Endocrine dysregulation in aneurysmal subarachnoid haemorrhage.

INTRODUCTION: Aneurysmal Subarachnoid haemorrhage (aSAH) is one of the most common causes of neurocritical care admission. Consistent evidence has been suggestive of endocrine dysregulation in aSAH. This review aims to provide an up-to-date presentation of the available evidence regarding endocrine dysregulation in aneurysmal subarachnoid haemorrhage. METHODS: A comprehensive literature search was performed using PubMed database. All available evidence related to endocrine dysregulation in hypothalamic-pituitary hormones, adrenal hormones and natriuretic peptides after aSAH, published since 2010, were reviewed. RESULTS: There have been reports of varying prevalence of dysregulation in hypothalamic-pituitary and adrenal hormones in aSAH. The cause of this dysregulation and its pattern remain unclear. Hypothalamic-pituitary and adrenal dysregulation have been associated with higher incidence of poor neurological outcome and increased mortality. Whilst there is evidence that long-term dysregulation of these axes may also develop, it appears to be less frequent than the acute-phase dysregulation and transient in pattern. Increased levels of catecholamines have been reported in the hyper-acute phase of aSAH with reported inconsistent correlation with the outcomes and the complications of the disease. There is growing evidence that of a causal link between the endocrine dysregulation and the development of hyponatraemia and delayed cerebral ischaemia, in the acute phase of aSAH. However, the pathophysiological mechanism and pattern of endocrine dysregulation which could be causally associated with these complications still remain debatable. CONCLUSION: The evidence, mainly from small observational and heterogeneous in methodology studies, is suggestive of adverse effects of the endocrine dysregulation on the outcome and the incidence of complications of the disease. However, the cause of this dysregulation and a pathophysiological mechanism that could link its presence with the development of acute complications and the outcome of the aSAH remain unclear. Further research is warranted to elucidate the clinical significance of endocrine dysregulation in subarachnoid haemorrhage.

Multiple Organ Dysfunction Syndrome.

Multiple organ dysfunction syndrome (MODS) is one of the most common syndromes of critical illness and the leading cause of mortality among critically ill patients. Multiple organ dysfunction syndrome is the clinical consequence of a dysregulated inflammatory response, triggered by clinically diverse factors with the main pillar of management being invasive organ support. During the last years, the advances in the clarification of the molecular pathways that trigger, mitigate, and determine the outcome of MODS have led to the increasing recognition of MODS as a distinct disease entity with distinct etiology, pathophysiology, and potential future therapeutic interventions. Given the lack of effective treatment for MODS, its early recognition, the early intensive care unit admission, and the initiation of invasive organ support remain the most effective strategies of preventing its progression and improving outcomes.

A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis.

In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to-treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708.

Multiple Organ Dysfunction Secondary to Herpes Simplex Virus -1 Reactivation After Treatment With Dexamethasone and Sarilumab for Covid-19 Disease.

Introduction: The immunological response to the SARS-CoV-2 virus and the treatment of COVID-19 disease present a potential susceptibility to viral reactivation, particularly Herpes simplex virus-1 (HSV-1). Case Presentation: A 49-year-old female presented to hospital with severe COVID-19 pneumonitis and was given sarilumab and dexamethasone. She was intubated and ventilated in the intensive care unit (ICU) and initially demonstrated biochemical and clinical evidence of improvement. This was followed by a severe acute deterioration in respiratory, renal, and cardiovascular function, accompanied by a vesicular rash on the face. Polymerase chain reaction confirmed HSV-1 reactivation and treatment with acyclovir was commenced. After 49 days in ICU the patient was successfully weaned from all organ support, and she made a satisfactory recovery. Conclusions: HSV-1 reactivation is common in COVID-19 and likely contributes to poorer clinical outcomes. The mechanism causing susceptibility to viral reactivation is not clearly defined, however, the development of critical illness induced immunosuppression via dysfunction of interferon and interleukin pathways is a likely mechanism. This effect could be perpetuated with immunosuppressant medications, although further research is needed to characterise this phenomenon.

Enhanced analysis of somatosensory evoked potentials at 20-30 milliseconds can predict neurological outcome after cardiac arrest.

