Navigating invasive fungal infections in unconventional hosts — insights and strategies

At a recent symposium organized by Pfizer, in collaboration with the Society of Infectious Disease Singapore, A/Prof Carolina García-Vidal, Senior Specialist, Infectious Diseases Department at Hospital Clínic de Barcelona, Spain, shared valuable insights on managing invasive fungal infections (IFIs) in nontraditional hosts. The session was chaired by Dr Jasmine Chung, Senior Consultant and Director of the Antimicrobial Stewardship Unit, Singapore General Hospital.

IFIs in ‘other’ populations
Most pathogenic fungi thrive in opportunistic conditions, predominantly affecting immunocompromised individuals due to factors such as HIV infection, cancer, or transplantation. “Beyond the traditional risk groups, a rising concern is the susceptibility of non-haematology and nontransplant patients to IFIs,” Chung said. “Identifying, diagnosing, and treating these infections pose significant challenges.”

García-Vidal’s recent study at her institution revealed that 80 percent of IFI patients lacked haematological conditions, and almost 90 percent of those with fungal infections were non-neutropenic. Notably, corticosteroid use (41.4 percent) and prior viral infections (31.3 percent) emerged as the predominant risk factors for IFIs. Among aspergillosis cases, 15.3 percent had solid-organ malignancies affecting the bronchi, while 35 percent had chronic lung disease and other immunocompromised conditions. These findings underscore the need for a thorough re-evaluation of factors contributing to the high-risk profile for fungal infections. [Med Mycol 2023;61(3):myad021]

“Prior use of corticosteroids not only facilitates fungal infections due to immunosuppression, it also actively promotes fungal growth. Even brief periods of use elevate the risk for fungal infection,” García-Vidal explained. [Microbiology (Reading) 1994;140:2475-2479]

For decades, reports have highlighted the complication of severe influenza infections by invasive pulmonary aspergillosis even in immunocompetent patients, often leading to fatal outcomes. [JAMA 1979;241:1943-1944; Emerg Infect Dis 2010;51:971-973; Curr Infect Dis 2018;31:471-480]

In patients admitted to the ICU with influenza, approximately 20 percent may develop invasive pulmonary aspergillosis. Aspergillus-related conditions are associated with almost twofold mortality rate compared to those without the conditions. [Lancet Respir Med 2018;6:782-792]

“In periods of circulating respiratory viruses, including influenza, a lower airborne mould spore load was required for invasive aspergillosis [IA] to occur. Additionally, the time from spore inhalation to IA diagnosis was shorter, suggesting a rapid onset. [Clin Microbiol Infect 2014;20:O939-O945]

Optimal IFI diagnosis
Diagnostic approach for invasive aspergillosis in neutropenic vs non-neutropenic hosts
“In neutropenic patients, inhaled fungal spores rapidly transform into invasive hyphae, causing lung thrombosis and necrosis — a manifestation visible as a halo sign on CT scans (Figure 1A). Serum testing for galactomannan provides an indirect diagnosis. [Clin Infect Dis 2016;63:e1-e60; J Clin Microbiol 2017;55:2153-2161]

Conversely, non-neutropenic patients exhibit diverse CT scan manifestations, resembling pneumonia, with hyphae, spores, and immune cells present (Figure 1B). Bronchoalveolar lavage with calcofluor white staining offers a fast but low-sensitivity option. Culture remains crucial for diagnosis, especially amid evolving fungal epidemiology and resistance. Antifungigram, biomarkers, and DNA testing are recommended. [Rev Iberam Micol 2014;31:219-228; Thorax 2015;70:270-277]

García-Vidal also stressed the importance of clinical context. When patients with underlying conditions, such as viral infection, or corticosteroid use, exhibit signs of fungal infection, empirical treatment is crucial, she said.

