Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation

Sebastian O Decker, Annette Sigl, Christian Grumaz, Philip Stevens, Yevhen Vainshtein, Stefan Zimmermann, Markus A Weigand, Stefan Hofer, Kai Sohn, Thorsten Brenner, Sebastian O Decker, Annette Sigl, Christian Grumaz, Philip Stevens, Yevhen Vainshtein, Stefan Zimmermann, Markus A Weigand, Stefan Hofer, Kai Sohn, Thorsten Brenner

Abstract

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% (n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp.

Keywords: ">d-glucan; interleukin-17A; mid-regional proadrenomedullin; mycoses; next-generation sequencing; sepsis; septic shock; β-.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Identification of fungal pathogens in patients with septic shock (n = 50).
Figure 2
Figure 2
Time course (fungal) SIQ analyses compared with conventional clinical microbiology data of septic patients. The anti-infective treatment regime and (fungal) SIQ scores for species identified via NGS of the respective plasma samples are reported for a time course of 28 days (indicated by the x-axis) for patients S16 (A), S25 (B), and S35 (C). Only species identified by SIQ-score analyses are indicated at the left side. Red colored boxes reveal ranking of highest SIQ scores for the respective species in every patient. Pertinent (clinical microbiology) laboratory results are marked using arrows to indicate the day the clinical specimen was obtained. (A) A 73-year old male patient presented with a tumor of his bile duct with the need for a palliative resection. The surgical procedure included resections of the bile duct as well as the gallbladder and was followed by a double bypass procedure (biliodigestive anastomosis and gastrojejunal anastomosis). Four days after the initial operation the patient suffered from septic shock due to a duodenal ulcer perforation with the need for a total pancreatectomy. Shortly after, the patient suffered from another small bowel leakage, so that an additional small bowel resection had to be performed. Blood cultures at sepsis onset were shown to be negative, and meropenem (MEM) was administered in terms of an empiric antibiotic therapy. However, the patient suffered from a therapy-refractory course of the disease and C. albicans could be isolated from abdominal drainage fluids 6 days after sepsis onset. Accordingly, an additional antifungal treatment with fluconazole (FLC) was initiated. Due to the development of candidemia at 14 days after sepsis onset, this antifungal treatment regime was secondarily escalated towards caspofungin (CFG). These findings were in good agreement with next generation sequencing (NGS) diagnostics in plasma, since the SIQ-score was positive for C. albicans at the same timepoint. Abbreviations: NGS, next generation sequencing; SIQ, sepsis indicating quantifier; MEM, meropenem; IPM:CIL, imipenem/cilastatin; FLC, fluconazole; DOR, doripenem; CFG, caspofungin; BC, blood culture; CVC, central venous catheter; TS, tracheal secretion; (B) A 65-year old male patient suffered from a Klatskin tumor with the need for a right-sided hemihepatectomy. Due to an abscess at the resection site, the patient suffered from septic shock with the need for an interventional drainage 22 days after the initial operation. The further course was complicated by the development of a right-sided pleural empyema as well as recurrent intra-abdominal abscesses, which were both treated with repeated placements of interventional drainages. Empiric antibiotic therapy at sepsis onset included imipenem/cilastatin (IMP:CIL) in terms of a monotherapy. Culture-based microbiological diagnostics revealed no bacterial growth, whereas C. glabrata could be detected in both fluids of already positioned drainages as well as fresh puncture materials respectively. Based on these microbiological findings, the patient was classified as infected, so that an administration of caspofungin was started at 14 days after sepsis onset. Blood cultures remained negative for fungi at all time points. Contrariwise, a next generation sequencing (NGS)-based diagnostic approach in plasma samples of septic patients was able to support the presence of an invasive fungal infection already at 7 days after sepsis onset, since