OBJECTIVE: This study attempted to test the effectiveness of an enhanced analysis of the 20-30 ms complex of somatosensory evoked potentials, in predicting the short-term outcome of comatose survivors of out of hospital cardiac arrest and compare it with the current clinical practice. METHODS: Single-centre, prospective, observational study. Median nerve SSEP recording performed at 24-36 h post-return of spontaneous circulation. Recording was analysed using amplitude measurements of P25/30 and Peak-To-Trough of 20-30 ms complex and thresholds to decide P25/30 presence. Neurological outcome was dichotomised into favourable and unfavourable. RESULTS: 89 participants were analysed. 43.8% had favourable and 56.2% unfavourable outcome. The sensitivity, specificity, positive and negative predictive values of the present SSEP and favourable outcome were calculated. P25/30 presence and size of PTT improved positive predictive value and specificity, while maintained similar negative predictive value and sensitivity, compared to the current practice. Inter-interpreter agreement was also improved. CONCLUSIONS: Enhanced analysis of the SSEP at 20-30 ms complex could improve the short-term prognostic accuracy for short-term neurological outcome in comatose survivors of cardiac arrest. SIGNIFICANCE: Peak-To-Trough analysis of the 20-30 ms SSEP waveform appears to be the best predictor of neurological outcome following out of hospital cardiac arrest. It is also the easiest and most reliable to analyse.

Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents.

The circulating levels of several angiogenic cytokines [angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF)] were evaluated in 174 consecutive patients with newly diagnosed, symptomatic, multiple myeloma (MM). Circulating levels of Ang-1/Ang-2 were reduced in myeloma patients compared to controls, whereas VEGF and angiogenin levels were increased. Reduced angiopoietin-1/angiopoietin-2 ratio correlated with advanced disease features including international staging system (ISS)-3 stage, renal impairment and extensive bone disease. Based on immunohistochemical results in 20 patients (10 with the higher and 10 with the lower values of circulating angiopoietin-2) we found that angiopoietin-2 is expressed by myeloma cells and correlates with increased microvessel density in subsets of patients. Furthermore, Ang-1/Ang-2 ratio correlated with survival. Patients with circulating Ang-1/Ang-2 below or equal to the median value (6.03) had a median survival of 26.3 months compared to 53 months of all others (p = 0.002). Interestingly, this was mainly observed in patients who received first-line therapy with novel agent-based regimens (65% of our patients). Furthermore, a subset of ISS-3 patients with serum Ang-1/Ang-2 above the median value had favourable prognosis (median survival: 45 months versus 17 months of all others; p = 0.0001). The multivariate analysis revealed that low Ang-1/Ang-2 ratio could independently predict for inferior survival in our cohort of patients (relative risk (RR) 2.07, 95% CI 1.50-2.42; p < 0.001). These results highlight the role of angiopoietins pathway in the biology of MM and reveal novel targets for the development of antimyeloma agents.

XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis.

BACKGROUND: The aim was to compare two standard chemotherapy regimens combined with bevacizumab as first-line treatment in patients with metastatic colorectal cancer. METHODS: Patients previously untreated for metastatic disease were randomized in: group A (irinotecan, capecitabine, bevacizumab, every 3 weeks; XELIRI-bevacizumab) and group B (irinotecan, leucovorin, fluorouracil, bevacizumab, every 2 weeks; FOLFIRI-bevacizumab). Primary endpoint was progression-free survival (PFS). Plasma concentrations of nitric oxide, osteopontin, TGF-ß1 and VEGF-A were measured at baseline and during treatment. RESULTS: Among 285 eligible patients, 143 were randomized to group A and 142 to group B. Fifty-five patients (38.5%) in group A and 57 (40.1%) in group B responded (p = 0.81). After a median follow-up of 42 months, median PFS was 10.2 and 10.8 months (p = 0.74), while median OS was 20.0 and 25.3 months (p = 0.099), for groups A and B, respectively. Most frequent grade 3-4 toxicities (group A vs group B) were neutropenia (13% vs 22%, p = 0.053) and diarrhea (19% vs 11%, p = 0.082). Baseline plasma osteopontin concentrations demonstrated prognostic significance for both PFS and OS. CONCLUSIONS: This trial did not show significant differences in efficacy between the groups. However, the toxicity profile was different. Baseline plasma osteopontin concentrations demonstrated independent prognostic significance. ( REGISTRATION NUMBER: ACTRN12610000270011).

Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents.

Multiple myeloma (MM) comprises 1% of all malignancies and 13% of hematological malignancies in the Caucasian population. Yearly incidence is 4/100,000 in the US and is higher in blacks and males [1]. The pathogenesis of the disease is relatively unknown; several chromosomal abnormalities have been related to the development of the disease,but none is characteristic of MM. Cyclin-D1 is a protein encoded by the CCND1 (bcl-1) gene on chromosome 11q13, and is an important regulator of G1 to S phase progression.

Short progression-free survival predicts for poor overall survival in older patients with multiple myeloma treated upfront with novel agent-based therapy.

