution of immunity with antiretroviral therapy for human immunodeficiency virus (HIV) infection. Heightened clinical awareness of fungal infections and the availability of improved diagnostics contribute to their increased recognition, and the availability of newer antifungal drugs provides broader therapeutic options.
Fungi are eukaryotic microorganisms that grow as yeasts or molds. Endemic fungi such as Blastomyces dermatitidis and Histoplasma capsulatum, reviewed in the preceding chapter, are considered dimorphic fungi, growing as molds at room temperature and yeast or yeastlike forms at body temperature. Yeasts are unicellular fungi and exist as single rounded or elongated cells and reproduce primarily by budding. The primary opportunistic yeasts reviewed here are Candida and Cryptococcus . In contrast, molds are multicellular filamentous fungi composed of hyphae that grow by branching with extension at the hyphal apices. Clinically relevant opportunistic molds are often categorized on the basis of their hyphae. Septate hyphae contain cross walls that divide the hyphae into compartments, whereas aseptate or sparsely septate hyphae either lack or infrequently demonstrate these cross walls, respectively. This distinction can be used in identifying molds in respiratory samples and tissue histopathology. Aseptate (or sparsely septate) hyphae are seen in mucormycosis, caused by molds such as Mucor and Rhizopus (historically referred to as Zygomycetes ). Opportunistic molds producing septate hyphae are further subdivided as hyaline or dematiaceous molds. Hyaline molds produce colorless or lightly pigmented hyphae in tissue and infections are referred to hyalohyphomycosis . Dematiaceous or black molds are septate molds that contain melanin in their cell walls, resulting in brown pigmentation, which can be seen in histopathology specimens and under direct microscopic examination. Infections with the dematiaceous molds are referred to as phaeohyphomycoses .
This chapter discusses the most common opportunistic mycoses of the respiratory tract and their epidemiology, clinical characteristics, diagnosis, and treatment. The chapter begins with discussion of the currently available antifungal agents.
Rapid initiation of antifungal therapy is essential in the management of invasive fungal infections (IFIs). The primary classes of antifungal agents target either the plasma membrane or the cell wall. Amphotericin B (AmB) was previously the primary antifungal agent for IFIs; however, newer antifungals, including the extended spectrum azoles and echinocandins, have broadened the therapeutic options, and lipid formulations of AmB have less toxicity. In addition, combination therapy should be considered in certain IFIs. The following section is a broad overview of the major antifungal agents. Tables 38-1 and 38-2 summarize details of the available agents including their spectrum of activity, primary toxicities, interactions, recommendations for therapeutic drug monitoring, and the U.S. Food and Drug Administration (FDA) approved indications.
|Antifungal Therapy||Fungal Spectrum of Activity||Therapeutic Drug Monitoring||* Major Adverse Effects||* Major Drug Interactions|
|Amphotericin B deoxycholate (AmB-d, Fungizone) |
Lipid formulations of AmB:
Liposomal AmB (LAmB, AmBisome)
AmB Lipid Complex (ABLC, Abelcet)
AmB Colloidal Dispersion (ABCD, Amphotec)
|Aspergillus (resistance in A. terreus, reduced susceptibility in others including A. nidulans , A. ustus ) |
Candida (resistance in C. lusitaniae )
Dematiaceous molds (e.g., Alternaria , Bipolaris , Cladophialophora , Exserohilum, Rhinocladiella )
Endemic fungi (e.g., blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, Penicillium marneffei, Sporotrichosis)
Mucormycosis (e.g., Rhizopus , Rhizomucor, Mucor)
Non- Aspergillus hyaline molds (resistance in some species including Fusarium and Scedosporium , also Purpureocillium lilacinum)
|TDM not recommended||Normocytic, normochromic anemia, hypokalemia, hypomagnesemia |
Infusion-related reactions (e.g., chills/rigors, fever, nausea, vomiting; can be reduced with preinfusion acetaminophen and diphenhydramine; meperidine may be used for rigors)
Nephrotoxicity (can be reduced with hydration, often 500 mL normal saline given before and after infusion)
Nephrotoxicity may be reduced with the lipid formulations of AmB
|Close monitoring when used with other nephrotoxic therapies|
|Fluconazole (FLU, Diflucan)||Candida (intrinsic resistance with C. krusei , variable susceptibility to C. glabrata ) |
Some activity against endemic mycoses (e.g., coccidioidomycosis)
|TDM not recommended |
Renal dose adjustment is required
|Alopecia (with prolonged therapy |
GI effects (diarrhea, nausea, vomiting)
Cardiac effects (has been associated with QT prolongation and torsades de pointes in patients with other risks
|Fluconazole is a potent CYP2C9 inhibitor and moderate CYP3A4 inhibitor |
May interact with drugs metabolized through these enzyme systems
Drugs that reduce FLU concentration: rifampin, rifabutin
FLU increases concentration of carbamazepine, phenytoin, midazolam rifabutin, sirolimus, some NSAIDs, tacrolimus, vinca alkaloids, zidovudine
–QT prolongation with astemizole, haloperidol, macrolides
–Potentiation of warfarin
–CNS side effects with all-trans retinoic acid
–Increased risk of rhabdomyolysis with atorvastatin, fluvastatin, simvastatin
|Itraconazole (ITRA, Sporanox)||Aspergillus (resistance in some isolates) |
Candida (including C. krusei , C. glabrata, and C. tropicalis )
Endemic mycoses (including paracoccidioidomycosis)
ITRA is not usually active against mucormycosis or many Fusarium and Scedosporium spp
|TDM is recommended |
Random concentration measured after ≥ 2 weeks of therapy with goal ≥ 1 µg/mL
For HPLC, the goal concentration is sum of ITRA and active metabolite, hydroxy-ITRA
Capsules: take with food and acidic beverage (e.g., cola); avoid proton pump-inhibitors and H2 blockers, which decrease absorption
Solution: take on empty stomach
Blood concentrations ~30% higher with ITRA solution vs. ITRA capsule formulation
|Adrenal insufficiency (long-term use, rare) |
CHF (avoid in patients with ventricular dysfunction or history of CHF)
GI effects (diarrhea, nausea, vomiting)
QT prolongation and torsades de pointes in patients with multiple risks
|ITRA is a potent CYP3A4 inhibitor and substrate of CYP3A4; may interact with drugs metabolized through this enzyme system |
Drugs that decrease ITRA concentration: carbamazepine, nevirapine, phenytoin, rifabutin, rifampin
Drugs that increase ITRA concentration: macrolide antibiotics, protease inhibitors
ITRA increases concentration of busulfan, cyclosporine, carbamazepine, digoxin, dihydropyridines, midazolam, rifabutin, ritonavir, sirolimus, tacrolimus, vinca alkaloids
–QT prolongation with dofetilide, pimozide, quinidine
–Increased risk of rhabdomyolysis with atorvastatin, fluvastatin, simvastatin
|Posaconazole (POSA, Noxafil)||Aspergillus |
Endemic fungi, limited data (blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis)
Non- Aspergillus hyaline molds (species-dependent, limited data)
|TDM is recommended when POSA used for prophylaxis and treatment of systemic infections. Recommendations apply to POSA suspension. See text regarding extended-release tablet and intravenous formulation. |
Trough concentrations measured ≥ day 8 of therapy with goal concentration ≥ 0.7 µg/mL
In patients not responding to treatment, consider troughs > 1 to 1.25 µg/mL
Administer with high-fat meal, acidic beverage (e.g., cola, ginger ale) and avoid proton pump inhibitors
Note that dose escalation beyond 800 mg/day is unlikely to result in higher concentration as absorption is saturable; increased concentration is best achieved with more frequent dosing intervals (e.g., 400 mg twice daily should be changed to 200 mg by mouth four times daily)
Does not require renal dose adjustment
|GI effects (diarrhea, nausea, vomiting) |
