Invasive Aspergillosis in Cancer Patients

Dr. Bow has written a useful article summarizing manyaspects of the present state of risk factors, prophylaxis, and prevention ofinvasive aspergillosis with additional comments about treatment. To amplify someof his points, I will look back over the last 5 years from the perspective of anarticle I wrote in 1995 for the Annales de Medecine Interne (the Frenchequivalent to the Annals of Internal Medicine).[1] In it, I posed severalquestions concerning the management of invasive aspergillosis, as follows:

Do a patient’s underlying risk factors alter thediagnostic approach?

Does treatment differ according to patient group?

Does the neutrophil count or function influence response?

Does the rate of progression of invasive aspergillosisaffect outcome?

Does the body organ affected influence outcome?

Does surgical intervention affect outcome?

Is susceptibility testing of Aspergillus useful to predictclinical management?

In this brief overview, I will touch on these points andsummarize the state of clinical management 5 years later. This is importantbecause the incidence of invasive aspergillosis continues to rise and mortalityrates remain high.

Do a Patient’s Underlying Risk Factors Alter the DiagnosticApproach?

There have been clear advances in the diagnosis of invasiveaspergillosis in the neutropenic leukemic patient. The use of computedtomography (CT) scans during neutropenia has allowed earlier interventions(including surgery and switching of therapy) and better outcomes.[2] Caillot etal in Dijon, France, pioneered the use of systematic CT scanning in patientswith febrile neutropenia.[2] This allows recognition of the halo sign (groundglass opacification around a nodule or consolidation)—a particularly usefulradiologic feature that is transient and best seen within the first 10 days ofinvasive aspergillosis during neutropenia. There are both false-positive andfalse-negative appearances (approximately 3% to 10%), and there may be somedifficulty in interpreting thick-slice CT scans because of partial averagingeffects.

The other major advance in the diagnosis of invasiveaspergillosis in neutropenic/leukemic patient is the use of Aspergillus antigentesting.[3] The antigen test has a sensitivity of 93% and a specificity of 95%for invasive aspergillosis. Two positive samples are required to define apositive case. This test has allowed earlier diagnoses to be made (5 to 14 daysearlier) and has also been a trigger for a CT scan of the chest and/or sinuses.It may be useful in following response to therapy, but that is not entirelyclear as of yet.

The CT scan and Aspergillus antigen tests are also useful inallogeneic stem cell transplant patients, but there are issues of timing. In thegroup that presents with invasive aspergillosis during the early neutropenicphase, these tests perform as they would in leukemic/neutropenic patients. Inthe later phase with graft-vs-host disease, systematic CT scanning is difficultto implement because of the long periods of time during which the patients areat risk. Likewise, Aspergillus antigen detection may not permit a diagnosisearly enough to alter outcome as samples are collected less frequently,particularly as response to treatment of these patients is far fromsatisfactory.

The other area of progress in the allogeneic stem celltransplant patient, however, is the use of polymerase chain reaction in blood,which was pioneered by the Transplant Group in Tuebingen, Germany.[4] It is notyet clear whether polymerase chain reaction screening adds diagnostically to Aspergillus antigen detection in this population, but it is certainly more laborintensive and expensive. Further research in this area is ongoing.

In other patient groups with invasive aspergillosis, thediagnosis has to be made as it has been for the last 20 years, namely via amixture of suspicion, imaging, culture, microscopy, and biopsy. There are one ortwo hints that Aspergillus antibody testing may be useful in the setting ofsolid-organ transplantation, but the variable tests that have been used and therelatively poor sensitivity and standardization of the relevant antigensemphasizes the need for additional work in this area. The same is true forpatients with solid tumors, patients with AIDS, and other lessimmunocompromised patients who might have invasive aspergillosis.

Does Treatment Differ According to Patient Group?

Only two drugs are useful for the treatment of invasiveaspergillosis—amphotericin B and itraconazole (Sporanox). Response rates to alipid-associated amphotericin B are similar to those achieved with standardamphotericin B, but the therapeutic ratio has improved, especially with respectto nephrotoxicity. Randomized studies of oral itraconazole vs intravenousamphotericin B were unsuccessful and thus comparative response rates can only beestimates. The response rate to amphotericin B varies from approximately 1%(cerebral aspergillosis in immunocompromised patients) to 60% to 80% in heartand renal transplant patients with pulmonary or cutaneous infection. Collectedseries suggest an overall response rate of approximately 35%.[ 5,6]

