Review

Pulmonary aspergillosis: a clinical update

O.S. ZMEILI and A.O. SOUBANI

Division of Pulmonary, Allergy, Critical Care and Sleep, Wayne State University School of Medicine,

Detroit, USA

Summary

Aspergillus spp may cause a variety of pulmonarydiseases, depending on immune status and thepresence of underlying lung disease. These mani-festations range from invasive pulmonary aspergil-losis in severely immunocompromised patients, tochronic necrotizing aspergillosis in patients withchronic lung disease and/or mildly compromisedimmune systems. Aspergilloma is mainly seen inpatients with cavitary lung disease, while allergicbronchopulmonary aspergillosis is described inpatients with hypersensitivity to Aspergillus

antigens. Recent major advances in the diagnosisand management of pulmonary aspergillosis includethe introduction of non-invasive tests, and thedevelopment of new antifungal agents, such asazoles and echincandins, that significantly affect themanagement and outcome of patients with pulmo-nary aspergillosis. This review provides a clinicalupdate on the epidemiology, risk factors, clinicalpresentation, diagnosis and management of themajor syndromes associated with pulmonaryaspergillosis.

Introduction

Aspergillus spp are ubiquitous fungi acquired by

inhalation of airborne spores and may cause life-

threatening infections especially in immunocom-

promised hosts. Aspergillus spp are commonly

isolated from the soil, plant debris, and the indoor

environment, including hospitals. Pulmonary dis-

ease caused by Aspergillus, mainly A. fumigatus,

presents with a spectrum of clinical syndromes in

the lung (Figure 1).1

Invasive pulmonary aspergillosis (IPA) is a severe

disease, and a major cause of mortality in severely

immunocompromised patients. Critically ill patients

without malignancy may also develop IPA without

having the classic risk factors. Chronic necrotizing

Aspergillosis (CNA), which is locally invasive, is

another pulmonary disease caused by Aspergillus

spp. CNA is seen mainly in patients who are mildly

immunocompromised or have chronic lung disease.

Aspergilloma and allergic bronchopulmonary

aspergillosis (ABPA) are non-invasive pulmonary

diseases caused by Aspergillus: aspergilloma is a

fungus ball that develops in a pre-existing cavity in

the lung parenchyma, while ABPA is a hypersensi-

tivity disease of the lungs that almost always affects

patients with asthma or cystic fibrosis.We put forward an outline for this review that

systematically described the main clinical syn-

dromes associated with pulmonary aspergillosis

according to incidence, risk factors, clinical pre-

sentation, radiological features, diagnostic criteria,

management options and outcome. Then we

performed a comprehensive literature search using

the PubMed/Medline [http://www.pubmed.gov],

and the phrase ’pulmonary aspergillosis’. Articles

up to December 2006 were reviewed, and clinically

relevant articles that satisfied the above outline

were selected and studied. The reference lists of

the selected articles were evaluated for

Address correspondence to Dr A.O. Soubani, Division of Pulmonary, Allergy, Critical Care and Sleep, HarperUniversity Hospital, 3990 John R-3 Hudson, Detroit, MI 48201, USA. email: asoubani@med.wayne.edu

! The Author 2007. Published by Oxford University Press on behalf of the Association of Physicians.All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Q J Med 2007; 100:317–334doi:10.1093/qjmed/hcm035

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additional papers. We also included articles fromthe authors’ personal files.

Invasive pulmonary aspergillosis(IPA)

IPA was first described in 1953.2 The incidence ofIPA has increased during the past two decades dueto widespread use of chemotherapy and immuno-suppressive agents.3 Groll et al. documented thatthe rate of invasive mycoses increased from 0.4 to3.1% of all autopsies performed between 1978 and1992.4 In addition, invasive aspergillosis increasedfrom 17% of all mycoses found on autopsy at thebeginning of the study to 60% at the end of the14-year study period. The mortality rate of IPAexceeds 50% in neutropenic patients, and 90% inhematopoietic stem-cell transplantation (HSCT)recipients.5,6

Risk factors

IPA occurs predominantly in immunocompromisedpatients. Major risk factors for IPA (Table 1) includeneutropenia, haematopoietic stem-cell and solid-organ transplantation, prolonged and high-dosecorticosteroid therapy, haematological malignancy,cytotoxic therapy, advanced AIDS, and chronicgranulomatous disease (CGD).1,7,8

Neutropenia, especially absolute neutrophilcount <500 cells/mm3, is the most important riskfactor, and IPA is strongly related to the duration anddegree of neutropenia. The risk of IPA in neutro-penic patients is estimated to be 1% per day for thefirst 3 weeks, after which time it increases to 4% perday.7 Solid organ transplantation, especially lungtransplantation, and HSCT are also significant riskfactors for IPA.9,10 There are several factors that

predispose patients who underwent transplantation

to have IPA: multiple immune defects including

prolonged neutropenia in the pre-engraftment phase

of HSCT, the use of multiple anti-rejection or anti-

graft-vs.-host disease (GVHD) therapy, such as

corticosteroids and cyclosporine, parenteral nutri-

tion, use of multiple antibiotics, and prolonged

hospitalization.In the case of HSCT, IPA is a major problem, with

a steady rise in the documented cases of IPA

following transplantation. The risk for IPA is much

higher following allogeneic HSCT than following

autologous transplantation (incidence 0.5–4%

in autologous HSCT vs. 2.3–15% in allogeneic

HSCT6, 11–14). In allogeneic HSCT, the highest risk

is in patients with severe GVHD (grade III–IV).

