Antifungal Management in Patients with Hematological Malignancies: From Primary Prophylaxis to Empirical and Diagnosis-Driven Treatment

Abstract

Invasive fungal diseases (IFDs) remain a significant cause of morbidity and mortality among patients with hematological malignancies, especially those undergoing intensive chemotherapy or hematopoietic stem cell transplantation (HSCT). This text provides a comprehensive risk-adapted framework for antifungal prophylaxis, stratifying patients into high-, intermediate-, and low-risk categories. Mold-active prophylaxis, primarily with posaconazole, is recommended for high-risk patients such as those with acute myeloid leukemia during remission induction or those with grade III-IV graft-versus-host disease following allogeneic HSCT. Fluconazole remains an option for yeast-active prophylaxis in intermediate-risk patients, while low-risk groups generally do not require prophylaxis. The evolving landscape of targeted therapies such as venetoclax, FMS-like tyrosine kinase 3 inhibitors, and CD19 chimeric antigen receptor T-cell (CAR-T) therapy poses new challenges, particularly due to drug-drug interactions with triazole antifungals. In patients receiving venetoclax, azole co-administration necessitates significant dose adjustments. We also present algorithms for antifungal management in the context of CD19 CAR-T therapy and novel agents, emphasizing the role of individualized risk assessment. Beyond prophylaxis, timely diagnosis and early treatment of IFDs are critical. The role of thoracic computed tomography, serum and bronchoalveolar lavage galactomannan, and fungal biomarkers is discussed within diagnostic-driven strategies. We outline treatment pathways for suspected pulmonary or sinus fungal infections, including when to escalate antifungal therapy or consider surgical intervention. This content offers a practical and evidence-based guide for clinicians navigating antifungal strategies in a rapidly changing therapeutic landscape, aiming to reduce IFD-related mortality while balancing toxicity, resistance, and healthcare costs.

Introduction

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in patients with hematological malignancies. The risk of IFDs varies widely by disease type and treatment phase, reaching its highest levels in acute leukemia and following allogeneic hematopoietic stem cell transplantation (HSCT), where prolonged neutropenia, mucosal damage, and intensive immunosuppression markedly increase susceptibility. Primary antifungal prophylaxis has therefore become a cornerstone of supportive care in high-risk settings, particularly during acute myeloid leukemia (AML) remission induction and in selected post-transplant scenarios. However, the therapeutic landscape of hematology has evolved substantially. The widespread use of targeted agents, venetoclax-based regimens, and immune-based therapies such as CD19 chimeric antigen receptor T-cells (CAR-T cells) has altered traditional fungal risk profiles while introducing clinically relevant drug-drug interactions with triazole antifungals.

These developments necessitate a modern risk-adapted approach that extends beyond prophylaxis alone. This study summarizes current evidence and guideline-based recommendations for antifungal management across the continuum of care, from primary prophylaxis to empirical and diagnosis-driven treatment, providing practical algorithms tailored to contemporary hematological practice.

Scope and Methods

The narrative review offered by this study provides a practical, risk-adapted framework for the prevention and early management of IFDs in adults with hematological malignancies, including recipients of HSCT and patients treated with contemporary targeted and cellular therapies; pediatric management is beyond its scope. Recommendations are based on current international guidelines, principally the updated European Conference on Infections in Leukaemia (ECIL-10) guidelines [1], together with relevant guidance from the Infectious Diseases Society of America [2, 3], the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)-European Confederation of Medical Mycology-European Respiratory Society [4], and the European Organisation for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) [5, 6]. Where applicable, recommendations are annotated with the ECIL/ESCMID strength-of-recommendation (A-D) and quality-of-evidence (I-III) grades. Throughout the text, IFD is categorized as proven, probable, or possible according to the 2020 EORTC/MSGERC consensus definitions [6].

Why Is Primary Antifungal Prophylaxis Needed?

Patients with acute leukemia, particularly during remission induction chemotherapy, frequently experience profound neutropenia lasting longer than 10 days. This condition predisposes them to severe infections, most notably invasive aspergillosis caused by mold species [1, 7, 8, 9, 10, 11, 12, 13].

Reduction of morbidity and mortality: IFDs represent a major cause of morbidity and mortality in patients with acute leukemia. Effective prophylaxis significantly decreases both the incidence of these infections and the associated mortality [14].

Treatment costs: Empirical or targeted antifungal therapies initiated after the onset of IFDs are costly and frequently prolong hospitalization. Prophylaxis can mitigate these additional expenses and lessen the overall burden on healthcare resources [15].

How Should Hematological Malignancies Be Stratified for Antifungal Prophylaxis?

