Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020).

OBJECTIVES: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France. METHODS: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality. RESULTS: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006). DISCUSSION: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management.

Cryptococcus neoformans Infections Differ Among Human Immunodeficiency Virus (HIV)-Seropositive and HIV-Seronegative Individuals: Results From a Nationwide Surveillance Program in France.

Among 1107 cryptococcosis cases from the French surveillance network (2005-2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus.

Invasive fungal diseases in patients with autoimmune diseases: a case series from the French RESSIF network.

OBJECTIVES: We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality. METHODS: We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP). RESULTS: From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia <1500/mm3 was frequent (132/179, 73.7%) even if CD4+T cell count exceeded 200/mm3 in 56/78 patients (71.8%) (median 472.5/mm3, IQR 160-858). CONCLUSION: IFD associated with AID occurs primarily in RA, AAV and IBD, especially when treated with GCs and immunosuppressants. Mortality is high, especially for patients on high-dose GCs. Lymphopenia may help identify risk of PCP, but normal CD4+T cell count does not rule out the risk. Further studies are needed to assess the individual risk factors for IFD.

Candida haemulonii complex, an emerging threat from tropical regions?

BACKGROUND: Candida haemulonii complex-related species are pathogenic yeasts closely related to Candida auris with intrinsic antifungal resistance, but few epidemiological data are available. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed clinical and demographic characteristics of patients with fungemia due to C. haemulonii complex and related species (C. pseudohaemulonii, C. vulturna) reported in France during 2002-2021, and compared them to data of C. parapsilosis fungemia, as they all can be commensal of the skin. We also conducted a study on adult inpatients and outpatients colonized by C. haemulonii complex, managed at the University Hospital of Martinique during 2014-2020. Finally, we performed a literature review of fungemia due to C. haemulonii complex and related species reported in Medline (1962-2022). In total, we identified 28 fungemia due to C. haemulonii complex in France. These episodes were frequently associated with bacterial infection (38%) and high mortality rate (44%), and differed from C. parapsilosis fungemia by their tropical origin, mainly from Caribbean and Latin America. All isolates showed decreased in vitro susceptibility to amphotericin B and fluconazole. In Martinique, we found that skin colonization was frequent in the community population, while colonization was strongly associated with the presence of foreign devices in ICU patients. The literature review identified 274 fungemia episodes, of which 56 were individually described. As in our national series, published cases originated mainly from tropical regions and exhibited high crude mortality. CONCLUSIONS/SIGNIFICANCE: Multidrug-resistant C. haemulonii complex-related species are responsible for fungemia and colonization in community and hospital settings, especially in tropical regions, warranting closer epidemiological surveillance to prevent a potential C. auris-like threat.

ß-D-Glucan Assay in the Cerebrospinal Fluid for the Diagnosis of Non-cryptococcal Fungal Infection of the Central Nervous System: A Retrospective Multicentric Analysis and a Comprehensive Review of the Literature.

BACKGROUND: Except for cryptococcosis, fungal infection of the central nervous system (FI-CNS) is a rare but severe complication. Clinical and radiological signs are non-specific, and the value of conventional mycological diagnosis is very low. This study aimed to assess the value of ß1,3-D-glucan (BDG) detection in the cerebrospinal fluid (CSF) of non-neonatal non-cryptococcosis patients. METHODS: Cases associated with BDG assay in the CSF performed in 3 French University Hospitals over 5 years were included. Clinical, radiological, and mycological results were used to classify the episodes as proven/highly probable, probable, excluded, and unclassified FI-CNS. Sensitivity and specificity were compared to that calculated from an exhaustive review of the literature. RESULTS: In total, 228 episodes consisting of 4, 7, 177, and 40 proven/highly probable, probable, excluded, and unclassified FI-CNS, respectively, were analysed. The sensitivity of BDG assay in CSF to diagnose proven/highly probable/probable FI-CNS ranged from 72.7% [95% confidence interval {CI}: 43.4%‒90.2%] to 100% [95% CI: 51%‒100%] in our study and was 82% in the literature. For the first time, specificity could be calculated over a large panel of pertinent controls and was found at 81.8% [95% CI: 75.3%‒86.8%]. Bacterial neurologic infections were associated with several false positive results. CONCLUSIONS: Despite its sub-optimal performance, BDG assay in the CSF should be added to the diagnostic armamentarium for FI-CNS.

