Management of mould pneumonia in resource-limited settings in Asia: A Delphi-based consensus statement by the Asia Fungal Working Group

Abstract

Mould pneumonia can be life-threatening, and its incidence is increasing in Asia. Due to significant variability in diagnostic setups and the availability of antifungal agents, especially in resource-limited settings, the current treatment practices and recommendations for local clinicians are poorly described. This study aimed to develop a consensus statement on the clinical management of mould pneumonia in Asia, particularly within resource-limited settings. Clinicians and infectious disease experts from the Asia Fungal Working Group answered questions about the regional epidemiology as well as diagnostic and resource-limited treatment approaches of mould pneumonia. Guided by a literature review, 22 initial questions were generated and voted upon anonymously using a Delphi-based methodology with predefined consensus criteria. The study comprised two rounds: one to generate summary statements based on the panelists’ questionnaire responses, and the other to review, confirm and rate the level of agreement of the consensus statements using a five-point Likert scale. The panelists generated 21 summary statements on the epidemiology (5), diagnosis (8), and treatment (8) of mould pneumonia, 20 of which achieved ≥ 70% consensus. Through a consensus-building exercise, clinical experts from Asia developed a set of 21 consensus statements for the diagnosis and management of mould pneumonia in resource-limited settings.

Introduction

Invasive mould infection (IMI), which describes the systemic infection of moulds in tissues or organs,¹ is responsible for > 1.6 million deaths annually.² It is especially life-threatening for individuals who are immunocompromised, including those with prolonged neutropenia, those who recently underwent hematopoietic stem cell or solid organ transplant, or those who have inherited or acquired immunodeficiencies. IMI is primarily manifested as pneumonia,³ which is difficult to suspect, diagnose, and treat.⁴ Globally, the incidence of IMIs is increasing; this is particularly evident among patients managed in intensive care units (ICUs), those with chronic obstructive pulmonary disease (COPD), and those receiving novel chemotherapy and immunomodulatory agents.^5–8

Because of its larger vulnerable patient population and tropical/subtropical climate where fungi thrive easily and contaminate the environment, Asia is believed to have a substantially higher IMI burden than other regions worldwide.⁹ However, surveys of local physicians have shown that the diagnosis and management of IMI vary considerably throughout much of Asia, primarily due to differences in available resources.^9,10 Although most physicians surveyed had access to diagnostic tools such as direct microscopy and histopathology, fewer had access to molecular and serological fungal diagnosis, and international guideline-recommended antifungal agents.^9,10

Two of the most clinically significant IMIs in Asia are aspergillosis and mucormycosis.¹¹ Invasive aspergillosis (IA), caused by the Aspergillus species, is the most frequently reported IMI in immunocompromised individuals in the region.¹¹ While often underreported, mucormycosis is caused by a group of moulds in the subphylum Mucoromycotina and is increasingly prevalent in Asia, including China, India, Iran, and Pakistan.¹²

International guidelines on the diagnosis and treatment of IMIs, specifically aspergillosis and mucormycosis, have been published by various organizations around the world.³,^13–15 These guidelines were developed to maximize patient outcomes using the highest quality evidence, and therefore generally assume optimal conditions for managing the disease, including access to advanced diagnostic tools and antifungal agents. Not surprisingly, the approach to managing IMIs in many Asian countries has been inconsistent.⁹ This is mainly due to the lack of national IMI treatment guidelines and non-adherence to international guidelines due to cost or non-availability of diagnostic tests and first-line antifungal agents.⁹

These challenges have resulted in notable region-specific knowledge gaps in the epidemiology, diagnosis, and treatment of IMIs. Furthermore, although infrequently reported in the literature,¹⁶ aspergillosis–mucormycosis dual infections may be more common than generally believed, perhaps related to inadequate diagnostics.¹⁷ Ultimately, improving clinical outcomes in Asia will require a clearer understanding of region-specific practices and recommendations to diagnose and treat IMIs in settings with limited resources.

Here, we report results from a modified Delphi consensus-forming exercise focused on managing mould pneumonia (MP)—specifically aspergillosis and mucormycosis—in Asia. The statement was developed by the Asia Fungal Working Group (AFWG), which comprises 14 mycologists and infectious diseases specialists from throughout the region. The Delphi-based method was chosen as a means of capturing experts’ opinions on the highly variable diagnostic and treatment differences in the region. In addition to the consensus statement, which provides broadly applicable strategies to local practicing physicians, we have included a noteworthy case study with specific suggestions and considerations when diagnosing and treating MP in resource-constrained environments.

Materials and methods

Delphi panelists and background

The consensus statement was developed by members of AFWG (https://www.afwgonline.com/), a working group under the International Society for Human and Animal Mycology (ISHAM).

The clinical problem addressed by the consensus statement was limited to MP, specifically aspergillosis and mucormycosis in both classical and non-classical risk groups. The setting was hospitals and clinics in regions represented by the AFWG; however, the literature review more broadly included all Asian countries.

The manuscript was developed using the ACcurate COnsensus Reporting Document guidelines^18,19 to report consensus study outcomes (Supplementary Table 1), and additional details related to the study methodology can be found in the Online Supplementary File.

Literature review

We conducted a preparatory literature review to assist the development of clinical questions of interest on IMIs and MP. The scope of the literature review included the treatment, risk factors, diagnosis, and prophylaxis of both aspergillosis and mucormycosis. See Online Supplementary File for complete search queries and summary tables of corresponding publications.

Delphi questionnaire

Three clinical considerations guided the development of the Delphi questionnaire: (1) the epidemiology of aspergillosis and mucormycosis in Asia; (2) available and preferred diagnostic tools; and (3) disease management in resource-limited settings.

