Post-cardiac surgery fungal mediastinitis : clinical features, pathogens and outcome

doi:10.21203/rs.3.rs-2126203/v1

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Research Article

Post-cardiac surgery fungal mediastinitis : clinical features, pathogens and outcome

https://doi.org/10.21203/rs.3.rs-2126203/v1

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Journal Publication

published 06 Jan, 2023

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Objectives

The occurrence of mediastinitis after cardiac surgery remains a rare and severe complication associated with poor outcomes. Whereas bacterial mediastinitis have been largely described, little is known about their fungal etiologies. We report incidence, characteristics, and outcome of post-cardiac surgery fungal mediastinitis.

Methods

Multicenter retrospective study among 10 Intensive Care Units (ICU) in France and Belgium, of proven cases of fungal mediastinitis after cardiac surgery (2009–2019).

Results

73688 cardiac surgery procedures were reviewed, and of those, 40 patients developed fungal mediastinitis. Among them, five were supported with left ventricular assist device and five with veno-arterial ExtraCorporeal Membrane Oxygenation before initial surgery. Twelve patients received prior heart transplantation. Interval between initial surgery and mediastinitis was 38 [17–61] days. Only half of the patients showed local signs of infection. Septic shock was uncommon at diagnosis (12.5%). Forty-three fungal strains were identified: Candida spp (34 patients), Trichosporon spp (5 patients) and Aspergillus spp (4 patients). Hospital mortality was 58%. Survivors were younger (59 [43–65] vs 65 [60–73] yo; p = 0.013), had lower Body Mass Index (24 [20–26] vs 30 [24.5–32.7] kg/m²; p = 0.028) and lower Simplified Acute Physiology Score II score at ICU admission (37 [28–40] vs 54 [34–61]; p = 0.012).

Conclusion

Fungal mediastinitis is a very rare complication after cardiac surgery, associated with a high mortality rate. This entity should be suspected in patients with a smoldering infectious postoperative course, especially those supported with short or long-term cardiac devices, or following heart transplantation.

cardiac surgery

mediastinitis

nosocomial infection

healthcare-associated infection

fungus

Candida

Aspergillus

Trichosporon

Post-cardiac surgery fungal mediastinitis is a rare complication, mostly related to Candida species, with a mortality rate of 58%. Smoldering course should raise the possibility of fungal cause.

Our findings highlight the need for a high level of suspicion for fungal mediastinitis after cardiac surgery, especially in immunocompromised patients, such as heart transplant recipients. An empiric antifungal therapy should be discussed in these patients who have evidence of mediastinitis but negative bacteriological culture.

Postoperative mediastinitis is one of the most severe complications after cardiac surgery. The overall incidence of mediastinitis after sternotomy ranges from 0.25 to 5%¹, depending on both surgical procedure and patient’s conditions. Despite advances in cardiac surgery and perioperative care, mortality associated with postoperative mediastinitis remains high, ranging from 8 to 50% depending on the case mix^2,3. Although bacteria remain the most common cause of mediastinitis⁴, fungi are a rising cause of postoperative mediastinitis, with up to 5% of all cases of mediastinitis⁵. However, the true incidence of this disease is difficult to estimate, as most of data come from small cohort studies, and are either recorded as primary infection or coded as superinfection⁶. Compared to bacterial etiologies, fungal mediastinitis appears to be associated with a worse prognosis, leading to frequent systemic dissemination, increased duration of mechanical ventilation and greater mortality from multiple organ failure⁶. Those findings are in line with studies showing high morbidity and mortality in critically ill patients diagnosed with invasive candidiasis⁷. Other fungi, such as filamentous and emerging yeasts, have also been implicated in postoperative mediastinitis, but the rarity of those forms make their analysis difficult. So, data on prevalence, presentations and outcome of fungal mediastinitis are clearly lacking after cardiac surgery, making a real gap of knowledge in the fields of peri-operative care, cardiac surgery and infectious diseases.

Our multicenter study aimed to describe the characteristics of post-cardiac surgery fungal mediastinitis, to report associated morbidity and mortality and to identify potential factors associated with mortality from these infections.

