Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study

Summary

Background

Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis.

Methods

We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with non-immunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group).

Findings

Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63–10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids.

Interpretation

Influenza was identified as an independent risk factor for invasive pulmonary aspergillosis and is associated with high mortality. Future studies should assess whether a faster diagnosis or antifungal prophylaxis could improve the outcome of influenza-associated aspergillosis.

Funding

None.

Introduction

Invasive pulmonary aspergillosis typically occurs in a severely immunocompromised host, and isolation of Aspergillus species in the immunocompetent host is mostly considered colonisation.1, 2 The 6-week mortality of invasive pulmonary aspergillosis is 20–30%3, 4 but is much higher in patients who are critically ill.4, 5 Influenza is a common viral respiratory tract infection. In a subset of patients with influenza, intensive care admission might be needed because of bacterial superinfection,1, 6, 7 but influenza itself can also cause severe acute respiratory distress syndrome (ARDS), which is associated with a mortality of 14–41%.8, 9

Influenza-associated aspergillosis was occasionally described decades ago, and several small case series have been reported in the past 5–10 years.1, 9, 10 65% of the reported cases did not have classic host factors for invasive pulmonary aspergillosis as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG).1, 11 These EORTC/MSG criteria are used to classify patients with a fungal infection into proven, probable, or possible aspergillosis but are not necessarily applicable to the intensive care unit (ICU) setting. For the ICU setting, an algorithm (AspICU algorithm) was described by Blot and colleagues¹² to distinguish invasive pulmonary aspergillosis from Aspergillus colonisation in patients who are critically ill.

Research in context

Evidence before this study

We searched PubMed for articles published between Jan 1, 1963, and Oct 31,2017, using the search terms “influenza” and “aspergillus” or “aspergillosis”. This search yielded case series which described invasive pulmonary aspergillosis in patients admitted to the intensive care unit (ICU) with influenza. Yet, a systematic evaluation of the risk of invasive pulmonary aspergillosis in a large population of ICU patients with influenza over several consecutive influenza seasons was missing. Also, it remained to be demonstrated if influenza was independently associated with aspergillosis.

Added value of this study

This study is, to our knowledge, the largest study ever performed on the risk for invasive pulmonary aspergillosis in 432 ICU patients with influenza. It is also the first to evaluate this complication over several consecutive seasons in a large number of ICUs. Furthermore, by comparing non-immunocompromised influenza-positive and influenza-negative patients, we aimed to show that influenza was an independent risk factor for invasive pulmonary aspergillosis. Several conclusions could be drawn. First, the incidence of invasive pulmonary aspergillosis was higher than 10% in each of the seven seasons and was almost equal in patients with influenza A and those with influenza B. Therefore, once a patient with influenza needs intensive care support, the risk for invasive pulmonary aspergillosis does not depend on the influenza season and influenza subtype. Second, the overall incidence of aspergillosis was 19% and was as high as 32% in the subgroup of patients who were also immunocompromised at the time of their influenza infection. The overall mortality in the patients with invasive pulmonary aspergillosis was very substantial at 51%. Finally, we compared 315 non-immunocompromised (ie, no EORTC/MSG host factor) influenza-positive patients with an equal number of non-immunocompromised influenza-negative patients with severe community-acquired pneumonia for the occurrence of invasive pulmonary aspergillosis. We showed that influenza was independently associated with invasive pulmonary aspergillosis (aOR 5·19, 95% CI 2·63–10·26, p<0·0001).

Implications of all the available evidence

The independent association between influenza and IPA and the high mortality, calls for increased awareness and a more aggressive diagnostic approach. Future studies should evaluate if prophylaxis is useful.

In 2012, Wauters and colleagues⁹ reported an incidence of 23% of proven or probable invasive pulmonary aspergillosis in 44 patients with H1N1 influenza in two consecutive influenza seasons (2009–11). Remarkably, 44% of patients with invasive pulmonary aspergillosis did not have any of the classical EORTC/MSG host factors. A Dutch study¹³ described 23 (16%) of 144 patients with invasive pulmonary aspergillosis who were admitted to the ICU with influenza during the 2015–16 influenza season. These observations suggest that influenza infection that requires ICU admission is a risk factor for invasive pulmonary aspergillosis and that incorporation of influenza as a host factor in the current diagnostic criteria might be appropriate. However, whether influenza is independently associated with the occurrence of invasive pulmonary aspergillosis and whether the risk varies from season to season remains unclear. This study aimed to describe the epidemiology and outcome of invasive pulmonary aspergillosis in patients admitted to the ICU over seven consecutive influenza seasons and to assess whether influenza was independently associated with invasive pulmonary aspergillosis.