High-risk group: This category includes patients with AML during remission induction, those with intermediate- or high-risk myelodysplastic syndrome (MDS) receiving AML-like induction chemotherapy, and allogeneic HSCT recipients who develop grade III-IV graft-versus-host disease (GVHD) after engraftment [9, 10]. Primary antifungal prophylaxis is strongly recommended in this group (A-I) [1].

Intermediate-risk group: This group includes patients with AML in consolidation, those with acute lymphoblastic leukemia (ALL) receiving induction therapy, allogeneic HSCT recipients in both pre- and post-engraftment phases, and autologous HSCT recipients [1, 9]. Yeast-active prophylaxis is generally recommended in this group, with mold-active prophylaxis reserved for those with additional mold risk factors.

Low-risk group: This category encompasses the remaining hematological malignancies, including chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and low-risk MDS (Figure 1). Routine antifungal prophylaxis is not recommended for these patients (D-II) [7, 12].

Figure 1.

Risk-adapted antifungal prophylaxis for adult patients with hematological malignancies.

AML: Acute myeloid leukemia; MDS: myelodysplastic syndrome; HSCT: hematopoietic stem cell transplantation; GVHD: graft-versus-host disease; ALL: acute lymphoblastic leukemia; CLL: chronic lymphocytic leukemia; CML: chronic myeloid leukemia; MPN: myeloproliferative neoplasm; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; HL: Hodgkin lymphoma; IFD: invasive fungal disease; L-AmB: liposomal amphotericin B; PPIs: proton pump inhibitors; H2: histamine-2; IV: intravenous; ANC: absolute neutrophil count; allo: allogeneic; ECIL: European Conference on Infections in Leukaemia; ESCMID: European Society of Clinical Microbiology and Infectious Diseases.

What Does “Mold-Active” and “Yeast-Active” Prophylaxis Mean?

High-risk patients with hematological malignancies are at risk of developing both yeast- and mold-related IFDs during induction chemotherapy. Among these infections, Aspergillus and Candida species account for most cases. Aspergillus fumigatus is the predominant Aspergillus species, while mucormycosis represents the second most common cause of invasive mold infection after aspergillosis. Both pathogens are associated with a high risk of mortality [4, 15, 16].

The risk is influenced by multiple factors including the chemotherapy regimen, the duration of neutropenia, and the underlying disease status (i.e., newly diagnosed, in remission, relapsed, or refractory). Environmental factors such as construction and intense exposure to dust, as well as respiratory viral pathogens like the influenza virus or severe acute respiratory syndrome coronavirus 2, are also known risk factors for IFDs.

Mold-active prophylaxis: Patients at risk for aspergillosis include those receiving intensive or multiple chemotherapy regimens and those with increased iron overload, delayed engraftment (e.g., after umbilical cord transplantation), or prolonged corticosteroid exposure (≥1 mg/kg/day of methylprednisolone or prednisone-equivalent for at least 3 weeks).

Yeast-active prophylaxis:Candida infections are strongly associated with severe mucositis and the presence of a central venous catheter.

Which Antifungal Agent Should Be Chosen Based on Patient Characteristics?

In patients with AML undergoing induction therapy, the risk of invasive mold infections is particularly high; therefore, posaconazole prophylaxis is strongly recommended based on evidence from randomized controlled trials, including subsequent independent randomized studies confirming the initial findings. In allogeneic HSCT recipients undergoing transplantation at centers with a high incidence of invasive aspergillosis, antifungal prophylaxis with voriconazole or posaconazole may be considered during the pre-engraftment period in the setting of profound and prolonged neutropenia (>10 days, <500/mm³). However, in the early post-engraftment phase, patients with GVHD requiring corticosteroid therapy should receive mold-active prophylaxis. Posaconazole is the preferred agent for AML and high-risk MDS remission-induction prophylaxis (A-I) [1, 13, 15, 17]. Isavuconazole and micafungin, the latter having been upgraded from C-II to B-II in the ECIL-10 guidelines, are acceptable alternatives, particularly when posaconazole is inappropriate because of hepatic dysfunction, QTc prolongation, drug-drug interactions, or impaired enteral absorption (both B-II) [1, 18, 19]. Itraconazole is a further pre-engraftment option but is limited by tolerability and variable absorption; classic itraconazole was downgraded to C-I in the ECIL-10 guidelines, whereas SUBA-itraconazole is graded C-II [1]. Recipients of haploidentical allogeneic HSCT with post-transplant cyclophosphamide are now classified as being of low risk for IFD by the ECIL-10 panel and do not warrant intensified mold-active prophylaxis on that basis alone [1].

