Predictors for Prolonged Hospital Stay Solely to Complete Intravenous Antifungal Treatment in Patients with Candidemia: Results from the ECMM Candida III Multinational European Observational Cohort Study.

BACKGROUND: To date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx). METHODS: Each participating hospital (number of eligible hospitals per country determined by population size) included the first ~ 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx. FINDINGS: Hospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 - 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 - 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 - 0.45; p < 0.03). INTERPRETATION: Hospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis.

Chronic Candida albicans meningitis following critical COVID-19 and serial measurements of (1,3)-ß-D-glucan in cerebrospinal fluid.

Co-infections with invasive candidiasis have been reported to be overrepresented in severe COVID-19. This report presents an unusual case of chronic Candida meningitis following intensive care for COVID-19.

Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study.

BACKGROUND: The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes. METHODS: In this observational cohort study, 64 participating hospitals located in 20 European countries, with the number of eligible hospitals per country determined by population size, included the first ten consecutive adults with culture-proven candidaemia after July 1, 2018, and entered data into the ECMM Candida Registry (FungiScope CandiReg). We assessed ECMM Quality of Clinical Candidaemia Management (EQUAL Candida) scores reflecting adherence to recommendations of the European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America guidelines. FINDINGS: 632 patients with candidaemia were included from 64 institutions. Overall 90-day mortality was 43% (265/617), and increasing age, intensive care unit admission, point increases in the Charlson comorbidity index score, and Candida tropicalis as causative pathogen were independent baseline predictors of mortality in Cox regression analysis. EQUAL Candida score remained an independent predictor of mortality in the multivariable Cox regression analyses after adjusting for the baseline predictors, even after restricting the analysis to patients who survived for more than 7 days after diagnosis (adjusted hazard ratio 1·08 [95% CI 1·04-1·11; p<0·0001] in patients with a central venous catheter and 1·09 [1·05-1·13; p<0·0001] in those without one, per one score point decrease). Median duration of hospital stay was 15 days (IQR 4-30) after diagnosis of candidaemia and was extended specifically for completion of parenteral therapy in 100 (16%) of 621 patients. Initial echinocandin treatment was associated with lower overall mortality and longer duration of hospital stay among survivors than treatment with other antifungals. INTERPRETATION: Although overall mortality in patients with candidaemia was high, our study indicates that adherence to clinical guideline recommendations, reflected by higher EQUAL Candida scores, might increase survival. New antifungals, with similar activity as current echinocandins but with longer half-lives or oral bioavailability, are needed to reduce duration of hospital stay. FUNDING: Scynexis.

Leishmania infantum infection after visiting southern Spain in patients on biological treatment; an observational, longitudinal, cohort study.

BACKGROUND: Reports of leishmaniasis in immunosuppressed patients after visiting the Mediterranean Basin are becoming increasingly common. Still, awareness of the risk of infection and its clinical manifestations may be insufficient among healthcare professionals in the travellers' home countries. METHODS: This observational, longitudinal study included 47 patients from Sweden with rheumatic disease and ongoing immunomodulatory treatment, who visited a rehabilitation centre in southern Spain where leishmaniasis is endemic. Patients were evaluated for clinical signs of leishmaniasis at baseline and after three years. Patients with leishmaniasis were followed for 4-5 years. The treatment outcome was assessed by clinical evaluation and determination of the cell-mediated immunological response to Leishmania by a whole blood cytokine release assay. RESULTS: Seven patients (15%) were diagnosed with leishmaniasis. The median time from exposure to the onset of symptoms was 3 [1-17] months. The median delay between the onset of symptoms and treatment start was 9 [1-12] months. All patients with leishmaniasis responded well to treatment. Only one patient had a relapse, which occurred within the first year. CONCLUSION: Healthcare professionals need to be aware of the increased risk of leishmaniasis for travellers who are immunosuppressed. Knowledge of the symptoms is crucial for a timely diagnosis and early treatment.

Treatment With Reduced-Dose Trimethoprim-Sulfamethoxazole Is Effective in Mild to Moderate Pneumocystis jirovecii Pneumonia in Patients With Hematologic Malignancies.

