Invasive pulmonary aspergillosis in cirrhotic patients: analysis of a 10-year clinical experience

Patients with cirrhosis are at risk of developing infection, sepsis and sepsis-induced organ failure [1]. Indeed, about 30% of cirrhotic patients admitted to an intensive care unit (ICU) have acquired or will acquire infections, most frequently involving the respiratory tract, urinary tract or ascites [2]. This high incidence of infection can partly be explained by cirrhosis-associated immune dysfunction. This state of immunodeficiency is a complex multifactorial process resulting from bacterial translocation, with the continuous stimulation of immune system cells, deficiencies in the complement system, the downregulation of monocytes and depressed neutrophil phagocytosis [3]. Recent studies have shown that some opportunistic infections, such as Pneumocystis jirovecii and cytomegalovirus infection, are seen in this specific population [4, 5]. Increasing numbers of fungal infections are also being observed [6, 7]. Among these pathogens, Aspergillus species, especially in respiratory samples, have emerged as an important cause of life-threatening infections in cirrhotic patients [8–13]. In immunocompromised patients, neutropenia and/or undergoing hematopoietic stem cell or solid organ transplantation, invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality [14]. Because of a delayed diagnosis due to a low index of suspicion, the same prognosis has been reported in cirrhotic patients than in this critically ill non-neutropenic population [9, 10, 15]. Its clinical and radiological signs are usually non-specific or absent [16]. Fungal cultures provide limited information because upper airway colonisation is common. Finally, galactomannan antigen test in serum and bronchoalveolar lavage (BAL) still needs to be validated in non-neutropenic populations [17].

Given the paucity of available of data, the aim of our study was therefore to identify factors for IPA in patients with a positive Aspergillus sp. culture in respiratory samples, to analyse different rules for the diagnosis and to evaluate its impact on outcome.

Between January 2005 and December 2015, 9176 patients were admitted to the liver ICU in our institution. Among these, 986 (10.7%) had histologically proven or clinically diagnosed cirrhosis. The median age in cirrhotic population was 57 ± 12.3 years; 71% were men and their liver disease was most frequently alcohol related. The cumulative incidences of ICU and hospital mortality were 29% (285 out of 986) and 37% (364 out of 986), respectively. Three hundred and forty-one patients (34.5%) required mechanical ventilation for at least 48 h.

Positive Aspergillus patients characteristics

Finally, 60 patients fulfilled the study criteria (positive culture of Aspergillus sp.) and were included in this monocentric retrospective analyse. With the increase in the number of patients hospitalised in liver ICU between 2005 and 2015, the occurrence of IPA and/or respiratory tract colonisation by Aspergillus in cirrhotic patients has increased in the past 10 years (Fig. 1). The demographic features, risk factors and outcome data of the 60 patients included are summarised in Table 2. Overall, 85% of the patients were male and their median age was 55.4 ± 12.6 years. Their cirrhosis was alcohol related (42%) or viral related (38%). The most common primary diagnoses at ICU admission were sepsis (n = 24, 40%), acute variceal bleeding (n = 17, 28%) or hepatic encephalopathy (n = 12, 20%). Twenty patients (33%) were admitted with respiratory failure. Among the patients with alcoholic cirrhosis, 11 (18%) had histologically proven severe acute alcoholic hepatitis and had been treated with corticosteroids (with a duration of 7–13 days), during the 3 months prior to their hospitalisation in the liver ICU. In addition, four patients received immunosuppression treatment (steroids for autoimmune cirrhosis n = 2 and azathioprine for psoriasis n = 1 or CREST syndrome n = 1). The Child–Turcotte–Pugh scores of all patients were B or C (22% and 78%, respectively). The mean MELD score and SOFA score were 21 ± 11.2 and 9.8 ± 7.3, respectively. Forty-three patients (72%) fulfilled the criteria for Acute-On-Chronic Liver Failure. No patient had a history of fungal infection or fungal prophylaxis at the time of diagnosis.

