Predictors for IAPA and poor outcome (multivariate analysis)
Asthma (OR 12.0 [95% confidence interval (CI) 2.1-67.2]) and days
of mechanical ventilation (OR 1.1 [95% CI 1.1–1.2]) were
independent predictors for IAPA (figure 2). IAPA (OR 28.8 [95% CI
3.3-253.4]), infection with influenza A (OR 3.3 [95% CI 1.4-7.8])
and illness severity (Simplified Acute Physiology Score, SAPS II) (OR
1.1 [95% CI 1.05-1.10]) were independently associated with poor
outcome (figure 2). IAPA was associated with significantly longer median
ICU-LOS (29 [95% CI: 11-17] days vs. 5 [95% CI: 4-8] days,
p<0.001; figure 3).
Discussion
This study on critically ill influenza patients in seven tertiary care
hospitals in Switzerland found an IAPA prevalence of 10.8% over two
influenza seasons. IAPA was independently associated with asthma and
duration of mechanical ventilation and was an independent risk factor
for poor outcome. Other independent predictors of poor outcome were
influenza A and higher SAPS II.
IAPA patients needed more and longer organ supportive therapies
including mechanical ventilation and vasoactive support and had longer
ICU-LOS. Complications and ICU-mortality were more frequent in IAPA.
To our knowledge, asthma was identified as an independent risk factor
for IAPA for the first time. This seems biologically plausible. Viral
infections like influenza can cause severe exacerbations in patients
with asthma and chronic obstructive pulmonary disease
(COPD)20,21. Standard treatment of bronchial asthma
consists of inhaled and/or systemic corticosteroids and inhaled
bronchodilators. Prednisone treatment within 28 days prior to influenza
infection has been recognized as a risk factor for developing
IAPA1 and corticosteroid treatment is a risk factor
for invasive fungal infection in lung disease22.
Corticosteroid treatment was also shown to cause a higher fungal burden
in the lung23. Therefore, application of inhaled
and/or systemic corticosteroids in asthma patients could explain the
higher risk for IAPA. Our data also show more frequent corticosteroid
treatment in asthma patients during hospitalization. In addition, asthma
patients have altered mucociliar clearance of the lung that explains
higher rates of fungal growth and colonization in these
patients24. High clinical suspicion, early and regular
screening for IAPA are therefore warranted in asthma patients.
Similarly, this underlines the importance of influenza vaccination for
patients with asthma as recommended in Swiss
guidelines25.
The colonization with Aspergillus spp. – a prerequisite for the
development of IAPA - likely occurs prior to ICU admission as suggested
by the POSA-flu trial, where posaconazole prophylaxis started on ICU
admission but failed to prevent IAPA or lower mortality in influenza
patients15. The authors therefore concluded that
development of invasive fungal disease occurs early after influenza
infection as 71% of IAPA cases were diagnosed within 24h of ICU
admission. This seems plausible since colonization withAspergillus spp. is a known risk factor for developing invasive
aspergillosis26. Identification of asthma as a risk
factor for IAPA further strengthens this pathophysiologic hypothesis
since asthma patients are frequently colonized with Aspergillusspp. 24, 27.
This study identified IAPA, high SAPS II and infection with influenza A
as predictors for poor outcome in critically ill patients with
influenza. High mortality in patients with IAPA has been reported by us
and others1, 14. Interestingly, influenza A was
associated with poor outcome that was also shown in a recent
meta-analysis of 14 studies of IAPA28. An association
of influenza A with an increased risk of bacterial respiratory
infections and mortality has been previously
suggested29-31, even though it was recently
challenged32.
The proportion of IAPA among influenza patients requiring ICU care in
Switzerland was similar in the 2017/18 and the 2019/20
seasons14 which were characterized by influenza B with
Yamagata (2017/18) predominance vs. similar presence of influenza
A(H1N1)pdm09 and B Victoria (2019/20). This is in line with previous
reports1, 12 suggesting that IAPA is not restricted to
a selected influenza seasons1.
This study is limited by its retrospective design. To optimize
pre-analytics and screening of IAPA in influenza patients a screening
algorithm was installed at the beginning of the influenza season 2019/20
in all participating ICUs. Despite the recommended screening algorithm
for IAPA, sampling of respiratory material and testing for GM was
underutilized. This could have resulted in an underestimation of IAPA
diagnosis and growth of Aspergillus spp. in respiratory samples
in the non-IAPA group. However, growth of Aspergillus spp. was
only observed in one patient in the non-IAPA group in which 59% had at
least one respiratory sample taken. We therefore assume that most IAPA
patients were correctly classified and identified and results can be
generalized to critically-ill influenza patients. Because the setting
was ICU-specific no conclusions can be made regarding IAPA in patients
in an ambulatory setting or hospitalized on the ward. Also,
generalizability of results is limited by small numbers of IAPA
patients. The observation of a higher risk of IAPA in asthmatic patients
does not prove causality and should be confirmed in larger preferably
prospective cohort studies.
Interpretation
In conclusion, our data stress the importance of diagnosing IAPA in
patients with influenza in the ICU. IAPA was a frequent complication of
influenza with high associated mortality, frequent need of organ
supportive therapies and longer stay in the ICU. Furthermore, asthma was
newly identified as a risk factor for IAPA. We call for increased
awareness of IAPA in critically ill asthma patients with influenza,
including more intense screening strategies. Prevention efforts through
influenza vaccination should be improved in asthma patients as well.