BACKGROUND: Recent studies have reported that reduced-dose trimethoprim-sulfamethoxazole (TMP-SMX) may be effective in the treatment of Pneumocystis jirovecii pneumonia (PJP), but data are lacking for patients with hematologic malignancies. METHODS: This retrospective study included all adult hematologic patients with PJP between 2013 and 2017 at 6 Swedish university hospitals. Treatment with 7.5-15 mg TMP/kg/day (reduced dose) was compared with >15-20 mg TMP/kg/day (standard dose), after correction for renal function. The primary outcome was the change in respiratory function (Δpartial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2]) between baseline and day 8. Secondary outcomes were clinical failure and/or death at day 8 and death at day 30. RESULTS: Of a total of 113 included patients, 80 patients received reduced dose and 33 patients received standard dose. The overall 30-day mortality in the whole cohort was 14%. There were no clinically relevant differences in ΔPaO2/FiO2 at day 8 between the treatment groups, either before or after controlling for potential confounders in an adjusted regression model (-13.6 mm Hg [95% confidence interval {CI}, -56.7 to 29.5 mm Hg] and -9.4 mm Hg [95% CI, -50.5 to 31.7 mm Hg], respectively). Clinical failure and/or death at day 8 and 30-day mortality did not differ significantly between the groups (18% vs 21% and 14% vs 15%, respectively). Among patients with mild to moderate pneumonia, defined as PaO2/FiO2 >200 mm Hg, all 44 patients receiving the reduced dose were alive at day 30. CONCLUSIONS: In this cohort of 113 patients with hematologic malignancies, reduced-dose TMP-SMX was effective and safe for treating mild to moderate PJP.

T2Candida Assay in the Diagnosis of Intraabdominal Candidiasis: A Prospective Multicenter Study.

The T2Candida magnetic resonance assay is a direct-from-blood pathogen detection assay that delivers a result within 3-5 h, targeting the most clinically relevant Candida species. Between February 2019 and March 2021, the study included consecutive patients aged >18 years admitted to an intensive care unit or surgical high-dependency unit due to gastrointestinal surgery or necrotizing pancreatitis and from whom diagnostic blood cultures were obtained. Blood samples were tested in parallel with T2Candida and 1,3-ß-D-glucan. Of 134 evaluable patients, 13 (10%) were classified as having proven intraabdominal candidiasis (IAC) according to the EORTC/MSG criteria. Two of the thirteen patients (15%) had concurrent candidemia. The sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were 46%, 97%, 61%, and 94% for T2Candida and 85%, 83%, 36%, and 98% for 1,3-ß-D-glucan. All positive T2Candida results were consistent with the culture results at the species level, except for one case of dual infection. The performance of T2Candida was comparable with that of 1,3-ß-D-glucan for candidemic IAC but had a lower sensitivity for non-candidemic IAC (36% vs. 82%). In conclusion, T2Candida may be a valuable complement to 1,3-ß-D-glucan in the clinical management of high-risk surgical patients because of its rapid results and ease of use.

Fungal Tracheobronchitis in Lung Transplant Recipients: Incidence and Utility of Diagnostic Markers.

Fungal tracheobronchitis caused by Aspergillus and Candida spp. is a recognized complication after lung transplantation, but knowledge of the incidence of Candida tracheobronchitis is lacking. The diagnosis relies on fungal cultures in bronchoalveolar lavage fluid (BALF), but cultures have low specificity. We aimed to evaluate the one-year incidence of fungal tracheobronchitis after lung transplantation and to assess the utility of diagnostic markers in serum and BALF to discriminate fungal tracheobronchitis from colonization. Ninety-seven consecutively included adult lung-transplant recipients were prospectively followed. BALF and serum samples were collected at 1, 3 and 12 months after transplantation and analyzed for betaglucan (serum and BALF), neutrophils (BALF) and galactomannan (BALF). Fungal tracheobronchitis was defined according to consensus criteria, modified to include Candida as a mycologic criterion. The cumulative one-year incidence of Candida and Aspergillus tracheobronchitis was 23% and 16%, respectively. Neutrophils of >75% of total leukocytes in BALF had 92% specificity for Candida tracheobronchitis. The area under the ROC curves for betaglucan and galactomannan in BALF to discriminate Aspergillus tracheobronchitis from colonization or no fungal infection were high (0.86 (p < 0.0001) and 0.93 (p < 0.0001), respectively). To conclude, the one-year incidence of fungal tracheobronchitis after lung transplantation was high and dominated by Candida spp. Diagnostic markers in BALF could be useful to discriminate fungal colonization from tracheobronchitis.

