mycoses

Diagnosis,Therapy and Prophylaxis of Fungal Diseases

Review article

Our 2015 approach to invasive pulmonary aspergillosis € nke,5 G. Michels,5 B. Liss,1,2 J. J. Vehreschild,1,2,3 C. Bangard,4 D. Maintz,4 K. Frank,5 S. Gro A. Hamprecht,6 H. Wisplinghoff,6 B. Markiefka,7 K. Hekmat,8 M. J. G. T. Vehreschild1,2,3 and O. A. Cornely1,2,3,9,10 Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany, 2Center for Integrated Oncology CIO K€ olnBonn, University of Cologne, Cologne, Germany, 3German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany, 4Department of Radiology, University Hospital of Cologne, Cologne, Germany, 5Department III of Internal Medicine, Heart Centre of the University of Cologne, Cologne, Germany, 6 Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany, 7Institute of Pathology, University Hospital of Cologne, Cologne, Germany, 8Department of Cardiothoracic Surgery, University Hospital of Cologne, Cologne, Germany, 9Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany and 10Clinical Trials Centre Cologne, ZKS K€oln, University of Cologne, Cologne, Germany 1

Summary

At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72–96 h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA.

Key words: Aspergillosis, mould pneumonia, neutropaenia, voriconazole, liposomal amphotericin B, caspofungin.

Introduction Current guidelines and recommendations of professional societies are important sources of information. As they might not always be applicable to specific clinical Correspondence: Prof. O. A. Cornely, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. Tel.: +49 221 478 6494. Fax: +49 221 478 3611. E-mail: [email protected] Submitted for publication 5 March 2015 Revised 9 March 2015 Accepted for publication 9 March 2015

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settings, we describe our institutional standard clinical approach to invasive pulmonary aspergillosis.1–4 Invasive pulmonary aspergillosis is a major challenge in the management of immunocompromised patients, due to a unique combination of high attributable mortality of ~70% and notorious diagnostic difficulties.5 Incidence rates depend on the underlying disease and on treatments received. In solid organ transplant recipients incidence rates are 1.8–2.7%,6,7 and in haematological malignancy range from 4.7 to 13.1%.5 Despite protection of patients with long-term neutropaenia receiving posaconazole prophylaxis, in general the incidence of invasive aspergillosis is increasing.4,8–10 This

doi:10.1111/myc.12319

B. Liss et al.

development may be due to rising patient numbers in vulnerable populations,11 as well as more frequent use of aggressive therapies.12 Patients in intensive care units (ICU) apparently are at increased risk, but this is not yet understood, owing to the heterogeneity of their underlying diseases and the lack of a definition of ICU itself. Susceptibility in any of these patient groups is enhanced by factors as diverse as use of glucocorticosteroids and other immunosuppressants,13 preexisting structural lung damage14–16 and genetic predisposition.17,18 Timely treatment reduces mortality rates,19 but is often hampered by a lack of specific clinical signs and symptoms,20 and by unreliable in vitro diagnostic assays.21 A standardised approach may increase physician compliance and thus diagnostic yield allowing earlier targeted treatment and subsequently lead to improved outcome.22–24 At our university hospital, we follow standard operating procedures (SOP) for diagnosis and treatment of infections in neutropaenic hosts. In an additional poster format the ‘febrile neutropaenia SOP’ are readily available on our haematology and stem cell transplant wards. In addition, they are web-based 25 (Fig. 1 and Fig. 2) for easy reference. They follow published evidence and guideline documents of professional societies, e.g. ECMM, ESCMID, DGHO and are frequently updated.1–4

Diagnostic strategy Patients with acute myelogenous leukaemia, myelodysplastic syndrome (AML/MDS) or severe aplastic anaemia and recipients of allogeneic haematopoietic stem cell transplantation receive posaconazole prophylaxis at our institution.4,9,10,26 Posaconazole prophylaxis has been included into the appropriate chemotherapy regimes in our ordering software. Patients ineligible for azole prophylaxis, e.g. those with acute lymphoblastic leukaemia, undergo serum galactomannan screening three times weekly.27,28 The most prevalent, but unspecific sign of invasive pulmonary aspergillosis, is persistent fever despite broadspectrum antibiotic treatment, reported in up to 100% of patients.20,29 A computer tomographic scan is ordered after 72–96 h of persistent fever and is performed within 24 h, usually on the same day. This thoracic CT scan without contrast enhancement is a rapid procedure, thus not interfering with planned examinations in our radiology department. In any patient with lower respiratory tract symptoms a CT scan is ordered independent of the presence and duration of fever.30 Diagnostic imaging is of utmost importance as all further diagnostic and therapeutic decisions depend on CT findings. We broadly categorise into no infiltrate, infiltrate not suggestive of invasive pulmonary aspergillosis, and infiltrate suggestive of invasive pulmonary aspergillosis, i.e.