Invasive bone and joint infections from the French Scedosporiosis/lomentosporiosis Observational Study (SOS) cohort: no mortality with long-term antifungal treatment and surgery.

Little is known about localized osteoarticular Scedosporiosis (LOS). Most data come from case reports and small case series. Here we present an ancillary study of the nationwide French Scedosporiosis Observational Study (SOS), describing 15 consecutive cases of LOS diagnosed between January 2005 and March 2017. Adult patients diagnosed with LOS defined by osteoarticular involvement without distant foci reported in SOS were included. Fifteen LOS were analyzed. Seven patients had underlying disease. Fourteen patients had prior trauma as potential inoculation. Clinical presentation was arthritis (n = 8), osteitis (n = 5), and thoracic wall infection (n = 2). The most common clinical manifestation was pain (n = 9), followed by localized swelling (n = 7), cutaneous fistulization (n = 7), and fever (n = 5). The species involved were Scedosporium apiospermum (n = 8), S. boydii (n = 3), S. dehoogii (n = 1), and Lomentospora prolificans (n = 3). The species distribution was unremarkable except for S. boydii, which was associated with healthcare-related inoculations. Management was based on medical and surgical treatment for 13 patients. Fourteen patients received antifungal treatment for a median duration of 7 months. No patients died during follow-up. LOS exclusively occurred in the context of inoculation or systemic predisposing factors. It has a non-specific clinical presentation and is associated with an overall good clinical outcome, provided there is a prolonged course of antifungal therapy and adequate surgical management.

Localized osteoarticular scedosporiosis mostly occurs following direct inoculation. Management was most often based on voriconazole therapy and concomitant surgery. Unlike other invasive scedosporiosis, no patient died during follow-up.

Gradient concentration strip-specific epidemiological cut-off values of antifungal drugs in various yeast species and five prevalent Aspergillus species complexes.

OBJECTIVES: To determine the epidemiological cut-off values (ECVs) of ten antifungal agents in a wide range of yeasts and Aspergillus spp. using gradient concentration strips. METHODS: The minimum inhibitory concentrations for amphotericin B, anidulafungin, caspofungin, micafungin, flucytosine, fluconazole, itraconazole, isavuconazole, posaconazole, and voriconazole, determined with gradient concentration strips at 35 French microbiology laboratories between 2002 and 2020, were retrospectively collected. Then, the ECVs were calculated using the iterative method and a cut-off value of 97.5%. RESULTS: Minimum inhibitory concentrations were available for 17 653 clinical isolates. In total, 48 ECVs (including 32 new ECVs) were determined: 29 ECVs for frequent yeast species (e.g. Candida albicans and itraconazole/flucytosine, and Candida glabrata species complex [SC] and flucytosine) and rare yeast species (e.g. Candida dubliniensis, Candida inconspicua, Saccharomyces cerevisiae, and Cryptococcus neoformans) and 19 ECVs for Aspergillusflavus SC, Aspergillusfumigatus SC, Aspergillusnidulans SC, Aspergillusniger SC, and Aspergillusterreus SC. CONCLUSIONS: These ECVs can be added to the already available gradient concentration strip-specific ECVs to facilitate minimum inhibitory concentration interpretation and streamline the identification of nonwild type isolates.

Cryptococcal Meningitis in Kidney Transplant Recipients: A Two-Decade Cohort Study in France.

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Active Surveillance Program to Increase Awareness on Invasive Fungal Diseases: the French RESSIF Network (2012 to 2018).