Serum-based diagnosis of Pneumocystis pneumonia by detection of Pneumocystis jirovecii DNA and 1,3-ß-D-glucan in HIV-infected patients: a retrospective case control study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is one of the most common HIV-related opportunistic infections. The diagnosis of PCP is based on analyses from respiratory tract specimens which may require the invasive procedure of a diagnostic bronchoscopy. The objective of this study was to evaluate the diagnostic potential of Pneumocystis jirovecii PCR in serum combined with the 1,3-ß-D-glucan (betaglucan) test for the diagnosis of PCP in HIV-infected patients. METHODS: This was a retrospective case-control study including serum samples from 26 HIV-infected patients with PCP collected within 5 days prior to the start of PCP treatment, 21 HIV-infected control subjects matched by blood CD4+ cell counts, and 18 blood donors. The serum samples were analyzed for Pneumocystis jirovecii PCR and betaglucan. The reference standard for PCP was based on previously described microbiological and clinical criteria. RESULTS: All patients with PCP had detectabe Pneumocystis jirovecii DNA in serum yielding a sensitivity for the Pneumocystis jirovecii PCR assay in serum of 100%. All blood donors had negative Pneumocystis PCR in serum. The specificity when testing HIV-infected patients was 71%, but with a PCR Cycle threshold (Ct) value of 34 as cut-off the specificity was 90%. At a putative pretest probaility of 20%, the negative and positive predictive value for the Pneumocystis PCR assay in serum was 0.99 and 0.71, respectively. Betaglucan with cut-off level 200 pg/ml combined with a positive Pneumocystis jirovecii PCR result had sensitivity and specificity of 92 and 90%, respectively. The concentration of Pneumocystis jirovecii DNA in serum samples, expressed by the PCR Ct values, correlated inversely to the betaglucan levels in serum. CONCLUSION: In this case-control study including 70% of all HIV-infected patients with PCP treated at Sahlgrenska University Hospital during a time period of 13 years, Pneumocystis PCR analysis on serum samples had a very high sensitivity and negative predictive value for the diagnosis of PCP in HIV-infected patients. A serum-based diagnostic procedure either based on Pneumocystis jirovecii PCR alone or in combination with betaglucan analysis may thus be feasible and would facilitate the care of HIV-infected patients with suspected PCP.

Species distribution and antifungal drug susceptibilities of yeasts isolated from the blood samples of patients with candidemia.

Candida albicans is the most frequently isolated fungal species in hospital settings worldwide. However, non-albicans Candida species with decreased susceptibility to antifungals have emerged as an important cause of fungemia. The aims of this study were to determine the species distribution of fungi isolated from the blood samples of patients at a Swedish University Hospital and to define the in vitro susceptibilities of these isolates to nine antifungal agents. In total, 233 yeast isolates from 143 patients were included in this study. Antifungal susceptibility testing was performed using broth dilution Sensititre YeastOne panels, which comprised amphotericin B, 5-flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. The most common species in all age groups was C. albicans (n = 93, 65%), followed by C. glabrata (n = 27, 19%) and C. parapsilosis (n = 15, 10%). C. glabrata was mostly found in elderly individuals, while C. parapsilosis was found mainly in young children (p = 0.008). Antifungal resistance was low in the Candida species, except for reduced susceptibility to fluconazole among C. glabrata strains. C. albicans is the most frequent colonizer of Swedish patients. In general antifungal resistance is uncommon in Candida species. Nevertheless, reduced susceptibilities to fluconazole and echinocandins were found in C. glabrata and C. parapsilosis, respectively.

Microbiological findings in bronchoalveolar lavage fluid from lung transplant patients in Sweden.