QT prolongation (less common than with ITRA or VORI)
|POSA is an inhibitor of CYP3A4 and substrate of P-glycoprotein; may interact with drugs metabolized via these systems |
Drugs that decrease POSA concentration: cimetidine, efavirenz, esomeprazole, phenytoin, rifabutin
POSA increases concentration of atazanavir, cyclosporine, digoxin, dihydropyridines, midazolam, rifabutin, ritonavir, sirolimus, tacrolimus, vinca alkaloids
–QT prolongation with pimozide, quinidine
–Increased risk of rhabdomyolysis with atorvastatin, lovastatin, simvastatin
–Avoid use with ergot alkaloids
|Voriconazole (VORI, VFEND)||Aspergillus |
Endemic fungi, limited data (blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis)
Non- Aspergillus hyaline molds including Acremonium, Fusarium , Paecilomyces , Scedosporium, and Trichoderma
VORI is not active against mucormycosis
|TDM for prophylaxis and treatment of systemic infections is recommended |
Trough concentration measured ≥ day 5 of therapy with goal trough ≥ 1.0 µg/mL to 5.5 µg/mL; some argue for target of ≥ 2 µg/mL for treatment
Administer 1 hour before or after a meal
Dose adjustment of the IV formulation is required in patients with CrCl < 50 mL/min due to potential accumulation of sulfobutyl ether beta-cyclodextrin sodium (solubilizing vehicle)
|Fluorosis and periostitis |
GI effects (diarrhea, nausea, vomiting)
Skin rash, photosensitivity
Visual disturbances (e.g., photopsia, color-vision change, photophobia, other visual hallucinations), rare optic neuritis and papilledema
Long-term use and association with skin cancer (see text)
|VORI is substrate of CYP2C19, CYP2C9, and CYP3A4 and is an inhibitor of CYP3A4 |
May interact with drugs metabolized via these systems
Drugs that decrease VORI concentration: carbamazepine, efavirenz, phenobarbital, phenytoin, rifabutin, rifampin, ritonavir, St. Johns wart
Drugs that increase VORI concentration: fluconazole, certain oral contraceptives
VORI increases concentration of cyclosporine, efavirenz, fentanyl, methadone, some NSAIDs, phenytoin, rifabutin, sirolimus, tacrolimus
–QT prolongation with astemizole, pimozide or quinidine
–Potentiation of warfarin
–Avoid use with ergot alkaloids
|Caspofungin (CAS, Cancidas) |
Micafungin (MICA, Mycamine)
Anidulafungin (ANI, Eraxis)
|Aspergillus (fungistatic) |
Candida spp (fungicidal, elevated MICs reported with C. parapsilosis and C. guilliermondii )
Echinocandins have moderate activity against the mycelial phase of dimorphic fungi but lack activity against the yeast phase and are not used in treatment of endemic mycoses
Echinocandins lack significant activity against mucormycosis, dematiaceous molds, non- Aspergillus hyaline molds (although some use in combination therapy, see text)
|TDM not recommended |
No dosage adjustment required for renal dysfunction
|GI effects (diarrhea, nausea, vomiting) |
Infusion reactions (histamine-induced, greatest with CAS)
Injection site thrombophlebitis
|Minimal drug interactions compared with other antifungal drugs |
In general, poor CYP substrates (CAS/MICA) and/or weak CYP inhibitors of 3A4 (MICA) and not affected by P-glycoprotein
ANI undergoes no hepatic metabolism, only chemical degradation
CAS concentration decreased with rifampin, efavirenz, nevirapine, phenytoin, carbamazepine
MIC increases sirolimus and nifedipine concentration
|Flucytosine (5-FC, Ancobon)||Aspergillus |
Dematiaceous fungi (some, including Phialophora and Cladosporium spp)
Sporothrix schenckii (variable MICs)
5-FC is used in combination therapy, typically with AmB
|Cryptococcal infection: concentration measured on day 3 to 5 of therapy, 2 hours after dose, target: 30 to 80 µg/mL |
When TDM not available both renal function and cell counts must be closely monitored
Renal dose adjustment is required
|Bone marrow suppression |
GI effects (abdominal pain, diarrhea, nausea, vomiting)
|Aluminum hydroxide or magnesium hydroxide suspension (delays 5-FC absorption) |
Cytarabine (cytosine arabinoside, competitive inhibitor of 5-FC)
Close monitoring when used with other nephrotoxic and myelosuppressive therapies
|Terbinafine (TBF, Lamisil)||Aspergillus |
Some activity (usually in combination therapy) against non- Aspergillus hyaline molds (species dependent), dematiaceous molds (species dependent)
|TDM not recommended |
Clearance is decreased by 50% when CrCl ≤ 50 mL/min
|Depressive symptoms |
Smell and taste disturbances
|TBF is an inhibitor of CYP2D6 |
May interact with drugs metabolized via this system, including tricyclic antidepressants, selective serotonin reuptake inhibitors, beta blockers, antiarrhythmic class 1C (e.g., flecainide, propafenone)
Drugs that decrease TBF: rifampin
Drugs that increase TBF: fluconazole
TBF may decrease cyclosporine concentration
|Antifungal Agent||FDA Approved Indications|
|Amphotericin B deoxycholate (Fungizone), Apothecon |
Generic available (U.S.): yes
|Treatment of potentially life-threatening fungal infections:|
|Mucormycosis (including susceptible species of the genera Absidia , Mucor , and Rhizopus and infections due to related susceptible species of Conidiobolus and Basidiobolus)|
|Amphotericin B lipid complex, ABLC (Abelcet), Sigma-Tau Pharmaceuticals |
Generic available (U.S.): no
|Treatment of invasive fungal infections in patients who are refractory or intolerant of conventional amphotericin B therapy|
|AmB Colloidal Dispersion, ABCD (Amphotec), Alkopharma |
Generic available (U.S.): no
|Treatment of invasive aspergillosis in patients with renal impairment or who are refractory or intolerant of conventional amphotericin B therapy|
|Liposomal amphotericin B (AmBisome), Astellas Pharma US |
Generic available (U.S.): no
|Aspergillosis and candidiasis (in patients with renal impairment or who are refractory or intolerant of conventional amphotericin B therapy)|
|Cryptococcosis (in HIV patients with cryptococcal meningitis and for cryptococcal infections in patients with renal impairment or who are refractory or intolerant of conventional amphotericin B therapy)|
|Empirical therapy for presumed fungal infection in febrile neutropenic patients|
|Fluconazole (Diflucan), Pfizer |
Generic available (U.S.): yes
|Candidiasis (including chronic mucocutaneous candidiasis, esophageal and oropharyngeal candidiasis, Candida urinary tract infection and peritonitis, other systemic Candida infections including candidemia, disseminated candidiasis and pneumonia, vaginal candidiasis)|
|Prophylaxis for patients undergoing HSCT who receive cytotoxic chemotherapy and/or radiation therapy|
|Itraconazole (Sporanox), Janssen Pharmaceuticals |
Generic available (U.S.): yes
|Aspergillosis (pulmonary and extrapulmonary in patients who are intolerant or refractory to amphotericin B)|
|Blastomycosis (pulmonary and extrapulmonary infection)|
|Histoplasmosis (chronic pulmonary disease and disseminated nonmeningeal infection)|
|Onychomycosis of the fingernails and toenails due to dermatophytes (non-immunocompromised only)|
|Posaconazole (Noxafil), Merck & Co., Inc. |
Generic available (U.S.): no
|Treatment of oropharyngeal candidiasis including that which is refractory to itraconazole and/or fluconazole|
|Prophylaxis of invasive aspergillosis and invasive candidiasis (in severely immunocompromised patients such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy)|
|Voriconazole (VFEND), Pfizer |
Generic available (U.S.): yes
|Candidiasis (esophageal candidiasis, candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds)|
|Serious infections caused by Scedosporium apiospermum and Fusarium species, including Fusarium solani , in patients intolerant of, or refractory to, other therapy|
|Caspofungin (Cancidas), Merck & Co., Inc |
Generic available (U.S.): no (approval pending)
|Aspergillosis (invasive disease in patients who are refractory to or intolerant of other therapies such as amphotericin B, lipid formulations of amphotericin B or itraconazole).|
