aspergilosis pulmonar.pdf

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Review

Pulmonary aspergillosis: a clinical updateO.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 pulmonary

diseases, 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 diagnosis

and 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 byinhalation 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 pulmonarydiseases 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 ofthe 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: [email protected]

! The Author 2007. Published by Oxford University Press on behalf of the Association of Physicians.All rights reserved. For Permissions, please email: [email protected]

Q J Med2007; 100:317334doi:10.1093/qjmed/hcm035
http://www.pubmed.gov/http://www.pubmed.gov/


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setting of CMV disease increases by 13.3-fold(95%CI 4.737.7).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


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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 of

the host. In immunocompetent patients, isolationofAspergillus 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.4951 In the immunocompetent patientwithAspergillusisolated 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 8090%.50,52,53 However,sputum samples that are negative do not rule out

IPA; 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 the

course 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 showingAspergillus acute branch hyphae invading a bloodvessel 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 nodulesconsistent with Aspergillusbrain involvement.

320 O.S. Zmeili and A.O. Soubani


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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 were

ill-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.50,52,6670 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 detectingAspergillusantigens 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. WhileA. fumigatusis the most commoncause of IPA, there are increasing reports of IPAin cancer patients due to other species such asA. niger, A. terreusandA. flavus.7276 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 factors

and outcome forA. terreusinfection were similar tothose forA. fumigatusinfection, 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 againstA. 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 recently

approved 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 were

diagnosed 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 was9298% and the positive predictive value was2562%.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 HSCTrecipient with severe GVHD, showing multiple nodularlesions. Thoracoscopic lung biopsy confirmed thediagnosis of IPA.

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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-gas 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 prolonged

neutropenia 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 is

construction, 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.129131

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 16 monthsduration, 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 Adjacent

pleural 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 forAspergillusby 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 oflung tissue, acute or chronic inflammation of the

cavity wall, and presence of hyphae consistent withAspergillus species.135 However, the yield of

transbronchial biopsy specimens or percutaneousaspirates is relatively poor, and a thoracoscopic or

open-lung biopsy is rarely performed in thesepatients. Confirmation of the diagnosis is thus

difficult, and delayed diagnosis is common, whichmay contribute to the morbidity and mortality

associated with CNA. Therefore, early diagnosisneeds a high index of suspicion. The combination

of characteristic clinical and radiological findingsand either serological results positive for Aspergillus

or the isolation of Aspergillus from respiratorysamples is highly indicative of CNA.136 Denning

et al. have proposed criteria for diagnosis of chronic

pulmonary aspergillosis, including CNA, whichcould be helpful to in the earlier diagnosis andtherapy 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 wasintially used, in doses of 0.51 mg/kg/day (45 mg/kg/day for the lipid formulation) with favourable

results.130,131 Itraconazole later became an effectivealternative 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 200 mg wasgiven twice daily for a period of 424 weeks as

primary or salvage therapy for 39 patients withCNA,96 a complete or partial response was seen in

43% of patients, and improvement or stability in80%. The authors concluded that voriconazole was

a safe and effective treatment to be used as aprimary 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 pulmonarysymptoms, falling inflammatory markers and total

serum IgE level, improvement in paracavitaryinfiltrates, and eventually a reduction in cavity

size.133

Surgical resection plays a minor role in the

treatment of CNA, being reserved for healthyyoung patients with focal disease and good pul-monary reserves, patients not tolerating antifungaltherapy, 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 andmay be limited by incomplete follow-up.131

Mortality was 39% in the reported Americanexperience, but less than 10% in European reports

using itraconazole.131

AspergillomaAspergilloma is the most common and best recog-nized form of pulmonary involvement due toAspergillus. 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 orsystemic symptoms, including at leastone of: weight loss; productivecough; haemoptysis

No overt immunocompromisingconditions (e.g. haematologicalmalignancy, neutropenia, organtransplantation)No dissemination

Radiological Cavitary pulmonary lesion withevidence of paracavitary infiltratesNew cavity formation, or expansionof cavity size over time

Laboratory Elevated levels of inflammatorymarkers (C-reactive protein, plasmaviscosity, or erythrocyte sedimentationrate)Isolation ofAspergillus spp from

pulmonary or pleural cavity, orPositive serum AspergillusprecipitintestExclusion of other pulmonarypathogens, by results ofappropriate cultures and serologicaltests, that are associated with similardisease presentation, includingmycobacteria 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 andbulla, 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 cavitiessecondary to tuberculosis, 11% had radiological

evidence of aspergilloma.141 Less frequently, asper-

gilloma has been described in cavities caused byother fungal infections.142,143

Inadequate drainage is thought to facilitate thegrowth ofAspergilluson 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 exceptionshave 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, ormechanical irritation of the exposed vasculature

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

The mortality rate from haemoptysis related toaspergilloma ranges between 2% and 14%.150154

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 bacterialsuperinfection 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 usuallybased on the clinical and radiographic features,combined with serological or microbiologic evi-dence ofAspergillusspp. Chest radiography is usefulin demonstrating the presence of a mass in apre-existing cavity. Aspergilloma appears as an

upper-lobe, mobile, intra-cavitary mass with anair crescent in the periphery.156 A change in theposition of the fungus ball after moving the patienton his side or from supine to prone position is aninteresting but variable sign.157 Chest CT scan maybe necessary to visualize aspergilloma that is notapparent on chest radiograph.157 These radiologicalappearances may be seen in other different condi-tions such as haematoma, neoplasm, abscess,hydatid cyst, and Wegeners granulomatosis.Aspergilloma may coexist with any of the abovementioned conditions.158,159 Sputum cultures forAspergillusspp are positive only in 50% of cases.160

Serum IgG antibodies to Aspergillusare positive inalmost every case, but may be negative in patientson corticosteroid therapy.145 Aspergillus antigenhas been recovered from the bronchoalveolarlavage fluid of patients with aspergilloma, but thediagnostic value of this test is variable.161,162

Treatment

There is no consensus on the treatment of aspergil-loma. Treatment is considered only when patientsbecome symptomatic, usually with haemoptysis.

Inhaled, intracavitary, and endobronchial instilla-tions of antifungal agents have been tried andreported in small numbers of patients, withoutconsistent success.153,163,164

Administration of amphotericin B percutaneouslyguided by CT scan can be effective for aspergilloma,especially in patients with massive haemoptysis,with resolution of haemoptysis within fewdays.165,166 The role of intravenously administeredamphotericin 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 patientshaving a complete response.168170 Itraconazoleis a useful agent for aspergilloma management,because it has a high tissue penetration. In a recentstudy, significant itraconazole levels withinthe aspergilloma cavities were demonstratedafter using the standard dose of itraconazole(100200 mg/day).171 The major limitation ofitraconazole is that it works slowly and would notbe useful in cases of life-threatening haemoptysis.161



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voriconazole demonstrated significant clinical andserological improvements.199

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