BACKGROUND: Lung transplant patients experience a high risk of airway infections and microbial colonization of the lung due to constant exposure to the environment through inhaled microorganisms, denervation, reduced ciliary transport, and decreased cough. METHODS: In this nationwide prospective study on Swedish lung transplant patients, we evaluated the microbiological panorama of bacteria, fungi, and virus found in bronchoalveolar lavage fluid (BALF) obtained the first year after lung transplantation (LTx). Differences in microbiological findings depending of concomitant signs of infection and background factors were assessed. RESULTS: A total of 470 bronchoscopies from 126 patients were evaluated. Sixty-two percent (n = 293) of BALF samples had positive microbiological finding(s). Forty-six percent (n = 217) had bacterial growth, 29% (n = 137) fungal growth, and 9% (n = 43) were positive in viral PCR. In 38% of BALF samples (n = 181), a single microbe was found, whereas a combination of bacteria, fungi or virus was found in 24% (n = 112) of bronchoscopies. The most common microbiological findings were Candida albicans, Pseudomonas aeruginosa and coagulase negative Staphylococcus (in 42 (33%), 36 (29%), and 25 (20%) patients, respectively). Microbiological findings were similar in BALF from patients with and without signs of lung infection and the frequency of multidrug resistant (MDR) bacteria was low. No significant association was found between background factors and time to first lung infection. CONCLUSION: This study gives important epidemiologic insights and reinforces that microbiological findings have to be evaluated in the light of clinical symptoms and endobronchial appearance in the assessment of lung infections in lung transplant patients.

Prospective evaluation of a combination of fungal biomarkers for the diagnosis of invasive fungal disease in high-risk haematology patients.

We prospectively evaluated a combination of fungal biomarkers in adult haematology patients with focus on their clinical utility at different time points during the course of infection. In total, 135 patients were monitored once to twice weekly for serum (1-3)-ß-d-glucan (BG), galactomannan (GM), bis-methyl-gliotoxin and urinary d-arabinitol/l-arabinitol ratio. In all, 13 cases with proven or probable invasive fungal disease (IFD) were identified. The sensitivity of BG and GM at the time of diagnosis (TOD) was low, but within 2 weeks from the TOD the sensitivity of BG was 92%. BG >800 pg/mL was highly specific for IFD. At a pre-test probability of 12%, both BG and GM had negative predictive values (NPV) >0.9 but low positive predictive values (PPV). In a subgroup analysis of patients with clinically suspected IFD (pre-test probability of 35%), the NPV was lower, but the PPV for BG was 0.86 at cut-off 160 pg/mL. Among IFD patients, 91% had patterns of consecutively positive and increasing BG levels. Bis-methyl-gliotoxin was undetectable in 15 patients with proven, probable and possible IA. To conclude, BG was the superior fungal marker for IFD diagnosis. Quantification above the limit of detection and graphical evaluation of the pattern of dynamics are warranted in the interpretation of BG results.

Heparin-binding protein, lysozyme, and inflammatory cytokines in bronchoalveolar lavage fluid as diagnostic tools for pulmonary infection in lung transplanted patients.

Pulmonary infection is a common complication after lung transplantation, and early detection is crucial for outcome. However, the condition can be clinically difficult to diagnose and to distinguish from rejection. The aim of this prospective study was to evaluate heparin-binding protein (HBP), lysozyme, and the cytokines interleukin (IL)-1ß, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF) in bronchoalveolar lavage fluid (BALF) as potential biomarkers for pulmonary infection in lung-transplanted patients. One hundred thirteen BALF samples from 29 lung transplant recipients were collected at routine scheduled bronchoscopies at 3 and 6 months, or on clinical indication. Samples were classified into no, possible, probable, or definite infection at the time of sampling. Rejection was defined by biopsy results. HBP, lysozyme, and cytokines were analyzed in BALF and correlated to likelihood of infection and rejection. All biomarkers were significantly increased in BALF during infection, whereas patients with rejection presented low levels that were comparable to noninfection samples. HBP, IL-1ß, and IL-8 were the best diagnostic markers of infection with area under the receiver-operating characteristic curve values of 0.88, 0.91, and 0.90, respectively. In conclusion, HBP, IL-1ß, and IL-8 could be useful diagnostic markers of pulmonary infection in lung-transplanted patients.

Imported Case of Lassa Fever in Sweden With Encephalopathy and Sensorineural Hearing Deficit.

We describe an imported case of Lassa fever with both encephalopathy and bilateral sensorineural hearing deficit. Absence of fever during hospitalization, initially nonspecific symptoms, and onset of hearing deficit in a late stage of disease probably contributed to delayed diagnosis (14 days after admittance to hospital). The pathogenesis of neurological manifestations of Lassa fever is poorly understood and no specific treatment was given. A total of 118 personnel had close contact with the patient, but no secondary cases occurred. This case highlights the importance of considering Lassa fever as a differential diagnosis in patients with recent travel to endemic areas.