Study design

Retrospective study in 10 ICU of cardiac surgery centers in France and Belgium.

Patients

We retrospectively screened patients admitted to ICU during 11 years (01.01.2009 to 30.01.2019).

Each case was extracted through medical charts, using the following keywords: “mediastinitis”, or “sternitis”, or “sternal osteomyelitis”, or “fungal infection”, or “fungemia”, or “deep surgical wound infection”, or “postoperative infection” and “cardiac surgery” and “sternotomy”.

Inclusion criteria were: patient over 18 years of age; patient undergoing cardiac or ascending aorta surgery with sternotomy; occurrence of a post-sternotomy mediastinitis according to the Amsterdam consensus definition and formal identification of a fungus within the surgical site⁸. Post-sternotomy mediastinitis was defined as an infection occurring within one year (regardless of whether an implant is in place or not), and infection appearing related to the operative procedure, with at least one of the following criteria : 1) patient has micro-organisms cultured from mediastinal tissue or fluid obtained during a surgical operation or needle aspiration, 2) patient has evidence of mediastinitis confirmed during a surgical operation or histopathological examination, 3) patient has at least one of the following signs or symptoms with no other recognized cause : fever (> 38°C), chest pain, or sternal instability; 4) at least one of the following : purulent discharge from mediastinal area, organisms cultured from blood or discharged from mediastinal area, radiological evidence of an infective process in the mediastinum.

Exclusion criteria were defined as follows: unproven mediastinitis, fungemia from other source, esophageal or cervico-facial surgery requiring sternotomy.

Variables and outcomes

The following variables were collected: EuroSCORE II⁹, timing of surgery (emergent, urgent, elective), type of surgery (coronary, valvular, ascending aorta surgery, heart transplantation or left ventricular assist device (LVAD) implantation), duration of procedure, duration of cardio-pulmonary bypass and aortic cross-clamping (in case of extra-corporeal circulation), SAPS II (Simplified Acute Physiology Score II)¹⁰ and SOFA (Sequential Organ Failure Assessment) scores at initial ICU admission, use of catecholamines, implantation of veno-arterial ExtraCorporeal Membrane Oxygenation (V-A ECMO), organ failure, mediastinitis and mycological data (type of fungus, species, resistance profile, associated fungemia), and antifungal treatment. Finally, hospital mortality was recorded.

Statistical analysis

Categorical variables are described as number and percentages, and continuous variables as median [interquartile range]. We compared survivors and non-survivors to identify variables associated with mortality. Comparisons between groups were made using chi-square test for categorical variables and by t-test or Mann-Whitney test for continuous variables. P-value < 0.05 was considered statistically significant. Analyses were performed using R statistical platform, version 3.0.2 (https://cran.r-project.org/).

Patient’s characteristics

During this 11-year study period, 40 patients with documented fungal mediastinitis were identified among 73688 cardiac surgery procedures, that is an incidence of 0.05% of procedures. Main characteristics are depicted in Table 1. Briefly, thirty-two (80%) were men, with a median age of 61 [25–79]. Main comorbidities were chronic heart failure (72%) and diabetes (50%). Five patients were supported with LVAD and 5 by peripheral VA-ECMO before initial surgery. The preoperative Euroscore II was 11.8 [4.2–21.2] % and initial ICU admission SOFA score was 9 [5–10]. Eighteen patients underwent coronary artery bypass graft (CABG) or valve replacement surgery, and 12 heart transplantation. Other procedures were LVAD implantation (n = 2), total artificial heart (n = 2) and thoracic paraganglioma removal requiring cardiopulmonary bypass (n = 1).