Using information from the literature review, a preliminary Delphi questionnaire with 43 open-ended and multiple-choice questions was developed by a sub-group within the AFWG, and subsequently reviewed by four AFWG steering committee members, who had access to summary Population, Intervention, Comparison, and Outcome tables from the literature review. The steering committee also proposed new questions when deemed necessary.

The AFWG held a face-to-face meeting on August 1, 2024, during which the initial questions were reviewed and openly discussed by all 14 panelists, ultimately producing a questionnaire with 16 multiple-choice questions. After incorporating subsequent comments from individual panelist and with confirmation from the steering committee, the Delphi questionnaire was finalized. The final questionnaire consisted of 22 multiple-choice questions in English, including 3 ranking and 19 select-all-that-apply questions (see Supplementary Table 2 for the complete questionnaire).

Delphi voting and consensus statement

All 14 panelists answered the finalized questions online using eDelphi, a Delphi method software (https://www.edelphi.org/; Metodix Ltd, Espoo, Finland). Responses were collected anonymously from all panelists and summarized collectively using eDelphi’s summary functionality. Optional open-ended responses were explicitly included for 18 of the 22 questions if the predetermined options were considered insufficient, and the panelists could elaborate on the topic of each question by adding a comment. Neither the project coordinator nor the funding sponsor had voting rights.

There were two rounds of voting: one round to generate questionnaire responses and a second round to review the consensus statements based on results from the first round (Supplementary Figure 1). The algorithm for evaluating the consensus process was modified from a published methodology.²⁰

The purpose of Round 1 voting was to review the questionnaire responses provided by the panelists, calculate the value and strength of consensus for each question, and generate candidate summary statements. For each select-all-that-apply and multiple-choice question, summary statements were generated using the corresponding answers that reached a positive consensus (> 75% of collective agreement among the voters), if applicable. For the ranking questions, summary statements were generated using the top five answers selected by the panelists during Round 1. Steering committee members voted to accept, revise, or reject each summary statement, and their feedback was incorporated in the improved summary statements that were reviewed during Round 2 voting.

The purpose of Round 2 voting was to have the improved summary statements reviewed by all panelists and finalized to generate a final set of consensus recommendations. Additionally, the panelists rated their level of agreement with each summary statement using a five-point Likert scale (‘Strongly Agree,’ ‘Agree,’ ‘Neither Agree nor Disagree,’ ‘Disagree,’ and ‘Strongly Disagree’). The percentage of total votes received for either ‘Agree’ or ‘Strongly Agree’ for each statement was computed and presented in Table 1.

Table 1.

Outcomes of voting rounds and steering committee review during consensus statement generation.

Category	Round 1 voting			Steering committee review	Round 2 voting						Level of agreement*
	#	Type	Answers with consensus		#	SA	A	N	D	SD
Regional epidemiology	1	SATA	2 out of 6	Approved	1	10	3	0	0	0	100%
	2	Ranking	NA	Approved	2	10	1	1	1	0	84.6%
	3	Ranking	NA	Approved	3	8	4	1	0	0	92.3%
	4	SATA	2 out of 6	Approved	4	7	4	1	1	0	84.6%
	5	SATA	1 out of 6	Approved	5	6	4	3	0	0	76.9%
Diagnostic approach	6	SATA	2 out of 7	Approved	6	6	6	0	1	0	92.3%
	7	SATA	3 out of 4	Approved	7	4	9	0	0	0	100%
	8	SATA	10 out of 16	Revised	8	9	3	0	1	0	92.3%
	9	SATA	9 out of 12	Revised	9	8	4	0	1	0	92.3%
	10	SATA	2 out of 8	Revised	10	4	7	0	1	0	91.7%
	11	SATA	3 out of 5	Revised	11	7	5	0	0	0	100%
	12	SATA	1 out of 6	Removed	NA
	13	SATA	6 out of 7	Approved	12	5	6	1	0	1	84.6%
	14	MC	1 out of 4	Removed	NA
	15	SATA	5 out of 7	Revised	13	7	5	0	0	1	92.3%
Resource-limited treatment	16	SATA	1 out of 9	Revised	14	7	4	2	0	0	84.6%
	17	SATA	1 out of 9	Removed	NA
	18	SATA	5 out of 8	Revised	15	6	4	1	1	0	83.3%
	19	SATA	5 out of 7	Revised	16	9	3	0	1	0	92.3%
	20	SATA	NA	Revised	17	4	7	2	0	0	84.6%
					18	8	4	0	1	0	92.3%
					19	9	3	0	1	0	92.3%
	21	SATA	3 out of 12	Revised	20	7	6	0	0	0	100%
	22	SATA	3 out of 7	Revised	21	4	5	3	1	0	69.2%

^*Level of agreement indicates combined votes received for ‘Strongly Agree’ or ‘Agree.’

SATA, select-all-that-apply; MC, multiple choice; NA, not applicable; SA, Strongly Agree; A, Agree; N, Neither Agree nor Disagree; D, Disagree; SD, Strongly Disagree.

Results

The consensus statements were developed between May 2024 and February 2025, with the questionnaire developed between May and July, both rounds of voting occurring between July and October, and the consensus statements finalized between October 2024 and February 2025. All 14 AFWG members were invited to participate in both rounds of voting.