In these patients, the timeline for IPA infection

follows a bimodal distribution, with a peak in the

first month following HSCT, which is associated

with neutropenia. The second peak is during the

treatment for GVHD (median 78–112 days post

transplantation).6,12,15 The first peak is currently

less significant, because the routine use of stem

cells instead of bone marrow for transplantation,

non-myeloablative regimens, the use of colony-

stimulating factors during neutropenia, and the

widespread use of antifungal agents have all

significantly decreased the incidence of IPA

during this period.12,16

On the other hand, the incidence of IPA during

the treatment of GVHD has become more signifi-

cant, especially with the higher incidence of GVHD

associated with unrelated allogeneic transplanta-

tion, and treatment with intensive immunosuppres-

sive therapy, including corticosteroids, cyclosporine

A, and anti-TNF agents.12,13,17–19 In the study by

Marr et al., the probability of IPA reached approxi-

mately 5% at 2 months, 9% at 6 months, and 10% at

1 year following allogeneic HSCT; by the third year

after transplantation, the probability of IPA had

increased slightly to 11.1%.13 There is also evidence

that CMV infection in these patients increases

the risk of IPA;13,20 the hazard ratio for IPA in the

Inhalation of aspergillus spores

Colonization

Cavitary lungdisease

Chronic lung disease orMild ICH

ICH AsthmaNormal host

No sequel Chronic necrotizingaspergillosis

ABPAAspergilloma IPA

Figure 1. The clinical spectrum of conditions resulting

from inhalation of aspergillus spores. ICH, immunocom-

promised host; IPA, invasive pulmonary aspergillosis;

ABPA, allergic bronchopulmonary aspergillosis. Reprinted

by permission from Soubani and Chandrasekar (Chest

2002;121:1988-1999).

Table 1 Major risk factors for IPA

Prolonged neutropenia (<500 cells/mm3 for410 days)

or neutrophil dysfunction

Transplantation (highest risk is with lung and HSCT)

Prolonged (43 weeks) and high-dose corticosteroid

therapy.

Haematological malignancy (risk is higher with

leukaemia)

Cytotoxic therapy

Advanced AIDS

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setting of CMV disease increases by 13.3-fold(95%CI 4.7–37.7).6

Neutrophil dysfunction, which is primarily seen inCGD, is another risk factor for IPA, and IPA is animportant cause of mortality in these patients.21

On the other hand, IPA is relatively uncommon inpatients with HIV infection, especially with theroutine use of highly active anti-retroviral therapy. Ina recent report, the incidence of IPA in HIV-infectedpatients with Aspergillus isolated from theirsputum was 2%.22 A low CD4 count, generally<100 cells/mm3, is present in almost all casesof AIDS-associated aspergillosis, and 50% of HIV-infected patients with IPA have coexistent neutro-penia or are on corticosteroid therapy. The rest ofthe cases appear to have no particular risk factorsother than advanced AIDS.23–25 There is increasedincidence of trachebronchial involvement in thesepatients in addition to the usual clinical picture ofIPA.25,26 A histopathological diagnosis is usuallyrequired to establish the diagnosis of IPA in AIDSpatients, since isolation of Aspergillus from respira-tory secretions has poor predictive value for invasivedisease.27 Response to therapy tends to be particu-larly poor in this patient population.22–25,27

Recent reports have documented invasive IPA inimmunocompetent patients. Two at-risk groupsstand out: patients with severe COPD and criticallyill patients. Among 13 cases of IPA diagnosed inCOPD patients admitted to an intensive care unitwith acute respiratory distress, the only risk factorwas corticosteroid treatment.28 Patients with COPDhave increased susceptibility to IPA for severalreasons, including structural changes in lung archi-tecture, prolonged use of corticosteroid therapy,frequent hospitalization and antibiotics treatment,and co-morbid illnesses such as diabetes mellitus,alcoholism, or malnutrition. The vast majority ofcases in the literature describe a fatal outcome.28–30

IPA is also becoming an important infectiousdisease in ICU patients without the classical riskfactors for this condition. Aspergillus spp are isolatedfrom lower respiratory tract samples in 0.7–7% ofcritically ill patients, and in around half of thesepatients, this finding represents IPA.31–35 In oneretrospective study, 89 cases (70%) of invasiveaspergillosis were found in patients admitted tothe medical ICU without leukaemia or cancer.34

In another study of 172 critically ill patients who hadpositive sputum for Aspergillus, 83 had invasivedisease, and 60% of these patients had no classicrisk factors for IPA. The most common underlyingproblems in these patients were COPD and corti-costeroid therapy.31 Although many of the criticallyill patients with IPA do not have the classic riskfactors for IPA (neutropenia, leukaemia, HSCT),

they usually have conditions that affect theirimmune system such as COPD, systemic corticoster-

oid therapy, non-haematological malignancy, liverfailure, diabetes mellitus, or extensive burns.31–34

The clinical signs and symptoms of IPA andradiographic features are often non-specific in the

ICU patients, and the finding of Aspergillus spp inrespiratory tract samples in these patients should not

be routinely discarded as colonization, even if thesepatients are immunocompetent.31 Further diagnostic

evaluation and early antifungal therapy should beconsidered once IPA is suspected in critically ill

patients.36,37 IPA in this patient population carriesan attributable mortality of 18.9% after adjusting forconfounding factors.34 A recent report suggests that

the isolation of Aspergillus from lower respiratorytract samples was associated with a worse ICU

outcome, regardless of whether finding representedIPA or colonization.38

Clinical presentation

Aspergillus is most often introduced to the lower

respiratory tract by inhalation of the infectiousspores. Less commonly, IPA may start in locations

other than the lungs, like sinuses, the gastrointestinaltract, or the skin (intravenous catheters, prolonged

skin contact with adhesive tapes, or burns).39–42

Patients present with symptoms that are usuallynon-specific, and consistent with bronchopneumo-nia: fever unresponsive to antibiotics, cough,

sputum production, and dyspnoea. Patients mayalso present with pleuritic chest pain (due to

vascular invasion leading to small pulmonaryinfarcts) and haemoptysis, which is usually mild,

but can be massive. IPA is one of the most commoncauses of haemoptysis in neutropenic patients, and

may be associated with cavitation that occurs withneutrophil recovery.43 Aspergillus may cause atracheobronchitis with severe inflammation of the

airways and associated with ulcerations and plaqueformation, most often in AIDS patients and lung

transplant recipients.44,45 Aspergillus infection mayalso disseminate and spread haematogenously to

other organs, most commonly the brain (leading toseizures, ring-enhancing lesions, cerebral infarc-

tions, intracranial haemorrhage, meningitis, andepidural abscess), and less frequently other organssuch as skin, kidneys, pleura, heart, oesophagus,

and liver may be involved46 (Figure 2).

Diagnosis

The diagnosis of IPA remains challenging. Earlydiagnosis of IPA in severely immunocompromised

patients is difficult, and a high index of suspicion

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is necessary in patients with risk factors for invasivedisease.

