Allergic diseases and fungal exposome: prevention is better than
cure
Jean-Pierre GANGNEUX*1, Cendrine
GODET2, David W. DENNING3
1. Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche
en santé, environnement et travail) – UMR_S 1085, 35000 Rennes, France
2. Assistance Publique - Hôpitaux de Paris, Hôpital Bichat, Service de
Pneumologie, Paris, France
3. Manchester Fungal Infection Group, Core Technology Facility Grafton
Street, University of Manchester, Manchester Academic Health Science
Centre, Manchester, UK
ORCID ID JPG : 0000-0001-5626-2251
ORCID ID DWD : 0000-0002-4974-5607
* Corresponding author: Prof Jean-Pierre GANGNEUX
e-mail :jean-pierre.gangneux@chu-rennes.fr
Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en
santé, environnement et travail) – UMR_S 1085, 35000 Rennes, France
Fungal exposure can result in a wide spectrum of diseases from
infections to intoxication and allergy. The burden of fungal diseases
has long been neglected and includes not only individual and societal
impacts in terms of morbi-mortality but also major healthcare costs. The
global burden of allergic broncho-pulmonary aspergillosis (ABPA) could
probably exceeds 4.8 million people worldwide (given its high frequency
in the India sub-continent), but prevalence field studies on allergic
fungal diseases such as ABPA or severe asthma with fungal sensitization
(SAFS; also called “fungal asthma”) are few (1). Knowledge of which
airborne fungi, determination of the fungal exposome and fungal disease
itself are all necessary to optimize diagnosis and management. Joana
Vitte and colleagues propose a very informative review in this issue
summarizing fungal allergic diseases and the unmet needs for diagnosis
and management (2). Among them, the authors underline the significance
of fungal sensitization on lung function and its prevalence, and call
for optimization of measurement tools from standard culturomic to
high-throughput biological and biostatistical methods.
Because fungal exposome is universal, including not only indoor and
outdoor air but also our microbiota, we must prioritize research in this
topic in the 21st century to intelligently fight both
direct but also indirect impacts of fungal exposure. In particular
evaluation of prevention strategies should be a cornerstone for a better
outcome of fungal respiratory diseases that should be considered both by
public health, but also in planning and optimizing the indoor built
environment. Recent awareness of the strong links
between Aspergillus airway infection/colonization and/or
sensitization and asthma severity and exacerbations, COPD exacerbations
and bronchiectasis, worse lung function in CF patients and after
tuberculosis, some or all of which could be amenable to antifungal
therapy, or prevented or improved with exposure reduction.
Two major prevention strategies for allergic fungal respiratory diseases
may be identified (Fig. 1):
(i) Environmental prevention . Multiple and repeated exposures to
fungal exposome may contribute to sensitization, fungal asthma and an
increase in severe asthma-related complications (3). Environmental
prevention has been demonstrated to prevent the onset of asthma and
secondary prevention can ameliorate asthma symptoms and prevent
exacerbations. Most individuals spend more than 50% of their time at
home and so minimizing dampness and fungal growth at home will improve
health and quality of life for chronic respiratory diseases (4). The
value of home interventions implemented by trained healthcare workers
and combining both education-based methods and a global allergen
avoidance method may offer an opportunity for control of asthma severity
for some patients, but prospective multicentric randomized studies are
still needed (5-6). In a similar way, identification and minimization of
at-risk exposures during school or work remains an active prevention
strategy for workers to improve quality of life and save healthcare
costs. Of course, air pollution control is an additional and mandatory
challenge, for all countries.
(ii) Pharmacological prevention with antifungals and/or
biologics. There are many indirect data indicating that early
recognition and management of exacerbation or relapse during ABPA, SAFS
or even chronic pulmonary aspergillosis can delay the onset of
bronchiectasis and chronic complications. Thus, an appropriate
antifungal treatment and maintenance therapy acting as secondary
prophylaxis is a good strategy to limit relapses and irreversible
sequelae. However, the scarce randomized clinical trials that evaluated
different approaches of maintenance therapy during ABPA or SAFS such as
oral azoles or nebulized liposomal-amphotericin B showed only trends of
clinical improvement (7-8). Of note, delayed occurrence of exacerbation
or relapse, or reduction of the number of exacerbation episodes are
clinical elements of major importance regarding patient comfort and
disease stability. The
variability
of individual response to long term maintenance antifungal therapy
creates clinical equipoise for further research. Identification of
outcome criteria such as disease stabililty rather than cure, and
quality of life rather than quantitative endpoints might be considered.
Besides, one challenge in real life conditions will be to select the
optimal antifungal drug and delivery system on a case-by-case basis
based on the structure of the underlying lung, the comorbidities of the
patient, and the pharmacological properties each. The goal to reach is a
target concentration in the different lung compartments such as lung
tissue, walls of cavity, fungus ball or epithelial cells, with very
different penetration between relatively avascular areas to mucus and
lipid-rich membranes of host cells. New antifungal drugs and especially
the new route of administration via nebulization are in clinical
development and have differing chemical and physical attributes
resulting in high local concentration, prolonged lung retention, slow
absorption and low plasma concentrations. There are three companies
developing inhaled azole antifungals currently. Topical antifungal
therapy is attractive as it minimizes the potential of systemic
toxicity, avoiding significant drug-drug interaction, while maximizing
exposure in the lung. Finally, another pharmacological prevention of
recurrent exacerbations could rely on anti-IgE or anti-Th2 biologics
(10). At present, there are few data and no comparative randomized
studies on prolonged treatment of ABPA or SAFS with biologics. Further
randomized trials are needed in order to evaluate the efficacy and
safety of such long term (and often expensive) biologics treatments,
that could be avoided with prevention or lower cost antifungals.
Primary and secondary prophylaxis are more elegant approaches than cure.
Modern environmental considerations and new promising antifungal drugs
and monoclonal antibodies give hope for more improved clinical outcomes
for those in need. Evaluation of preventive strategies is surely an
essential unmet need against fungal exposome!