Table 1

Characteristics of patients with post cardiac surgery mediastinitis.
Baseline characteristics	n = 40
Age (yo)	63 [56–69]
Male	32 (80)
BMI (kg/m²)	26 [22.6–32]
Euroscore II (%)	11.8% [4.2–21.2]
SAPS II	44 [30–56]
Admission SOFA	9 [5.5–10.5]
Comorbidity, n (%)
Chronic heart failure	29 (72)
COPD	7 (17)
Chronic kidney disease	6 (15)
-Dialysis	1 (2.5)
Diabetes mellitus	20 (50)
-under insulin	10 (25)
Immunosuppression	5 (13)
-including heart transplant recipients	4 (10)
LVAD	5 (13)
Recent hospitalization (< 3 months)	22 (55)
Malnutrition	9 (23)
Active smoker	9 (23)
Timing of initial surgery, n (%)
Elective	12 (30)
Emergent	13 (32)
Urgent	15 (37)
Initial surgery, n (%)
CABG	9 (22.5)
Valve replacement	9 (22.5)
Combined (CABG + valve)	5 (12.5)
Heart transplantation	12 (30)
Other	5 (13)
Surgical procedure duration (min)	309 [233–437]
CPB duration (min)	144 [93–206]
ACC duration (min)	88 [61–147]
BMI, Body mass index. SAPSII, Simplified acute physiology score II. SOFA, Sequential organ failure assessment. COPD, chronic obstructive pulmonary disease. LVAD, Left ventricular assist device. CABG, Coronary artery bypass graft. CPB, cardiopulmonary bypass. ACC, Aortic cross clamping.
Data are expressed as number (percentage) or median [IQR], as appropriate.

Clinical presentation, diagnosis and impact of mediastinitis

Of all the cases, only 20 patients showed clinical local signs suggestive of mediastinitis (Fig. 1); the other cases were diagnosed following postoperative fever, raised biological inflammatory markers or positive cultures. Five of the remaining cases had a radiological diagnosis without clinical or biological symptoms. Septic shock was the primary clinical presentation for five patients (Table 2). The median interval between initial surgery and mediastinitis diagnosis was 38 [17–61] days; 22 patients were diagnosed during the initial ICU stay with a median interval of 27 [15–41] days, whilst patients who were diagnosed after ICU discharge had a median interval of 57 [42–150] days. Eight patients were supported with peripheral VA-ECMO when they developed mediastinitis, and 2 had LVAD. Nineteen patients developed septic shock after surgical treatment of fungal mediastinitis; seventeen patients required renal replacement therapy.

Table 2

Presentation of patients with post cardiac surgery fungal mediastinitis.
Presentation of mediastinitis	N (%)
Clinical signs
Local signs (inflammatory/purulent sternotomy)	20 (50)
Fever (temperature > 38°5C)	5 (13)
Septic shock	7 (18)
Biological signs
Biological inflammatory syndrome (WBC > 12 G/L)	7 (18)
Positive mediastinal culture	15 (38)
Imaging signs
Mediastinal collection on CT-scan	7 (18)
CT-scan: computed tomography scan; WBC: white blood cell.
Data are expressed as number (percentage).

In-hospital mortality was 58% (23 patients). After ICU discharge, hospital length of stay was 31 [21–49] days.

Microbiological documentation and pathogens

The microbiological documentation was obtained from intraoperative samples in 31 patients, trans-sternal puncture for 6 patients, superficial sampling for 2 patients and pericardial puncture for one patient. We identified 43 fungal strains among 40 patients, with 3 patients having co-infection with two species of Candida (Table 3). More than 80% of fungal strains were Candida spp, mainly Candida albicans. Among the patients infected with Candida spp, 8 were heart transplant recipients. Other strains were Trichosporon spp (5 cases, including 2 heart transplant recipients) and Aspergillus spp (4 cases, including 2 heart transplant recipients) (Table 3). Six strains were resistant to fluconazole (4 C. glabrata and 2 C. parapsilosis). Associated fungemia was present in 14 patients (35%).