Histopathological diagnosis, by examining lungtissue obtained by thoracoscopic or open-lungbiopsy, remains the ’gold standard’ in the diagnosisof IPA.47 The presence of septate, acute, branchinghyphae invading the lung tissue samples, alongwith a culture that is positive for Aspergillus fromthe same site, is diagnostic of IPA (Figure 3).Histopathological examination also allows for theexclusion of other diagnoses, such as malignancy ornon-fungal infectious diseases. The histopathologi-cal findings associated with IPA have been recentlyshown to differ according to the underlying host.In patients with allogeneic HSCT and GVHD, thereis intense inflammation with neutrophilic infiltration,minimal coagulation necrosis, and low fungalburden. On the other hand, IPA in neutropenicpatients is characterized by scant inflammation,extensive coagulation necrosis associated withhyphal angio-invasion, and high fungal burden.Dissemination to other organs is equally high inboth groups.3

The significance of isolating Aspergillus spp insputum samples depends on the immune status ofthe host. In immunocompetent patients, isolationof Aspergillus spp. from the sputum almost alwaysrepresents colonization with no clinical conse-quences. In a study of 66 elderly hospitalizedpatients with Aspergillus isolated from the sputum,92% were consistent with colonization, and only4.5% had IPA.48 Similar observations were reportedby others.49–51 In the immunocompetent patientwith Aspergillus isolated from the sputum, antifungaltherapy is generally not indicated, but appropriate

diagnostic studies should be considered to excludeIPA. On the other hand, isolation of an Aspergillusspecies from sputum is highly predictive of invasivedisease in immunocompromised patients. Studieshave shown that sputum samples that are positivefor Aspergillus in patients with leukaemia, or inthose who have undergone HSCT, have a positivepredictive value of 80–90%.50,52,53 However,sputum samples that are negative do not rule outIPA; negative sputum studies have been noted in70% of patients with confirmed IPA.53,54 Bloodcultures are rarely positive in patients with con-firmed IPA.55

The chest radiograph is of little use in the earlystages of disease, because the incidence of non-specific changes is high. Usual findings includerounded densities, pleural-based infiltrates thatare suggestive of pulmonary infarctions, and cavita-tions. Pleural effusions are uncommon.56,57 ChestCT scan, especially when combined with highresolution images (HRCT), is much more useful.The routine use of HRCT of the chest early in thecourse of IPA leads to earlier diagnosis andimproved outcomes in these patients.58,59 It alsoaids further diagnostic studies such as bronchoscopyand open-lung biopsy.60 The typical chest CT scanfindings in patients suspected to have IPA includemultiple nodules and the halo sign, which is mainlyseen in neutropenic patients early in the courseof infection (usually in the first week), and appearsas a zone of low attenuation due to haemorrhagesurrounding the pulmonary nodule (Figure 4).

Figure 2. Open-lung biopsy specimen showing

Aspergillus acute branch hyphae invading a blood

vessel causing thrombus formation (Methenamine silver/

GMS stain). Figure 3. Brain CT image from a patient with acute

myelogenous leukemia, neutropenia, and disseminated

aspergillosis, showing multiple bilateral dense nodules

consistent with Aspergillus brain involvement.

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Another late radiological sign is the air crescent sign,which represents crescent-shaped lucencyin the region of the original nodule secondary tonecrosis.57,61 Neither sign, however, is sensitive orpathognomic of IPA. The halo sign may be found asa result of metastasis, bronchoalveolar carcinoma,bronchiolitis obliterans organizing pneumonia,eosinophilic pneumonia, or other fungal infection.62

Greene et al. found that 94% of 235 patients witha confirmed diagnosis of IPA had at least onenodular region.63 In another report on HRCT chestfindings in febrile neutropenic patients withpneumonia, the findings associated with IPA wereill-defined nodules (67%), ground glass appearance(56%), and consolidation (44%).64 In a retrospectivestudy done on 45 patients, none of the earlyHRCT signs (nodule, consolidation, peribronchialinfiltrates) predicted patient outcome or the devel-opment of pulmonary haemorrhage.65 However,pulmonary haemorrhage is expected to occurin the presence of large cavitating nodules orconsolidations located close to larger pulmonaryvessels.

Bronchoscopy with bronchoalveolar lavage (BAL)is generally helpful in the diagnosis of IPA,especially in patients with diffuse lung involvement.The sensitivity and specificity of a positive result ofBAL fluid are about 50% and 97%, respectively.This diagnostic yield of BAL in the diagnosis of IPAis not consistent, and much lower yields have beenreported.50,52,66–70 BAL is however a safe and usefultool in high-risk patients suspected to have IPA. Inaddition to obtaining samples for fungal stain andculture, it may also be useful in detecting Aspergillusantigens in the BAL fluid, and excluding otherinfections. Transbronchial biopsies usually do not

add much to the diagnosis of IPA, and are associatedwith increased risk of bleeding, so are seldomperformed.52

In the setting of diagnostic work-up for IPA, it isimportant to send samples such as sputum, BALfluid, or lung tissue for culture as well as forhistological examination. This is because otherfungal species, such as zygomyces, scedosporium,pseudallescheria, and fusarium, may have similarhistological appearance to Aspergillus.71

Furthermore, different species of Aspergillus maylead to IPA. While A. fumigatus is the most commoncause of IPA, there are increasing reports of IPAin cancer patients due to other species such asA. niger, A. terreus and A. flavus.72–76 Some of thesespecies (such as A. terreus and A. nidulans) areresistant to amphotericin B.73,76

In a review of 300 cases with proven IPA,A. terreus was the second most common species,isolated with a frequency of 23%. The risk factorsand outcome for A. terreus infection were similar tothose for A. fumigatus infection, but the former wassignificantly more likely to be nosocomial in origin,and more likely to be resistant to amphotericin B.75

The new triazole antifungal agents such as vorico-nazole and posaconazole have significantly betterefficacy against A. terreus.73,74,77

The most recent advances in the diagnosis ofIPA are related to detecting Aspergillus antigens inbody fluids. Galactomannan is a polysaccharidecell-wall component that is released by Aspergillusduring growth. A double-sandwich ELISA for thedetection of galactomannan in serum was recentlyapproved by the Food and Drug Administration forthe diagnosis of IPA, with a threshold of 0.5 ng/ml.Serum galactomannan can be detected several daysbefore the presence of clinical signs, an abnormalchest radiograph, or positive culture. This may allowearlier confirmation of the diagnosis, and serialdetermination of serum galactomannan values maybe useful in assessing the evolution of infectionduring treatment.78,79

A meta-analysis study was undertaken by Pfeifferet al. to assess the accuracy of a galactomannanassay for diagnosing IPA. Twenty-seven studies from1996 to 2005 were included, and cases werediagnosed with IPA according to the EuropeanOrganization for Research on Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria.Overall, the assay had a sensitivity of 71% andspecificity of 89% for proven cases of invasiveaspergillosis. The negative predictive value was92–98% and the positive predictive value was25–62%.80 Pfeiffer and colleagues concluded thatgalactomannan assay is more useful in patients whohave haematological malignancy or who have

Figure 4. Chest CT image from an allogeneic HSCT

recipient with severe GVHD, showing multiple nodular

lesions. Thoracoscopic lung biopsy confirmed the

diagnosis of IPA.

