Introduction
Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice.
Method
Group of clinicians and scientists with a special interest in mycology from Asia, Australia, Brazil, Europe and North America was invited to attend the advisory board. All attendees had published extensively in the field of pre-clinical and clinical mycology and clinical trials, were members of international and national guidelines groups, or were members of international bodies representing mycology [e.g. International Society for Human and Animal Mycology (ISHAM), ESCMID and ECMM]. One expert, J.P.D., chaired the meeting and helped design the pre- and post-meeting questionnaires sent to attendees.
Results
Breakthrough IA on mould-active prophylaxis
The experts stated that around 5%–10% of patients in their practice receiving mould-active prophylaxis (typically posaconazole but other triazoles and micafungin were considered) would develop probable or proven IA. The proportion would be considerably higher if ‘possible’ infection1 was considered a criterion for prophylaxis failure and initiating IA therapy. Where there is clinical suspicion of IA, it was considered essential to ensure adequate drug levels prior to stopping prophylaxis; measuring posaconazole, particularly when the oral suspension isused, or voriconazole levels at 2–5 days after starting prophylaxis, depending on the drug and formulation used, and making suitableadjustments as needed. When patients have ad-equate drug levels, investigations for breakthrough mould diseaseshould commence as symptoms occurring more than 3 days afterstarting adequate prophylaxis would be considered more consistent with breakthrough infection, whereas the consensus was thatsymptoms within 3 days of starting prophylaxis would be moreconsistent with a pre existing infection.
Where mould disease is suspected, aggressive attempts to confirm the pathogen for instance by obtaining targeted samples and testing for several biomarkers are considered essential particularly as infections due to one of the agents of mucormycosis, a triazole-resistant Aspergillus species or a rare mould with unpredictable susceptibility, would require an immediate change to a different class of antifungal agent. The therapeutic antifungal should be changed for every patient with adequate exposure where there is clinical or diagnostic evidence for breakthrough infection. A change to a lipid amphotericin B (e.g. AmBisomeVR) should be initiated when there is diagnostic evidence for breakthrough mould disease. However, if infection with a susceptible Aspergillus species is confirmed, isavuconazole or voriconazole may be considered an option if sub-therapeutic levels of posaconazole have been identified.
IA failing treatment with a triazole:
‘refractory disease
The experts estimated that, in their practice, 10%–15% of patients receiving a triazole for primary therapy of acute IA might require a change of therapy due to a lack of a response or an inadequate response. Another group of patients might require a change of therapy as a result of intolerance, but this group was not considered further as this does not represent true failure of therapy. Defining the need for second-line therapy for ‘refractory disease’ can be categorized according to the number of days since initiation of primary antifungal therapy. The group agreed that primary therapy, with confirmed therapeutic drug levels where appropriate, should be given for at least 8 days to show an effect.
Proven triazole resistance
The experts reported that azole resistance is becoming a global problem and has been identified in up to 20% of clinical isolates of Aspergillus fumigatus in the Netherlands and Belgium, 5%–8% in Taiwan, 1% of haemato-oncology patients in France,Germany and Spain, and 5% of isolates in a national survey in the USA. In many regions, routine surveillance data are not available, so reliable epidemiological predictions based on local findings are difficult. Triazole-resistant IA is associated with a high mortality. This is probably due to the overall difficulty in diagnosing IA, as well as difficulties in determining resistance leading to delays in implementing a change to appropriate therapy. As triazole-resistant IA portends a dismal outcome on continuing azole treatment, a change of therapy is required immediatelyon identifying an azole-resistant isolate, irrespective of the duration and dose of the primary azole therapy.
IA in patients receiving immunomodulating
and molecular targeted anti-cancer drugs
There was less consensus on managing these patients as the body of evidence is limited, although growing. Whilst all the experts were aware of the data showing the risks of IFDs in patients receiving BTKIs such as ibrutinib, or mTOR inhibitors, not everyone had treated such cases or been consulted about them. The experts felt that the risk of IA was variable, with most experts considering the risk as being intermediate, one expert considering the risk to be very high and about one-third considering the risk as very low. It should be noted that the risks may include fungal infections other than IA, which can occur alone or concomitantly with IA. In the available publications, IA infections among patients on ibrutinib or mTOR inhibitors generally occur in those with other risk factors for fungal infections, such as prior or concomitant use of potent cancer therapies.
A small number of the experts felt the risk in their institutions was sufficiently high to justify antifungal prophylaxis. Administering many of these agents together with a CYP3A4 inhibitor such as an azole increases exposure to the immune modulating agent, potentially leading to toxicity. More than half of the experts would treat a patient diagnosed with IA who is receiving ibrutinib or another agent that potentially interacts with triazoles (e.g. venetoclax46) with liposomal amphotericin B until the infection was under control or until dose-limiting toxicity required a change of therapy, subsequently switching to the most appropriate available mould active azole. This would minimize the need for changes in doses of BTKI or mTOR inhibitors, with the aim being to optimize therapy for the underlying haematological malignancy.
Stable disease
Stable disease was not considered treatment failure in the real-world setting. If patients were consistently neutropenic or otherwise severely immunocompromised, then stable disease, particularly if there had been previous rapid progression, would be deemed a success whilst awaiting immune recovery. If patients are able to tolerate further chemotherapy for their underlying disease whilst on treatment for IA, then the experts would generally continue the primary antifungal agent. Patients with stable disease should have their IA actively managed until either a response occurs or until it is deemed futile to continue.
Discussion
When deciding if a patient is refractory to primary antifungal therapy, considerations include performing serial CT using the same methodology, such as high-resolution CT. Switching from one modality to another will not allow for an accurate comparison of the lesion. Ideally, the same scanner should be used for serial scans. For diagnostic purposes, GM may be detected in several different body fluids, including serum, BAL fluid and CSF. For the purposes of monitoring response to treatment, subsequent serum GM levels are useful. If the immune status of a patient remains unchanged in the context of worsening diagnostic test results, then the patient should be considered refractory. If the neutrophil count is recovering or immunosuppression is being reduced, and a lesion is increasing in size on radiology, with GM unchanged or declining, then this is less likely to be refractory IA and could be a manifestation of immune reconstitution. Treatment of IA is challenging, and we have provided pragmatic criteria to assist the clinician in deciding when to change therapy for breakthrough or progressive infection.
Source: BMonica A Slavin, Yee-Chun Chen, Catherine Cordonnier, Oliver A Cornely, Manuel Cuenca-Estrella, J Peter Donnelly, Andreas H Groll, Olivier Lortholary, Francisco M Marty, Marcio Nucci, John H Rex, Bart J A Rijnders, George R Thompson, III, Paul E Verweij, P Lewis White, Ruth Hargreaves, Emma Harvey, Johan A Maertens, When to change treatment of acute invasive aspergillosis: an expert viewpoint, Journal of Antimicrobial Chemotherapy, Volume 77, Issue 1, January 2022, Pages 16–23, https://doi.org/10.1093/jac/dkab317.