the SIQ-score was shown to be positive for C. glabrata at this time point. Unfortunately, a further evaluation of the patient’s course of the disease beyond 14 days after sepsis onset was not possible, since the patient denied further participation in the study. Abbreviations: CFG, caspofungin; IMP:CIL, imipenem/cilastatin; na, not available; nd, not detectable; NGS, next generation sequencing; SIQ, sepsis indicating; (C) A 71-year-old female patient presented with a right pleural empyema caused by a liver abscess with the need for a video-assisted thoracoscopy (VATS). One day after VATS, the patient suffered from an acute abdomen with septic shock due to a perforation of the sigmoid colon, so that a removal of the sigmoid colon had to be performed. A second explorative laparotomy was necessary at 10 days after sepsis onset, due to a messy drainage fluid with a suspicion of another bowel leakage. However, during the revision surgery no clear focus could be found. Empiric anti-infective treatment consisted of imipenem/cilastatin (IMP:CIL) in combination with fluconazole (FLC), which was further supplemented by vancomycin (VAC) for 2 days in the early phase after sepsis onset. Anti-infective treatment was stepwise deescalated, so that the patient was free of any antibiotics or antimycotics at 12 days after sepsis onset. In the further course of the disease, the administration of caspofungin (CFG) was started at 20 days after sepsis onset, since the patient did not recover well and drainage fluids were shown to be positive for Candida spp. repeatedly starting from 3 days after sepsis onset. In parallel, next generation sequencing (NGS)-based diagnostics revealed a positive SIQ-score for C. glabrata also at 3 days after sepsis onset, whereas blood cultures were found to be negative for fungi throughout the whole observation period. The end of the 28 day-observation period was further characterized by an insufficiency of the stump by Hartmann as well as the development of severe pneumonia with the key bacteria Pseudomonas aeruginosa and Enterococcus faecalis, so that another antibiotic treatment phase with piperacillin/tazobactam as well as inhaled tobramycin was initiated. Abbreviations: BC, blood culture; BL, bronchoalveolar lavage; CFG, caspofungin; FLC, fluconazole; IMP:CIL, imipenem/cilastatin; n.a, not available; NGS, next generation sequencing; SIQ, sepsis indicating quantifier; TBC, inhaled tobramycine, TS, tracheal secretion; TZP, piperacilline/tazobactam; VAC, vancomycin.
Figure 2
Figure 2
Time course (fungal) SIQ analyses compared with conventional clinical microbiology data of septic patients. The anti-infective treatment regime and (fungal) SIQ scores for species identified via NGS of the respective plasma samples are reported for a time course of 28 days (indicated by the x-axis) for patients S16 (A), S25 (B), and S35 (C). Only species identified by SIQ-score analyses are indicated at the left side. Red colored boxes reveal ranking of highest SIQ scores for the respective species in every patient. Pertinent (clinical microbiology) laboratory results are marked using arrows to indicate the day the clinical specimen was obtained. (A) A 73-year old male patient presented with a tumor of his bile duct with the need for a palliative resection. The surgical procedure included resections of the bile duct as well as the gallbladder and was followed by a double bypass procedure (biliodigestive anastomosis and gastrojejunal anastomosis). Four days after the initial operation the patient suffered from septic shock due to a duodenal ulcer perforation with the need for a total pancreatectomy. Shortly after, the patient suffered from another small bowel leakage, so that an additional small bowel resection had to be performed. Blood cultures at sepsis onset were shown to be negative, and meropenem (MEM) was administered in terms of an empiric antibiotic therapy. However, the patient suffered from a therapy-refractory course of the disease and C. albicans could be isolated from abdominal drainage fluids 6 days after sepsis onset. Accordingly, an additional antifungal treatment with fluconazole (FLC) was initiated. Due to the development of candidemia at 14 days after sepsis onset, this antifungal