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undergone allogeneic HSCT, than in solid-organtransplant recipients or non-neutropenic patients.

Galactomannan is found in food, and may beabsorbed by the digestive tract, especially in patientswith postchemotherapy mucositis, resulting in afalse-positive reaction. Also, medications such asb-lactam antibiotics (e.g. piperacillin/tazobactam)may be associated with a false-positive assay, whileantifungal agents with activity against Aspergillusmay lead to a false-negative result.81–84

One of the major limitations of the galactoman-nan test is the species-specificity of the assay.Consequently, it is not possible to exclude theinvolvement of other moulds such as Fusarium,Zygomycetes, and dematiaceous fungi.85 Galacto-mannan detection does not remove the need forcareful microbiological and clinical evaluations.

There is evidence that galactomannan is dete-cted in other body fluids such as BAL, urine,and cerebrospinal fluid, and that these tests maybecome positive prior to clinical and radiologicalfindings suggestive of IPA.85–88 Prospective studiesare needed to study and compare the performanceof Aspergillus antigen detection in samples otherthan serum. In a retrospective study, incorporat-ing galactomannan assay and quantitative PCRassay into standard BAL fluid analysis appeared toenhance bronchoscopic identification of Aspergillusspecies as the cause of pulmonary disease in HSCTrecipients.86

Polymerase chain reaction (PCR) is another wayto diagnose IPA, by the detection of AspergillusDNA in BAL fluid and serum. A positive AspergillusPCR in BAL fluid has an estimated sensitivity of67–100% and specificity of 55–95% for IPA.89 PCRsensitivity and specificity have also been reported as100% and 65–92%, respectively, in serum sam-ples.89–92 However this test is often associated withfalse-positive results, because it does not discrimi-nate between colonization and infection. PCR forAspergillus nucleic acid detection remains restrictedto highly specialized laboratories, and cannot beconsidered a routine exam.

Detection of serum (1! 3)-b-D-glucan, a fungalcell wall constituent, has recently received Foodand Drug Administration approval, and is a highlysensitive and specific test for invasive deep mycosis,including candidiasis, fusariosis, and aspergillosis,that could be useful in immunocompromisedpatients.93 However, the utility of this assay innon-neutropenic and in allogeneic HSCT recipientsat high risk for IPA is not yet known.

The role of galactomannan and other serologicalstudies in the diagnosis of IPA is evolving.Furthermore, their role in different hosts, as surveil-lance tools, and their impact on the outcome of

patients, are all unclear. Ongoing prospectivestudies are attempting to address these issues, butuntil solid data are available, these tests should beconsidered as adjunct diagnostic studies, and shouldnot replace appropriate clinical and radiologicalevaluation (and in selected cases, invasive proce-dures) to confirm the diagnosis of IPA.

The EORTC/MSG has proposed several criteria forthe diagnosis of invasive fungal infections.94 Thesecriteria consist of host factors, microbiologicalfactors, and minor and major clinical criteria(Table 2). Two consecutive positive serum galacto-mannan measurements, with the appropriate hostand clinical factors, can be considered ’probable’IPA.94 However, the EORTC/MSG criteria areneither evidenced-based, nor prospectively vali-dated. They are meant to serve as a guide forclinical and epidemiological research, and need notbe present in every patient to treat for IPA.

Treatment

Treatment of IPA is difficult, and mortality remainshigh despite the introduction of several new

Table 2 Diagnostic criteria for IPA

Diagnosis Criteria

Proven IPA Histopathological or cytopathological

examination of lung tissue showing

hyphae from needle aspiration, or biopsy

specimen with evidence of associated

tissue damage; OR

Positive culture result for Aspergillus

from a sample obtained by sterile

procedure from the lung and clinically

or radiologically abnormal site consistent

with infection

Probable IPA Host risk factor (Table 1); AND

Microbiological criteria (positive

Aspergillus microscopy or culture from

the sputum or BAL, or positive

galactomannan assay); AND

Clinical criteria consistent with the

infection (1 major or 2 minor)�

Possible IPA Host risk factor (see Table 1); AND

Microbiological criteria (positive

Aspergillus microscopy or culture from

the sputum or BAL, or positive

galactomannan assay); OR

Clinical criteria consistent with the

infection (1 major or 2 minor)�

�Major clinical criteria: new characteristic infiltrates on CT

imaging (halo sign, air-crescent sign, or cavity within area

of consolidation). Minor clinical criteria: symptoms of

LRTI (cough, chest pain, haemoptysis, or dyspnoea);

physical finding of pleural rub; any new infiltrate not

fulfilling major criteria; pleural effusion.

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antifungal agents. Therapy should be considered assoon as there is a clinical suspicion of IPA, andwhile a workup is underway. For many years,amphotericin B has been the first line of therapyfor IPA, recommended dose 1–1.5mg/kg/day.However, amphotericin B can cause serious side-effects, including nephrotoxicity, electrolyte distur-bances, and hypersensitivity. For these reasons,newer lipid-based preparations of amphotericin B(e.g. liposomal amphotericin B and lipid complexamphotericin B) have been introduced to reducethese side-effects. Higher doses of the lipid for-mulations are needed for equivalent antifungalefficacy to the older version.