All panelists participated in Round 1 voting, and at least one answer from all 22 questions voted on by the panelists achieved a positive consensus per the prespecified definition (Table 1). The steering committee reviewed the 22 corresponding summary statements and voted to approve 8 statements, revise 11 statements, and remove 3 statements. The committee also recommended subdividing statement 20, originally a ranking question, into three separate statements. The 21 revised summary statements were voted on by 13 of the 14 panelists during Round 2 voting, and one panelist abstained from voting on 3 summary statements. At the end of the consensus-building exercise, 13 of those 21 statements achieved > 90% level of agreement (LoA; defined as combined votes received for ‘Strongly Agree’ or ‘Agree’), 7 statements reached 75%–89% LoA, and 1 statement had < 75% LoA (Table 2).

Table 2.

Final consensus statements on epidemiology, diagnosis, and treatment of mould pneumonia in Asia.

Category	Consensus statement
Regional epidemiology	1. Aspergillosis and mucormycosis are the major causes of MP in Asia.
	2. Risk factors for invasive pulmonary aspergillosis in Asia include hematological malignancies, hematopoietic stem cell transplantation, solid-organ transplantation, high-dose or prolonged corticosteroid use, and severe viral pneumonia (COVID-19 or influenza).
	3. Risk factors for invasive pulmonary mucormycosis in Asia include poorly controlled diabetes with or without ketoacidosis, hematological malignancies, hematological stem cell transplantation, high-dose and prolonged corticosteroid use, and solid organ transplantation.
	4. Aspergillus fumigatus and Aspergillus flavus are the most common isolated species responsible for invasive pulmonary aspergillosis in Asia.
	5. Rhizopus arrhizus is a common causative agent of invasive pulmonary mucormycosis in Asia.
Diagnostic approach	6. Physicians may suspect MP in patients from Asia with risk factors for invasive fungal infection when: (1) fever is not responding to empirical or apparently appropriate antibacterial therapy, and (2) imaging findings are suspicious of MP.
	7. It can be difficult to differentiate between invasive pulmonary aspergillosis and invasive pulmonary mucormycosis, although certain risk factors and radiological signs may suggest the presence of one over the other (e.g., the presence of invasive fungal disease breaking through voriconazole suggests mucormycosis).
	8. When mould pneumonia is suspected, the following non-invasive/minimally invasive diagnostic tests can be considered: (1) chest X-ray; (2) CT chest/thorax; (3) KOH or calcofluor wet mount of sputum; (4) endotracheal aspirate for fungal microscopy and culture (for mechanically ventilated patients); (5) serum galactomannan by ELISA or LFA; (6) respiratory samples for Aspergillus PCR; and (7) blood Aspergillus and Mucorales PCR.
	9. For invasive procedures, transthoracic tissue histopathology (biopsy) or bronchoscopy (for BAL) with or without transbronchial biopsy may be performed when mould pneumonia is suspected, depending on the location of the lesion and the equipment and skills available. Consideration should be given to risks such as bleeding (e.g., in thrombocytopenic patients) and appropriate precautions taken. The following tests may also be performed on the samples obtained from these procedures: fungal microscopy and culture, galactomannan (only applicable to BAL fluid) using ELISA and/or LFA, and Aspergillus and Mucorales PCR.
	10. In patients with neutropenia, the halo and reversed halo signs are important radiological signs in the diagnosis of invasive pulmonary aspergillosis and invasive pulmonary mucormycosis. The halo sign is classically associated with invasive pulmonary aspergillosis, but may also be seen in pulmonary mucormycosis. The reversed halo sign is classically associated with invasive pulmonary mucormycosis. In patients without neutropenia, the bird’s nest sign may suggest mucormycosis. In addition to imaging results, risk factors should always be taken into consideration when differentiating between invasive aspergillosis and mucormycosis.
	11. Physicians may consider using serum galactomannan to diagnose MP when: (1) there is suspicion of invasive pulmonary aspergillosis, and/or (2) invasive sampling is not possible. Physicians may use serum galactomannan as part of a pre-emptive approach to diagnose invasive aspergillosis in neutropenic patients at moderate to high risk of the disease if they are not on effective anti-mould prophylaxis.
	12. Overall, physicians may consider microscopy, culture, galactomannan and beta-D-glucan testing, invasive sampling using bronchoscopy, and invasive sampling for histopathology, such as transbronchial or transthoracic biopsy for diagnosing MP.
	13. Point-of-care testing with Aspergillus LFA may be considered for MP: (1) in serum and BAL from patients suspected with fungal pneumonia; and (2) in settings with limited laboratory equipment, low testing volume, or when specimens are tested in batches. In resource-limited settings, Aspergillus LFA may be considered as a substitute for galactomannan ELISA if the latter is unavailable.
Resource-limited treatment approach	14. Antifungal prophylaxis for MP may be considered: (1) in patients with acute myeloid leukemia and myelodysplastic syndrome on induction or salvage chemotherapy, especially in areas with a high prevalence of fungal infections; and (2) in post-hematopoietic stem cell transplant patients with graft-versus-host disease on high-dose steroids.
	15. Physicians may consider initiating antifungal therapy before confirming MP in high-risk patients when clinical symptoms and signs, plus new-onset pulmonary infiltration, suggest MP. In the appropriate clinical context, physicians should seriously consider starting anti-fungal therapy if any of the following are positive: (1) smear or culture of respiratory specimens, (2) serum antigen (galactomannan or beta-D-glucan), (3) serum or whole blood PCR, or (4) BAL galactomannan/PCR.
	16. Physicians should initiate targeted anti-fungal therapy for MP when histopathology examinations show invasive fungal disease, or there is positive tissue PCR. They can consider modifying anti-fungal therapy when: (1) identification of the causative fungus is available at the genus, complex or species level; and (2) antifungal susceptibility test results are available.
	17. When the mould is unknown in suspected MP, amphotericin B product (preferably liposomal formulations) or isavuconazole is recommended for treatment.
	18. For invasive pulmonary aspergillosis, recommended first-line therapies include voriconazole, isavuconazole, or posaconazole, with amphotericin B product (preferably liposomal formulations) being recommended as an alternate therapy. Amphotericin B product is also recommended for azole-resistant or -intolerant cases.
	19. For invasive pulmonary mucormycosis, the recommended first-line therapy is amphotericin B product (preferably liposomal formulations), and isavuconazole or posaconazole can be used as step-down or salvage therapy.
	20. Antifungal susceptibility testing, therapeutic drug monitoring, molecular-based identification (i.e., PCR), galactomannan, and beta-D-glucan are not widely available in Asian clinical settings with limited resources.
	21. Amphotericin B deoxycholate is equally efficacious to liposomal amphotericin B in treating mucormycosis. In resource-limited settings, amphotericin B deoxycholate may be prescribed when liposomal amphotericin B is unavailable, as long as measures like saline loading before antifungal administration or slow infusion are performed to reduce the toxicity of the deoxycholate formulation. Posaconazole or isavuconazole is recommended as step-down or salvage therapy.