Table 3

**Postoperative mediastinitis causative pathogens and time to diagnosis.** Data are expressed as number (percentage) or median [IQR], as appropriate.
Microbiological strains (total n = 43)	N (%)	Mortality (%)	Time to diagnosis (days)
-Candida spp	34 (85)	21 (61)	35 [16–57]
Candida albicans	19 (48)	9 (47)	41 [18–68]
Non albicans Candida	15 (3)	11 (80)	34 [15–46]
Candida parapsilosis	6 (15)
Candida glabrata	5 (13)
Candida tropicalis	2 (5)
Candida lusitaniae	1 (3)
Candida krusei	1 (3)
-Trichosporon spp	5 (13)	4 (80)	31 [18–61]
Trichosporon inkin	2 (5)
Trichosporon ashaii	1 (3)
Trichosporon undefined	2 (5)
-Aspergillus fumigatus	4 (10)	0 (0)	269 [217–318]

To note, delay between initial surgery and the diagnosis of fungal mediastinitis was longer in patients with Aspergillus spp mediastinitis, compared to Candida spp mediastinitis (269 [217–318] vs 35 [16–57] days, respectively, p = 0.05) (Table 3).

Antifungal and surgical treatment

Echinocandins were used as first line antifungal therapy in 23 (57%) patients, whereas 15 (37%) patients received azoles and 3 were treated with amphotericin B; one patient received initially a combination of azole and echinocandin (Table 4).

Table 4

**Antifungal and surgical treatment according to survival.** Data are expressed as number (percentage) or median [IQR], as appropriate.
Treatment and outcomes	Survivors (n = 17)	Non-survivors (n = 23)	p	OR
First line treatment, n (%)
Echinocandin	10 (59)	13 (56)	0.88
Azole	6 (35)	9 (39)	0.81
Amphotericin B	1 (6)	2 (9)	0.74
Intervention, n (%)
Redon vacuum	14 (82)	19 (83)	1
Open-chest	1 (6)	3 (13)	1
Mediastinal irrigation	1 (6)	4 (17)	0.62
Vacuum assisted closure	5 (29)	5 (22)	0.37
Organ dysfunction, n (%)
Norepinephrine administration more than 48h	14 (82)	18 (78)	0.26
Renal replacement therapy	3 (18)	14 (61)	0.002	7.2 [1.6–32]
Mechanical ventilation	6 (35)	15 (65)	0.05	3.4 [0.9–12.8]
Duration of mechanical ventilation (days)	12 [2–31]	25 [12–40]	0.17

Surgical treatment was performed in all but one patient, of which 33 had multiple high-vacuum redon catheters, four were left open-chest, ten had negative-pressure wound therapy and five had mediastinal irrigation. More than one surgical debridement was required for 20 patients (50%).

Trends in incidence of mediastinitis

Comparing the first and second half of the decade of this study (2009–2014 and 2015–2019), we found a 3-fold increase in the number of fungal mediastinitis cases during the second interval, i.e. 10 and 30 cases respectively, with corresponding mortality rates of 70% and 53%.

Survivors vs non-survivors

Considering baseline characteristics, survivors where younger (59 [43–65] vs 65 [60-72.5] yo; p = 0.013), had lower BMI (24 [20–26] vs 30 [24.5–32.7] kg/m²; p = 0.028) and lower SAPSII score at admission (37 [28–40] vs 54 [34–61]; p = 0.012). There was no statistically significant difference between the two groups regarding the type or length of surgery, or the surgical treatment used (Table 5).