Reported rates of breakthrough IFDs (predominantly invasive aspergillosis) during echinocandin prophylaxis generally cluster around 5%-7%, although figures ranging as widely as 1% to 28% have been described across different series [20]. These rates tend to exceed those reported with mold-active azole prophylaxis. In line with this, one study identified echinocandin prophylaxis as an independent predictor of breakthrough IFD when compared to voriconazole- or posaconazole-based regimens during induction chemotherapy for acute leukemia [21]. In a prospective randomized phase II trial with HSCT recipients, no significant difference in the incidence of IFDs was observed between micafungin and fluconazole prophylaxis (7.3% vs. 8.2%; p=0.786); 100-day mortality was likewise similar between the two arms (9.1% vs. 12.9%; p=0.345). This finding supports the conclusion that micafungin does not offer superior mold protection over fluconazole in this population [22]. A study from Türkiye identified caspofungin use as a significant risk factor for Saprochaete capitata fungemia [23], while another Turkish study reported a notable rise in echinocandin minimum inhibitory concentration values among Candida species in parallel with increasing echinocandin consumption [24]. Taken together, these findings suggest that micafungin prophylaxis may be more appropriately reserved for specific situations such as significant drug-drug interactions or bioavailability concerns rather than being used as a routine choice.

In allogeneic HSCT recipients without a specific risk for mold infection, oral fluconazole at 400 mg/day is recommended for Candida prophylaxis [1, 9, 25]. Autologous HSCT recipients do not routinely require prophylaxis; however, in cases of severe mucositis, Candida prophylaxis may be considered [26]. As noted above, allogeneic HSCT recipients who develop grade III-IV GVHD and receive methylprednisolone (or prednisone-equivalent) at ≥1 mg/kg/day should receive mold-active prophylaxis, to be continued while significant immunosuppression persists [1, 27, 28].

For mold-active prophylaxis, delayed-release posaconazole tablets are preferred, with a loading dose of 300 mg twice daily on day 1, followed by 300 mg once daily as a maintenance dose. The oral suspension of posaconazole demonstrates highly variable bioavailability, with significant interpatient variability in absorption. To address this limitation, a delayed-release tablet formulation was developed, providing more consistent and higher plasma concentrations while minimizing the impact of food intake [1, 29].

Posaconazole prophylaxis should be initiated on the same day as chemotherapy, or on the last day of anthracycline administration in patients receiving anthracycline-based regimens. The drug should be discontinued if another antifungal agent is initiated for therapeutic purposes. Concomitant use of proton pump inhibitors and histamine-2 receptor antagonists should be avoided; if unavoidable, a minimum separation of 2 h is recommended. In the presence of severe mucositis, nausea, or vomiting, the intravenous formulation should be used. In cases of grade III-IV GVHD, posaconazole prophylaxis should be continued until immunosuppressive therapy is discontinued or another antifungal agent is introduced for treatment [13, 15, 28, 29].

In intermediate-risk patients, fluconazole at 400 mg once daily should be started concurrently with chemotherapy and continued until neutropenia resolves, defined as an absolute neutrophil count of >500/mm³ sustained for at least 7 consecutive days. The drug should be discontinued if the patient is switched to another antifungal agent for therapeutic purposes (Figure 1).

Antifungal Prophylaxis in Patients with MDS or Receiving Hypomethylating Agents

Patients with low- or intermediate-risk MDS managed with supportive care or erythropoiesis-stimulating agents are not at increased risk of IFD and do not require antifungal prophylaxis (D-I). In contrast, patients with high-risk MDS undergoing intensive AML-like induction chemotherapy should receive prophylaxis as for AML (A-I). An important ECIL-10 update concerns intermediate- and high-risk MDS (and AML) treated with hypomethylating agents (HMAs): the risk of IFD is highest during the first four cycles, with reported incidences of approximately 3%-12%, being higher in cohorts where prophylaxis was infrequently used. Accordingly, mold-active prophylaxis, most commonly entailing posaconazole, is now recommended during the first four cycles of azacitidine-based therapy for these patients (B-IIu) [1, 30, 31, 32, 33, 34].

Which Patients Do Not Require Antifungal Prophylaxis?

For MM, MDS patients not receiving AML-like therapy, CML, other MPNs, CLL, and lymphomas (Hodgkin and non-Hodgkin), the risk of IFDs is estimated to be approximately 1%-2%. Antifungal prophylaxis is not recommended for these patient groups (D-II) [1].

