This study documents the epidemiology of aspergillosis in cirrhotic patients over an 11-year period. We observed that (1) Aspergillus sp. lower respiratory tract specimen culture was positive in 6% of cirrhotic patients admitted to the liver ICU, and (2) COPD was a risk factor for IPA in patients when respiratory samples were positive in culture for Aspergillus sp. In addition, our results led us to consider this infection as more common and as being associated with high hospital and 1-year mortality rates.
IPA is an infection that mainly occurs in patients with neutropenia, receiving immunosuppressive therapy in the context of solid organ transplant or haematological malignancies. Aside from these high-risk groups, many cases of IPA have been reported in non-traditional hosts, especially cirrhotic patients [8, 9, 11]. In this era of advanced organ-targeted therapy in critical care, we know that the key to improve ICU survival in cirrhotic patients is to adopt a more aggressive management [20, 21]. For some years now, more patients with cirrhosis are being admitted to ICU, pathophysiology of cirrhosis is better understood, and new therapies are available [22]. In our experience, the number of cirrhotic patients admitted in ICU increases, in an order of 5–10% each year. Our findings concerning the incidence of aspergillosis colonisation are consistent with previously published data [12, 13, 23, 24]. Indeed, the rate of fungal colonisation can reach 25% in critically ill cirrhotic patients, with Aspergillosis up to 3% [25]. Further, the data regarding the incidence of IPA ranged from 0.288% in a tertiary centre in China [8] to 16% among patients with severe alcoholic hepatitis [10]. According to our result, the alcoholic cirrhotic patients with organ failure and having a COPD comorbidity is at high risk of Aspergillus colonisation.
In a context of Aspergillus sp.-positive cultures, discriminating between colonisation and infection remains challenging. According to the European Organisation for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG), IPA is categorised as a proven, probable or possible fungal infection [26]. This categorisation requires histopathological evidence or the presence of a combination of host factors, clinical and radiological features and positive mycology. However, in most ICU patients, the entry criterion is an positive Aspergillus culture in lower tract. A simple clinical algorithm has thus been proposed to discriminate Aspergillus sp. respiratory tract colonisation from putative IPA [18]. During our study, we chose to use this algorithm to evaluate the incidence of IPA in cirrhotic patients and found that among 60 patients with an Aspergillus-positive culture, nearly one in three had an IPA. Because of the high mortality associated with IPA, it could be important to identify the risk factors for this condition. Early diagnosis and prompt antifungal therapy may improve the outcome. Also, a history of COPD, in our study, was the only factor associated with IPA in cirrhotic patients with positive Aspergillus cultures in respiratory samples. A baseline MELD score > 24 and corticosteroid therapy have both been identified as risk factors for IPA [10]. In our experience, neither the mean MELD score nor the number of patients with a MELD score > 24 were different between the group with IPA and those with the colonised group. In addition, the notion of immunosuppressive treatment (p = 0.09) was not IPA risk factors. These conflicting results may be due to the population studied. Gustot et al. [25] included all cirrhotic patients and compared patients with and without IPA, while we studied cirrhotic ICU patients with a positive Aspergillus culture and compared those with IPA and those only colonised. However, even though it was not statistically significant, more patients in the IPA group received immunosuppressive treatment (41% vs. 19%) and the need of mechanical ventilation was higher (71% vs. 44%).
We found that patients with COPD have an increasingly recognised risk of developing IPA [27,28,29]. This can be explained by the fact that cirrhotic and COPD patients have a greater susceptibility to IPA, as impairment of the defence mechanisms in the airways, repeated short-term use of corticosteroids, frequent hospitalisation and broad-spectrum antibiotics with pathogen selection and conditions for comorbidity. We did not find an association between IPA and the presence of other pathogens (such as H1N1 infection). This result may be at odds with our previous observation [29]. Indeed, in seven patients with liver disease an association between co-infection by A. fumigatus and S. maltophilia has been observed [30]. However, in this previous work, we were not able to distinguish between S. maltophilia infection and colonisation, which made it difficult to reach conclusions on the specific role of the bacterium in the respiratory pathology.
The mortality rate in cirrhotic patients with IPA exceeded 50% in an overview report [22, 31] even though there has been a trend in recent years towards a decline [9]. In our series, hospital mortality was higher among IPA patients than in those colonised by Aspergillus. However, this difference was not observed at 1 year, probably because the mid-term prognosis of cirrhotic patients with organ failure and hospitalised in the ICU is poor at 1 year, with or without infection [19]. The poor prognosis of IA in cirrhotic patients may be explained by a higher immunosuppression state in patients with end-stage liver disease, the late diagnosis or/and lower efficiency of antifungal therapy used in the context of multiorgan failure.
More studies are necessary in order to improve estimates concerning the survival rate of patients with IPA and cirrhosis. Meanwhile, because IPA in cirrhotic patients is associated with high mortality, a prophylactic strategy, especially in patients with severe alcoholic hepatitis that have an incidence of 15.8% [10], could be proposed as soon as when Aspergillus-positive samples are found, and might be more effective than a therapeutic approach. This also needs to be evaluated.
The retrospective nature of our study was its first limitation, with a certain bias affecting the reports (e.g. a greater tendency to search for Aspergillus over time). Indeed, we observed a rise in the incidence of Aspergillus respiratory tract colonisation and IPA as the study period advanced. Our study is not supposed to describe the epidemiology of aspergillosis in cirrhotic but describe the characteristics and outcome of cirrhotic patients with positive Aspergillus culture. If we consider that patients without respiratory samples do not have IPA, a positive culture of Aspergillus spp. and proven or putative IPA were found in, respectively, 6% and 1.7% of cirrhotic patients admitted to the ICU. Secondly, although cirrhosis is associated with a state of immunodeficiency, it is not recognised as a risk factor according to the EORTC/MSG criteria. In ICU patients, Blot et al. observed that only 41% were immunocompromised and proposed to use as criteria either the presence of a host risk factor or a semi-quantitative Aspergillus-positive culture of BAL fluid. In our study, 15 patients had host risk factors (immunosuppression treatment in the severe hepatitis alcoholic context or autoimmune cirrhosis [10]) and five had an Aspergillus sp.-positive culture of BAL fluid in the IPA group. However, in light of a review of aspergillosis cases described in cirrhotic patients [31], we believe that cirrhosis could be seen as a host risk factor. In our study, however, even if cirrhosis had been considered as a host risk factor in the colonisation group, no patients had compatible signs or symptoms or/and abnormal medical imaging findings that enabled a diagnosis of IPA. Thus, we think that decompensated cirrhosis should be added to the list of host risk factors in the algorithm developed by Blot et al. [18].
In conclusion, our study was able to confirm that the occurrence of IPA or respiratory tract colonisation by Aspergillus sp. in cirrhotic patients is increasing in the past 10 years, probably in relation to the number of cirrhotic patients admitted in liver ICU. In addition, following the publication of Gustot et al. [10], we were sensitised to this infection, with more frequent research. Moreover, this Aspergillus infection is associated with higher mortality. Based on our results, we recommend that cirrhotic patients with sepsis admitted to ICUs should be screened for fungal infections (bronchial aspiration, chest CT, biological markers, etc.), especially in cases of strong suspicion (hepatitis alcoholic, fewer persistence, etc.). This could also be useful to obtain an early diagnosis of IPA and a swift treatment of this complication, particularly in cirrhotic patients with COPD.