Variables	Whole population n = 60	IPA n = 17	Aspergillus spp. colonisation n = 43	p value
Age (years), mean (SD)	55.4 (12.6)	56 (14.5)	55.2 (11.8)	0.64
Gender (male), n (%)	51 (85)	15 (88)	36 (84)	0.65
Aetiology of cirrhosis, n (%)				0.60
Alcohol	25 (42)	8 (47)	17 (40)
Viral	23 (38)	7 (41)	16 (37)
Other	12 (20)	2 (12)	10 (23)
Severe alcoholic hepatitis, n (%)	11 (18)	6 (35)	5 (12)	0.06
Comorbidities, n (%)
Diabetes	14 (23)	2 (12)	12 (28)	0.18
COPD	23 (38)	11 (65)	12 (28)	0.008
Smoking history	23 (38)	6 (35)	17 (40)	0.76
Heart disease	3 (5)	0 (0)	3 (7)	0.26
Immunosuppressive treatment	15 (25)	7 (41)	8 (19)	0.09
Ascites	24 (40)	9 (53)	15 (35)	0.19
Encephalopathy	17 (28)	9 (53)	8 (19)	0.007
Life support n (%)
Mechanical ventilation	31 (52)	12 (71)	19 (44)	0.06
Catecholamine	30 (50)	12 (71)	18 (42)	0.04
Renal replacement therapy	13 (22)	7 (41)	6 (14)	0.02
Liver support	7 (12)	4 (24)	3 (7)	0.07
Laboratory data, mean (SD)
INR	2.01 (1.64)	2.2 (1.5)	1.9 (1.7)	0.56
Serum bilirubin (µmol/l)	131 (159)	172 (169)	115 (154)	0.16
Serum creatinine (µmol/l)	155 (151)	180 (151)	145 (152)	0.14
Serum sodium (mmol/l)	135 (5.3)	134 (5.8)	135 (5.3)	0.61
Albumin (g/L)	31 (8)	34 .4 (8.6)	30.9 (7.9)	0.20
Leucocytes (/mm3)	10.9 (8.4)	13.8 (12.4)	9.9 (6.3)	0.69
Platelets (/mm3)	123 (81)	109 (69)	127 (85)	0.66
Prognostic score, mean (SD)
Child–Pugh score	11.2 (2.8)	11.8 (3.1)	10.8 (2.6)	0.17
SAPS II	46 (20)	48 (25)	45 (18)	0.32
MELD score	21 (11.2)	23.2 (13.3)	20.1 (10.4)	0.44
SOFA score	9.8 (7.3)	13.4 (8.5)	8.3 (6.4)	0.002
ACLF grade n (%)				0.17
ACLF grade 0	17 (28)	4 (24)	13 (30)
ACLF grade 1	11 (18)	1 (6)	10 (23)
ACLF grade 2	9 (15)	2 (12)	7 (16)
ACLF grade 3	23 (38)	10 (59)	13 (30)
Outcome, n (%)
Hospital mortality	20 (33)	12 (71)	8 (19)	< 0.001
One-year mortality	41 (68)	14 (82)	27 (63)	0.14
Liver transplantation	5 (8)	1 (6)	4 (9)	0.66

Significant parameters (p value < 0.05)

IPA invasive pulmonary aspergillosis, COPD chronic obstructive pulmonary disease, MELD Model of End-Stage Liver Disease, ACLF Acute-On-Chronic Liver Failure, ICU intensive care unit, SAPS II Simplified Acute Physiology Score

Outcomes

There was no difference between positive Aspergillus and negative Aspergillus in respiratory samples of patients regarding in-hospital mortality and number of liver transplantation (Table 1). Among the patients with positive Aspergillus, the overall hospital and 1-year mortality rates were 33% (20 out of 60 patients) and 68% (41 out of 60 patients), respectively (Fig. 2). The probability of hospital mortality was significantly higher among patients with IPA than in patients with colonisation [12/17 (71%) vs. 8/43 (19%), p = 0.0001]. However, no statistically significant difference in the 1-year mortality rate was observed between these two groups [14/17 (82%) vs. 27/43 (63%); p = 0.14]. In patients with IPA, 12 patients died during the hospital stay, among whom four before the diagnosis. For others, the time span between the diagnosis and death was 12 days (2–28). The main cause of death was multiple organ failure secondary to septic shock. Among these patients, five patients were listed for liver transplantation, but only one was transplanted (28 days after the IPA diagnosis) and then treated with voriconazole for 1 year.

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 [27–29]. 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.