Antifungal prophylaxis is generally not indicated for autologous HSCT recipients. In cases of severe mucositis (grade 3-4), however, yeast-active prophylaxis may be considered.

What Is the Optimal Duration of Antifungal Prophylaxis?

Antifungal prophylaxis, both primary and secondary, should be continued until neutrophil recovery is achieved. In the setting of secondary prophylaxis, after discontinuation of therapy, patients require close monitoring for an additional 2-4 weeks with fungal biomarkers such as galactomannan (GM), supplemented by thoracic computed tomography (CT) imaging when clinically indicated [1, 2].

For patients receiving repeated courses of myelosuppressive therapy, prophylaxis is recommended to be continued throughout the entire treatment period. For allogeneic HSCT recipients, antifungal prophylaxis should be continued until the discontinuation of immunosuppressive therapy.

Who Should Receive Secondary Antifungal Prophylaxis, and Which Agents?

Secondary prophylaxis is recommended for patients with a history of invasive aspergillosis who are expected to develop prolonged neutropenia lasting longer than 14 days during subsequent myelosuppressive therapy. Voriconazole is considered an appropriate option for secondary prophylaxis in this setting. Liposomal amphotericin B or posaconazole should be used for secondary prophylaxis in patients who experienced mucormycosis. Secondary prophylaxis choices should be individualized based on the patient’s clinical response to the initial IFD treatment course [1, 35].

How Should Antifungal Prophylaxis Be Managed in the Era of Novel Therapies?

Contemporary treatment of hematological malignancies increasingly relies on targeted small molecules, monoclonal and bispecific antibodies, and cellular therapies. For most of these agents, the intrinsic risk of IFD is low and so routine antifungal prophylaxis is generally not required; the dominant fungal-related consideration is instead the potential for clinically significant interactions between triazole antifungals and agents metabolized by CYP3A4. Prophylaxis should therefore be individualized according to the underlying disease, the depth and duration of neutropenia, corticosteroid exposure, and the specific agent used. This section summarizes the principal targeted agents and the antifungal implications of the most relevant drug-drug interactions [1].

The targeted agents currently used in cases of hematological malignancies include the following:

AML: FMS-like tyrosine kinase 3 inhibitors (quizartinib, midostaurin, sorafenib, gilteritinib), B-cell lymphoma 2 (BCL-2) inhibitor (venetoclax), monoclonal antibody gemtuzumab ozogamicin, Hedgehog pathway inhibitor glasdegib, isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors (ivosidenib, enasidenib), and liposomal cytarabine-daunorubicin (CPX-351) [36, 37].

ALL: Blinatumomab (anti-CD19), inotuzumab ozogamicin (anti-CD22), and tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib, ponatinib).

NHL: Bruton tyrosine kinase (BTK) inhibitor ibrutinib, monoclonal antibodies such as rituximab and ofatumumab, phosphoinositide 3-kinase (PI3K) inhibitor idelalisib, and bispecific antibodies.

HL: Brentuximab vedotin (anti-CD30) and immune checkpoint inhibitor nivolumab (programmed cell death 1).

MM: Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), monoclonal antibodies (daratumumab [anti-CD38], elotuzumab), anti-B-cell maturation antigen therapies, and bispecific antibodies.

CLL: BTK inhibitors (ibrutinib, zanubrutinib, acalabrutinib), monoclonal antibodies (ofatumumab, obinutuzumab), PI3K inhibitor idelalisib, and BCL-2 inhibitor venetoclax.

In patients with AML receiving venetoclax in combination with hypomethylating agents, both mold- and yeast-active prophylaxis may be considered. Given the significant pharmacokinetic interactions, venetoclax dosing should be adjusted as follows: reduced to 25% of the standard dose when combined with posaconazole, and to 50% when combined with fluconazole. For quizartinib (a QT-prolonging CYP3A4 substrate), the dose should be reduced by approximately 50% with posaconazole and by approximately 30% with voriconazole; because both are strong CYP3A4 inhibitors, therapeutic drug monitoring and QTc surveillance are advised. For ivosidenib, concomitant posaconazole should be avoided due to additive QTc prolongation (this combination is listed as contraindicated on the posaconazole label); when a triazole is unavoidable, ivosidenib should be reduced to 250 mg once daily (a 50% reduction) with close QTc monitoring. In addition, mold-active triazoles (posaconazole, voriconazole) are contraindicated with vincristine-containing regimens, which are particularly relevant to ALL, because CYP3A4 inhibition markedly potentiates vincristine neurotoxicity; where antifungal prophylaxis is required in this setting, mold-active triazoles are not recommended (D-II) and fluconazole or isavuconazole may be considered with caution (C-III) (Figure 2) [1, 36, 37, 38].