BAL, bronchoalveolar lavage; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay; MP, mould pneumonia; KOH, potassium hydroxide; LFA, lateral flow assay; PCR, polymerase chain reaction.

Discussion

This study was undertaken to address knowledge gaps and unmet needs related to the clinical management of IMIs in Asia. Using Delphi-based consensus methodology, a panel of clinical experts generated 21 consensus statements focusing on MP, covering regional epidemiology, diagnostic approach, and resource-limited treatment approach. In this section, we included additional rationale and explanations for each consensus statement by incorporating information from the published literature and comments from the panelists provided during the voting and review rounds.

Regional epidemiology

Five consensus statements describing the regional epidemiology of IMIs were generated and approved by the panelists (Table 2).

The panelists unanimously agreed that aspergillosis and mucormycosis are the major causes of MP in Asia, which aligns with existing literature from the region.^11,12,21 They also identified Aspergillus fumigatus and A. flavus as the most frequently isolated species responsible for invasive pulmonary aspergillosis (IPA) in Asia. The published frequency of Aspergillus species across Asia varies depending on region; in some parts of Asia, A. flavus is the primary cause, while in others, A. fumigatus predominates.²¹ A systematic review of patients with IPA in China found that most patients were infected with A. fumigatus (75.14%), followed by A. flavus (12.25%) and A. niger (6.14%).²² Additionally, the panelists identified Rhizopus arrhizus as a common cause of pulmonary mucormycosis in Asia, which is largely supported by global observational data.²³ Notably, assays that differentiate between species are unavailable in some Asian regions,¹² and therefore the prevalence of certain subspecies may be under-reported or absent from the published literature.

The risk factors for IPA and invasive pulmonary mucormycosis (IPM) in Asia, as prioritized by the panelists, generally agree with published data. In a large Taiwanese study, the primary underlying risk factor was hematological malignancies (45.9%) for aspergillosis and diabetes (60.8%) for mucormycosis.²⁴ Along with traditional risk factors, critically ill patients admitted to the ICU with COPD or chronic liver disease are also at risk for developing IMIs.²⁵

Although mucormycosis is less common than aspergillosis, it has been associated with outbreaks, particularly in India during the COVID-19 pandemic,²⁶ and increased mortality.²⁷ Interestingly, COVID-19-associated mucormycosis has not been reported with the same prevalence in other Asian countries. Factors such as healthcare infrastructure, prevalence of diabetes, environmental factors, and the use of steroids during COVID-19 treatment may contribute to these regional differences in outbreak frequency and severity. A prospective study in India identified uncontrolled diabetes (56.8%) as the predominant risk factor for IPM,²⁸ and a review estimating percentages from three studies^29–31 identified the most prevalent risk factors as hematological malignancy (32%–40%), diabetes (32%–56%), hematopoietic stem cell transplant (1%–9.8%), and solid organ transplant (6.5%–9%).¹² Uncontrolled diabetes is especially concerning in Asia because > 60% of the world’s diabetic population resides there.³² Mucormycosis has also been identified in patients with human immunodeficiency virus and lung transplant recipients.^33,34

Diagnostic approaches

The panelists agreed upon eight consensus statements related to diagnosing aspergillosis and mucormycosis (Table 2).

The panelists commented that having mycological findings to support the diagnosis is preferable, although clinicians may not always have the full complement of laboratory tests available. They could not reach a consensus for suspecting MP after a new onset of hemoptysis or blood-tinged sputum, new onset of pleuritic pain, elevated C-reactive protein and negative procalcitonin (PCT), or on negative findings after initial diagnostics. This is not surprising, as hemoptysis and pleuritic chest pain can be associated with a wide array of diagnoses. The panelists also could not reach a consensus on the role of procalcitonin as it has poor sensitivity and specificity in diagnosing invasive fungal infections;³⁵ although PCT was higher in bloodstream infections caused by gram-negative bacteria, the discriminatory power of this difference was ‘too low to guide therapeutic decisions’.³⁶

Physicians may suspect the presence of MP through chest computed tomography (CT) imaging results suggestive of angioinvasion, such as nodules with the halo sign.^37,38 However, as noted by the panelists, it is challenging to differentiate between IPA and IPM because both diseases have a similar clinical presentation.³⁹ A large, retrospective study of IMI in five Asian countries found that pleuritic chest pain was only observed in patients with aspergillosis,²¹ but this is a non-specific symptom. A systematic review in patients with high-risk hematological disorders found that mucormycosis occurred more frequently following voriconazole breakthrough, and aspergillosis after posaconazole breakthrough.⁴⁰ For mucormycosis, clinicians should be attentive to its possibility when faced with rhino-orbital infections, especially when there is blackening of the skin and/or oral mucosa.⁴¹