Chest CT without contrast

Infiltrate suggestive of fungal infection (nodule, halo, cavity, air-crescent)

Unspecific infiltrate

No infiltrate

Invasive mold infection likely Bronchoalveolar lavage – specific test: Galactomannan, PCP Respiratory viruses Bacteria (including TBC)

High probability of invasive aspergillosis

Yes

Microscopy with septate hyphae or galactomannan (≥0.5 BAL or 2x in serum)

Other pathogen identified

No

Targeted aspergillosis therapy

Targeted therapy

No pathogen identified

No targeted therapy

Figure 1 Diagnostic algorithm for persistently febrile patients at risk of invasive pulmonary aspergillosis.

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Approach to invasive pulmonary aspergillosis

Posaconazole prophylaxis received? No

Yes

Liposomal amphotericin B 3 mg/kg QD i.v.

Voriconazole 6 mg/kg BID d1 4 mg/kg BID i.v.

Caspofungin d1 70 mg QD 50 mg QD i.v.

CT at d7 and d14 Respone/stable

Progression at 14 d

Figure 4 Invasive pulmonary aspergillosis in a patient with Consider oral treatment after at least 7 d i.v. treatment

AML: Infiltrates in both lungs with ‘air-crescent sign’ in the largest infiltrate. Consider biopsy

Figure 2 Therapeutic algorithm for patient with high probability

of invasive pulmonary aspergillosis.

Figure 3 Invasive pulmonary aspergillosis in a patient with mul-

tiple myeloma: Two spiculated infiltrates in the left upper lobe, each with surrounding halo.

• •

Nodular shape, with or without halo (Fig. 3), Cavity within area of consolidation or ‘air-crescent’ (Fig. 4). A reversed halo sign demands immediate attention, too. Suggestive of mucormycosis it is beyond the topic of this perspective article and has been dealt with elsewhere.3,31,32

Decision tree guided by CT findings Persistent fever without infiltrate

This is the case in 34.5% of our patients at risk (Fig. 5). Invasive pulmonary aspergillosis is ruled out. If the patient received posaconazole prophylaxis, this

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will be continued. No empiric antifungals are initiated and this approach is safe and effective.33 In this clinical situation any single diagnostic test will have a low yield, but identifying the cause of fever prevents polypragmatic treatment. In the absence of local symptoms during immunosuppression imaging of the paranasal sinuses rules out sinusitis. Repeated blood cultures can help identify blood stream infection by difficult to culture organisms or, e.g. Candida spp.34 Posaconazole serum concentration may be determined if the oral suspension is used, although no uncontroversial target level has been defined.35–38 Serum concentration is difficult to predict despite the use of complex models identifying correlating factors.39,40 Use of posaconazole tablets renders therapeutic drug monitoring generally obsolete.41 If the patient was not receiving posaconazole prophylaxis, empiric antifungal treatment is considered.42,43 Additional blood cultures are mandatory before the empiric antibiotic regimen may be switched,43 and abdominal infection should be considered.44,45 MRI can help identify aspergillosis of bones and joints.46 If fever of unknown origin persists, thoracic CT scans will be repeated weekly. Infiltrate non-suggestive of invasive pulmonary aspergillosis

This situation is encountered in 36.6% of our patients (Fig. 5). Invasive pulmonary aspergillosis is possible and needs to be ruled out. If galactomannan screening results were negative, or not done, e.g. in the case of posaconazole prophylaxis, bronchoalveolar lavage (BAL) is indicated. While we test BAL fluid for bacterial and viral infection, we in particular aim at

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28.9% 34.5%

Persistent fever without infiltrate Infiltrate non-suggestive of invasive pulmonary aspergillosis Infiltrate suggestive of invasive pulmonary aspergillosis

36.6%

Figure 5 Distribution of CT findings in

persistently febrile patients at risk for IPA.