Figure 2.

Antifungal prophylaxis algorithm for patients receiving CD19 CAR-T cell therapy or novel targeted agents.

CAR-T cell: Chimeric antigen receptor T-cell; AML: acute myeloid leukemia; BCL-2: B-cell lymphoma 2; IDH1/2: isocitrate dehydrogenase 1/2; TKIs: tyrosine kinase inhibitors; NHL: non-Hodgkin lymphoma; BTK: Bruton tyrosine kinase; PI3K: phosphoinositide 3-kinase; PD-1: programmed cell death 1; IMiDs: immunomodulatory imide drugs; BCMA: B-cell maturation antigen; HSCT: hematopoietic stem cell transplantation; CRS/ICANS: cytokine release syndrome/immune effector cell-associated neurotoxicity syndrome; HMA: hypomethylating agent; ALL: acute lymphoblastic leukemia.

Are There Any Other Drug-Drug Interactions During Posaconazole or Voriconazole Prophylaxis?

Both agents carry a significant risk of drug-drug interactions, although the risk is generally lower with posaconazole. It is imperative to consult a verified drug-drug interactions database (e.g., Lexicomp, Micromedex) and perform a comprehensive review of all medications including over-the-counter drugs, chemotherapy, immunosuppressants, and antiemetics prior to prescribing [4, 29].

Is Therapeutic Drug Monitoring Required During Posaconazole or Voriconazole Prophylaxis?

Despite a lack of controlled studies, therapeutic drug monitoring of voriconazole is recommended in the prophylactic setting because of its highly unpredictable pharmacokinetics; a trough concentration of approximately 1-1.5 mg/L is generally targeted for prophylaxis, whereas troughs above 5-6 mg/L are associated with toxicity. The delayed-release tablet and intravenous formulations of posaconazole provide more reliable exposure than the oral suspension; nonetheless, subtherapeutic concentrations may still occur with persistent diarrhea or concomitant interacting drugs. Therefore, therapeutic drug monitoring is advised in these situations, targeting a steady-state trough above 0.7 mg/L for prophylaxis. In contrast to the oral suspension, hypoalbuminemia and mucositis do not meaningfully alter exposure to the delayed-release tablet [39, 40].

When Is Antifungal Prophylaxis Indicated During CD19 CAR-T Cell Therapy?

CD19-directed CAR-T cell therapy is approved for B-cell ALL, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, and it is associated with a distinct, time-dependent risk of infection [1, 41].

Fungal risk after CAR-T therapy is best considered in two phases. Pre-infusion risk reflects the cumulative burden of prior therapy, encompassing relapsed or refractory disease, multiple prior treatment lines, prolonged neutropenia, and previous HSCT. Post-infusion risk is driven by the depth and duration of neutropenia, hypogammaglobulinemia, and above all the intensity and duration of immunosuppression used to manage cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), particularly corticosteroids and tocilizumab. Consistent with ECIL-10, mold-active prophylaxis is recommended for high-risk patients during both the pre- and post-infusion periods, including those with pre-existing prolonged neutropenia, underlying acute leukemia, or grade ≥3 CRS/ICANS requiring corticosteroids for 7 days or longer, whereas yeast-active prophylaxis is appropriate for lower-risk patients (B-II). Although invasive mold disease is uncommon after CAR-T therapy, mucormycosis has been increasingly reported and causes high mortality rates, underscoring the importance of mold-active coverage and environmental precautions in the highest-risk patients [1, 41].

In addition to appropriate chemoprophylaxis for preventing invasive mold infections, it should not be overlooked that it is crucial to protect patients from all situations that expose them to dust. Awareness in this regard should be increased for both patients and healthcare workers.

When Should IFD Be Suspected in a Febrile Neutropenic Patient?

The risk factors for IFD are duration and severity of neutropenia, antibiotic use, and number of treatment cycles. Therefore, IFD is most commonly encountered in the setting of persistent or recurrent fever. Suspicion of IFD develops in high-risk patients with persistent or recurrent fever after 4-7 days of broad-spectrum antibacterial therapy and without an identified source of fever [2, 7, 42].

If the expected duration of neutropenia is more than 7 days and the patient is not on mold-active prophylaxis, serum GM antigen monitoring should be performed at centers, where available, at least twice a week starting on the first day of chemotherapy until the resolution of neutropenia. A positive test result should trigger evaluation of the patient for invasive aspergillosis even if there are no signs or symptoms (Figure 3) [2, 4, 42].During mold-active prophylaxis, the sensitivity of serum GM is reduced; a negative serum test does not exclude IFD, and GM testing of bronchoalveolar lavage (BAL) fluid is preferred when clinically feasible [4].

