Filamentous Fungi in Respiratory Infections. What Lies Beyond Aspergillosis and Mucormycosis?

Abstract

Respiratory tract infections are globally responsible for one-third of infectious disease–associated mortality, accounting for 4.3 million annual deaths. Among these, fungal infections of the respiratory tract are largely unrecognized, and the true burden is elusive [1]. Despite treatment, most invasive fungal infections are associated with high mortality rates of >50% [2]. In general, fungal infections of the respiratory tract are considered synonymous with invasive pulmonary infections caused by Aspergillus spp. and in some centers by Mucorales. However, over the last decade, a number of uncommon filamentous fungi, such as Scedosporium, Fusarium, Penicillium, melanized moulds, and basidiomycetes, have emerged as etiological agents of well-characterized respiratory disorders. It is therefore that the term “respiratory mycosis” has now broadened to include not just invasive disease but also lesser-recognized entities such as fungal ball, severe asthma with fungal sensitization (SAFS), fungus-associated chronic cough (FACC), allergic bronchopulmonary mycosis (ABPM), and allergic fungal rhinosinusitis (AFRS) [3–6]. Notably, both FACC and SAFS have recently been recognized as distinct clinical entities [7,8]. The former manifests as chronic intractable cough in response to pharyngeal colonization by filamentous basidiomycetes, which has been associated with allergic sensitization [7]. The latter, on the other hand, is a reference to poorly controlled asthma, despite optimal management, with evidence of fungal sensitization (short of being labelled ABPM) [6]. Aspergillus spp. are considered to be the major culprit of SAFS, although a range of other fungi, such as Alternaria and Cladosporium spp., are also involved [8]. Both conditions respond favourably to oral antifungal agents, thereby proving a definite role of fungi [9,10]. Moreover, new pathophysiological associations hitherto unknown, such as fungal sensitization and ABPM in patients with chronic obstructive pulmonary disease (COPD), are unfolding [11,12]. Further, emergence of resistance in filamentous fungi to azole antifungal drugs used as mainstay of therapy is another challenging scenario witnessed in the last two decades. This emerging problem is primarily attributed to the widespread usage of azole fungicides in the environment for agricultural and material preservation practices [13]. Here, we aim to provide an overview of the ever-expanding spectrum of human respiratory mycoses and the fungi involved, excluding Aspergillus and Mucorales.