In this study, the Delphi panelists considered radiology,⁴² serum-based tests,⁴³ and biomarkers identified from blood draws as minimally invasive diagnostic tests,⁴⁴ while endotracheal aspirate was accepted as a non-invasive modality.⁴⁵ Tissue examination provides definitive results and a confirmed diagnosis, but all tests aimed at obtaining tissue to clinch an etiologic agent of pneumonia are invasive, and whether the patient’s condition allows invasive procedures must be considered. For example, a trans-thoracic tissue biopsy is only possible in peripheral lesions, and centrally located lesions would be better accessed via bronchoscopy, endobronchial ultrasound, and bronchoalveolar lavage (BAL). A tissue biopsy can provide a definitive diagnosis through various methods, including histopathology examination, direct examination using KOH, and culture. The biopsies also allow deoxyribonucleic acid extraction from tissue samples, enabling polymerase chain reaction (PCR) testing for Mucorales and Aspergillus species.

The Infectious Diseases Society of America (IDSA) guidelines strongly recommend bronchoscopy with BAL in patients suspected of IPA. BAL is an invasive procedure, and the guidelines identify significant comorbidities such as severe hypoxemia, bleeding, and platelet transfusion-refractory thrombocytopenia as potential contraindications.³ There are no agreed-upon standards for when to conduct a bronchoscopy, whether patients with neutropenia or those with cavitary lesions should receive a bronchoscopy, and how the BAL should be performed, including the volume instilled.³ The diagnostic yield of BAL varies depending on the lesion, with higher diagnostic yield in symptomatic patients (vs. asymptomatic) and those with alveolar infiltrates (vs. reticular and nodular infiltrates).⁴⁶ The guidelines recommend sending BAL samples for cytologic assessment, Gram staining, fungal staining, culture, and galactomannan (GM) test, although not all these tests are available throughout Asia.¹²

The panelists considered the clinical value of the halo and reversed halo signs, particularly in neutropenic hosts. Although the halo sign is classically suggestive of IPA and the reversed halo of IPM, these radiological signs are generally nonspecific.⁴⁷ The timing of CT imaging is important because the halo sign is typically detectable at the beginning of angioinvasion,⁴⁸ and therefore, the window during which IPA/IPM can be detected early is narrow.⁴⁹ While it may be challenging to secure an early CT imaging appointment in resource-limited settings, CT thorax—if available—should ideally be performed early in neutropenic patients with antibiotic-refractory fever, as the halo sign can disappear as quickly as in < 5 days. Radiological features of IMIs may be nonspecific, like consolidation, parenchyma infiltrates, and characteristic nodules with or without a halo sign, especially in non-neutropenic hosts, although the unique clinical setting may suggest a particular IMI. For example, the halo sign has high specificity for IPA in patients with prolonged neutropenia who have a fever that does not respond to broad-spectrum antibiotics.⁴⁷

In non-neutropenic patients with aspergillosis (such as influenza-associated pulmonary aspergillosis), the pathophysiology is different from aspergillosis in neutropenic patients. In non-neutropenic patients, imaging often does not have the traditional characteristics of aspergillosis, such as the halo sign.⁵⁰ Less is known about the prevalence of the halo sign in subgroups of patients with IPM, likely because it is comparably infrequent.⁴⁷

The detection of GM, a fungal cell wall component, is supported by substantial evidence as a diagnostic indicator of IMI. GM can be detected by lateral flow assay (LFA) or enzyme-linked immunosorbent assay (ELISA), the latter of which can be done in serum, plasma, cerebrospinal fluid, or BAL fluid. While systematic reviews support the role of GM in diagnosing IPA, the performance depends on the cutoff value.^51–53 The pooled performance of GM detection by serum showed 76% sensitivity and 92% specificity,⁵³ by BAL fluid showed 79% sensitivity and 92% specificity,⁵² and by LFA showed 78% sensitivity and 87% specificity.⁵⁴

Although guidelines on diagnosing IMI (including IA) require a microbiologic and/or histopathologic diagnosis to establish infection,^1,3 these tests should not be conducted in patients with contraindications for an invasive procedure. Serum GM and beta-D-glucan (BDG) tests have comparably high pooled sensitivity and specificity for diagnosing IA,⁵⁵ although they are not available in many settings throughout Asia.⁹ Microscopy and culture-based diagnostic approaches should be first-line diagnostics for MP.

While LFA was initially shown to have a lower sensitivity and specificity than ELISA,⁵⁶ recent comparative studies have demonstrated comparable diagnostic performance and high agreement between the two methods.⁵⁷ In fact, serum LFA may be recommended in resource-limited settings where GM ELISA is not feasible or unavailable. Compared with ELISA, LFA is considered more straightforward (i.e., minimal infrastructure requirements), faster, and more cost-effective in identifying IPA,⁵⁸ and its speed can be essential for critically ill patients—particularly those in low- and middle-income countries (LMICs)—requiring prompt treatment. While LFA alone or GM-LFA can be used as diagnostic tools for IA, performance heterogeneity emphasizes the importance of validating specific LFA products in the intended patient population before clinical implementation.^3,59

LFA may be used as an initial screening test while waiting for GM ELISA results (if and when available), as the early and prompt diagnosis of IA, followed by targeted antifungal therapy, has the potential to significantly improve survival. Of note, GM-LFA is useful for rapid decision-making when immediate results are needed, as the test can produce results in approximately 20 min.⁵⁷

Resource-limited treatment

The panelists generated nine consensus statements on the resource-limited treatment approaches for aspergillosis and mucormycosis (Table 2).