Figure 3.

Approach to mold-active antifungal therapy in neutropenic patients.

GM: Galactomannan; CT: computed tomography; US: ultrasound; MRI: magnetic resonance imaging; IFD: invasive fungal disease; BAL: bronchoalveolar lavage; L-AmB: liposomal amphotericin B; CNS: central nervous system; IV: intravenous; q: every; PO: orally; GFR: glomerular filtration rate.

What Imaging Studies Are Recommended for Early Diagnosis of IFD? How Should They Be Tailored to Clinical Symptoms?

In the early stages of infection, clinical features may be nonspecific and fever may be the only sign of IFD. In high-risk patients with persistent or recurrent fever, clinical site-specific reassessment, imaging, and diagnostic testing for IFD are essential for early diagnosis [2].

A site-specific evaluation should be conducted, including the oral cavity and esophagus; the abdomen, liver, and rectum; the paranasal sinuses; the lungs; the skin, soft tissues, and vascular access sites; the urinary tract; and the central nervous system. The lungs are the most common site of IFD. In neutropenic patients with fever, thoracic CT scanning (low-dose, multislice, multidetector, spiral, high-resolution) should be performed when there are signs or symptoms of lower respiratory tract infection, including cough, shortness of breath, chest pain, or hemoptysis. In addition, because pulmonary IFD is frequently clinically occult in neutropenia, thoracic CT should also be performed for patients with prolonged or persistent/recurrent febrile neutropenia (typically beyond 4-7 days of broad-spectrum antibacterial therapy) even in the absence of respiratory signs or symptoms. An abdominal CT scan (preferred) or ultrasound should be utilized to investigate abdominal pain and/or diarrhea. Laboratory tests should include measurements of transaminases, alkaline phosphatase, and bilirubin levels. If symptoms such as headache, sinus pain, or localized pain radiating to the eye are present, a sinus CT scan and, if necessary, orbital magnetic resonance imaging (MRI) should be performed. Additional symptoms may include sinus tenderness, rhinorrhea, nasal ulcers with black eschar, and palatal ulceration. Cranial CT or MRI should also be considered in the presence of headaches or neurological symptoms [2, 5, 6].

What Radiological Findings Are Suggestive of Pulmonary IFD?

Recent data suggest that high-resolution CT is the preferred imaging modality over chest X-ray, MRI, and positron emission tomography for diagnosing invasive pulmonary aspergillosis (IPA) and pulmonary mucormycosis in adults. In addition to its role in early diagnosis, CT can aid in distinguishing fungal from non-fungal pulmonary infections [5, 6].

The primary radiological feature of IPA on CT is the presence of well-circumscribed rounded or irregular opacities (nodules). Nodules or masses accompanied by ancillary signs, such as the halo sign (a surrounding zone of ground-glass attenuation), are considered more suggestive of IPA [4, 5, 6].

Less specific and less common findings include bronchopneumonia, consolidation (a homogeneous increase in pulmonary parenchymal attenuation that obscures the margins of vessels and airway walls, with or without an air bronchogram), pleural-based wedge-shaped consolidations, cavitary lesions, pleural effusions, ground-glass opacities, and the tree-in-bud pattern (centrilobular branching opacities resembling a budding tree). Additional findings include atelectasis, the reversed halo sign (a focal rounded area of ground-glass opacity surrounded by a ring of consolidation), the hypodense sign (a central area of lower attenuation within a nodule or mass), and the air crescent sign (a peripheral crescent-shaped area of cavitation within a nodule or mass). Bronchoinvasive forms may manifest as tracheal or bronchial wall thickening [4, 5, 6].

The presence of nodular or cavitary lesions is highly suggestive of invasive filamentous fungal infections; however, differential diagnoses such as pneumonia caused by Mycobacterium, Nocardia, Pneumocystis jirovecii, or Pseudomonas aeruginosa should be considered [4, 5, 43].

The reversed halo sign is more specific for fungal pneumonia caused by Mucorales strains, though differential diagnoses including tuberculosis, sarcoidosis, or cryptogenic organizing pneumonia must also be ruled out. Multiple nodules (>10) and pleural effusions are more frequently observed in Mucorales infections. Diffuse bilateral perihilar infiltrates, patchy areas of ground-glass attenuation, cysts, septal thickening, consolidation, and centrilobular nodules are more characteristic of Pneumocystis jirovecii pneumonia [4, 5, 44].