galactomannan and fungal culture to confirm presence of Aspergillus spp.47–49 We only initiate antifungal treatment after mycological confirmation, although empiric treatment is an option in patients who did not receive posaconazole prophylaxis.42 We repeat thoracic CT imaging weekly if no diagnosis established despite all the efforts described above. Infiltrate suggestive of invasive pulmonary aspergillosis

In 28.9% of our patient population such infiltrates are found (Fig. 5). Invasive aspergillosis is highly likely, but not proven. Due to our early CT imaging policy, we usually find early CT signs. So the majority of these infiltrates are nodular and with or without characteristic halo sign. Air-crescent signs develop later in the course of aspergillosis.23,50 Actually, we rarely see cavities within areas of consolidation or air-crescent signs even in follow-up CT imaging of invasive pulmonary aspergillosis. We do not know whether this is due to early detection and treatment. In high-risk patients we still complete the diagnostic work-up to facilitate targeted treatment, but initiate treatment independent of further confirmation.51 If no galactomannan or cultural proof of aspergillosis on bronchoalveolar lavage fluid is established, mucormycosis remains a concern that might drive antifungal choice.31,52 CT-guided percutaneous biopsy

CT-guided biopsy has a high diagnostic yield in patients with haematological malignancies.53 With every CT scan revealing new infiltrates of unknown aetiology, we discuss diagnostic options with the radiologist. It is

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important that biopsies undergo both, histological and cultural evaluation. Only fungal culture warrants reliable pathogen identification and in addition allows susceptibility testing. To sample enough material for histological and cultural evaluation we perform true-cut CT-guided coaxial biopsies. A 17,5 gauge coaxial needle is introduced into the nodule or the consolidating infiltrate, the trocar is removed, the semi-automatic biopsy needle is introduced, and five to ten 18 gauge, 2 cm long true-cut biopsies are taken. The first samples are for microbiological work-up and the last ones are fixed in formalin for histological examination. We avoid transgression of emphysematous lung parenchyma and lung fissures. If necessary, platelets are transfused one concentrate right before and one during the intervention, to ensure a platelet count of 50 000 ll 1. To lose no time (and platelets) that count is not verified prior intervention. To ensure maximum diagnostic yield all clinical samples are examined by microscopy, microbiological culture and histopathology analysis. For culture, specimen are inoculated on non-selective agars, enrichment broth and agars selective for fungi (Sabouraud) and incubated at 30 and 37°C for 7–14 days. Histological samples are processed and evaluated in a predefined manner. Necessary staining, haematoxylin – eosin, periodic acid-Schiff and silver stain as well as microscopic features to be evaluated, i.e. general morphology, width, branching angle and septation of hyphae are standardised. Treatment

For the treatment of invasive pulmonary aspergillosis antifungal choice depends on prior posaconazole

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Approach to invasive pulmonary aspergillosis

prophylaxis, as we prefer to switch antifungal class. If no posaconazole prophylaxis was given, voriconazole1,54 is our primary choice owing to superior response rates and lower toxicity compared to conventional amphotericin B deoxycholate.55,56 Isavuconazole may find its place in this indication.57 If voriconazole is used, therapeutic drug monitoring is considered, as serum levels can vary considerably.58 However, neither target levels nor specifics of clinical implementation been firmly established. In the rare cases of breakthrough infection during posaconazole prophylaxis, we choose liposomal amphotericin B.1,54,59 Liposomal amphotericin B efficacy appears unhampered by prior azole exposure, in particular fluconazole, itraconazole and voriconazole, and clinically we extrapolate these findings to posaconazole.60 If both compounds are contraindicated, e.g. in patients with substantially elevated liver function tests or renal impairment, caspofungin is a reasonable alternative.61 Further treatment decisions build on clinical, mycological and radiological response. Despite adequate treatment, radiological findings may progress in the early phase of the disease, and several authors have reported peak volumes after 7 days of treatment, followed by a slow decline.50,62,63 In our experience, CT infiltrates should stabilise within 14 days of treatment initiation. Furthermore, air-crescent signs or cavities may become apparent, which are predictive of treatment success.62,63 For these reasons, we always perform CT scans after 7 and 14 days of treatment, allowing us to evaluate treatment success in awareness of the expected peak volume at day 7. Any progression of lung infiltrates in absence of air signs beyond 2 weeks of treatment is suggestive of treatment failure and associated with poor outcome. In this situation, renewed diagnostic efforts, especially biopsies for histological and cultural evaluation, may be lifesaving. The role of surgery