|Candidiasis (esophageal candidiasis, candidemia, and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections)|
|Empirical therapy for presumed fungal infections in febrile neutropenic patients|
|Micafungin (Mycamine), Astellas Pharma US |
Generic available (U.S.): no
|Treatment of candidiasis (esophageal candidiasis, candidemia, acute disseminated candidiasis, peritonitis, and abscesses)|
|Prophylaxis of Candida infections in patients undergoing HSCT|
|Anidulafungin (Eraxis), Pfizer |
Generic available (U.S.): no
|Treatment of candidiasis (esophageal candidiasis, candidemia, and other forms of Candida infections including intra-abdominal abscess and peritonitis)|
|Flucytosine (Ancobon), Valeant Pharmaceuticals |
Generic available (U.S.): yes
|Candidiasis (susceptible strains causing septicemia, endocarditis, urinary tract infections, and pneumonia)|
|Cryptococcosis (susceptible strains causing meningitis, pulmonary infections, septicemia, and urinary tract infections|
|Note that flucytosine should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to flucytosine monotherapy|
|Terbinafine (Lamisil), Novartis |
Generic available (U.S.): yes, product dependent
|Treatment of onychomycosis of the toenail or fingernail due to dermatophytes|
The polyenes were the first antifungals in clinical use and include nystatin and AmB. AmB binds to ergosterol, an essential component of the fungal cell membrane. AmB binding increases membrane permeability and causes fungal cell death. AmB also induces proinflammatory cytokines by activating Toll-like receptor 2, which contributes to the acute side effects of fever and myalgias, and may augment host responses to fungal infection. AmB has activity against multiple fungal pathogens including Aspergillus, Candida, the endemic mycoses (e.g., blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis) and mucormycosis. However, certain fungi, including Aspergillus terreus, Candida lusitaniae, Scedosporium prolificans, and Trichosporon beigelii, may be intrinsically resistant to AmB, and other pathogens such as Fusarium species and the dematiaceous molds may have high minimal inhibitory concentrations (MICs) to AmB.
The lipid formulations of AmB were introduced to reduce nephrotoxicity seen with conventional amphotericin, termed amphotericin B desoxycholate (AmB-d). The lipid formulations of AmB are now often used first-line, particularly in patients with renal dysfunction or on concurrent nephrotoxic medications. Lipid formulations include liposomal AmB (LAmB) and AmB lipid complex (ABLC). Due to its ten- to sixty-fold lower cost compared with the lipid formulations, conventional AmB-d continues to have an important role in treatment of patients at low risk of toxicity, such as outpatients without comorbidities.
Certain drugs containing an imidazole ring have antimicrobial activity. N-substituted azoles, termed triazoles, have antifungal activity and acceptable host toxicity, and have emerged as a primary class of antifungals for treatment and prevention of IFIs. For the purpose of brevity, the antifungal triazoles are commonly termed azoles, as they are in this chapter. The most widely used azoles are fluconazole, itraconazole, posaconazole, and voriconazole. These agents act on the fungal cell membrane by inhibiting the cytochrome P-450–dependent 14-α-demethylase, a critical enzyme in the conversion of lanosterol to ergosterol. The azoles are fungistatic or fungicidal, depending on the specific azole and fungal species. Immunomodulating effects have been described with azoles and may contribute to their efficacy. While earlier azoles, such as fluconazole, are active against yeasts, the expanded spectrum azoles, including voriconazole and posaconazole, are active against yeasts and molds. Fluconazole is active against Cryptococcus and Candida, and has variable activity against endemic fungi, including Coccidioides. Candida krusei is intrinsically resistant to fluconazole and high-level resistance is emerging among some non- albicans Candida species, including C. glabrata . Itraconazole has little role in treatment of opportunistic fungal infections; its principal indications are treatment of indolent, non– central nervous system (CNS) blastomycosis or histoplasmosis, and as an alternative to fluconazole for treatment of indolent non-CNS coccidioidomycosis. Itraconazole is also indicated in treatment of allergic bronchopulmonary aspergillosis (ABPA). Itraconazole exhibits highly variable absorption and pharmacokinetics; therapeutic drug monitoring is essential to guide optimal dosing for an individual patient.
The extended-spectrum azoles have activity against many molds, including Aspergillus, non- Aspergillus hyaline hyphomycetes such as Fusarium, Scedosporium, and Paecilomyces, and some dematiaceous molds. Voriconazole is the drug of choice for the treatment of invasive Aspergillus infections. Among the azoles, only posaconazole has activity against the agents of mucormycosis.
The echinocandins, including caspofungin, micafungin, and anidulafungin, are increasingly used given their efficacy, tolerability, lack of drug interactions, and the prevalence of azole-resistant Candida species. Unlike AmB and the azoles, the echinocandins act on the fungal cell wall via inhibition of (1→3)-β-D-glucan synthase, thereby inhibiting production of (1→3)-β-D-glucan (β-D-glucan), an essential component of the fungal cell wall. Echinocandins are fungicidal against multiple Candida species, including C. albicans, C. dubliniensis, C. glabrata, and C. krusei; however, certain Candida species, such as C. guilliermondii and C. parapsilosis, typically have higher MICs. The echinocandins are fungistatic rather than fungicidal against filamentous fungi such as Aspergillus species because their activity is restricted to sites where the fungal cell wall is actively growing (i.e., hyphal tips and branching junctional cells), and are not active on subapical hyphal cells. Echinocandins lack significant activity against other fungal pathogens such as Cryptococcus, Mucorales, and Trichosporon species and the endemic fungi. The immunostimulatory effects of echinocandins on monocytes and monocyte-derived macrophages may be of particular importance against Aspergillus.
Flucytosine is an antimetabolite that inhibits fungal DNA and protein synthesis. It is used in combination with other antifungal agents given the high frequency of emergence of resistance with monotherapy. It is fungistatic or fungicidal, depending upon the organism, and is most often used in combination with AmB against Cryptococcus and in severe Candida infections such as endocarditis and CNS infections.
Terbinafine is a synthetic allylamine that exerts its antifungal effects via inhibition of fungal squalene epoxidase, an enzyme involved in ergosterol formation. Terbinafine is fungicidal and is used most commonly for dermatophyte infections and the treatment of chromoblastomycosis. In vitro synergy data have led to its use in combination, most often with extended-spectrum azoles and AmB, for the management of severe or refractory mold infections such as Scedosporium, Fusarium, and other hyaline and dematiaceous molds.
Cryptococcus neoformans has a global distribution and can be isolated from the soil and excreta of birds such as pigeons. C. neoformans var. grubii (serotype A) is the predominant pathogen worldwide; however, infections with C. neoformans var neoformans (serotype D) are prevalent in Northern Europe. C. gattii can cause disease in immunocompetent patients. Until recently, C. gattii was found in Australia, Southeast Asia, and Central Africa, often associated with eucalyptus and fir trees. Recently, serious infections with C. gattii have been recognized in Vancouver, British Columbia, and in the Pacific Northwest United States. Most cryptococcal infections are seen in immunocompromised hosts, including patients with advanced HIV infection, malignancies, solid organ transplants (SOT), and other conditions.