Table 5

Parameters including baseline characteristics, microbiological identification, management and impact of mediastinitis in surviving and dead patients
Characteristics	Survivors (n = 17)	Non-survivors (n = 23)	p	OR
Age (yo)	59 [43–65]	65 [61–73]	0.013	1.1 [1.02–1.19]
Male	14 (82)	18 (78)	1
BMI (kg/m²)	24 [20–26]	30 [24.5–32.7]	0.028	1.21 [1.01–1.47]
Euroscore II (%)	12 [4.23–19.4]	11.7 [4.6–25]	0.84
SAPS II	37 [28–40]	54 [34–61]	0.012	1.07 [1-1.7]
Admission SOFA	9 [5–11]	9 [6–10]	0.93
Comorbidity n (%)
Chronic Heart failure	12 (70)	17 (74)	1
COPD	2 (11)	5 (21)	0.68
Chronic kidney disease	3 (18)	3 (13)	0.79
-Dialysis	1 (6)	0 (0)	0.42
Diabetes mellitus	8 (47)	12 (52)	0.75
-Insulin	5 (29)	5 (21)	0.57
Immunosuppression	3 (18)	2 (9)	0.63
Heart transplanted	2 (11)	2 (9)	1
Recent hospitalization (< 3 months)	10 (59)	12 (52)	0.68
Malnutrition	6 (35)	3 (13)	0.13
Active Smokers	4 (24)	5 (21)	1
Initial surgery
-Type of surgery, n (%)
CABG	3 (18)	6 (27)	0.52
Valve replacement	4 (24)	5 (22)	1
Combined (CABG + valve)	1 (6)	4 (17)	0.37
Heart transplantation	8 (47)	4 (17)	0.08
LVAD	1 (6)	1 (4)	1
Other	2 (12)	1 (4)	0.56
Surgery duration (min)	354 [281–397]	278 [172–457]	0.19
CBP duration (min)	186 [138–211]	133 [86–185]	0.19
ACC duration (min)	107[69–166]	87 [51–116]	0.09
BMI, Body mass index. SAPSII, Simplified acute physiology score II. SOFA, Sequential organ failure assessment. COPD, chronic obstructive pulmonary disease. LVAD, Left ventricular assist device. CABG, Coronary artery bypass graft. CPB, cardiopulmonary bypass. ACC, Aortic cross clamping. Data are expressed as number (percentage) or median [IQR], as appropriate.

Non-survivors were more likely to require renal replacement therapy and had prolonged mechanical ventilation (Table 4). Interestingly, time between initial surgery and diagnosis of mediastinitis was longer in survivors (53 [17–166] vs 34 [17–57] days; p = 0.03). Fungal strains among survivors and non-survivors are reported in Fig. 2.

In this 11-year study in high-volume cardiac surgery centers, the incidence of fungal mediastinitis after cardiac surgery was low, accounting for around 0.05% of initial surgical procedures. Candida spp were the main causative agents. Prognosis was poor, with almost two thirds of patients dying within a month of diagnosis.

Our data brings new insights to the current literature, as this is to date the largest multicenter study on post-cardiac surgery fungal mediastinitis. Indeed, mycological data in critically ill patients are poorly reported and are mainly available for invasive Candida and Aspergillosis infections, or in hematological population.

While some risk factors are shared between fungal and bacterial mediastinitis, such as malnutrition, obesity or diabetes mellitus¹¹ our study attempted to identify specific factors associated with higher mortality in the fungal variants.

As previously described, a higher Euroscore II and a higher SAPS II score seem to be associated with higher complication rates in patients with fungal mediastinitis. Also, more than half of cases were previously hospitalized before surgery, suggesting a possible association between fungal infection and comorbidities requiring multiple hospital attendance.

With only half of the patients showing local signs at clinical presentation, fungal mediastinitis appears more indolent than bacterial mediastinitis (Table 2). The latter is almost systematically associated with local signs¹². Finally, time to diagnosis of fungal mediastinitis after surgery looks prolonged compared to current literature on bacterial mediastinitis, with a median of 38 days¹³. The non-bacterial nature and delayed onset of mediastinitis may explain a lower rate of septic shock in our population, given that some data suggest that early onset of mediastinitis is associated with septic shock¹³.

Thirty percent of cases were cardiac transplant recipients with immunosuppressive agents, making them at higher risk of fungal colonization and opportunistic infections. Previous data suggest that the detection of post-cardiac transplant bacterial mediastinitis is very challenging, with fewer leukocytosis and fever¹⁴. Keeping a high level of suspicion for bacterial and non-bacterial healthcare-associated infections is of paramount importance to improve early diagnosis and prognosis. Our data suggest that the diagnosis of fungal mediastinitis may be significantly delayed and that septic shock in this population occurs latter in about 50% of cases. In order to reduce the diagnosis delay, the fungal wall biomarker β-D-glucan could regularly assayed in high-risk patients, notably V-A ECMO or heart transplants recipients. If this biomarker could be useful for Aspergillosis spp and Candida spp, it has never been evaluated in this setting and cannot be used in case of Trichosporon spp infections.

After initial surgery, one in five patients were supported by V-A ECMO for a cardiogenic shock when mediastinitis was diagnosed. Although the higher prevalence of fungal infections on V-A ECMO remains controversial^15,16, circulatory support reflects a more severe patient condition, leading to a potential increased susceptibility to infections.