Outside of the two populations described in the consensus statement, whose evidence for prophylactic anti-fungal treatment is supported by high-quality clinical data, there is limited evidence supporting its usefulness. However, patients believed to be neutropenic for prolonged periods, such as those on venetoclax, may benefit from anti-fungal prophylaxis.⁶⁰ Universal prophylaxis or preemptive therapy is also recommended for lung transplant recipients, while targeted prophylaxis is favored for liver and heart transplant recipients.⁶¹ While prophylactic treatment significantly decreases the specificity of mould-specific Aspergillus PCR, it does not impact sensitivity, suggesting the need for caution in interpreting PCR results in a patient already on mould prophylaxis.⁶²

MP is associated with high mortality rates, and beginning treatment early has been associated with improved outcomes, especially in high-risk patients.⁸ By definition, targeted therapy occurs late in disease development since it implies that the target (causative organism) has been identified. Based on epidemiology alone, a neutropenic patient with a pulmonary nodule should be started on voriconazole, but if BAL or biopsy shows aseptate hyphae, they should receive mucormycosis-specific targeted therapy such as amphotericin B (preferably the liposomal formulation), isavuconazole, or posaconazole.

The panelists strongly recommend identifying fungi at the species level, if possible, and stressed the importance of microscopy and dedicated fungal cultures. Findings from both methods should be cross-referenced to confirm the clinical significance of the fungi isolated from culture and seen in tissue.^63,64 Filamentous hyphae in biopsy tissue or other relevant clinical specimens are sufficient to start anti-fungal therapy.⁶⁵ However, cultures allow susceptibility testing to be performed if a fungus is grown, and identification to species level permits interpretation of susceptibility results. Even in the absence of susceptibility results, species identification alone may guide treatment decisions, eg, A. terreus is known to be inherently resistant to amphotericin B.

Voriconazole, isavuconazole, and posaconazole are commonly recommended as first-line treatments for IA and other mould infections due to their broad-spectrum activity and favorable safety profiles.^66,67 Voriconazole has higher response rates than amphotericin B deoxycholate and fewer severe drug-related adverse events in IA, and isavuconazole is an effective alternative for treating both aspergillosis and mucormycosis.⁶⁸ An evaluation of triazole susceptibility in 372 invasive moulds in the Asia-Pacific region collected between 2011 and 2019 demonstrated comparable activity of mould-active triazoles against most Aspergillus species.⁶⁹

In a recent network meta-analysis, it was reported that isavuconazole and posaconazole are similarly efficacious to voriconazole.⁷⁰ Combination antifungal therapy with voriconazole and an echinocandin showed a trend toward improved survival in IA, with the post hoc subgroup analysis of a randomized controlled trial suggesting potential benefit in patients with probable IA based on GM positivity (which may be a function of the certainty of diagnosis). However, the study lacked adequate power due to higher than expected mortality and smaller treatment differences, precluding definitive conclusions and requiring confirmatory studies.⁷¹

Triazole antifungals carry significant adverse effects and drug interactions, which should be considered carefully by clinicians and necessitate the use of therapeutic drug monitoring.^72,73 Triazoles can cause hypokalemia, which is a significant concern for patients with pre-existing metabolic conditions.⁷² Triazoles, especially voriconazole, can also lead to liver dysfunction, making them difficult to use in patients with existing liver disease or those at risk of hepatic impairment.^72,73 Prolongation of the QT interval is a rare but serious side effect of some triazoles, including fluconazole, itraconazole, voriconazole and posaconazole, and a baseline ECG is important.⁷² Long-term voriconazole use has also been associated with fluorosis and an increased risk of cutaneous squamous cell carcinoma in individuals with a lung transplant or hematopoietic cell transplant.^74,75 Finally, the safety of triazoles in pregnant or lactating women is not well established, and their use is generally contraindicated unless absolutely necessary.⁷⁶

Combining antifungal therapy with surgical debridement is considered the most effective approach to managing IPM.⁷⁷ Addressing underlying comorbid conditions, such as diabetes, neutropenia, or immunosuppression, is crucial in disease management, including adjusting immunosuppressive therapy or managing metabolic conditions to reduce the risk of infection progression.

Amphotericin B, particularly in its liposomal form, is recommended for treating azole-resistant or azole-intolerant IA. This recommendation is supported by various studies highlighting its efficacy against azole-resistant strains of A. fumigatus, a common causative agent of IA. Liposomal amphotericin B is particularly advantageous due to its broad antifungal spectrum and reduced toxicity compared to traditional formulations. In clinical settings, liposomal amphotericin B has been used successfully in cases of azole-resistant central nervous system aspergillosis, where it was administered both intravenously and intraventricularly, leading to patient survival despite the resistance.⁷⁸

Amphotericin B treatment requires intensive monitoring due to potential side effects, and its use is often limited to IA cases where azoles are not viable options due to resistance or intolerance.⁷⁹ Indeed, the 2016 IDSA practice guidelines recommend using amphotericin B deoxycholate in resource-limited settings.³ Despite the superior safety profile of liposomal formulations, many LMICs continue to predominantly use amphotericin B deoxycholate due to the high cost of liposomal amphotericin B and limited availability of generic formulations.^23,80