Voriconazole is a new broad-spectrum triazolethat has been approved as the initial treatment ofinvasive aspergillosis, and is currently consideredthe treatment of choice in many patients withIPA.95–97 In a large prospective, randomized, multi-centre trial, voriconazole was compared to ampho-tericin B as the primary therapy for IPA.98 Patientsreceiving voriconazole had a higher favourableresponse rate at week 12 (53%, vs. 32% in patientsreceiving amphotericin B), and a higher 12-weeksurvival (71% vs. 58%). Voriconazole is available inboth intravenous and oral formulations. The recom-mended dose is 6mg/kg twice daily intravenouslyon day one, followed by 4mg/kg/day. After sevendays, switching to 200mg PO twice daily may beconsidered. Voriconazole has a milder side-effectprofile, and is much better tolerated than amphoter-icin B. The most frequent adverse effect is visualdisturbances, described as blurred vision, photo-phobia, and altered colour perception. Liver func-tion test abnormalities and skin reactions are lesscommon side-effects. Voriconazole is howeverassociated with significant number of drug–druginteractions, such as with cyclosporine, warfarin,terfenadine, carbamazepine, quinidine, rifampin,statins, and sulfonylureas.95

Posaconazole is another broad-spectrum triazolethat is effective and safe as salvage therapy inpatients with invasive aspergillosis refractory tostandard antifungal therapy.21,77,99

Echinocandin derivatives such as caspofungin,micafungin, and anidulafungin are effective agentsin the treatment of IPA refractory to standardtreatment, or if the patient cannot tolerate first-lineagents.100,101 Since echinocandins inhibit the(1! 3)-b-D-glucan constituent of the fungal cellwall, unlike polyenes and azoles which target thefungal cell membrane, combination antifungaltherapy could be a strategy to treat refractoryIPA.102,103 There are no prospective randomizedstudies that show improved efficacy with combina-tion therapy (rather than single agents) in the

management of primary IPA. There are howeverin vitro and limited clinical studies (case reports andretrospective case series) that suggest a benefit fromcombining antifungal agents as salvage therapy inrefractory IPA.103–106 The combination of caspofun-gin and liposomal amphotericin B as a salvagetherapy showed a an overall response rate of 42%,although in patients with progressive documentedIPA, the response rate was only 18%.103 A survivaladvantage of voriconazole plus caspofungin com-pared with voriconazole alone was reported in oneretrospective analysis of salvage therapy for IPA.105

On the other hand, another report showed nodifference in the response rate between patientswho received micafungin alone or those whoreceived it in combination with other antifungalagents as primary or salvage therapy for acuteIPA.107 Combination therapy of an echinocandinwith either a lipid formulation of amphotericin B ortriazole agent appears promising, but cannot berecommended for the routine treatment of primaryIPA. Controlled randomized prospective studies areneeded to document the value of this approach.Because galactomannan is covalently bound to(1!3)-b-D-glucan in the fungal cell wall, an initialincrease in circulating galactomannan might beexpected in patients treated with echinocandins.108

Surgical resection has a limited role in the manage-ment of patients with IPA, but should be consideredin cases of massive haemoptysis, or pulmonarylesions close to the great blood vessels or peri-cardium, or the resection of residual localizedpulmonary lesions in patients with continuingimmunosuppression or those who are expected tohave immunosuppressive therapy in the future.Several reports have shown the relative efficacyand safety of surgical intervention (in addition toantifungal therapy) in these situations.59,109–114

Immunomodulatory therapy, such as usingcolony-stimulating factors (i.e. granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating therapy) or interferon-g could be used todecrease the degree of immunosuppression, and asan adjunct to antifungal therapy for the treatment ofIPA. Colony-stimulating factors stimulate the bonemarrow to produce more neutrophils, and havebeen shown to augment the phagocytic activity ofneutrophils against fungi, including Aspergillusspp.115–117 There is a theoretical advantage fromadding these agents to the treatment of neutropenicpatients suspected to have IPA.In one randomized study in patients receiving

chemotherapy for acute myelogenous leukemia,prophylaxis with GM-CSF led to a lower frequencyof fatal fungal infections compared withplacebo (1.9 vs. 19%, respectively) and reduced

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overall mortality.118 It is recommended to considercolony-stimulating factors in neutropenic patientswith serious infections, but there are no definitivestudies that show benefit in patients with IPA.119

Interferon-g is another cytokine that has beenshown in vitro and in animal models to augmentimmunity by increasing neutrophil and monocyteactivity against Aspergillus,116,120,121 and it hasbeen used to decrease the risk of Aspergillusinfection in patients with CGD.122 Evidence on thevalue of adding interferon-g as an adjunct treatmentof IPA is limited to case reports and small reports,and there are no guidelines on its role in thetreatment of IPA.123 There was a concern about theuse of interferon-g in allogeneic HSCT recipients,since it may worsen GVHD; however in a recenttrial, GVHD actually improved during thistherapy.124

Granulocyte transfusion is another potentialsupportive therapy for patients with prolongedneutropenia and life-threatening infections refrac-tory to conventional therapy. It has been shown thatit is safe for potential donors to donate neutrophilsby granulocytophoresis, but there are no random-ized studies that prove the benefit of adjuvantgranulocyte transfusion in the treatment of IPA.125

It is also important in patients with IPA, wheneverpossible, to decrease the dose of systemic cortico-steroids and immunosuppressive agents.

The management of IPA is difficult, and animportant approach to this problem is prophylaxisin patients at increased risk for IPA. Avoiding thehospitalization of patients in areas where there isconstruction, and the use of high-efficiency particu-late air (HEPA) filtration, with or without laminarair flow ventilation, have both proven useful.126

A meta-analysis suggested that itraconazole waseffective in preventing fungal infections in neutro-penic patients.127 Preliminary data also suggestthe efficacy of posaconazole as IPA prophylaxisin patients with acute myelogenous leukemia ormyelodysplastic syndrome.128 Currently, chemo-prophylaxis trials using other antifungal agents(such as voriconazole, caspofungin, micafungin)are underway in high-risk patients.