treatment regime was secondarily escalated towards caspofungin (CFG). These findings were in good agreement with next generation sequencing (NGS) diagnostics in plasma, since the SIQ-score was positive for C. albicans at the same timepoint. Abbreviations: NGS, next generation sequencing; SIQ, sepsis indicating quantifier; MEM, meropenem; IPM:CIL, imipenem/cilastatin; FLC, fluconazole; DOR, doripenem; CFG, caspofungin; BC, blood culture; CVC, central venous catheter; TS, tracheal secretion; (B) A 65-year old male patient suffered from a Klatskin tumor with the need for a right-sided hemihepatectomy. Due to an abscess at the resection site, the patient suffered from septic shock with the need for an interventional drainage 22 days after the initial operation. The further course was complicated by the development of a right-sided pleural empyema as well as recurrent intra-abdominal abscesses, which were both treated with repeated placements of interventional drainages. Empiric antibiotic therapy at sepsis onset included imipenem/cilastatin (IMP:CIL) in terms of a monotherapy. Culture-based microbiological diagnostics revealed no bacterial growth, whereas C. glabrata could be detected in both fluids of already positioned drainages as well as fresh puncture materials respectively. Based on these microbiological findings, the patient was classified as infected, so that an administration of caspofungin was started at 14 days after sepsis onset. Blood cultures remained negative for fungi at all time points. Contrariwise, a next generation sequencing (NGS)-based diagnostic approach in plasma samples of septic patients was able to support the presence of an invasive fungal infection already at 7 days after sepsis onset, since the SIQ-score was shown to be positive for C. glabrata at this time point. Unfortunately, a further evaluation of the patient’s course of the disease beyond 14 days after sepsis onset was not possible, since the patient denied further participation in the study. Abbreviations: CFG, caspofungin; IMP:CIL, imipenem/cilastatin; na, not available; nd, not detectable; NGS, next generation sequencing; SIQ, sepsis indicating; (C) A 71-year-old female patient presented with a right pleural empyema caused by a liver abscess with the need for a video-assisted thoracoscopy (VATS). One day after VATS, the patient suffered from an acute abdomen with septic shock due to a perforation of the sigmoid colon, so that a removal of the sigmoid colon had to be performed. A second explorative laparotomy was necessary at 10 days after sepsis onset, due to a messy drainage fluid with a suspicion of another bowel leakage. However, during the revision surgery no clear focus could be found. Empiric anti-infective treatment consisted of imipenem/cilastatin (IMP:CIL) in combination with fluconazole (FLC), which was further supplemented by vancomycin (VAC) for 2 days in the early phase after sepsis onset. Anti-infective treatment was stepwise deescalated, so that the patient was free of any antibiotics or antimycotics at 12 days after sepsis onset. In the further course of the disease, the administration of caspofungin (CFG) was started at 20 days after sepsis onset, since the patient did not recover well and drainage fluids were shown to be positive for Candida spp. repeatedly starting from 3 days after sepsis onset. In parallel, next generation sequencing (NGS)-based diagnostics revealed a positive SIQ-score for C. glabrata also at 3 days after sepsis onset, whereas blood cultures were found to be negative for fungi throughout the whole observation period. The end of the 28 day-observation period was further characterized by an insufficiency of the stump by Hartmann as well as the development of severe pneumonia with the key bacteria Pseudomonas aeruginosa and Enterococcus faecalis, so that another antibiotic treatment phase with piperacillin/tazobactam as well as inhaled tobramycin was initiated. Abbreviations: BC, blood culture; BL, bronchoalveolar lavage; CFG, caspofungin; FLC, fluconazole; IMP:CIL, imipenem/cilastatin; n.a, not available; NGS, next generation sequencing; SIQ, sepsis indicating quantifier; TBC, inhaled tobramycine, TS, tracheal secretion; TZP, piperacilline/tazobactam; VAC, vancomycin.
