Influenza Coinfection: Be(a)ware of Invasive Aspergillosis.

To the Editor—Uyeki et al [1] recently published the 2018 update of the clinical practice guideline regarding the diagnosis, chemoprophylaxis, and institutional outbreak management of seasonal influenza. The document discusses several aspects related to influenza, including the occurrence and management of coinfections. Although the guideline is primarily aimed to guide US clinicians, the recommendations are implemented in many countries worldwide. We therefore draw attention to recent observations regarding invasive aspergillosis as coinfection in patients with severe influenza in some regions [2]. Although the guideline states that invasive fungal coinfection is rare in adults with influenza, 3 cohort studies performed in Belgium and the Netherlands showed that influenza-associated aspergillosis (IAA) had occurred in 16%–23% of influenza patients in the intensive care unit (ICU) [3-5]. The largest cohort study investigated 7 ICUs over a period of 7 flu seasons and showed that influenza and the use of corticosteroids before ICU admission were independent risk factors for IAA [5]. IAA was observed in every flu season and both in patients with influenza A and influenza B pneumonia [5]. The mortality of severe influenza patients with IAA was 51% compared with 28% in those without IAA [5]. Furthermore, IAA coinfection occurred in patients with a broad variety of underlying conditions, and up to 30% of patients had been previously healthy [4, 5].

Influenza virus has been shown to cause ulceration of the tracheobronchial epithelium, thus providing an opportunity for Aspergillus to cause invasive infection [6]. Indeed, up to 25% of patients with IAA present with Aspergillus tracheobronchitis, a manifestation of invasive aspergillosis where the infection is primarily confined to the tracheobronchial tree. Invasive Aspergillus tracheobronchitis is difficult to diagnose as the main radiologic feature is tracheal and bronchial thickening, and therefore visualization of epithelial plaques through bronchoscopy is the recommended diagnostic procedure [7].

The frequency of IAA may vary between geographic regions, but IAA cases have been reported in at least 16 countries, including the United States [8, 9]. Furthermore, the epidemiology of IAA may be underestimated due to cases remaining undiagnosed since respiratory deterioration is considered to be caused by bacterial coinfection rather than fungal infection and appropriate diagnostics are not performed. International surveys are needed to investigate diagnostic procedures commonly used in influenza patients with suspected coinfection and to determine the frequency of IAA. However, at this point, guidelines, such as the one published by Uyeki et al, should include the aforementioned observations to overcome lack of awareness of coinfection with Aspergillus in ICU patients with influenza.

Given the high mortality of IAA it is recommended to consider IAA as a possible cause of coinfection in adult patients with severe influenza irrespective of their underlying condition and to perform a diagnostic workup for invasive aspergillosis, including bronchoscopy and bronchoalveolar lavage (BAL) [10]. Microbiological analysis should include microscopy, fungal culture, and galactomannan testing of BAL and serum if BAL is not available. If any of these tests indicate the presence of Aspergillus, immediate antifungal therapy is indicated. This approach will help to diagnose and treat patients with IAA early and to determine the true epidemiology of this coinfection.