Chronic necrotizing aspergillosis(CNA)

Chronic necrotizing aspergillosis, also called semi-invasive or subacute invasive aspergillosis, was firstdescribed by Gefter et al. and Binder et al. in1981.129,130 It is an indolent, cavitary, and infe-ctious process of the lung parenchyma secondaryto local invasion by Aspergillus species, usually

A. fumigatus.131 In contrast to IPA, CNA runs aslowly progressive course over weeks to months,and vascular invasion or dissemination to otherorgans is unusual. This syndrome is rare, and theavailable literature is based on case reports andsmall case series.129–131

Risk factors

CNA usually affects middle-aged and elderlypatients with altered local defences, associatedwith underlying chronic lung diseases such asCOPD, previous pulmonary tuberculosis, thoracicsurgery, radiation therapy, pneumoconiosis, cysticfibrosis, lung infarction, or (less commonly) sarcoi-dosis.132 It may also occur in patients who aremildly immunocompromised due to diabetes melli-tus, alcoholism, chronic liver disease, low-dosecorticosteroid therapy, malnutrition, and connectivetissue diseases such as rheumatoid arthritis andankylosing spondylitis.130

It may be difficult to distinguish CNA fromaspergilloma, especially if a previous chest radio-graph is not available.133 However, in CNA there islocal invasion of the lung tissue and a pre-existingcavity is not needed, although a cavity with a fungalball may develop in the lung as a secondaryphenomenon, due to destruction by the fungus. Ina recent report of aspergillomas in AIDS, progressionover time was seen, with considerable morbidityand some mortality.133 This probably reflects that anaspergilloma may invade the cavity wall, causinglocal parenchyma destruction, as seen in patientswith CNA.131

Clinical presentation and diagnosis

Patients frequently complain of constitutional symp-toms such as fever, weight loss of 1–6 months’duration, malaise, and fatigue, in addition to chronicproductive cough and haemoptysis, which variesfrom mild to severe.133 Occasionally, patients maybe asymptomatic.

The chest radiograph and chest CT scan usuallyshow consolidation, pleural thickening, and cavi-tary lesions in the upper lung lobes. Aspergillomamay be seen in nearly 50% of patients.130 Adjacentpleural thickening, which may progress to forma broncho-pleural fistula, is considered an earlyindication of a locally invasive process.129,134

Characteristically, these radiological findings tendto be progressive over weeks to months.134

The vast majority of patients with CNA havepositive serum IgG antibodies to A. fumigatus,which varies over time and may be negative atsome points in the course of CNA.133 Immediateskin reactivity for Aspergillus antigens is another

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helpful, but not diagnostic test. Sputum and

bronchoscopy samples may also be positive for

Aspergillus by culture.133

Confirmation of the diagnosis requires a histolog-

ical demonstration of tissue invasion by the fungus,

and the growth of Aspergillus species on culture.

Pathologically, CNA is characterized by necrosis of

lung tissue, acute or chronic inflammation of the

cavity wall, and presence of hyphae consistent with

Aspergillus species.135 However, the yield of

transbronchial biopsy specimens or percutaneous

aspirates is relatively poor, and a thoracoscopic or

open-lung biopsy is rarely performed in these

patients. Confirmation of the diagnosis is thus

difficult, and delayed diagnosis is common, which

may contribute to the morbidity and mortality

associated with CNA. Therefore, early diagnosis

needs a high index of suspicion. The combination

of characteristic clinical and radiological findings

and either serological results positive for Aspergillus

or the isolation of Aspergillus from respiratory

samples is highly indicative of CNA.136 Denning

et al. have proposed criteria for diagnosis of chronic

pulmonary aspergillosis, including CNA, which

could be helpful to in the earlier diagnosis and

therapy of CNA, and may thus improve the

prognosis for patients with this condition136

(Table 3).

Treatment

Antifungal therapy is the mainstay of treatment for

patients diagnosed with CNA. Amphotericin B was

intially used, in doses of 0.5–1mg/kg/day (4–5mg/

kg/day for the lipid formulation) with favourable

results.130,131 Itraconazole later became an effective

alternative to the relatively toxic amphotericin

B,131,137 and more recently, voriconazole has

emerged as a primary therapy for CNA. In a recent

prospective study, where voriconazole 200mg was

given twice daily for a period of 4–24 weeks as

primary or salvage therapy for 39 patients with

CNA,96 a complete or partial response was seen in

43% of patients, and improvement or stability in

80%. The authors concluded that voriconazole was

a safe and effective treatment to be used as a

primary or salvage therapy for patients with CNA.Treatment is best evaluated by following clinical,

radiological, serological, and microbiological para-

meters.133 Useful parameters of response include

weight gain and energy levels, improved pulmonary

symptoms, falling inflammatory markers and total

serum IgE level, improvement in paracavitary

infiltrates, and eventually a reduction in cavity

size.133

Surgical resection plays a minor role in thetreatment of CNA, being reserved for healthy

young patients with focal disease and good pul-monary reserves, patients not tolerating antifungal

therapy, and patients with residual localized butactive disease despite adequate antifungal therapy.

Binder et al. reported that 90% of patients whounderwent surgical resection had good responses,

but surgery was associated with significant post-operative complications.130

The reported mortality of CNA varies widely and

may be limited by incomplete follow-up.131

Mortality was 39% in the reported American

experience, but less than 10% in European reportsusing itraconazole.131

Aspergilloma

Aspergilloma is the most common and best recog-nized form of pulmonary involvement due to

Aspergillus. Pulmonary aspergilloma usuallydevelops in a pre-existing cavity in the lung.

The aspergilloma (fungus ball) is composed of

Table 3 Diagnostic criteria for CNA

Diagnostic criteria Characteristics

Clinical Chronic (41 month) pulmonary or

systemic symptoms, including at least

one of: weight loss; productive

cough; haemoptysis

No overt immunocompromising

conditions (e.g. haematological

malignancy, neutropenia, organ

transplantation)

No dissemination

Radiological Cavitary pulmonary lesion with

evidence of paracavitary infiltrates

New cavity formation, or expansion

of cavity size over time

Laboratory Elevated levels of inflammatory

markers (C-reactive protein, plasma

viscosity, or erythrocyte sedimentation

rate)

Isolation of Aspergillus spp from

pulmonary or pleural cavity, or

Positive serum Aspergillus precipitin

test

Exclusion of other pulmonary

pathogens, by results of

appropriate cultures and serological

tests, that are associated with similar

disease presentation, including

mycobacteria and endemic fungi

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fungal hyphae, inflammatory cells, fibrin, mucus,

and tissue debris. The most common species

of Aspergillus recovered from such lesions is

A. fumigatus; however, other fungi may cause the

formation of a fungal ball, such as Zygomycetes

and Fusarium. Many cavitary lung diseases are

complicated by aspergilloma, including tuberculo-

sis, sarcoidosis, bronchiectasis, bronchial cysts and

bulla, ankylosing spondylitis, neoplasm, and pul-

monary infection;138,139 of these, tuberculosis is

the most common associated condition.140 In a

study on 544 patients with pulmonary cavities

secondary to tuberculosis, 11% had radiological

evidence of aspergilloma.141 Less frequently, asper-

gilloma has been described in cavities caused by

other fungal infections.142,143

Inadequate drainage is thought to facilitate the

growth of Aspergillus on the walls of these cavities.