Figure 2
Figure 2
Time course (fungal) SIQ analyses compared with conventional clinical microbiology data of septic patients. The anti-infective treatment regime and (fungal) SIQ scores for species identified via NGS of the respective plasma samples are reported for a time course of 28 days (indicated by the x-axis) for patients S16 (A), S25 (B), and S35 (C). Only species identified by SIQ-score analyses are indicated at the left side. Red colored boxes reveal ranking of highest SIQ scores for the respective species in every patient. Pertinent (clinical microbiology) laboratory results are marked using arrows to indicate the day the clinical specimen was obtained. (A) A 73-year old male patient presented with a tumor of his bile duct with the need for a palliative resection. The surgical procedure included resections of the bile duct as well as the gallbladder and was followed by a double bypass procedure (biliodigestive anastomosis and gastrojejunal anastomosis). Four days after the initial operation the patient suffered from septic shock due to a duodenal ulcer perforation with the need for a total pancreatectomy. Shortly after, the patient suffered from another small bowel leakage, so that an additional small bowel resection had to be performed. Blood cultures at sepsis onset were shown to be negative, and meropenem (MEM) was administered in terms of an empiric antibiotic therapy. However, the patient suffered from a therapy-refractory course of the disease and C. albicans could be isolated from abdominal drainage fluids 6 days after sepsis onset. Accordingly, an additional antifungal treatment with fluconazole (FLC) was initiated. Due to the development of candidemia at 14 days after sepsis onset, this antifungal treatment regime was secondarily escalated towards caspofungin (CFG). These findings were in good agreement with next generation sequencing (NGS) diagnostics in plasma, since the SIQ-score was positive for C. albicans at the same timepoint. Abbreviations: NGS, next generation sequencing; SIQ, sepsis indicating quantifier; MEM, meropenem; IPM:CIL, imipenem/cilastatin; FLC, fluconazole; DOR, doripenem; CFG, caspofungin; BC, blood culture; CVC, central venous catheter; TS, tracheal secretion; (B) A 65-year old male patient suffered from a Klatskin tumor with the need for a right-sided hemihepatectomy. Due to an abscess at the resection site, the patient suffered from septic shock with the need for an interventional drainage 22 days after the initial operation. The further course was complicated by the development of a right-sided pleural empyema as well as recurrent intra-abdominal abscesses, which were both treated with repeated placements of interventional drainages. Empiric antibiotic therapy at sepsis onset included imipenem/cilastatin (IMP:CIL) in terms of a monotherapy. Culture-based microbiological diagnostics revealed no bacterial growth, whereas C. glabrata could be detected in both fluids of already positioned drainages as well as fresh puncture materials respectively. Based on these microbiological findings, the patient was classified as infected, so that an administration of caspofungin was started at 14 days after sepsis onset. Blood cultures remained negative for fungi at all time points. Contrariwise, a next generation sequencing (NGS)-based diagnostic approach in plasma samples of septic patients was able to support the presence of an invasive fungal infection already at 7 days after sepsis onset, since the SIQ-score was shown to be positive for C. glabrata at this time point. Unfortunately, a further evaluation of the patient’s course of the disease beyond 14 days after sepsis onset was not possible, since the patient denied further participation in the study. Abbreviations: CFG, caspofungin; IMP:CIL, imipenem/cilastatin; na, not available; nd, not detectable; NGS, next generation sequencing; SIQ, sepsis indicating; (C) A 71-year-old female patient presented with a right pleural empyema caused by a liver abscess with the need for a video-assisted thoracoscopy (VATS). One day after VATS, the patient suffered from an acute abdomen with septic shock due to a perforation of the sigmoid colon, so that a removal of the sigmoid colon had to be performed. A second explorative laparotomy was necessary at 10 days after sepsis onset, due to a messy drainage fluid with a suspicion of another bowel leakage. However, during the revision surgery no clear focus could be found. Empiric anti-infective treatment consisted of imipenem/cilastatin (IMP:CIL) in combination with fluconazole (FLC), which was further supplemented by vancomycin (VAC) for 2 days in the early phase after sepsis onset. Anti-infective treatment was stepwise deescalated, so that the patient was free of any antibiotics or antimycotics at 12 days after sepsis onset. In the further course of the disease, the administration of caspofungin (CFG) was started at 20 days after sepsis onset, since the patient did not recover well and drainage fluids were shown to be positive for Candida spp. repeatedly starting from 3 days after sepsis onset. In parallel, next generation sequencing (NGS)-based diagnostics revealed a positive SIQ-score for C. glabrata also at 3 days after sepsis onset, whereas blood cultures were found to be negative for fungi throughout the whole observation period. The end of the 28 day-observation period was further characterized by an insufficiency of the stump by Hartmann as well as the development of severe pneumonia with the key bacteria Pseudomonas aeruginosa and Enterococcus faecalis, so that another antibiotic treatment phase with piperacillin/tazobactam as well as inhaled tobramycin was initiated. Abbreviations: BC, blood culture; BL, bronchoalveolar lavage; CFG, caspofungin; FLC, fluconazole; IMP:CIL, imipenem/cilastatin; n.a, not available; NGS, next generation sequencing; SIQ, sepsis indicating quantifier; TBC, inhaled tobramycine, TS, tracheal secretion; TZP, piperacilline/tazobactam; VAC, vancomycin.
