Real‐world challenges and unmet needs in the diagnosis and treatment of suspected invasive pulmonary aspergillosis in patients with haematological diseases: An illustrative case study

Abstract

SummaryRecent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases. K E Y W O R D Sdiagnosis, invasive aspergillosis, isavuconazole, plasma level, treatment

Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: New leadership is about working together

“…[16][17][18][19][20] Moreover, new antifungal agents have recently become available or are being developed that warrant up-to-date guidance on optimal treatment of IFDs. [21][22][23] Finally, the increasing availability of new nucleic acid amplification assays, blood culture detection systems, lateral flow devices, as well as matrix-assisted laser desorption time of flight (MALDI-TOF) mass spectrometry for detection of medically important fungi and laboratory diagnosis of invasive mycoses warrants guidance in their use in clinical practice. [24][25][26][27] To respond adequately to these tasks, international societies of medical mycology have joined forces with a goal of improving diagnosis, treatment, prevention, and survival of persons with invasive fungal infections worldwide.…”

“…that cause disseminating IFD in severely immunosuppressed persons . Moreover, new antifungal agents have recently become available or are being developed that warrant up‐to‐date guidance on optimal treatment of IFDs . Finally, the increasing availability of new nucleic acid amplification assays, blood culture detection systems, lateral flow devices, as well as matrix‐assisted laser desorption time of flight (MALDI‐TOF) mass spectrometry for detection of medically important fungi and laboratory diagnosis of invasive mycoses warrants guidance in their use in clinical practice …”

Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

“…Consequently, fungal biomarkers such as galactomannan (GM), (1,3)-β-d-glucan (BDG), and extracellular glycoprotein, as well as molecular diagnostic tests (polymerase chain reaction (PCR)) applied to blood or bronchoalveolar lavage fluid (BALF), have emerged [7,11,[13][14][15][16]. However, performance of these biomarkers and diagnostic tests has been shown to be less than optimal for invasive aspergillosis (IA) in patients receiving mold-active prophylaxis or treatment, which has been shown to reduce sensitivity of diagnostic tests [13,[17][18][19][20][21][22]. In addition, sensitivity for molecular blood tests varies based on the degree of immunosuppression and neutrophil count, which triggers angioinvasive versus airway invasive growth in IA [23,24].…”

Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives

“…In contrast, isavuconazole is associated with a shortened QTc interval with a mean decrease of 36.5 ± 38.8 ms (7.4 ± 5.8%) compared to the pre-isavuconazole electrocardiogram in a recent study [22]. Overall, isavuconazole has been shown in clinical trials and also a limited number of real life studies to be better tolerated than particularly voriconazole and itraconazole and may therefore be a viable oral alternative in patients experiencing adverse events [23].…”

“…Importantly, sirolimus is contraindicated in those receiving voriconazole, and preemptive sirolimus dose reduction is required in those receiving itraconazole [27]. In those patients, isavuconazole, which has fewer drug-drug interactions with immunosuppressive drugs, may be a better alternative for treatment of CPA [23].…”