Regarding ventricular mechanical supports, it is important to highlight that five patients received LVAD before initial surgery, and that all benefited from transplantation. Three of them developed postoperative mediastinitis due to fungal pathogens, mostly non-Candida species. LVAD as destination therapies are at risk of infectious complications, through infection of the percutaneous site or pocket infection¹⁷, and prior LVAD before heart transplantation has been identified as a supplementary risk factor of bacterial mediastinitis after cardiac transplantation¹. These facts may suggest a specific vulnerability to fungal mediastinitis among transplanted patients previously on prolonged heart assistance¹⁸.

We presume that airborne contamination from Aspergillus spp spores may occur during the surgical procedure¹⁹. Spreading in the mediastinal area from a contiguous source or an hematogenous invasion is also conceivable, especially among immunosuppressed patients²⁰. For Candida spp and Trichosporon spp, direct inoculation from skin barrier rupture during surgery or cross-contamination is theoretically possible²¹.

The most common strains were Candida spp. The subspecies were consistent with the current Candida distribution described in critically ill population²². To note, Aspergillus mediastinitis is a very rare condition after cardiac surgery, with only few case reports^23–25. In our study, only 4 patients had postoperative Aspergillus mediastinitis and none of them died in ICU.

We reported 5 cases of postoperative mediastinitis caused by Trichosporon spp; four out of five patients died from these infections which makes this opportunistic pathogen the deadliest strain with non-albicans Candida, with a reserve of anecdotal evidence. However, the number of cases prevents us from drawing any conclusion about the respective virulence of these pathogens.

There is no specific recommendations to guide the management of fungal mediastinitis. In our study, all but one patient had surgical treatment, which is a cornerstone in the management of postoperative bacterial mediastinitis²⁶. Moreover, half of the patients required at least a second surgical debridement, underlining the difficulties in obtaining satisfying source control.

Most of patients were treated with echinocandin or azoles as a first line antifungal therapy. However, we found that 15% of fungal strains were resistant to azoles, which mainly involved C. glabrata and C. parapsilosis. Whereas fluconazole resistance is already described for these two species^27,28, our data strengthen the need to carefully choose the empirical antifungal therapy.

There is increased concern in the literature suggesting that non-albicans Candida can generate a biofilm, yielding issues to remove the fungal burden²⁹. Although, it seems that these strains remain sensitive to echinocandin³⁰. Additionally, our results suggest the need to consider non-albicans Candida species when choosing first line antifungal treatment. Echinocandin should be considered as first line empiric therapy in case of yeast identification in a mediastinal sample. If direct examination of a mediastinal sample shows filaments, thus suggesting an Aspergillus spp infection, voriconazole should be preferred as the first-line antifungal therapy³¹. In addition, high levels of suspicion for fungal mediastinitis should be kept in patients with peri-operative clinical evidence of mediastinitis and negative bacteriological cultures, especially in those who received heart transplantation. However, these therapeutic suggestions are extrapolated from other deep fungal surgical site infections, proposed from local experiences and based on this limited series. Unfortunately, no randomized trial could be built to answer to this too rare condition, due to a likely ultra-low recruitment rate. Firmer recommendations would rely on larger database.

Whereas the usual mortality rate of postoperative mediastinitis ranges from 30 to 50%³, this study highlights a higher mortality rate of nearly 60%. Fungal infections in the critically ill patients are associated with a high mortality rate, even if this reflects a large spectrum ranging from putative pulmonary aspergillosis to invasive candidiasis in hematological patients. Indeed, in the overall critically ill patients, invasive Candida infections are associated with roughly 50% mortality rate(1). A recent single-center retrospective study focusing on Candida spp postoperative mediastinitis underlined a significantly lower probability of survival than bacterial mediastinitis (43±8% vs 80±6.3%, respectively, p < 0.0001)³². One explanation might be the high prevalence of ECMO-supported patients (62%) and the over-representation of cardiac transplantation recipient in this cohort. However, this hypothesis must be interpreted with caution, since specific data on fungal mediastinitis is limited.