Diagnosis of mucormycosis
Distinguishing between IA and mucormycosis is challenging due to clinical and radiological similarities. Mucormycosis is often underdiagnosed due to biopsy and culture difficulties. [Clin Infect Dis 2012;54:1629-1636] A recent study demonstrated the efficacy of quantitative polymerase chain reaction (PCR) for the early diagnosis of mucormycoses in Europe. [Clin Infect Dis 2022;75:777-785]

Expecting the unexpected: Case discussion
Overview: A 70-year-old male ex-smoker with a history of hypertension, presents with a 3-day history of fever, persistent cough, and dyspnoea. Blood tests reveal elevated markers: C-reactive protein (CRP) at 18 mg/dL, lactate dehydrogenase (LDH) at 384 U/L, ferritin at 3244 ng/mL, lymphocytes at 700/mm³, and D-dimer at 700 ng/mL. He is negative for SARS-CoV-2 PCR, but positive for influenza by PCR.

Treatment: Treated with oseltamivir, but vital signs deteriorate a day later, leading to severe respiratory failure (fraction of inspired oxygen (FiO₂), 70 percent). Urgent transfer to the ICU and mechanical ventilation ensue.

Diagnosis: A bronchoscopy reveals Aspergillus fumigatus in lung cultures, but the serum galactomannan test is negative. This disparity suggests lung-focused infection, prompting immediate intervention. Despite the absence of a serum marker, swift treatment is critical to avert potential fatality.

Timely treatment is crucial
Early diagnosis and treatment has a positive impact on survival in patients with pulmonary aspergillosis or mucormycosis. Patients treated promptly exhibit significantly better outcomes, with mortality rates less than half compared to those receiving delayed treatment. [Clin Infect Dis 2007;44:373-379; Respiration 1995;62:341-347; Clin Infect Dis 2008;47:503-509]

Role of isavuconazole
Isavuconazole, an extended-spectrum triazole, is approved for the treatment of IA and mucormycosis. The 2020 ECMM/ISHAM consensus guidelines recommend isavuconazole as one of the preferred options for patients with COVID-19-associated pulmonary aspergillosis. [Lancet Infect Dis 2021;21:e149-e162]

Isavuconazole offers pharmacokinetic advantages over voriconazole in treating fungal infections. Voriconazole exhibits significant plasma level variations due to high interpersonal and intrapersonal variability. Thirty percent of individuals are fast metabolizers, leading to inadequate drug levels after 5 days, while 20 percent are slow metabolizers, resulting in potentially toxic levels. In contrast, isavuconazole maintains consistent levels across individuals after 5 days, with a higher minimum concentration (around 3 mg/L), enhancing its comparative efficacy and safety [Mensa J, et al. Antimicrobial Therapeutics Guide 2023. 33rd Ed. https://axon.es/ficha/libros/9788488825322/guia-de-terapeutica-antimicrobiana-2023]

“This pharmacokinetic difference is crucial, particularly in lung infection treatment, where isavuconazole’s distribution surpasses voriconazole. Clinicians must consider these drug-specific variations when selecting the optimal treatment for lung-related fungal infections,” García-Vidal emphasized.

Additionally, isavuconazole demonstrates lower inhibitory potency against hepatic enzymes compared to other azoles, resulting in fewer drug-drug interactions, and eliminating the risk of QT prolongation. Unlike its counterparts, isavuconazole does not require monitoring of plasma levels for dose adjustments, and can be safely used in patients with predisposing factors for QT prolongation. [Rev Esp Quimioter 2023;36:236-258; Pharmacotherapy 2015:35:1037-51]

Safety and tolerability
In a phase III, double-blind study, isavuconazole exhibited superior safety compared with voriconazole, with lower frequencies of hepatobiliary (9 percent vs 16 percent), eye (15 percent vs 27 percent), and skin disorders (33 percent vs 42 percent). The incidence of drug-related adverse events was significantly lower with isavuconazole (42 percent vs 60 percent). [Lancet 2016;387:760-769]

Real-world data also showed that isavuconazole was well-tolerated in patients intolerant to other azoles, and resulted in an impressive 81 percent clinical response rate. Another study confirmed the long-term safety (≥6 months) of isavuconazole in patients with haematologic malignancy. [Clin Infect Dis 2016:63:1529-1530; Clin Infect Dis 2019;69:1624-1627]