The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, P = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, P = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% (P < 0.0001). Yeast fungemia (n = 5,444) was due mainly to Candida albicans (55.6%) with stable proportions of species over time. Echinocandins became the main drug prescribed (46.7% to 61.8%), but global mortality rate remained unchanged (36.3% at 1 month). Pneumocystis jirovecii pneumonia (n = 2,106) was diagnosed mostly in HIV-negative patients (80.7%) with a significantly higher mortality than in HIV-positive patients (21.9% versus 5.4% at 1 month, P < 0.0001). Invasive aspergillosis (n = 1,661) and mucormycosis (n = 314) were diagnosed mostly in hematology (>60% of the cases) with a global mortality rate of 42.5% and 59.3%, respectively, at 3 months and significant changes in diagnosis procedure over time. More concurrent infections were also diagnosed over time (from 5.4% to 9.4% for mold IFDs, P = 0.0115). In conclusion, we observed an aging of patients with IFD with a significant increase in incidence only for yeast fungemia, a trend toward more concurrent infections, which raises diagnostic and therapeutic issues. Overall, global survival associated with IFDs has not improved despite updated guidelines and new diagnostic tools. IMPORTANCE The epidemiology of invasive fungal diseases (IFDs) is hard to delineate given the difficulties in ascertaining the diagnosis that is often based on the confrontation of clinical and microbiological criteria. The present report underlines the interest of active surveillance involving mycologists and clinicians to describe the global incidence and that of the main IFDs. Globally, although the incidence of Pneumocystis pneumonia, invasive aspergillosis, and mucormycosis remained stable over the study period (2012 to 2018), that of yeast fungemia increased slightly. We also show here that IFDs seem to affect older people more frequently. The most worrisome observation is the lack of improvement in the global survival rate associated with IFDs despite the increasing use of more sensitive diagnostic tools, the availability of new antifungal drugs very active in clinical trials, and a still low/marginal rate of acquired in vitro resistance in France. Therefore, other tracks of improvement should be investigated actively.

Is ß-d-glucan Relevant for the Diagnosis and Follow-Up of Intensive Care Patients with Yeast-Complicated Intra-Abdominal Infection?

The usefulness of (1,3)-ß-d-glucan (BDG) detection for the diagnosis of intra-abdominal candidiasis and treatment monitoring is unknown. A prospective, single-center study of consecutive patients admitted to an ICU with complicated intra-abdominal infection (IAI) over a 2-year period was conducted. BDG was measured in the peritoneal fluid and serum between day 1 (D1) and D10. Patients with a positive peritoneal fluid yeast culture (YP) were compared to those with a negative yeast culture (YN). The evolution of serum BDG was compared in the two groups. Seventy patients were included (sixty-five analyzed): YP group (n = 19) and YN group (n = 46). Median peritoneal BDG concentration during surgery was 2890 pg.mL-1 [IQR: 942-12,326] in the YP group vs. 1202 pg.mL-1 [IQR: 317-4223] in the YN group (p = 0.13). Initial serum BDG concentration was 130 pg.mL-1 [IQR: 55-259] in the YP group vs. 88 pg.mL-1 [IQR: 44-296] in the YN group (p = 0.78). No difference in evolution of serum BDG concentrations was observed between the groups (p = 0.18). In conclusion, neither peritoneal BDG nor serum BDG appear to be good discriminating markers for the diagnosis of yeast IAI. In addition, monitoring the evolution of serum BDG in yeast IAI did not appear to be of any diagnostic value.

Evaluation of Serum Mucorales Polymerase Chain Reaction (PCR) for the Diagnosis of Mucormycoses: The MODIMUCOR Prospective Trial.