Response rates to itraconazole appear to be approximately 40% to60%, again with a wide range in different patient groups and different settings.Fewer data are available on the efficacy of itraconazole than on amphotericin Bin more immunocompromised settings (such as allogeneic bone marrow transplantpatients) and persistently neutropenic patients, although the drug may beeffective in these settings. It is well known that response rates toamphotericin B do not exceed 15% in these difficult situations. Patients whofail amphotericin B may respond to itraconazole and the reverse is also true.[2]

High doses of itraconazole (800 mg daily) may be helpful forcerebral aspergillosis[7] but there are few data to support this strategy.Loading doses of itraconazole are important in patients with rapidly progressivedisease. The recent introduction of IV itraconazole provides an alternativeoption for these patients, but a small percentage of aptients may haveinadequate concentrations. There are numerous drug interactions withitraconazole. A serum itraconazole concentration of > 500 µg/mLseems to be important.[8]

Sinus aspergillosis responds better to amphotericin B than toitraconazole,[9] and airways aspergillosis may respond better to itraconazolethan to amphotericin B. Responses in other sites of disease appear to be similarwith both drugs.

Does the Neutrophil Count or Function Influence Response?

Patients with persistent profound neutropenia rarely survive.This is exemplified by patients with aplastic anemia in whom the mortality rateis around 90%.[10] Occasionally patients with neutrophil counts in the range of100 to 500 × 10⁶/L have survived for several weeks, but those with essentiallyno neutrophils rarely do.

Patients with neutrophil dysfunction such as those with chronicgranulomatous disease, HIV infection, and diabetes tend to suffer from subacuteor even chronic aspergillosis rather than acute disease. Responses to therapytend to be slow and incomplete, and the relapse rate high.

Does the Rate of Progressionof Invasive AspergillosisAffect Outcome?

The answer to this question is clearly yes. Allogeneic stem cellrecipients with graft-vs-host disease often present with disseminated invasiveaspergillosis and progress rapidly to death. Judging the pace of infection canbe difficult as this depends on when the diagnosis is first established. It isnow abundantly clear that early diagnosis improves outcome in those withreversible immunosuppression and that this is particularly true in the mostimmunocompromised patients. Additionally, the cumulative corticosteroid dose isan important factor in survival as demonstrated in allogeneic stem cellrecipients.[11]

Does the Affected Body Organ Influence Outcome?

In terms of outcome from invasive aspergillosis, there is ahierarchy of sites. The worst site to be affected is the brain, followed bypulmonary disease. Dissemination to other organs may be better or worse thanpulmonary disease, depending on whether the skin is involved. Patients with skindisease appear to do particularly well for reasons that are still unclear. Thereis also a range of responses in patients with pulmonary disease, in which thosewith extensive bilateral disease do poorly and those with a single small focalarea of disease do well. This partly reflects early diagnosis but alsounderlines immune response. An identical picture was seen in AIDS patients withcoccidioidomycosis—the mortality rate among patients with bilateral diseasewas 70% and for focal disease, it was 30%.[12]

Does Surgical InterventionAffect Outcome?

No randomized studies of surgery have been conducted. In fact,conducting such studies would be met with considerable difficulty due tocompounding variables. Retrospective analysis of the role of surgery inpulmonary mucormycosis showed a substantially higher survival rate.[13] Aconsensus has been reached on three indications for surgical intervention inpulmonary invasive aspergillosis. They are (1) in the immediate management ofpatients with disease abutting on the mediastinum; (2) in those withlife-threatening hemoptysis; and (3) as a debulking procedure, particularly inthose going on to transplantation. Complications from thoracic surgery in thecontext of profound neutropenia and thrombocytopenia appear to be minimal.[14]

Surgery also appears to be essential for patients withendocarditis, renal disease, and in making a diagnosis in unusual settings.Hemorrhage and infection is a significant postoperative problem in those withsinus aspergillosis who will be undergoing major surgery during neutropenia.[5]However, the role of surgery in cerebral aspergillosis, Aspergillus empyema,epidural abscesses, and osteomyelitis remains to be determined.

Is Susceptibility Testingof Aspergillus Useful toClinical Management?

Successful testing methodology has advanced substantially in thelast 5 years. Resistance in A fumigatus has been described in theliterature,[15-17] and is present in many different countries. However, thefrequency of resistance to itraconazole appears to be low—possibly 1% to 3%.Optimal methods for testing susceptibility to Aspergillus have yet to be agreedupon, although numerous methods do detect resistance. Most isolates resistant toitraconazole are not resistant to the new azoles.