Many of our patients will undergo subsequent periods of immunosuppression, specifically neutropaenia. Knowing the cause of previous infections allows estimating the risk of these subsequent procedures. Open lung biopsy using video-assisted techniques has been advocated for diagnosing aspergillosis and differentiating other causes of pulmonary infiltrates, if submitted for histopathology and microbiology.64 Surgery is effective in the treatment of aspergillosis and their complications,65 as well as in preventing relapse

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of fungal infections in patients undergoing HSCT.66 The current guideline of the Infectious Diseases Society of America (IDSA) supports surgery for histological diagnostics, removal of residual infiltrates prior to the next chemotherapy cycle, acute haemoptysis, prevention of bleeding in the case of fungal lesions with vessel involvement and reduction in fungal burden.67 In recent years, we actually reintroduced surgery into our algorithm and regularly discuss surgical intervention to diagnose infection or to reduce fungal burden. As a rule, optimal timing in the individual patient may be immediate surgery during neutropaenia in case of mucormycosis, while we prefer surgical resection after resolution of neutropaenia and thrombocytopaenia in invasive pulmonary aspergillosis. Unmet medical needs

Newer non-invasive diagnostic tools emerge, but await further validation and standardisation before integrated into clinical practice pathways. Detection of fungal nucleic acid in human specimens is currently under assessment by the EORTC/MSG consensus group.68 While some PCR-based methods appear especially promising not only in diagnosing aspergillosis but also in concurrently assessing resistance.69 Lateral flow devices have been helpful in some studies in diagnosing invasive aspergillosis in conjunction with imaging studies.70,71 1,3-b-D-glucan (BDG) is increasingly used to diagnose invasive fungal infections and has also been proposed as a marker to guide treatment.72 While BDG is listed among the criteria for probable invasive fungal disease its role is unclear in the haematological patient populations, where false positive results have been reported.73–76 Recently, fungal-specific T-cell response has been found useful in diagnosing invasive mould infection, but validation in independent cohorts is pending.13,77–80 Further areas requiring investigation and not covered by current guidelines include increasing azole resistance. Though the SEPIA study (unpublished data and 81) and others find azole resistance at low rates,82 high numbers of azole-resistant isolates in a similar population have been reported,83 too. Also as of March 2015 no well-designed trials concerning the treatment of breakthrough infection have been published or registered at EudraCT or clinicaltrials.gov, possibly due to the rarity of these events.33,84–87 Finally, the benefit of antifungal combination treatment remains a matter of debate, despite increasing utilisation and promising results in certain subgroups.88,89

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Conclusion Whether institutional guidelines are worth the effort depends on physician compliance. Maintaining their usefulness is particularly challenging in diseases that demand interdisciplinary concerted action. We are convinced of the value of institutional guidelines, informed by international consensus recommendations and supplemented by recent evidence from clinical studies. Local epidemiology needs to be explored and incorporated into clinical pathways. Such institutional guidance expedites diagnosis, enables treatment customised to the individual patient, and finally improves outcome.

Conflict of interest BL, CB, DM, KF, SG, AH, HW, BM, KH have nothing to disclose. JJV is supported by the German Federal Ministry of Research and Education (BMBF grant 01KI0771) and the German Centre for Infection Research. JJV has received research grants from Astellas, Gilead Sciences, Infectopharm, Merck, Pfizer and Essex/ScheringPlough; and served on the speakers’ bureau of Astellas, Merck Sharp Dohme/Merck, Gilead Sciences, Pfizer and Essex/Schering-Plough. GM reports personal fees from Novartis and Berlin-Chemie AG, outside the submitted work. MJGTV has served at the speakers’ bureau of Pfizer, Merck, Gilead Sciences and Astellas Pharma, received research funding from 3M, Astellas Pharma and Gilead Sciences and is a consultant to Berlin Chemie. OAC is supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1106), has received research grants from 3M, Actelion, Astellas, Basilea, Bayer, Celgene, Cubist/Optimer, Genzyme, Gilead, GSK, Merck/MSD, Miltenyi, Pfizer, Quintiles, Shionogi, Viropharma, is a consultant to 3M, Astellas, Basilea, Cidara, Cubist/Optimer, Da Volterra, Daiichi Sankyo, F2G, Genentech, Gilead, GSK, Merck/MSD, Merck Serono, Pfizer, Rempex, Sanofi Pasteur and Summit/Vifor, and received lecture honoraria from Astellas, Gilead, Merck/MSD and Pfizer.

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