BACKGROUND: Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of serum Mucorales quantitative polymerase chain reaction (qPCR) for the early diagnosis and follow-up of mucormycosis. METHODS: We prospectively enrolled 232 patients with suspicion of invasive mold disease, evaluated using standard imaging and mycological procedures. Thirteen additional patients with proven or probable mucormycosis were included to analyze DNA load kinetics. Serum samples were collected twice-a-week for Mucorales qPCR tests targeting the Mucorales genera Lichtheimia, Rhizomucor, and Mucor/Rhizopus. RESULTS: The sensitivity was 85.2%, specificity 89.8%, and positive and negative likelihood ratios 8.3 and 0.17, respectively in this prospective study. The first Mucorales qPCR-positive serum was observed a median of 4 days (interquartile range [IQR], 0-9) before sampling of the first mycological or histological positive specimen and a median of one day (IQR, -2 to 6) before the first imaging was performed. Negativity of Mucorales qPCR within seven days after liposomal-amphotericin B initiation was associated with an 85% lower 30-day mortality rate (adjusted hazard ratio = 0·15, 95% confidence interval [.03-.73], P = .02). CONCLUSIONS: Our study argues for the inclusion of qPCR for the detection of circulating Mucorales DNA for mucormycosis diagnosis and follow-up after treatment initiation. Positive results should be added to the criteria for the consensual definitions from the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC), as already done for Aspergillus PCR.

COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave.

The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10-4). For CAPA, the presence of several mycological criteria was associated with death (P < 10-4). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients (P = 0.001). Antimold treatment did not alter prognosis (P = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses. IMPORTANCE To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU.

Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis1.

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.

Temozolomide is a risk factor for invasive pulmonary aspergillosis: A case report and literature review.

BACKGROUND: Temozolomide is an oral alkylating agent incorporated in the treatment of glioblastoma multiforme (GBM) that can lead to lymphopenia. The standard treatment of GBM involves temozolomide chemotherapy with radiation, often with addition of corticosteroids for symptomatic management of cerebral edema. Some studies have reported an increased risk of opportunistic infections. CASE PRESENTATION: A 72-year-old man receiving Temozolomide for treatment of newly diagnosed GBM associated with radiotherapy and corticosteroids was admitted in an intensive care unit because a rapid deterioration of consciousness associated with acute respiratory failure. The diagnosis of invasive pulmonary aspergillosis (IPA) was made. The patient was successfully treated with voriconazole alone. CONCLUSIONS: This case shows that Temozolomide can be associated with severe invasive aspergillosis, which is in all likelihood associated with T lymphocyte immune dysfunction. Physicians should be aware of possible opportunistic infections when managing patients with glioblastoma, and patients exposed to this agent should be carefully monitored.

Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF ßDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. LAY SUMMARY: Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

Invasive Tracheobronchial Aspergillosis in Critically Ill Patients with Severe Influenza. A Clinical Trial.

Rationale: Invasive tracheobronchial aspergillosis (ITBA) is an uncommon but severe clinical form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree.Objectives: To analyze the diagnostic and prognostic differences between tracheobronchial aspergillosis and pulmonary aspergillosis without tracheobronchial lesions among patients admitted to the ICU with severe influenza.Methods: This retrospective, observational study included critically ill patients with influenza associated with pulmonary aspergillosis from three hospital ICUs between 2010 and 2019. Patient characteristics and clinical and mycologic data at admission and during ICU stay were collected in a database to evaluate variables in the two groups.Measurements and Main Results: Thirty-five patients admitted to the ICU with severe influenza and pulmonary aspergillosis were included. Ten patients were included in the group with ITBA (n = 10 of 35; 28.6%), and 25 patients were included in the group without ITBA. The group with ITBA comprised more patients with active smoking, diabetes mellitus, and higher severity scores (Simplified Acute Physiology Score II). Ninety-day mortality rates in the groups with and without ITBA were 90% and 44%, respectively (P = 0.02). Moreover, significantly higher serum 1,3-ß-d-glucan and galactomannan and BAL fluid galactomannan concentrations were observed in the group with ITBA compared with the group without ITBA (P < 0.0001, P = 0.003, and P = 0.008, respectively).Conclusions: ITBA was associated with higher severity scores, mortality, and serum and BAL fluid galactomannan and 1,3-ß-d-glucan concentrations than invasive pulmonary aspergillosis without tracheobronchial lesions. ITBA should be systematically researched by bronchoscopic examination in ICU patients with concomitant pulmonary aspergillosis and influenza.Clinical trial registered with www.clinicaltrials.gov (NCT04077697).