Amphotericin B resistance appears to be universal in Aterreus.[18,19] Some amphotericin B-resistant isolates of A fumigatus and Aflavus have been identified, as defined by extremely poor responses in animalmodels, but a testing methodology for use in the typical microbiology laboratoryhas yet to be developed.

In summary, significant advances have been made in invasiveaspergillosis over the last 5 years. The introduction of active new drugs suchas caspofungin, variconazole, and posaconazole should help reduce mortality. Defining the optimal primary therapy regimenand early diagnosis remain priorities.

References:

1. Denning DW: Issues in the management of invasiveaspergillosis. Ann Med Intern 146:106-110, 1995.

2. Caillot D, Casasnovas O, Bernard A, et al: Improvedmanagement of invasive pulmonary aspergillosis in neutropenic patients usingearly thoracic computed tomographic scan and surgery. J Clin Oncol 15:139-147,1997.

3. Maertens J, Verhaegen J, Demuynck H, et al:Autopsy-controlled prospective evaluation of serial screening for circulatinggalactomannan by a sandwich enzyme-linked immunosorbent assay for hematologicalpatients at risk for invasive aspergillosis. J Clin Microbiol 37:3223-3228,1999.

4. Hebart H, Löffler J, Meisner C, et al: Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerasechain reaction screening. J Infect Dis 181:1713-1719, 2000.

5. Bowden R, Chandrasekar P, White M, et al: A double-blindrandomised controlled trial of Amphocil (ABCD) vs amphotericin B (AmB) fortreatment of invasive aspergillosis in immunocompromised patients (abstract091). Presented at the International Immunocompromised Host Society Meeting,June 21-24, 1998, Davos, Switzerland.

6. Denning DW: Therapeutic outcome of invasive aspergillosis.Clin Infect Dis 23:608-615, 1996.

7. Denning DW, Lee JY, Hostetler JS, et al: NIAID Mycoses StudyGroup multicenter trial of oral itraconazole therapy of invasive aspergillosis.Am J Med 97:135-144, 1994.

8. Sanchez C, Mauri E, Dalmau D, et al: Treatment of cerebralaspergillosis with itraconazole. Do high doses improve the prognosis? ClinInfect Dis 21:1485-1487, 1995.

9. Hahn C, Sauerbruch T, Schmidt-Wolf IGH, et al: Definition ofan itraconazole target concentration for antifungal prophylaxis (abstract), inPrograms and abstracts presented at the 40th Interscience Conference onAntimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, September 17-20,2000.

10. Weinberger M, Elattar Inas PH, Marshall D, et al: Patternsof infection in patients with aplastic anemia and the emergence of Aspergillusas a major cause of death. Medicine (Baltimore) 71:24-43, 1992.

11. Ribaud P, Chastang C, Latge JP, et al: Outcome andprognostic factors of invasive aspergillosis after allogeneic bone marrowtransplantation. Clin Infect Dis 28:322-330, 1999.

12. Fish DG, Ampel NM, Galgiani JN, et al: Coccidioidomycosisduring human immunodeficiency virus infection. A review of 77 patients. Medicine(Baltimore) 69(6):384-391, 1990.

13. Tedder M, Spratt JA, Anstadt MP, et al: Pulmonarymucormycosis: Results of medical and surgical therapy. Ann Thorac Surg57(4):1044-1050, 1994.

14. Bernard A, Caillot D, Couaillier JF, et al: Surgicalmanagement of invasive pulmonary aspergillosis in neutropenic patients. AnnThorac Surg 64(5):1441-1447, 1997.

15. Denning DW, Venkateswarlu K, Oakley KL, et al: Itraconazoleresistance in Aspergillus fumigatus. Antimicrob Agents Chemother 41:1364-1368,1997.

16. Chryssanthou E: In vitro susceptibility of respiratoryisolates of Aspergillus species to itraconazole and amphotericin B. Acquiredresistance to itraconazole. Scand J Infect Dis 29:509-512, 1997.

17. Dannaoui E, Borel E, Persat F, et al: In-vivo itraconazoleresistance of Aspergillus fumigatus in systemic murine aspergillosis. J MedMicrobiol 48:1087-1093, 1999.

18. Sutton DA, Sanche SE, Revankar SG, et al: In vitroamphotericin B resistance in clinical isolates of Aspergillus terreus, with ahead-to-head comparison to voriconazole. J Clin Microbiol 37:2343-2345, 1999.

19. Johnson E, Oakley KL, Radford S, et al: Lack of correlationof in vitro amphotericin B susceptibility testing with outcome of in a murinemodel of Aspergillus infection. J Antimicrob Chemother 45:85-93, 2000.