Amphotericin B deoxycholate remains widely accessible in Asia, with 61% of 235 clinics that responded to a survey by the European Confederation of Medical Mycology and ISHAM reporting availability of the deoxycholate formulation, compared to 57% having access to liposomal amphotericin B and 29% to amphotericin B lipid complex.¹⁰ In Thailand, amphotericin B deoxycholate is still predominantly used over liposomal amphotericin B except in patients with contraindications [Chayakulkeeree M, personal communication]. Meanwhile, the public sector in Malaysia purchased 29 457 vials of amphotericin B deoxycholate in 2021 at ∼USD8 per vial compared to only 28 vials of liposomal amphotericin B at ∼USD91 per vial, demonstrating the significant barrier to access as a result of high drug costs.⁸⁰

Liposomal amphotericin B is the preferred first-line treatment over conventional amphotericin B for IPM, with the recommended dosage depending on disease severity.^77,81 It is favored over conventional amphotericin B due to its improved safety profile, particularly regarding nephrotoxicity, which is a significant concern.^82,83 Some studies have shown that the liposomal formulation is associated with better clinical outcomes, likely because of better tolerability, less toxicity (specifically reduced kidney function), and fewer treatment interruptions.^84–86 However, multiple systematic reviews have concluded that despite differences in safety profile, both formulations of amphotericin B are comparable regarding favorable clinical outcomes (e.g., cure rates and patient survival).^87,88

Ultimately, owing to its significantly improved toxicity profile, liposomal amphotericin B should be considered whenever it is available to replace deoxycholate. Specifically, efforts should be taken to make the liposomal formulation available, since many patients cannot tolerate high-dose deoxycholate amphotericin B, particularly those with diabetes and nephropathy. Amphotericin B deoxycholate can be administered with certain precautions for two weeks, followed by treatment with azole derivatives. After initial treatment with liposomal amphotericin B, step-down therapy with oral antifungals such as posaconazole or isavuconazole is recommended to prevent relapse and ensure the resolution of the infection.^89,90 Posaconazole and isavuconazole are also considered for salvage therapy in cases where the infection is refractory to initial treatment.⁹¹

In a Brazilian modeling study, conventional amphotericin B was found to be the most cost-effective, followed by liposomal amphotericin B and amphotericin B lipid complex.⁹² A modeling study in the United States found that in adult patients refractory to or intolerant of conventional amphotericin B, the liposomal formulation was more cost-effective than the lipid complex formulation.⁹³

There is substantial variation in the availability of diagnostic tests and treatments for IMI in hospitals and clinics throughout Asia. A recent survey of 235 medical centers in Asia revealed that most institutions had access to microscopy (98%) or culture-based diagnostic approaches (97%), and fewer had access to antigen detection (79%), molecular assays (66%), and antibody tests (63%).¹⁰ For the antifungal therapies, triazoles were accessible at 93% of institutions, but each therapeutic agent varied in its availability (78% of centers had access to voriconazole, 33% to isavuconazole, and 51% to posaconazole).¹⁰ Countries with higher gross domestic products generally had more access to specific antifungal agents (including triazoles) and therapeutic drug monitoring.¹⁰

PCR tests are broadly available in countries that are not resource-limited, although perhaps not mould-specific PCR. Notably, the utility of PCR testing was debated in the current IDSA guidelines.³ PCR tests, either those commercially available or developed in-house, should be appropriately validated and approved by local accreditation agencies.

The panelists emphasized the importance of monitoring the presence and emergence of new antifungal species in the region. Antifungal surveillance is a critical tool for tracking the prevalence of uncommon fungal species and increasing antifungal resistance worldwide. Even though some data from the SENTRY surveillance program have been published, data comparing results across many Asian countries remain scarce.⁶⁹

Triazole resistance and case study

Along with the consensus statements on treating unknown MP, IPA, and IPM, we wanted to provide recommendations for addressing and overcoming triazole resistance. Triazole resistance in treating MP, mainly caused by Aspergillus, is a growing concern in medical mycology.⁹⁴ Patients with triazole-resistant infections have significantly higher mortality rates compared to those with susceptible infections.^95,96 The primary resistance mechanism involves mutations in the gene encoding the triazole target enzyme for triazoles, reducing drug binding and efficacy.⁹⁷ Other resistance mechanisms include excessive use of azoles in agricultural production and prolonged azole exposure.⁹⁴

Triazole resistance rates in Asia are lower than in other geographic regions,⁹⁸ with an estimated prevalence between 1.9% and 11%, likely due to reduced agricultural usage.⁹⁹ However, there are notable gaps in our understanding of triazole resistance. These include a lack of a unified definition of resistance, limited published information in some geographical regions, and additional resistance mechanisms.¹⁰⁰

In cases of resistance, alternative treatments such as liposomal amphotericin B or combination therapies with echinocandins are recommended.⁹⁵ Liposomal amphotericin B is generally recommended with suspected or confirmed triazole resistance due to its broad-spectrum effectiveness.¹⁰¹ Combining triazoles such as voriconazole or posaconazole with echinocandins has shown promise in treating resistant infections and reducing the likelihood of resistance development.¹⁰¹ Although azole resistance is uncommon in some regions, its emergence highlights the need for ongoing surveillance and may influence future treatment guidelines.¹⁵ Resistance testing is recommended to guide appropriate treatment, especially in regions with high resistance rates.⁹⁵

We present a case highlighting the importance of liposomal amphotericin B in MP with unknown causative agents. A 52-year-old male patient with a medical history significant for diabetes mellitus and hypertension presented with a fever and a productive cough that had persisted for 40 days. He had a recent medical history of COVID-19 infection, which occurred one month before the onset of his current symptoms. During his COVID-19 management, he was treated with dexamethasone at a dosage of 6 mg per day for 22 days. Laboratory findings revealed a serum GM level of 0.45, an HbA1c of 12%, and positive sputum culture results for Pseudomonas aeruginosa. Additionally, a sputum fungal smear showed aseptate hyphae, and fungal cultures indicated the growth of both Aspergillus species and a mucoraceous fungus. Imaging studies demonstrated a cavity and consolidation in the lungs’ right upper and middle lobes (Fig. 1).