Cryptococcosis is one of the most common life-threatening fungal infections in HIV-infected patients, and is the third most common invasive fungal pathogen (behind Candida and Aspergillus ) in SOT recipients in whom it causes 8% of IFIs. Cryptococcus affects hematopoietic stem cell transplant (HSCT) patients less often, in whom it causes 0.6% of IFIs.
Infections with Cryptococcus are initiated by inhalation of small yeast or spores (produced through mating). Once in the alveoli, the outcome is determined by the virulence of the infecting strain, by host genetic polymorphisms, by innate and adaptive immune responses, and by the presence of comorbidities. The virulence of Cryptococcus is related to its polysaccharide capsule as well as the presence of specific enzymes including laccase (required for production of fungal melanin), phospholipase B, and inositol phosphosphingolipid-phospholipase. In the lungs, cryptococci replicate and synthesize a large polysaccharide capsule, which protects against phagocytosis. The cryptococci that are successfully phagocytosed reside and replicate in mature phagolysosomes and subsequently spread to other cells using multiple mechanisms.
Cryptococci encounter diverse elements of the innate immune response, including polymorphonuclear cells, macrophages, and dendritic cells, which produce the cytokines that drive a type 1 helper CD4 + T cell response. CD4 + cells are necessary to prevent dissemination from the lungs; both CD4 + and CD8 + cells are required for clearance of infection in mice. Defects in humoral immunity are less commonly associated with cryptococcal infections than are defects in cellular immunity, although antibody-mediated immunity contributes to control of cryptococci in mice. The presence of autoantibodies to granulocyte macrophage colony stimulating factors may predispose seemingly immunocompetent individuals to infection with C. gattii.
The clinical presentation of cryptococcal infections is determined by the immune status of the host, the Cryptococcus species, and the site of infection. The lungs are the most commonly involved primary site; the CNS is the most common site of dissemination. Pulmonary involvement ranges from asymptomatic colonization to multifocal consolidation and acute respiratory distress syndrome. Most pulmonary infections are asymptomatic or mildly symptomatic in immunocompetent hosts, and may be discovered incidentally on radiographic imaging. Cryptococcus is also believed to cause latent infection in the lung and reactivate in the setting of depressed immunity. In fact, most infections may represent reactivation, and transfer of infection with donor organs may contribute to risk in SOT patients. Dissemination may develop during primary infection or reactivation. Acute infection in the immunocompetent host may manifest with fever, fatigue, cough, and sputum production. In immunocompromised patients, severe symptoms, including fever, cough, and shortness of breath, can rapidly progress to respiratory failure and acute respiratory distress syndrome. In a prospective multicenter international study of 111 SOT recipients, cryptococcal infections typically were seen a median of 21 months after transplant, and pulmonary (60%) and CNS (58%) involvement were most common. In patients with advanced HIV infection, meningoencephalitis is the predominant presentation.
The radiographic findings in cryptococcal pulmonary infections commonly include focal or diffuse pulmonary nodules or patchy air-space consolidation ( eFig. 38-1 ). However, other findings include cavitation (see eFig. 90-24 ), mass lesions (i.e., cryptococcomas, (see eFigs. 90-23 and 90-24 ), reticulonodular patterns, ground-glass attenuation (see eFig. 90-21 ), and associated effusions or lymphadenopathy (see eFig. 90-24A and B ). In a study of computed tomography (CT) radiographic findings of cryptococcosis, immunocompromised patients had more extensive pulmonary involvement with cavitation and parenchymal consolidation than did immunocompetent hosts—a finding that contrasts with that in tuberculosis. Cryptococcomas in both the CNS and in the lungs are seen more commonly with C. gattii than with C. neoformans infection, and are more common in immunocompetent hosts.
The diagnosis of pulmonary cryptococcosis is based on symptoms, chest radiography, culture, and/or histopathologic findings ( Fig. 38-1 ) and cryptococcal antigen testing. Cryptococcus can be cultured from respiratory specimens including sputum and bronchoalveolar lavage (BAL); blood cultures are only positive in disseminated infections. Cryptococcus is easily identified under the microscope as 5 to 10 µm spherical to oval yeast cells with a surrounding capsule. Biochemical testing is used to confirm the identification; canavanine-glycine-bromothymol blue agar can be used for differentiating C. gattii from C. neoformans . New methods are under development for rapid identification and speciation of cryptococci, including polymerase chain reaction (PCR) and matrix – assisted laser desorption/ionization time of flight spectrometry.
In tissue samples, specialized stains such as Mayer’s mucicarmine, which stains fungal melanin, are also helpful in establishing a diagnosis. While the serum cryptococcal antigen assay has a high sensitivity and specificity in disseminated infection and cryptococcal meningoencephalitis, it can be negative in patients with isolated pulmonary infection. In a study of patients with SOT, serum cryptococcal antigen was detectable in 73% of patients (22 of 30) with isolated pulmonary involvement and was more likely to be negative with solitary pulmonary nodules than with multiple nodules and more extensive pulmonary disease. Titers of serum cryptococcal antigen were higher in those patients with concurrent extrapulmonary infection.
Determining the presence of disseminated infection and extent of organ involvement is crucial to the selection of appropriate therapy. Thus, cerebrospinal fluid evaluation (e.g., cell count, culture, and cryptococcal antigen) should be performed in all immunosuppressed patients with pulmonary cryptococcosis. Whether cerebrospinal fluid analysis is essential in immunocompetent patients with pulmonary cryptococcosis is less clear. Factors associated with higher likelihood of disseminated disease and the need for cerebrospinal fluid analysis include neurologic findings, signs of systemic infection, such as fever and weight loss, and serum cryptococcal Ag titer of at least 64.
The choice of therapy depends on the immune status of the host and the presence of extrapulmonary infection; current treatment recommendations are available from both the American Thoracic Society and Infectious Diseases Society of America (IDSA). For pulmonary cryptococcosis in patients with evidence of disseminated infection, CNS involvement, or severe pneumonia, the treatment is separated into induction, consolidation, and maintenance regimens. The antimicrobials, doses, and duration are dependent on the patient’s underlying risk group (e.g., HIV-infected, organ transplant recipient, and non-HIV infected, non-transplant recipient). Induction therapy is typically with AmB-d 0.7 to 1 mg/kg/day plus flucytosine 100 mg/kg/day. In transplant patients and patients with reduced renal function, lipid formulations of AmB (e.g., LAmB 3 to 4 mg/kg/day or ABLC 5 mg/kg/day) are substituted for AmB-d to minimize nephrotoxicity. Fluconazole is utilized for consolidation and maintenance therapy with doses ranging from 400 to 800 mg/day and 200 to 400 mg/day, respectively.
Mild-to-moderate infection isolated to the lungs is treated with fluconazole 400 mg/day for a minimum of 6 to 12 months. Some experts maintain that asymptomatic patients with resected solitary nodules, undetectable serum cryptococcal antigen, and no evidence of extrapulmonary infection may be observed closely without specific antifungal therapy. Infections with C. gattii have been associated with delayed clinical responses to antifungal therapy; potential explanations include high in vitro fluconazole MICs and a higher incidence of pulmonary and cerebral cryptococcomas with decreased drug penetration to these lesions.
Immune reconstitution inflammatory syndrome (IRIS) may complicate treatment of any opportunistic mycosis, but is most common in cryptococcosis. IRIS is usually characterized by worsening of clinical signs and symptoms of the original infection, which can be misinterpreted as progressive infection. IRIS arises most commonly with initiation of potent antiretroviral therapy in HIV infection and with abrupt improvement in immune competence in SOT recipients. Although less common, IRIS can also happen in patients with hematologic malignancies during neutrophil and monocyte recovery following myeloablative chemotherapy and with lymphocyte recovery after receipt of monoclonal antibodies such as alemtuzumab. The manifestations of IRIS in pulmonary disease may be severe and include acute respiratory distress syndrome. Transplant recipients developing IRIS associated with cryptococcal infection also have increased potential for allograft loss. Treatment of IRIS in transplant recipients includes adjustment of immunosuppressive drugs to moderate the symptoms without promoting progression of the infection. Nonsteroidal antiinflammatory drugs are often sufficient to ameliorate the symptoms of IRIS, but high-dose corticosteroids may be required to manage the complications of severe IRIS.