Which Diagnostic Tests Are Required to Confirm Pulmonary IFD?

While characteristic imaging findings and biomarkers such as serum or BAL fluid GM levels for aspergillosis are highly suggestive of IPA, definite diagnosis of IFD requires histopathological examination of sterile biopsy material or growth of the organism in sterile specimens. Every effort must be made to grow the pathogen in culture for species identification and antifungal susceptibility testing [4, 6].

In clinical practice, most patients are treated empirically or preemptively because of potential risks of biopsy or lack of resources. GM detection in body fluids (especially BAL) is more sensitive than culture for diagnosis of invasive Aspergillus (level of evidence: IA). A serum optical density index cut-off of 0.5 demonstrates high sensitivity and negative predictive value for invasive aspergillosis in neutropenic leukemia patients or allogeneic HSCT recipients during the pre-engraftment period who are not receiving mold-active prophylaxis. GM in BAL is a good tool to diagnose IPA with a cut-off value of 0.5-1.0. Aspergillus polymerase chain reaction, Aspergillus lateral flow device assay, and (1→3)-b-D-glucan monitoring are alternative diagnostic methods with the best results obtained when GM is combined with another test [4, 6].

What Is the Treatment Approach for Suspected Pulmonary IFD in Neutropenic Patients? How Does Prophylaxis History Influence the Choice?

Voriconazole or isavuconazole is recommended as first-line treatment for IPA in neutropenic patients in most international guidelines. Liposomal amphotericin B is an alternative. Diagnosis or suspicion of mucormycosis should prompt surgical debridement in addition to liposomal amphotericin B at 5-10 mg/kg/day, with higher doses (up to 10 mg/kg/day) reserved for central nervous system involvement. If renal insufficiency precludes amphotericin B, isavuconazole or posaconazole could alternatively be administered [3, 4, 16, 35].

Mold-active antifungal prophylaxis for AML patients undergoing induction chemotherapy has a significant influence in the therapeutic approach. Prophylaxis reduces invasive mold disease, but prolonged exposure may lead to the selection of azole-resistant Aspergillus strains such as those with CYP51A mutations or non-Aspergillus molds (strains of Mucorales, Fusarium, etc.). Mold-active prophylaxis may also blunt GM performance, thus decreasing its sensitivity. In general, it is recommended to switch to another antifungal class, such as from posaconazole or voriconazole to liposomal amphotericin B, when IFD is suspected. Intravenous voriconazole may be initiated or continued if an Aspergillus strain is the likely pathogen (positive GM, imaging features consistent with IPA, and absence of findings suggestive of mucormycosis) and any of the following conditions are present: a) subtherapeutic serum levels of the azole drug, b) profuse diarrhea during oral azole prophylaxis, or c) prophylaxis duration of less than 7 days [4, 16, 35, 42]. When azole-resistant Aspergillus fumigatus (e.g., CYP51A-mediated) is suspected because of a lack of clinical response despite adequate azole exposure, or in regions with a high prevalence of environmental resistance, antifungal susceptibility testing should be pursued and empirical therapy should be broadened to another class such as liposomal amphotericin B. A voriconazole minimum inhibitory concentration above the clinical breakpoint warrants a change of therapy [4].

What Clinical Signs and Symptoms Should Raise Suspicion of Fungal Sinusitis in Neutropenic Patients?

Invasive fungal sinusitis (IFS) is a rare infection associated with high morbidity and mortality, primarily caused by Aspergillus and Mucorales species. Clinical signs and symptoms are often nonspecific and delays in diagnosis may result in fatal outcomes [16, 45]. The infection typically originates in the paranasal sinuses and can extend to adjacent structures, such as the orbit, eye, brain, or nasal cavity, often through bone destruction. Common symptoms of IFS include fever, nasal congestion, facial pain, sinus tenderness, facial swelling, and rhinorrhea. In early stages, pallor and discoloration in the nasal cavity, as well as necrosis, ulceration, or eschar formation on the nasal septum, may be observed. As the disease progresses, proptosis, palatal or palpebral fistulas, visual disturbances, extraocular muscle weakness, and cranial neuropathies may develop [16, 45, 46].

Intranasal examination and nasal endoscopy are recommended in cases of suspected IFS. In early stages, if the infection is confined to the nasal cavity, distinguishing it from benign etiologies can be challenging. Direct visualization and biopsy of the involved sinus mucosa, turbinates, or septum using rigid nasal endoscopy play crucial roles in both diagnosis and differential diagnosis [16, 45, 46].