Figure 3
Figure 3
Plasma concentrations of β-d-glucan (BG) in patients with septic shock. Plasma concentrations of BG were measured in patients suffering from septic shock with a fungal infection (grey squared box), a fungal colonization (grey plane box) or without any fungal findings (white box). Plasma samples were collected at the onset of septic shock (T0), and 1 day (T1), 2 days (T2), 7 days (T3), 14 days (T4), 21 days (T5), and 28 days (T6) afterwards. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th as well as 90th percentile at the end of the whiskers.
Figure 4
Figure 4
Plasma concentrations of interleukin (IL)-17A in patients with septic shock. Legend: (A) Plasma concentrations of IL-17A were measured in patients suffering from septic shock with a fungal infection (grey squared box), a fungal colonization (grey plane box) or without any fungal findings (white box). Plasma samples were collected at the onset of septic shock (T0), and 1 day (T1), 2 days (T2), 7 days (T3), 14 days (T4), 21 days (T5), and 28 days (T6) afterwards. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th as well as 90th percentile at the end of the whiskers. Concerning symbolism and higher orders of significance: * p < 0.05, ** p < 0.01, *** p < 0.001; (B) Receiver operating characteristic (ROC) analysis with IL-17A in all participating patients at sepsis onset (T0), and 1 day (T1), 2 days (T2) as well as 7 days (T3) afterwards with regard to the prediction of a fungal infection up to day 28. Patients suffering from a fungal infection represented the target group, whereas both, patients with a fungal colonization as well as patients without any fungal isolates served as controls for this ROC-analysis.
Figure 5
Figure 5
Plasma concentrations of mid-regional proadrenomedullin (MR-proADM) in patients with septic shock. Legend: (A) Plasma concentrations of MR-proADM were measured in patients suffering from septic shock with a fungal infection (grey squared box), a fungal colonization (grey plane box) or without any fungal findings (white box). Plasma samples were collected at the onset of septic shock (T0), and 1 day (T1), 2 days (T2), 7 days (T3), 14 days (T4), 21 days (T5), and 28 days (T6) afterwards. Data in box plots are given as median, 25th percentile, 75th percentile with the 10th as well as 90th percentile at the end of the whiskers. Concerning symbolism and higher orders of significance: * p < 0.05, ** p < 0.01; (B) Receiver operating characteristic (ROC) analysis with MR-proADM in all participating patients at sepsis onset (T0), and 1 day (T1), 2 days (T2) as well as 7 days (T3) afterwards with regard to the prediction of a fungal infection up to day 28. Patients suffering from a fungal infection represented the target group, whereas both, patients with a fungal colonization as well as patients without any fungal isolates, served as controls for this ROC-analysis.
Figure 6
Figure 6
Early transcriptional host response of vulvovaginal RHE. Legend: (A) Hierarchical clustering of the set of 21 differentially expressed genes based on their fold changes. For each infected condition the uninfected control at the corresponding timepoint dealt as reference condition; (B) Expression values of late-stage Candida-induced cytokines compared to ADM.

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