The epidemiology of invasive Candida infections has evolved substantially in the past 2 decades. While Candida albicans remains the most common species associated with invasive disease overall, more than 17 Candida species have been associated with human disease and non- albicans species account for an increasing proportion of infections.
Candida infections of the thorax include empyema, tracheobronchial and mediastinal infection, and pneumonia. Candida pneumonia is rare and is most often found in the setting of candidemia with dissemination to the lung in immunocompromised patients. Rarely, primary pneumonia develops due to aspiration of oropharyngeal contents. Mediastinitis may complicate thoracic surgical procedures, and tracheobronchial disease can follow lung transplantation. Candida species have multiple virulence determinants; virulent strains consistently exhibit adherence to devices and tissues and form biofilms. Multiple human genetic polymorphisms have been identified that contribute heightened susceptibility to mucosal and invasive Candida infections. These include common and rare sequence variants in Toll-like receptors 1, 2, and 4, cytokine signaling ( interleukin [IL]-10, and the shared subunit of IL-12 and IL-23 receptors), and multiple genes whose products contribute to generating or responding to IL-17.
Manifestations of Candida pneumonia include cough, dyspnea, and fever. Radiographic findings are variable and can include lobar ( eFig. 38-2 ) and multilobar consolidation as well as cavitation. The diagnosis of Candida pneumonia is complicated by the generally low specificity and low positive predictive value of isolating Candida in respiratory specimens, which is often interpreted as colonization. Consequently, histopathologic evidence of tissue invasion is required to prove Candida pneumonia. Detection of the fungal cell wall component β-D-glucan in serum may assist in distinguishing colonization from invasive Candida infection. In patients with hematologic malignancy and in critically ill patients, detection of β-D-glucan has been shown to result in earlier diagnosis of candidemia and invasive candidiasis, although the specificity of this test is limited by multiple sources for false-positive tests and cross-reactivity due to synthesis of β-D-glucan by other fungi, and low positive predictive value. Molecular methods such as real-time PCR testing of blood for invasive candidiasis are under development but are not yet available for clinical use.
Given the increasing number of infections with non- albicans Candida species and the potential for infection with azole-resistant strains, echinocandins or lipid AmB preparations are preferred for initial therapy while awaiting species identification and susceptibility testing. Whereas the extended spectrum azoles such as voriconazole may be more active against C. glabrata than is fluconazole, there is frequent cross-resistance among the azoles. In addition, C. glabrata isolates have demonstrated resistance to echinocandins, often with poor outcomes. C. lusitaniae is intrinsically resistant to AmB, and C. tropicalis has shown increasing acquired resistance to azoles and to echinocandins. C. parapsilosis and C. guilliermondii tend to have higher MICs for the echinocandins than do other species, but the clinical significance is unclear. These observations emphasize the importance of knowing the local epidemiology and resistance patterns for Candida within an institution, identifying the infecting pathogen to the species level and, in non- albicans Candida infections, testing susceptibility to guide therapeutic decision making. Drainage of infected fluid collections, including those in the mediastinum or pleural space, is critical for cure.
Introduction and Epidemiology
Aspergillosis, caused by multiple species of the genus Aspergillus, is the most common mold infection worldwide. Aspergillus is a ubiquitous saprophytic fungus found indoors and outdoors in association with soil, organic debris, food, and water. The Aspergillus conidial head produces large numbers of 2 to 3 µm conidia (asexual spores), which easily enter the lungs via inhalation. Outbreaks often follow renovation and construction, activities that place a large number of Aspergillus conidia in the air. While the lung is the most common site of entry, Aspergillus may gain access to the host via other routes, including direct cutaneous inoculation. Among Aspergillus species, A. fumigatus is the most common pathogen, in part due to specific virulence factors, but non- fumigatus species including A. flavus, A. niger, and A. terreus, also cause human disease. A. terreus is notable for exhibiting in vitro resistance to AmB. A. nidulans, an otherwise rare pathogen, is second to A. fumigatus as the most common mold causing infection in patients with chronic granulomatous disease.
Aspergillus is a hyaline hyphomycete characterized by septate, narrow (3 to 6 µm) hyphae with acute angle (45 degrees) branching ( Fig. 38-2 ) in respiratory secretions and tissue specimens. The non- Aspergillus hyaline hyphomycetes, discussed later, have a similar appearance in clinical specimens and are differentiated from Aspergillus in culture based on the morphologic characteristics of their reproductive structures.
Aspergillosis may present as a skin/soft tissue, ocular, gastrointestinal, cardiac, sinus, CNS, or disseminated infection, but most commonly presents as infection limited to the lung. The five clinical entities addressed in the following sections include the two noninvasive forms, the saprophytic (aspergilloma) and allergic (ABPA) entities, as well as the three invasive forms, including invasive pulmonary aspergillosis (IPA), tracheobronchial aspergillosis (TBA), and chronic necrotizing pulmonary aspergillosis.
Although Aspergillus species are not obligate pathogens, their evolution to survive in decomposing organic matter has provided them with mechanisms that contribute to virulence in humans and other mammals. Through genome sequence analysis, studies of deletion mutants, and studies of infection in animal models, several determinants and mechanisms of Aspergillus pathogenesis have been identified. Aspergillus possesses multiple defenses against reactive oxygen intermediates; some of these anti–reactive oxygen intermediates defenses include melanin, catalases, superoxide dismutases, and glutathione transferases. At the same time, Aspergillus is able to survive in hypoxic environments, which may allow the fungus to survive in tissues that it renders hypoxic by invading blood vessel walls. Other mechanisms that may contribute to pathogenesis include production of diverse toxins, including gliotoxin and fumagillin, and secretion of elastase, which may promote tissue invasion.
Work in humans and in murine models has provided considerable insight into the elements and mechanisms of innate and adaptive immune responses that provide protection against invasive Aspergillus infections (see Chapters 12 and 13 ). Aspergillus spores possess a hydrophobic protein coat made up of rod-shaped structures (rodlets), which mask the cell wall and prevent recognition by innate immune receptors. This allows individuals to inhale millions of fungal spores every day without induction of an inflammatory response. Spores that swell and germinate before being killed expose the fungal cell wall that contains multiple pathogen-associated molecular patterns recognized by innate immune cells. In particular, β-D-glucan is recognized by host dectin-1, which initiates production of proinflammatory cytokines and chemokines, and modulates differentiation of CD4 + T cells. The importance of specific pathways of innate immune recognition has been demonstrated by finding that hematopoietic stem cell transplant patients who receive donor cells that possess sequence variants of Toll-like receptor 4 or dectin-1 are at increased risk for invasive Aspergillus infections. The chemokines produced early in infection recruit neutrophils and monocytes, both of which play important roles in ingesting and killing germinating spores and hyphae. Other important elements of innate immunity have been identified by finding that polymorphisms of mannose-binding lectin, chemokine (C-X-C motif) ligand 10 (CXCL-10), and plasminogen are associated with increased susceptibility to allergic or invasive aspergillosis in certain populations.
In humans and mice, CD4 + T cells also contribute to defense against invasive aspergillosis; both T-helper 1 and 17 cells contribute to optimal immunity. In contrast, excessive T-helper 2 responses contribute to the pathogenesis of ABPA.