Imaging is essential for early diagnosis of IFS. High-resolution CT and MRI are both recommended. While CT is mandatory for the initial evaluation and diagnosis, MRI is more sensitive in detecting early sinus involvement and assessing orbital or intracranial extension. Early CT findings may include sinonasal mucosal thickening, air-fluid levels, and infiltration of the periantral fat. Unilateral opacities should raise suspicion, and in more advanced stages, osseous erosion, considered a more specific finding, may be identified [16, 43].

What Is the Initial Treatment for Suspected Fungal Sinusitis While Awaiting Microbiological/Pathological Results?

The likelihood that Mucorales or other non-Aspergillus molds are responsible is considerably higher in cases of IFS than in pulmonary disease; liposomal amphotericin B is therefore recommended as empirical therapy. In the uncommon setting of a local outbreak of Aspergillus terreus or Aspergillus flavus in the hospital, voriconazole should be added until culture-based diagnosis is finalized [16].

How Should Treatment Response Be Monitored? When Should Therapy Be Adjusted or Discontinued?

The patient should be assessed daily during the initial phase of antifungal treatment. Symptoms attributable to IFD such as cough, hemoptysis, and sinus pain are to be monitored closely. Fever usually subsides in 5-7 days. A decrease in serum/BAL GM level by >50% suggests a good response in cases of invasive aspergillosis. Imaging studies may be repeated every 3-4 weeks unless there is clinical deterioration. Evolution of the halo sign to air crescent sign or cavity is common with the resolution of neutropenia. If feasible, therapeutic drug monitoring is recommended for voriconazole on days 3-5 and after the dose or formulation is changed, or after a potential interacting agent is started or discontinued [3, 4, 35].

The patient should be switched to another antifungal in the event of clinical deterioration (new fever, worsening of symptoms), radiological progression or persistent positive biomarker levels after at least 2 weeks of therapy, and rare cases of suspected breakthrough infection with another fungi. Combination treatment may be considered for refractory disease.

The duration of antifungal treatment depends on host factors (recovery from neutropenia), clinical response (resolution of symptoms), microbiological response (negative biomarkers), and radiological response (stable lesions such as residual scarring or nodules). In general, invasive aspergillosis is usually treated for 6-12 weeks (minimum of 4 weeks after neutrophil recovery), while mucormycosis is treated for much longer (up to 6 months) [3, 35].

A multidisciplinary team approach will enhance the likelihood of achieving the best possible treatment response and using limited resources effectively [47].

Conclusion

Antifungal strategies in patients with hematological malignancies must be individualized according to disease risk, treatment phase, and intensity of immunosuppression. Primary prophylaxis remains essential in high-risk settings such as AML induction and selected allogeneic HSCT scenarios, while unnecessary prophylaxis should be avoided in low-risk populations.

The increasing use of targeted and immune-based therapies has shifted antifungal management toward a more nuanced balance among infection prevention, drug-drug interactions, and toxicity. In this context, diagnostic test-driven approaches supported by early imaging and fungal biomarkers play critical roles in optimizing antifungal therapy. A structured, risk-adapted framework that integrates prophylaxis, timely diagnostics, and appropriate therapeutic escalation offers the most effective strategy for reducing the morbidity and mortality associated with IFDs while preserving antifungal efficacy in modern hematological care.

In practical terms, high-risk patients, such as those undergoing AML or high-risk MDS remission-induction (including HMA-based therapy during the first four cycles) and allogeneic HSCT recipients with grade III-IV GVHD on high-dose corticosteroids, warrant mold-active prophylaxis, preferably posaconazole (A-I), with isavuconazole or micafungin (B-II) as alternatives when posaconazole is unsuitable. Intermediate-risk patients generally require only yeast-active prophylaxis with fluconazole, whereas low-risk groups need no prophylaxis. For patients receiving targeted agents, the emphasis shifts from prophylaxis toward the management of triazole drug-drug interactions, while CAR-T recipients are stratified to mold- or yeast-active prophylaxis according to pre- and post-infusion risk.

Important evidence gaps remain, including the optimal prophylactic strategy in the era of hypomethylating and targeted therapy, the role and thresholds of biomarker-driven monitoring during mold-active prophylaxis, and the management of emerging azole resistance. The maturing antifungal pipeline, including agents with novel mechanisms such as olorofim, fosmanogepix, rezafungin, ibrexafungerp, and inhaled opelconazole, may broaden future options, particularly against resistant or difficult-to-treat molds.

Ultimately, antifungal stewardship and individualized, risk-adapted decision-making rather than uniform blanket prophylaxis offer the best balance between preventing IFD and limiting toxicity, drug-drug interactions, resistance, and cost [1, 47].