Figure 1.

Low- and high-powered histopathology images of pulmonary aspergillosis and mucormycosis dual infection. (A) Periodic acid-Schiff staining showing fungal colonies consistent with Aspergillus, (B) fungal colonies with Aspergillus (green arrow) and Mucorales (yellow arrow), (C) high-powered image showing Aspergillus (green arrow) and Mucorales (yellow arrow), and (D) high-powered image showing fungi consistent with Mucorales.

The management strategy for this patient involved initiating treatment with liposomal amphotericin B at a dosage of 3 mg/kg for 19 days, followed by surgical intervention in the form of a pneumonectomy. The final infectious disease diagnoses in this diabetic patient were community-acquired pulmonary mucormycosis and community-acquired pulmonary aspergillosis.

This case highlights the complex interplay between diabetes, recent COVID-19 infection, and the subsequent development of pulmonary fungal infections. The dual infections of aspergillosis and mucormycosis are a rare but serious condition. Several case studies have documented similar dual infections, most using liposomal amphotericin B as an effective treatment method.¹⁶,^102–107 In this case, the patient’s underlying health conditions significantly increased his susceptibility to opportunistic infection, underscoring the importance of liposomal amphotericin B in treating severe pulmonary infections in immunocompromised patients.

Special considerations in resource-limited settings

IMIs present significant diagnostic challenges in resource-limited settings in Asia due to a combination of factors, including limited access to advanced diagnostic tools and a lack of comprehensive epidemiological data. The diagnosis of IMIs relies heavily on imaging, histopathology, and microbiological tools, including culture and PCR, which are often not readily available or are cost-prohibitive in these regions.^108,109 In many Asian countries, the lack of awareness among healthcare providers and the absence of rapid diagnostic tests exacerbate these challenges, leading to delays in diagnosis and treatment.¹⁰⁸ To address these diagnostic issues, there is a call for developing point-of-care tests, healthcare worker training, and integrating fungal infection management into existing national health programs.^110,111

In addition, as mentioned above, guideline-recommended anti-fungal treatments can be inaccessible due to financial constraints and supply issues.¹⁰⁸ Proposed solutions include optimizing drug costs through access-related initiatives, developing guidelines specifically for managing IMIs in resource-limited settings (such as the consensus statements described here), and advocating for the usage of WHO-recommended antifungal agents.¹¹¹ Overall, a multifaceted approach that improves diagnostic capabilities, enhances treatment accessibility, and increases awareness and education among healthcare providers is essential for effectively managing IMIs in resource-limited settings in Asia.

Limitations of the study

This study has limitations. Although the AFWG panel comprised 14 specialist physicians from different parts of Asia, not all countries were represented (and panelist membership is not proportional to the population size of their respective regions). Due to the relatively small number of panelists, there is insufficient data to provide qualitative socioeconomic or geographical analyses of the voting results. Finally, although all qualitative summary statements were reviewed and approved by the steering committee before finalization, additional rounds of voting may have expanded the questionnaire coverage and provided a better understanding of non-consensus answers.

In conclusion, the AFWG used a Delphi-based methodology to generate consensus statements on the epidemiology, diagnosis, and treatment of IPA and IPM. By unifying diverse perspectives on significant clinical challenges, in conjunction with the detailed commentary and case study, these statements will hopefully provide regional mycologists and infectious disease specialists with the best available knowledge to improve disease management and treatment outcomes.

Ethical statement

The authors confirm that the study described in this manuscript adheres to the journal’s ethical policies, as noted on the journal’s author guidelines page. This study, which generated a consensus statement from anonymous responses using the Delphi-based methodology, meets the criteria for minimal-risk research and qualifies for exemption under Category 2(i) of the Revised Common Rule 45 CFR 46.104(d).

Author contributions

Methee Chayakulkeeree (Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Writing—original draft, Writing—review & editing), Ban hock Tan (Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Writing—original draft, Writing—review & editing), Yee-Chun Chen (Conceptualization, Data curation, Investigation, Supervision, Validation, Writing—original draft, Writing—review & editing), Atul Patel (Data curation, Investigation, Validation, Writing—original draft), Ruo Yu Li (Data curation, Investigation, Validation, Writing—original draft), Ariya Chindamporn (Data curation, Investigation, Validation, Writing—original draft), Mitzi Chua (Data curation, Investigation, Validation, Writing—original draft), Kauser Jabeen (Data curation, Investigation, Methodology, Validation, Writing—original draft), Lan Phu Huong Nguyen (Data curation, Investigation, Validation, Writing—original draft), Lee Lee Low (Data curation, Investigation, Validation, Writing—original draft), Pei-Lun Sun (Data curation, Investigation, Validation, Writing—original draft), Retno Wahyuningsih (Data curation, Investigation, Validation, Writing—original draft), Li-ping Zhu (Data curation, Investigation, Validation, Writing—original draft), and Arunaloke Chakrabarti (Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Writing—original draft, Writing—review & editing)

Declaration of interest

The authors declare no conflicts of interest with respect to the work undertaken for this study.