Epidemiology and Definitions.
An aspergilloma (or fungus ball) develops within a preexisting pulmonary cavity; it is a tangled mass of fungal hyphae, cellular debris, mucus, and fibrin that may or may not adhere to the cavity wall. Aspergillomas were previously most commonly found in cavities caused by tuberculosis, but aspergillomas develop in other cavities such as those caused by bullous emphysema, fibrocavitary sarcoidosis, lung cancer, cystic fibrosis (CF), or other fungal or nonfungal infections. Aspergillomas are most commonly caused by A. fumigatus but can also be seen with non- fumigatus Aspergillus and other molds. Chronic cavitary aspergilloma, also known as chronic cavitary pulmonary aspergillosis, is characterized by multiple cavities with or without intracavitary aspergillomas and with pulmonary and systemic symptoms. Chronic cavitary pulmonary aspergillosis does not invade the surrounding pulmonary parenchyma.
The natural history of aspergillomas is variable. Aspergillomas can remain stable over long periods, regress, spontaneously resolve, or progressively enlarge. Patients with aspergillomas are often asymptomatic, and the lesion may be discovered incidentally on chest radiography. The most common symptoms are cough and hemoptysis. Hemoptysis may develop in up to of 85% of cases and ranges from mild to life-threatening. Proposed mechanisms for the development of hemoptysis include vascular damage by mechanical effects of the fungus ball as well as by fungal toxins.
Imaging is key to the diagnosis of aspergillomas, which are typically found in the upper lung fields and classically appear as a solid rounded mass within a cavity ( Fig. 38-3 ). The mass may be mobile ( eFig. 38-3 ) or adherent to the cavity wall; peripheral lesions may be associated with pleural thickening. Nonradiographic diagnostic support includes positive serum precipitating antibodies to Aspergillus species, which are detectable in approximately 95% of patients. Respiratory cultures may grow Aspergillus species although the sensitivity and specificity are low.
Optimal treatment of aspergillomas depends on the patient’s symptoms, the location of the aspergilloma, and the host status. In patients with hemoptysis, the primary curative intervention is surgical resection. However, surgical resection remains a high-risk intervention in those with lung disease and poor pulmonary reserve. Potential complications from surgical resection include persistent hemorrhage, bronchopleural fistula development with further spread of the infection, and death. Therefore, resection to prevent future complications and disease progression must be approached cautiously. Bronchial artery embolization may be used in the setting of acute bleeding as a temporizing measure in nonsurgical candidates.
Systemic and/or topical (nebulized, or instilled into a cavity) antifungal therapy has been attempted in the management of aspergillomas. Systemic azole therapy is rarely curative and may be used for symptom improvement or stabilization and, in immunocompromised hosts, to prevent dissemination and invasive infection. The preponderance of data supports use of oral itraconazole. An international open-label study of 42 patients with aspergillomas treated with itraconazole at a dose of 100 to 400 mg per day for 18 to 780 days found symptomatic improvement in 62% of evaluable patients ( n = 34) and radiographic improvement in 12 (30%). Although fewer data are available, voriconazole is increasingly used instead of itraconazole. Major concerns with long-term azole administration are the emergence of resistance and toxicities, especially with voriconazole, which has been associated with development of skin cancers including squamous cell carcinoma. Direct intracavitary instillation of antifungal agents such as AmB, nystatin, natamycin, fluconazole, and itraconazole has been used via endobronchial and percutaneous CT-guided approaches and may further reduce fungal burden and the risk of recurrent bleeding, but it is not curative. The optimal management of aspergillomas remains to be defined, and randomized-controlled trials are lacking.
Allergic Bronchopulmonary Aspergillosis
Epidemiology and Pathogenesis.
ABPA (see also Chapter 48 ), first described in the early 1950s, is an allergic pulmonary disorder caused by hypersensitivity to Aspergillus antigens. It is most often encountered in steroid-dependent asthmatics and in upwards of 15% of patients with CF. ABPA is most commonly associated with A. fumigatus; however, non- fumigatus Aspergillus species as well as non- Aspergillus molds can cause a similar clinical presentation (the latter termed allergic bronchopulmonary mycosis or ABPM). In ABPA, Aspergillus conidia enter the airways, germination ensues, and the hyphae colonize but do not invade. Aspergillus contributes to pathogenesis by producing enzymes such as elastase, collagenase, and trypsin, with airway damage and release of inflammatory cytokines. A marked inflammatory response ensues, resulting in mucoid impaction and granulomatous inflammation, including bronchocentric granulomas. The immune mechanisms associated with ABPA include an exaggerated T-helper 2 CD4 + T-cell response to Aspergillus antigens, increased Aspergillus -specific and total IgE, and eosinophilia. The primary determinant of dysregulated immune responses in ABPA has not been identified. ABPA is common in patients with CF, and has been linked to polymorphisms in the CF transmembrane conductance regulator (CFTR) and pulmonary surfactant protein-A2 genes.
Clinical Presentation and Diagnosis
Symptoms of ABPA include acute attacks of wheezing, sputum expectoration containing brown plugs, pleuritic chest pain, and fever. Radiographic findings include transient pulmonary opacities, particularly in the upper lobes, bronchial wall thickening (ring sign), bronchiectasis (tram tracks), bronchial impaction, creating the so-called finger-in-glove appearance ( eFig. 38-4 ) and, in more advanced stages, fibrosis. The clinical criteria proposed for diagnosing ABPA differ based on the patient’s underlying disease. The minimal essential clinical criteria proposed by Greenberger et al for asthmatics include (1) asthma, (2) central bronchiectasis, (3) immediate cutaneous reactivity to Aspergillus species, (4) a total serum IgE greater than 1000 IU/mL, and (5) elevated Aspergillus -specific serum IgE or IgG. Asthmatics are designated as ABPA-central bronchiectasis or ABPA-seropositive, the latter lacking central bronchiectasis. Five stages of disease have been characterized, including (1) acute ABPA, (2) remission, (3) recurrent exacerbation, (4) steroid-dependent asthma, and (5) fibrosis. In patients with CF, the diagnosis is less straightforward, because frequent infections and CF exacerbations may present with symptoms similar to those of ABPA. However, clinical criteria have been proposed by the Consensus Conference of the Cystic Fibrosis Foundation to aid in the diagnosis: (1) acute or subacute pulmonary deterioration not attributable to another etiology; (2) total serum IgE greater than 500 IU/mL; (3) immediate cutaneous reactivity to Aspergillus or specific IgE antibodies to Aspergillus; and (4) one of the following: Aspergillus serum precipitins, elevated anti- Aspergillus IgG, or new or recent chest radiographic or chest CT abnormalities that have not cleared with antibiotics and chest physiotherapy.
The goal of therapy for ABPA is to manage acute disease and prevent relapse and progression to fibrosis. Corticosteroids remain the basis for therapy although there is a lack of guidance from randomized controlled trials assessing the optimal dose and duration. For acute management, oral prednisone at 0.5 mg/kg/day for 1 to 2 weeks, followed by alternate-day dosing for an additional 6 to 8 weeks with further taper is often used. Serum IgE concentrations, radiographic imaging, pulmonary function testing, and clinical symptoms are used to monitor response to therapy and to identify exacerbations.
Antifungal therapy aimed at reducing overall fungal burden, thereby blunting downstream immunologic response and airway inflammation is often used as an adjunctive intervention. The agent most studied for this indication is itraconazole. A meta-analysis identified three randomized controlled trials evaluating azoles in ABPA, including two trials with itraconazole. Although the studies used different end points, the collective results demonstrated reductions in systemic and airway inflammatory parameters, reductions in steroid dose, improvements in pulmonary function, and an increase in the length of time between exacerbations. Itraconazole was studied at a dose of 400 mg/day for 16 weeks; in clinical practice, some advocate continuing treatment for a minimum of 6 months. Efficacy has been demonstrated in patients with CF as well. Based on existing data, the IDSA recommends combination therapy with corticosteroids and antifungals. Given concerns for itraconazole tolerability, voriconazole and posaconazole have been substituted with good results. Additional therapeutic considerations include omalizumab, a humanized monoclonal antibody targeting IgE and approved for the treatment of severe allergic asthma. This agent has been used in asthmatic and CF ABPA patients with mixed results.