The fungus ball may move within the cavity,

but does not usually invade the surrounding lung

parenchyma or blood vessels, although exceptions

have been noted.144,145 In the majority of cases,

the lesion remains stable, but in 10% of cases the

aspergilloma may decrease in size or resolve

spontaneously without treatment.146 The aspergil-

loma rarely increases in size.

Clinical presentation

Most patients with aspergilloma are asymptomatic.

When symptoms are present, most patients will

experience mild haemoptysis, but severe and life-

threatening haemoptysis may occur, particularly in

patients with underlying tuberculosis.147 Bleeding

usually occurs from bronchial blood vessels, and

may be due to local invasion of blood vessels lining

the cavity, endotoxins released from the fungus, or

mechanical irritation of the exposed vasculature

inside the cavity by the rolling fungus ball.144,148,149

The mortality rate from haemoptysis related to

aspergilloma ranges between 2% and 14%.150–154

Less commonly, patients may develop cough,

dyspnoea that is probably more related to the

underlying lung disease, and fever, which may be

secondary to the underlying disease or bacterial

superinfection of the cavity.Several risk factors have been associated

with poor prognosis of aspergilloma. These include

the severity of the underlying lung disease, increas-

ing size or number of lesions as seen on chest

radiographs, immunosuppression (including corti-

costeroids), increasing Aspergillus-specific IgG

titers, recurrent large volume haemoptysis, under-

lying sarcoidosis, and HIV infection.155

Diagnosis

The diagnosis of pulmonary aspergilloma is usually

based on the clinical and radiographic features,

combined with serological or microbiologic evi-

dence of Aspergillus spp. Chest radiography is usefulin demonstrating the presence of a mass in a

pre-existing cavity. Aspergilloma appears as an

upper-lobe, mobile, intra-cavitary mass with an

air crescent in the periphery.156 A change in the

position of the fungus ball after moving the patienton his side or from supine to prone position is an

interesting but variable sign.157 Chest CT scan may

be necessary to visualize aspergilloma that is not

apparent on chest radiograph.157 These radiologicalappearances may be seen in other different condi-

tions such as haematoma, neoplasm, abscess,

hydatid cyst, and Wegener’s granulomatosis.

Aspergilloma may coexist with any of the above

mentioned conditions.158,159 Sputum cultures forAspergillus spp are positive only in 50% of cases.160

Serum IgG antibodies to Aspergillus are positive in

almost every case, but may be negative in patients

on corticosteroid therapy.145 Aspergillus antigenhas been recovered from the bronchoalveolar

lavage fluid of patients with aspergilloma, but the

diagnostic value of this test is variable.161,162

Treatment

There is no consensus on the treatment of aspergil-

loma. Treatment is considered only when patients

become symptomatic, usually with haemoptysis.

Inhaled, intracavitary, and endobronchial instilla-tions of antifungal agents have been tried and

reported in small numbers of patients, without

consistent success.153,163,164

Administration of amphotericin B percutaneously

guided by CT scan can be effective for aspergilloma,especially in patients with massive haemoptysis,

with resolution of haemoptysis within few

days.165,166 The role of intravenously administered

amphotericin B is uncertain, and some small studiesfailed to show a benefit.167

Oral itraconazole has been used, with radio-

graphic and symptomatic improvement in half

to two-thirds of patients, and occasional patients

having a complete response.168–170 Itraconazoleis a useful agent for aspergilloma management,

because it has a high tissue penetration. In a recent

study, significant itraconazole levels within

the aspergilloma cavities were demonstrated

after using the standard dose of itraconazole(100–200mg/day).171 The major limitation of

itraconazole is that it works slowly and would not

be useful in cases of life-threatening haemoptysis.161

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Surgical resection of the cavity and removal ofthe fungus ball is usually indicated in patients withrecurrent haemoptysis, if their pulmonary functionis sufficient to allow surgery. Surgical treatmentis associated with relatively high mortality rates,ranging from 7% to 23%.149–151,172–175 The mostcommon causes of death post-operatively are severeunderlying lung disease, pneumonia, acute myocar-dial infarction, and IPA.153,175 Other postoperativecomplications include haemorrhage, residualpleural space, bronchoalveolar fistula, empyema,and respiratory failure.

Bronchial artery embolization should be consid-ered as a temporary measure in patients with life-threatening haemoptysis, since haemoptysis usuallyrecurs due to the presence of massive collateralblood vessels.176 The role of newer antifungalazoles such as voriconazole in the treatment ofaspergilloma has yet to be determined.

Allergic bronchopulmonaryaspergillosis (ABPA)

ABPA is a pulmonary disease that results fromhypersensitivity to Aspergillus antigens, mostly dueto A. fumigatus. The majority of cases of ABPAoccur in people with asthma or cystic fibrosis. It isestimated that 7–14% of corticosteroid-dependentasthmatics and 6% of patients with cystic fibrosisdevelop ABPA.177,178 The pathogenesis of ABPA isnot completely understood: Aspergillus-specificIgE-mediated type I hypersensitivity reactions, spe-cific IgG-mediated type III hypersensitivity reactions,and abnormal T-lymphocyte cellular immuneresponses all appear to play important roles in itspathogenesis.179–182 In one study, 18 pathologicalspecimens were taken from patients diagnosedwith ABPA and the most significant findings wereinvolvement of the bronchi and bronchioles, withbronchocentric granulomas in 15 specimens andmucoid impaction in 11.183 Other findings includedgranulomatous inflammation consisting of palisad-ing histiocytes surrounded by lymphocytes, plasmacells, and eosinophils. Fungal hyphae were seen,but without evidence of tissue invasion.183

Clinical presentation and diagnosis

ABPA is usually suspected on clinical grounds, andthe diagnosis is confirmed by radiological andserological testing. Almost all patients have clinicalasthma, and patients usually present with episodicwheezing, expectoration of sputum containingbrown plugs, pleuritic chest pain, and fever.184

Chest radiograph findings may be normal in the

early stages of the disease. During acute exacerba-

tions, fleeting pulmonary infiltrates are characteristic

feature of the disease that tends to be in the upper

lobe and central in location. There may be transient

areas of opacification due to mucoid impaction

of the airways, which may present as band-like

opacities emanating from the hilum with rounded

distal margin (gloved finger appearance).185

The ’ring sign’ and ’tram lines’ are radiological

signs that represent the thickened and inflamed

bronchi may be seen on chest radiographs. Central

bronchiectasis and pulmonary fibrosis may develop

at later stages. Chest CT scan, with high-resolution

images, is helpful for better defining bronchiectasis

and more sensitive in demonstrating the above

changes (Figure 5). Typically, total serum IgE is

elevated, and sputum cultures reveal Aspergillus

spp. Serum IgE could be used as a marker for flare-

ups and responses to therapy.186 A positive sputum

culture is not necessary to diagnose ABPA.

