BUENOS AIRES, Argentina — There is little doubt about the importance of starting antifungal treatment promptly for invasive pulmonary aspergillosis when the clinical condition suggests it in high risk patients, because of the infection’s rapid progression and high morbidity and mortality. Yet the decision as to when to discontinue pharmacologic management is subject to many more questions. There is no solid evidence to guide the optimal time to take this measure, according to a German expert speaking at the XXII Congress of the Argentine Society of Infectious Diseases (SADI 2022).

“It is a critical decision, and there are no studies to determine it. And that is at the heart of the measured and judicious use of antimicrobials (stewardship),” said Oliver Cornely, MD, PhD, consultant for infectious diseases at Cologne University Hospital and director of the Center for Translational Research and Clinical Trials at the University of Cologne in Germany, as well as co-founder of the European Confederation of Medical Mycology (ECMM) Excellence Center initiative.

On one hand, stopping a successful treatment early increases the risk for relapse or recurrence of the infection. On the other hand, prolonging it beyond what is necessary has other downsides, “notably cost, toxicity, drug interactions, and — to a lesser extent — development of resistance, which has not been demonstrated so far,” Cornely told Medscape Spanish Edition.

In his presentation, Cornely mentioned a recent, well-executed Swiss retrospective study that evaluated treatment duration for 66 episodes of proven or probable invasive fungal infections. The investigation took place in a cohort of 61 adult patients who received allogeneic hematopoietic stem cell transplantation (HSCT). In cases where antifungal treatment was completed (48.2%), the median treatment duration was slightly more than 9 months, with an interquartile range (IQR) of 16 weeks to 2.2 years. Considering only the most common infection, invasive aspergillosis, the median was 8.6 months (IQR, 3.7 months to 5.2 years).

“But the study describes how long treatment is administered, not when it should be discontinued, thus highlighting the need for a controlled study,” said Cornely.

Another survey was conducted by four scientific societies and groups among 112 physicians from 16 European countries in 2017 and was published in 2020. Cornely was one of the co-authors, and the survey identified the following median durations of invasive pulmonary aspergillosis treatments associated with hematologic malignancies: 6 weeks (IQR: 3 to 12) in patients with acute myeloid leukemia or lymphoproliferative disease and 11 weeks (IQR: 4 to 12) in patients with allogeneic HSCT and graft-versus-host disease (GVHD), with significant differences between countries.

No Specific Guidelines

“Why has this question not been touched upon in clinical trials until now?” asked Medscape Spanish Edition.

“No standard has been defined as to when treatment can be safely discontinued. Clinical trials evaluating treatment duration can’t be used to support licensing, so there’s also no industry interest. A strategic study is required, but it would have a very complex decision tree to be evaluated in such a study,” replied Cornely.

The guidelines are also not specific to this topic. The Infectious Diseases Society of America guidelines, presented in 2016, recommend that antifungal therapy be continued for a minimum of 6-12 weeks, with a duration based on factors such as the severity of the infection, the duration of immunosuppression, and the response to the therapy.

The 2018 joint guidelines from the European Society of Clinical Microbiology and Infectious Diseases and the ECMM state that treatment duration should be based primarily on the response to treatment and immune reconstitution of GVHD. “The range of treatment duration (3 weeks to more than 50 weeks) is enormous, and the evidence base to support any particular recommendation is weak,” the document acknowledges.

“Invasive Aspergillus infections are typically treated for up to 12 weeks. However, depending on the underlying pathology, the clinical evolution, the images, and the control of the microbiological parameters, this period could be longer. To my knowledge, there are no data on the effective duration of therapies in our region, but it is possible that they tend to lengthen in some circumstances when there is difficulty in accessing control tests,” Ricardo Rabagliati, MD, told Medscape Spanish Edition. Rabagliati, professor of infectious diseases at the School of Medicine of the Pontifical Catholic University of Chile in Santiago, published a review article on the diagnosis and management of invasive aspergillosis in adult patients.

Determining Treatment Duration

Given this situation, Cornely shared a series of prerequisites that are followed at his center to determine the end of treatment. Clinically, there should be no signs or symptoms attributable to invasive pulmonary aspergillosis, there should be no fever, and the patient should have recovered from neutropenia. Mycologically, serum galactomannan levels should not be elevated.

The results of the images must also be considered: the reduction in the size of the lesion must exceed 90%, although the presence of residual marks can be accepted. And it is necessary to consider organizational aspects, for example, if the patient lives near centers with adequate infrastructure to carry out screenings that allow the early detection of eventual relapses.

Regarding the screening for recurrence of infection, Cornely noted that any of the following situations warrants a low-dose, noncontrast chest CT scan:

• Increased levels of C-reactive protein

• Body temperature higher than 38.6 °C (101.5 °F)

• Respiratory symptoms

• Elevation of serum galactomannan index

• Serum detection of 1,3-beta-D-glucan, which, although not an established biomarker of invasive pulmonary aspergillosis, could be an early marker with limited specificity.

“But we mustn’t forget about other possible causes,” he warned.

Cornely also told Medscape Spanish Edition that it would be conceivable that certain antifungal treatment regimens could be administered for shorter durations than the current ones, for example, a high-dose combination therapy (although studies are required to confirm this).

Patient-Focused Decision

Along the same lines as her German colleague, Armelle Pérez-Cortés Villalobos, MD, MSc, a Mexican infectious disease specialist who works on infections of transplanted and immunocompromised subjects, considered that expanding research on treatment duration for invasive aspergillosis is imperative, though she acknowledged that conducting this study presents multiple challenges.

“The cure and resolution of an invasive fungal infection does not only depend on the antifungal drug used or its duration, but also on the immune status of the host to fight the infection. For this reason, conducting controlled studies is difficult, given that patients who have this infection have a different history of immunosuppression: some are transplant recipients, others with cancer, others with exogenous immunosuppressants. All this would require that to standardize the study population, patients should be evaluated by groups of comorbidities and disease extension,” said Pérez-Cortés Villalobos, associate professor of infectious diseases at the University of Manitoba, Winnipeg, Canada, and member of the editorial committee of Medscape Spanish Edition.

“For this reason, until now, treatment duration for invasive aspergillosis is a clinical decision that we make based largely on the individuality of the patient and their response to treatment,” she concluded.

Cornely declared having received research, consulting, or speaking fees from Abbott, AbbVie, Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, AstraZeneca, Basel, Biocon, Biosys, BMBF, Cidara, Da Volterra, DZIF, Entasis Therapeutics, EU DG Research and Innovation, F2G, Gilead, GSK, Grupo Biotoscana/United Medical/Knight, HIKMA, IQVIA, Janssen, Matinas, MedPace, MedUpdate, Menarini, Merck/MSD, Molecular Partners, MSG-ERC, Mundipharma, Mylan, Noxxon, Octapharma, Paratek, Pardes, PSI, Pfizer, Pulmocide, Sanofi Pasteur, Scynexis, Seres, and Shionogi.

Pérez-Cortés Villalobos reports no relevant financial relationships.

Follow Matías A. Loewy of Medscape Spanish Edition on Twitter @MLoewy.

This article was translated from the Medscape Spanish edition.

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