Invasive Pulmonary Aspergillosis
Epidemiology and Pathogenesis.
IPA is the most severe form of pulmonary aspergillosis and is a major cause of fungal morbidity and mortality, seen most commonly in immunodeficient patients, including HSCT and SOT recipients and those with advanced HIV infection, chronic granulomatous disease, and hematologic malignancies. In a retrospective Italian cohort of nearly 12,000 patients with hematologic malignancies, more than half of the 538 proven or probable IFIs were due to molds, primarily Aspergillus, and patients with acute myelogenous leukemia were most commonly affected. The elevated risk in this population is primarily driven by prolonged neutropenia induced by cytotoxic chemotherapy. Multicenter, prospectively obtained epidemiologic data also confirm Aspergillus as the most common cause of invasive mold infection in both HSCT and SOT recipients. In HSCT recipients, Aspergillus is the most common IFI, predominantly seen during two periods: (1) early after transplantation, during neutropenia, and (2) after engraftment, in the setting of graft-versus-host disease. Of the SOT patients, lung transplant recipients are at highest risk for IPA. IPA is also increasingly reported in patients previously thought to be at low risk for invasive disease, including those with COPD on long-term corticosteroids and critically ill patients in the intensive care unit.
IPA is characterized by tissue invasion, frequently involving blood vessels. Hyphae within the alveoli penetrate the respiratory mucosa and alveolar capillaries into endothelial cells and pulmonary arterioles. Cell injury and inflammation contribute to intravascular thrombosis, local hypoxia, and necrosis. Angioinvasive disease is accompanied by tissue infarction and coagulative necrosis, whereas nonangioinvasive disease is more commonly associated with pyogranulomatous inflammation and inflammatory necrosis.
Clinical Presentation and Diagnosis.
The clinical presentation of IPA typically involves fever, cough, hemoptysis, and pleuritic chest pain. Angioinvasive IPA is seen predominantly in the setting of neutropenia and the course in neutropenic patients can be rapid, with clinical deterioration over hours to days. Patients with disseminated disease may have additional symptoms related to other sites of infection. Aspergillus can extend directly to surrounding areas, including the chest wall (see Fig. 90-27 ), mediastinum, and great vessels.
Early diagnosis of IPA is essential for prompt initiation of therapy, which has been associated with improved survival. However, multiple factors make the diagnosis difficult, including the lack of symptoms early in the course of illness, challenges in obtaining appropriate tissue for histopathology and culture in critically ill or cytopenic hosts, and the variable sensitivity and specificity of many of the available diagnostic tests. Imaging findings associated with IPA are often nonspecific, including nodules (see eFig. 90-27 , eFig. 90-28 , eFig. 91-10 ), consolidation (see eFig. 91-8 ), cavitation (see eFigs. 90-27 and 90-28 ), and effusions (see eFig. 91-10 ). The halo sign, demonstrated by ground-glass opacities surrounding a pulmonary nodule, is the result of alveolar hemorrhage around an infarcted area of the lung ( Fig. 38-4A ; see eFig. 91-10 ) and is typically seen early in the course of infection. The halo sign has a high specificity for IPA in neutropenic patients. The air-crescent sign tends to be seen later in the course of infection (typically with recovery of neutrophils in the neutropenic host) and represents air that has filled the space between necrotic and healthy lung tissue (see Fig. 38-4B ).
Direct microscopy of sputum or BAL lacks both sensitivity (reported ranges from 0% to 90%) and specificity. Histopathologic evaluation of tissue specimens using standard hematoxylin and eosin, periodic acid–Schiff, and/or Gomori’s methenamine silver staining with demonstration of characteristic hyphae supports the diagnosis of IPA, but culture or sequence data are required to confirm the identity of the pathogen (see Fig. 38-2 ). Furthermore, 48% to 70% of tissues with evidence of invasive septate hyphae fail to grow in culture. When positive, cultures for most Aspergillus species typically grow within 48 to 72 hours on standard mycologic media.
Noninvasive tests are increasingly used for patients at risk for IPA. These include assays for fungal galactomannan (GM) and β-D-glucan. GM is a heteropolysaccharide component of the cell wall of Aspergillus and other fungi that is released during hyphal growth. Platelia Aspergillus EIA (Bio-Rad Laboratories) is an FDA-approved, commercially available diagnostic for detecting GM in neutropenic and HSCT patients with invasive Aspergillus, including IPA. The positive cutoff value is an optical density (OD) index of 0.5. A meta-analysis of 27 studies from 1966 to 2005 using surveillance GM in immunocompromised hosts with invasive Aspergillus reported an overall sensitivity and specificity of 71% and 89%, respectively. Subgroup analysis showed that test performance was higher in patients with hematologic malignancy (sensitivity, 70%; specificity, 92%) and HSCT recipients (sensitivity, 82%; specificity, 86%) compared to SOT recipients (sensitivity, 22%; specificity, 84%). One potential explanation for the improved performance in patients with hematologic malignancies or HSCT recipients was gained from an in vitro model of the human alveolus showing that detection of GM correlated with its release into the circulation following angioinvasion, which is more common in neutropenic patients.
Assaying BAL specimens for GM by the same enzyme immunoassay may complement assays of serum. A meta-analysis of 30 studies evaluating BAL GM using a cutoff OD index of 0.5 for proven and probable invasive aspergillosis found a sensitivity of 87% and specificity of 89%. Compared to serum GM, BAL GM had a higher sensitivity but a lower specificity. By increasing the positive cutoff value to an OD index of 1, specificity was increased without decreasing sensitivity. This is particularly important in lung transplant patients in whom high rates of colonization with molds such as Aspergillus and Penicillium can result in false-positive tests for GM. In one study, lung transplant recipients (16 of 81) accounted for more than 40% of false-positive BAL test results for GM. Other factors that compromise the utility of the GM assay include cross-reactivity with other fungi (e.g., Alternaria, Fusarium, Geotrichum, Histoplasma, Paecilomyces, and Penicillium ) and false-positive results secondary to the presence of GM in antimicrobials, such as piperacillin-tazobactam, in nutritional supplements, and in Plasmalyte. However, the magnitude of serum GM was shown to have prognostic utility in a single-center study of invasive aspergillosis in allogeneic HSCT recipients, with higher values correlated with higher all-cause mortality. Use of the GM assay to monitor response to treatment and to detect relapse is under investigation.
β-D-glucan, another fungal cell wall component, is used in the diagnosis of invasive aspergillosis as well as other IFIs, including Candida and Pneumocystis . The FDA approved and commercially licensed assay in the United States is the Fungitell assay, which has a positive cutoff value of 80 pg/mL or greater (sensitivity, 64%; specificity, 92%) for patients with proven or probable invasive aspergillosis. β-D-glucan may be detectable earlier in the course of invasive aspergillosis than is GM. False-positive β-D-glucan results may be associated with hemodialysis using cellulose membranes, intravenous immunoglobulin, and bacterial bloodstream infections. In a study to assess the utility of serially monitoring lung transplant recipients with the β-D-glucan assay, 90% of subjects without an IFI had at least one positive β-D-glucan result (≥80 pg/mL), leading to a low positive predictive value (9%). Similar issues were encountered in a study using β-D-glucan to monitor for invasive candidiasis in an intensive care unit; 45% of subjects had false-positive results, which were ultimately attributed to receipt of intravenous immunoglobulin and hemodialysis.