Immediate skin test reactivity to A. fumigatus

antigens and elevated levels of serum IgG and

IgE antibodies to Aspergillus are usually

documented.179 Lung biopsies are rarely performed,

since ABPA is usually suspected on clinical rounds.

Greenberger and Patterson have standardized the

criteria for the diagnosis of ABPA (Table 4),184,186

not all of which need to be present for the diagnosis

to be made.Early detection and treatment of ABPA before

the development of all clinical symptoms and

bronchiectasis is paramount, since delayed

treatment may result in irreversible pulmonary

damage. Therefore, patients with ABPA can be

subdivided in two groups: patients with or with-

out central bronchiectasis (ABPA-CB and

Figure 5. High-resolution chest CT image from a patient

with ABPA, showing moderate bronchiectasis, with areas

of mucoid impaction and atelectasis of the right middle

lobe.

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ABPA-seropositive, respectively).1 The minimal

essential criteria to diagnose patients with ABPA-

central bronchiectasis include asthma, immediate

skin reactivity to Aspergillus antigens, serum IgE

level 41000 ng/ml, and central bronchiectasis.

On the other hand, the minimal criteria to diagnose

ABPA-seropositive patients include asthma, immedi-

ate skin reactivity to Aspergillus antigens, serum IgE

4 1000 ng/ml, history of pulmonary infiltrates, and

elevated levels of serum IgE and IgG antibodies to

A. fumigatus.187

Patterson et al. have also subdivided the clinicalcourse of ABPA into five stages that help to guide the

management of the disease.188 These stages need

not occur in order. The first four are potentially

reversible, with no long-term sequelae. Stage I

(acute stage) is the initial acute presentation with

asthma, elevated IgE level, peripheral eosinophilia,

pulmonary infiltrates, and IgE and IgG antibodies

to A. fumigatus. In practice, patients are seldom

identified in this stage. In Stage II (remission stage),

the IgE falls but usually remains elevated, eosino-

philia is absent, and the chest radiograph is clear.

Serum IgG antibodies to Aspergillus antigen may

be slightly elevated. Stage III (exacerbation stage)is the recurrence of the same findings as in Stage I

in patients known to have ABPA. IgE rises to

at least double the baseline level. Stage IV

(the corticosteroid-dependent stage) occurs in

patients who have asthma in which control of

symptoms is dependent on chronic use of high-dose

corticosteroid therapy and exacerbations are

marked by worsening asthma, radiographic

changes, and an increase in IgE level may occur.

Frequently, the chest CT scan will show central

bronchiectasis. Unfortunately, most patients are

diagnosed at this stage.189 In stage V (fibroticstage), bronchiectasis and fibrosis develop, and

usually lead to irreversible lung disease. Patients in

this stage, may present with dyspnoea, cyanosis,

rales, and cor pulmonale. Clubbing may be present.

The serum IgE level and eosinophil count might be

low or high. Fortunately, few patients progress to

this stage.

Treatment

Treatment of ABPA aims to treat acute exacerbations

of the disease, and to limit progressive lung diseaseand bronchiectasis. Oral corticosteroids target-ing the hypersensitivity have formed the mainaspect of treatment in ABPA. Corticosteroidssuppress the inflammatory response provoked by

A. fumigatus rather than eradicating the organism.Treatment with corticosteroids leads to the relief ofbronchospasm, the resolution of radiographicinfiltrates, and the reduction in serum total IgE and

peripheral eosinophilia.190,191 Two weeks of dailytherapy of oral prednisone (0.5mg/kg/day), followedby gradual tapering, has been recommended fornew ABPA infiltrates.192,193 The duration of therapyshould be individualized according to the patient’s

clinical condition. However, most patients requireprolonged low-dose corticosteroid therapy tocontrol their symptoms and decrease the rate ofrelapse.192,193 Total serum IgE serves as a marker

of ABPA disease activity, and should be checked6–8 weeks after the initiation of therapy, then every8 weeks for 1 year after that to determine a base-line range for each individual patient.194 Inhaledcorticosteroids may help to control symptoms of

asthma, but small studies have failed to demonstratethe efficacy of inhaled corticosteroids in preventingthe progression of lung damage in patients withABPA.195,196

Several studies have been done on the utility ofthe antifungal agent itraconazole in the manage-

ment of patients with ABPA. Itraconazole has beeneffective in improving symptoms, facilitating wean-ing from corticosteroids, decreasing Aspergillustitres, and improving radiographic abnormalities

and pulmonary function.161 A randomized,double-blind, placebo-control trial of itraconazole200mg twice daily for 16 weeks for patients withABPA already receiving corticosteroids was recentlyconducted by Steven et al.197 Forty-six percent of

patients treated with itraconazole achieved signifi-cant response, which was defined as a reduction ofat least 50% in the corticosteroid dose, decreaseof at least 25% in the serum IgE concentration, and

one of the following: a 25% improvement inexercise tolerance or pulmonary function testresults, or partial or complete resolution of pulmo-nary infiltrates. Importantly, however, itraconazole

may augment the activity of corticosteroids viainhibition of their metabolism, which may lead toabnormal ACTH stimulation and adrenal insuffi-ciency.198 There are no randomized trials on theefficacy of voriconazole in the management of

ABPA, but one study of small number of childrenwith cystic fibrosis and ABPA treated with

Table 4 Diagnostic criteria for ABPA

Asthma

Immediate skin reactivity to Aspergillus

Serum precipitins to A. fumigatus

Increased serum IgE and IgG to A. fumigatus

Total serum IgE41000 ng/ml

Current or previous pulmonary infiltrates

Central bronchiectasis

Peripheral eosinophilia (1000 cells/ml)

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voriconazole demonstrated significant clinical and

serological improvements.199

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