In our study, a short delay between surgery and infection was related to mortality. This finding was previously described in patients with post-sternotomy bacterial mediastinitis¹³. The early post-operative decrease and loss of function of lymphocytes³³ leads to an increased vulnerability to infection. Except for Aspergillus spp infections which have a longer time to onset, we did not find any difference in terms of infection delay between the causative agents.

Notably, we found an increased trend of post-cardiac surgery fungal mediastinitis between 2009 and 2019. This observation corroborates a similar tendency in pulmonary fungal infections and in general fungal disease³⁴. This could be related to an increased population of immunocompromised patients, including those who receive immunomodulatory agents. The indications of V-A ECMO have also largely increased worldwide over the last decade, exposing this high-risk population to nosocomial infections. It is noteworthy that the lack of record of actual number of VA-ECMO, LVAD or heart transplantation during the study period prevents us from providing trends of surgical procedures and specific complications in our centers. Moreover, the improvement of the diagnosis techniques of fungal infections³⁵ may have contributed to a greater identification rate of fungal mediastinitis, and clinicians awareness’s may have been raised by previous experiences. To note, no change in national or local antibioprophylaxis policy occurred during the study period.

Overall, firm evidence-based recommendations about treatments and survival following this cardiac surgical complication are likely to be uncertain, due to methodology issues and extremely low incidence. Our initiative opens the door to a larger sample experience with recruitment of international centers, in order to better appreciate “real-life” epidemiology, outcome, and treatment algorithms.

Our study presents several limitations. First, the inclusion period of these 40 cases lasted 11 years in 10 centers, involving potential changes related to surgical and medical management over the years. However, the extremely low incidence in our cohort would be unsuitable for prospective studies. Identification of mediastinitis may have differed between centers, and cases may have been underdiagnosed or diagnosed in other centers. So, the incidence should be viewed as an estimation. Whatever, it is very likely that the incidence would stay very low. Similarly, due to the sample size, no multivariable regression was possible to identify risk factors of onset. Second, our population was heterogenous, with cardiac transplantation representing a specific immunocompromised population which should probably be considered aside. Our study would have benefited from comparing patients after each specific procedures, notably, coronary/valvular surgery, ECMO/LVAD/heart transplantation recipients, so as to better identify specific patient or procedure risk factors. Larger database will have to indicate the volume of each surgical procedure. Third, we focused on post-cardiac surgery fungal mediastinitis, which does not allow the generalization of our results to other postoperative mediastinitis, including mediastinitis after esophageal or cervico-facial surgery. At least, in the absence of a control population of bacterial mediastinitis, we could not draw firm comparison between fungal and no-fungal mediastinitis: assertions regarding clinical presentations, risk factors and outcomes should be cautiously considered.

Fungal mediastinitis is an extremely rare but serious complication after cardiac surgery, with an ICU mortality rate of more than 50%. While Candida spp are the leading pathogens, our results are in line with a trend towards an increased prevalence of emergent yeasts and molds that cause infectious complications (Fig. 3).

We suggest holding a high level of suspicion among patients presenting sepsis after cardiac surgery, especially in case of latent, scarcely inflammatory sternal aspect and underlying immunodepression. An empiric antifungal therapy should be discussed in heart transplant recipients who have evidence of mediastinitis but negative bacteriological culture.

Further studies including larger samples and comparison groups are mandatory to promote more evidence-based strategies. An algorithm implemented by all involved specialists is likely to guide clinicians and strengthen analysis through standardization.