Nucleic acid-based tests including PCR have been explored in the diagnosis of invasive aspergillosis, although none of these have been incorporated into formal diagnostic criteria. A meta-analysis of PCR testing of blood, plasma, or serum reported a sensitivity and specificity of 75% and 87%, respectively. Avni and associates found comparable performance of BAL-PCR versus BAL GM testing (using an OD index of 0.5) as well as improved sensitivity with stable specificity when used together, suggesting a possible advantage to combination testing. To date there is no FDA-approved nucleic acid assay for Aspergillus in the United States. Attempts at standardization and the availability of a commercial PCR platform are necessary steps toward validation and routine clinical use. Newer diagnostics, including a lateral flow device incorporating a monoclonal antibody, JF5, to detect an Aspergillus extracellular glycoprotein antigen may provide rapid and inexpensive point-of-care testing.
Diagnostic criteria for IPA have been proposed by the Mycoses Study Group/European Organization for Research and Treatment of Cancer and include proven, probable, and possible invasive aspergillosis. A diagnosis of proven IFI requires microscopic evidence of Aspergillus tissue invasion or a positive culture from a normally sterile site. A diagnosis of probable IPA requires an at-risk host, corroborating radiographic findings, and direct (e.g., culture) or indirect mycologic evidence (e.g., positive serum, plasma, or BAL GM, or positive serum β-D-glucan). Other clinical algorithms continue to be introduced to assist in differentiating Aspergillus colonization from true invasive aspergillosis in critically ill intensive care unit patients without clear predisposing host factors but with positive respiratory specimens and/or clinical concern for invasive aspergillosis.
As with other IFIs, management of IPA may involve a combination of surgical, pharmacologic, and other adjunctive interventions. Attempts to restore host immunity should be made wherever feasible, being mindful of the risk for IRIS. Indications for surgical intervention include life-threatening hemoptysis, lesions contiguous to the great vessels and/or pericardium, and invasion of the chest wall, as well as isolated lesions in patients about to undergo intensive chemotherapy or HSCT. The drug of choice for IPA is voriconazole, based on recommendations from both the IDSA and American Thoracic Society and data from a large prospective randomized trial of invasive aspergillosis that demonstrated significantly better response and overall survival in those treated with voriconazole than those treated with AmB-d. The dose of voriconazole for IPA is 6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg every 12 hours thereafter. Therapy can be transitioned to the oral route once the patient is stable and tolerating oral medications. While most patients are treated for a minimum of 6 to 12 weeks, the total duration of pharmacologic therapy for IPA is not clearly defined and is dependent upon the immune status of the host and clinical response to treatment ( eFig. 38-5 ).
Posaconazole may be an effective alternative to voriconazole, although it is most often used as salvage therapy because it has not been studied as primary treatment. In patients with invasive aspergillosis refractory or intolerant to other antifungal therapies, response to posaconazole was superior (45/107, 42%) compared with the external control group (22/86, 26%), primarily treated with AmB or itraconazole. Other researchers have also shown success with posaconazole as salvage therapy.
Azole resistance in Aspergillus was first reported with A. fumigatus in 1997 and appears to be increasing in frequency. The known mechanism of resistance is due to sequence variation in the fungal cyp51A gene, which encodes the drug target, 14-α-demethylase. Many of these sequence variants result in cross-resistance between the azole compounds, namely itraconazole, voriconazole, and posaconazole. Although interpretive breakpoints defining clinical resistance have yet to be established for molds, standard methods for testing filamentous fungi have been validated, and epidemiologic cutoff values (which define susceptibility using the MIC distribution of wild-type Aspergillus strains lacking known azole resistance mechanisms) have been proposed. While epidemiologic cutoff values do not predict outcomes, they may aid in detecting isolates with potential resistance mutations, including those in cyp51A. Some experts advocate MIC testing as a screen for the presence of resistance mutations in patients with invasive aspergillosis that fail to respond to azole therapy.
Polyenes are used for the treatment of IPA in the setting where mucormycosis remains in the differential diagnosis or in patients intolerant or refractory to azoles. The lipid formulations of AmB are currently preferred because of their reduced nephrotoxicity compared with that of AmB-d. Currently, the IDSA recommends ABLC 5 mg/kg/day or LAmB 3 to 5 mg/kg/day for the treatment of IPA. LAmB 3 mg/kg/day was compared with LAmB 10 mg/kg/day in a double-blind trial of patients with proven or probable invasive aspergillosis to assess whether higher doses would improve response; there was no clinical advantage with the higher dose but there was significantly more hypokalemia and nephrotoxicity.
Echinocandins may be used in patients who are refractory or intolerant to other therapies, although randomized controlled trials evaluating echinocandins as primary therapy for invasive aspergillosis have not been performed. In one study, 83 adults with probable/proven invasive aspergillosis, including 64 with IPA were treated with caspofungin; 45% (50% of those with IPA) obtained a complete or partial response. Based on these data, caspofungin was cleared by the FDA as salvage therapy for invasive aspergillosis. For micafungin, a large report from Japan indicated a 71% (90 of 130) clinical response rate in patients with invasive aspergillosis treated with micafungin monotherapy (doses ranged from 50 to 300 mg/day) as first-line therapy.
Given the high mortality associated with IPA, combination therapy is often considered. While in vitro and in vivo data support a role for combination therapy, the IDSA does not recommend using combination therapy as first-line therapy for invasive aspergillosis, due to the lack of data from a randomized controlled trial. When combination therapy is used, echinocandins are most often paired with polyenes or azoles based on their activity at a different site (fungal cell wall) compared with the azoles and polyenes (fungal membrane). A randomized controlled trial comparing voriconazole monotherapy with voriconazole plus anidulafungin in patients with invasive aspergillosis is underway. Other adjunctive measures used to optimize outcomes of IPA include granulocyte or granulocyte-macrophage colony stimulating factor, interferon-gamma, and granulocyte infusions.
Epidemiology and Pathogenesis.
Tracheobronchial aspergillosis (TBA) should be considered as a spectrum, including mild tracheobronchitis and obstructive, ulcerative, and pseudomembranous TBA, often with more than one form present concurrently. Mild tracheobronchitis demonstrates only superficial mucosal inflammation; obstructive, ulcerative, and pseudomembranous forms may be superficial or progress to involve the entire bronchial wall with necrotizing tracheobronchitis and invasion of the surrounding tissue. A rare form of IPA, TBA is most commonly encountered in lung and heart-lung transplant recipients, although it has been reported in patients with advanced HIV and hematologic malignancies, including patients undergoing HSCT.
Clinical Manifestations, Diagnosis and Treatment.
In lung and heart-lung transplant recipients, TBA is often discovered early in the posttransplant period when patients may have ulceration and/or pseudomembrane formation at the bronchial anastomotic site visible by bronchoscopy ( Fig. 38-5 ), even without symptoms. In contrast, patients with hematologic malignancies are typically symptomatic at the time of discovery of TBA with productive cough, dyspnea, fever, wheezing, stridor, hemoptysis, and respiratory failure. Early diagnosis is crucial given the potential for progressive symptoms and disseminated infection and complications including bronchial obstruction, anastomotic rupture, and bronchopleural or bronchoarterial fistulas. While chest imaging may demonstrate bronchial wall thickening, luminal narrowing, and/or endobronchial lesions ( eFig. 38-6 ), it cannot make the diagnosis. Serum GM is of limited value for tracheobronchial aspergillosis. Diagnosis is made via bronchoscopy with visualization of plaques, ulceration, pseudomembranes, and obstructive mucous plugs and/or masses ( Fig. 38-6 ) together with pathologic and microbiologic findings.