BMI: Body Mass Index

CABG: Coronary Artery Bypass Graft

ICU: Intensive Care Unit

LVAD: Left Ventricular Assist Device

SAPS II: Simplified Acute Physiology Score II

SOFA: Sequential Organ Failure Assessment

V-A ECMO: Veno-Arterial ExtraCorporeal Membrane Oxygenation

AKNOWLEDGEMENTS

We thank the following colleagues for screening patients with potential fungal mediastinitis in their respective centers :

Dr Michael Piagnerelli, Département de Médecine Intensive, CHU-Charleroi, Charleroi Belgium

Pr Pierre Wauthy, Département de chirurgie cardiaque, Centre Hospitalier Universitaire Brugmann, Bruxelles, Belgium

Pr David De Bels, Réanimation polyvalente, CHU Brugmann, Bruxelles, Belgium

Dr Mélanie Dechamps, Soins intensifs cardio-vasculaires, Clinique Universitaire St-Luc, Bruxelles, Belgium

Dr Vincent Fraipont, Unité de Soins Intensifs, Centre Hospitalier Régional de la Citadelle, Liège, Belgium

Pr Pierre Damas, Département de Médecine Intensive, CHU Sart Tilman Liège, Belgium

Dr Yves Bouckaert, Service des Soins Intensifs, CHU Tivoli, La Louvière, Belgium

Pr Isabelle Michaux, Unité de soins intensifs cardiothoraciques, Mont-Godinne, CHU UCL Namur, Belgium

Dr Matthieu Jabaudon and Pr Emmanuel Futier, Anesthésie-réanimation, Nouvel Hôpital d’Estaing, Clermond-Ferrand, France

Dr Emmanuel Rineau, Département d’Anesthésie-Réanimation, CHU Angers, France

Dr Thomas Kerforne, Réanimation Chirurgicale Cardio-Thoracique et Vasculaire, CHU Poitiers, France

Dr Philippe Gaudard and Dr Norddine Zeroual, Département d’Anesthésie-Réanimation Arnaud de Villeneuve, CHU Montpellier, France

Pr Olivier Collange and Dr Anne-Claude Roche, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, France

Dr Guillaume Besch, CHU de Besançon, France

Dr Diane Lena, Institut Arnault Tzanck, France

Pr Marc-Olivier Fischer, CHU de Caen, France

Pr Jérôme Morel, CHU de Saint-Etienne, France

Pr Belaid Bouhemad, CHU de Dijon-Bourgogne, France

Dr Wulfran Bougouin, réanimation polyvalente, hôpital privé Jacques Cartier, Massy, France

Pr Bertrand Rozec, hôpital nord Laennec, CHU de Nantes, France

Dr Osama Abou-Arab, CHU d’Amiens, France

Pr Françoise Botterel and Dr Françoise Foulet, laboratoire de mycologie, CHU Henri Mondor, Créteil, France

Pr Alexandre Ouattara, Service d’Anesthésie-réanimation GH Sud, CMC Magellan, Hopital Haut-Lévêque, CHU de Bordeaux,

Ethical Approval

The study was approved by Ethical committees in France (Comité d’Ethique pour la Recherche en Anesthésie-Réanimation, IRB 00010254-2018-178) and Belgium (Comité d’Ethique hospitalo-facultaire, Hôpital Erasme, ULB, P2019/167). Given the retrospective design, patient’s consent was waived.

Authors' contributions

GH and MG contributed equally and should be considered as co-first authors.

AB and NM contributed equally and should be considered as co-last authors.

DG, AB and NM conceived and designed the study. MG and VB made substantial contributions to the conception of the work. MG, VB, SC, EG, AK, NS, EB, FD, DL, JI, DG AB and NM collected the data for the original study. GH, MG and NM wrote the manuscript. All the authors reviewed the final manuscript, tables and figures prior to submission and approved the final version. All the authors confirm they have full access to all of data in the study and accept responsibility to submit for publication

Availability of data and materials

The storage of anonymized data is computerized and centralized at the principal investigator's office, who guarantees their protection. Data could be shared on reasonable request to the corresponding author.

Conflicts of interest

The authors have not disclosed any conflict of interest related to this manuscript.

Funding

No funding was received for this study.

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No competing interests reported.

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published 06 Jan, 2023

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Post-cardiac surgery fungal mediastinitis : clinical features, pathogens and outcome

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Introduction

Patients And Methods

Study design

Patients

Variables and outcomes

Statistical analysis

Results

Patient’s characteristics

Clinical presentation, diagnosis and impact of mediastinitis

Microbiological documentation and pathogens

Antifungal and surgical treatment

Trends in incidence of mediastinitis

Survivors vs non-survivors

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