OBJECTIVES: To assess the importance of the quality of response and of early relapse in unselected elderly patients with myeloma treated upfront with novel agents. METHODS: We analyzed 135 unselected transplant-ineligible patients older than 65 yr who were treated upfront with novel agent-based regimens in a single center. RESULTS: On intent to treat, 81% of patients achieved a response (28% sCR/CR, 23% VGPR, and 30% PR). Median progression-free survival (PFS) for patients who achieved sCR/CR was 31 vs. 20 months for VGPR and 23 months for PR (P = 0.048). Median overall survival (OS) for patients with sCR/CR was 62 months, 53 months for VGPR and 38 months for patients with PR (P = 0.028). Early relapse (PFS < 12 months) was more common in patients with PR (39% vs. 21% for VGPR vs. 3% for sCR/CR). Patients who relapsed or progressed < 12 months from initiation of treatment had a median OS of 15.4 months compared with 53 months (P < 0.001) for patients who had a PFS > 12 months despite the fact that after relapse or progression most patients were treated again with novel agents. In multivariate analysis, short PFS was the most significant adverse prognostic factor affecting OS, associated with a 7.25-fold (P < 0.0001) increase in the risk of death. CONCLUSION: In newly diagnosed patients over 65 yr, treated upfront with novel agents achievement of CR and a PFS ≥ 12 months is associated with improved outcome. Patients who fail to respond or experience early relapse after primary therapy with novel agent-based regimens should be encouraged to participate in clinical trials of novel agents and combinations.

A case of COVID-19 reinfection in the UK.

Protective immunity following COVID-19 infection is not yet fully understood. An understanding of COVID-19 reinfection will be key in guiding government and public health policy decisions in the coming months. This report describes two distinct infective episodes of COVID-19 occurring in the same individual, at the time of writing the first published case in the UK. In April 2020 a 25-year-old UK doctor exhibited classical COVID-19 symptoms, including fevers, headaches, and fatigue. A COVID-19 nucleic acid amplification test (NAAT) at the time returned negative. However, a follow-up antibody test in May 2020 returned positive. In October 2020 the same individual exhibited coryzal symptoms and headaches. He was COVID-19 NAAT tested and found to be positive. There was exposure to high viral load prior to reinfection. Overall the second infection was symptomatically milder, with a faster recovery. This evidence for reinfection poses challenges for public health and vaccination efforts to protect against the COVID-19 pandemic.

Burkitt's lymphoma in pregnancy with bilateral breast involvement: case report with review of the literature.

BACKGROUND: Burkitt's lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far. CASE REPORT: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable. CONCLUSIONS: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach.

Microdialysis-Assessed Adipose Tissue Metabolism, Circulating Cytokines and Outcome in Critical Illness.

Microdialysis (MD) can provide continuous information about tissue composition. To assess in critically ill patients adipose tissue metabolic patterns, the relationships between metabolic patterns and blood cytokine concentration associations of adipose tissue energy metabolism and clinical outcome we studied 203 mechanically ventilated general intensive care unit (ICU) patients. Upon ICU admission an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh to measure lactate (L), glucose, pyruvate (P), and glycerol. Serum concentrations of IL-10, IL-6, IL-8, and TNF-α were determined within 48 h from ICU admission. Mitochondrial dysfunction was defined as L/P ratio >30 and pyruvate ≥70 µmol/L, ischemia as L/P ratio >30 and pyruvate <70 µmol/L and no ischemia/no mitochondrial dysfunction (i.e. aerobic metabolism) was as L/P ratio ≤30. Metabolism was aerobic in 74% of patients. In 13% of patients there was biochemical evidence of ischemia and in 13% of patients of mitochondrial dysfunction. Mitochondrial dysfunction was associated with poor outcome. In conclusion, MD showed that about two thirds of critically ill patients have normal aerobic adipose tissue metabolism. Mitochondrial dysfunction was not common but was associated with poor outcome. Identifying subgroups of critically ill patients is crucial as different treatment strategies may improve survival.

Adipose Tissue Lactate Clearance but Not Blood Lactate Clearance Is Associated with Clinical Outcome in Sepsis or Septic Shock during the Post-Resuscitation Period.

No study has directly measured tissue lactate clearance in patients with sepsis during the post-resuscitation period. In this study we aimed to assess in ICU patients with sepsis (n = 32) or septic shock (n = 79)—during the post-resuscitation phase—the relative kinetics of blood/tissue lactate clearances and to examine whether these are associated with outcome. We measured serially—over a 48-h period—blood and adipose tissue interstitial fluid lactate levels (with microdialysis) and we calculated lactate clearance. Statistics included mixed model analysis, Friedman’s analysis of variance, Wilcoxon’s test, Mann-Whitney’s test, receiver operating characteristics curves and logistic regression. Forty patients died (28-day mortality rate = 28%). Tissue lactate clearance was higher compared to blood lactate clearance at 0⁻8, 0⁻12, 0⁻16, 0⁻20 and 0⁻24 h (all p < 0.05). Tissue lactate clearance was higher in survivors compared to non-survivors at 0⁻12, 0⁻20 and 0⁻24 h (all p = 0.02). APACHE II along with tissue lactate clearance <30% at 0⁻12, 0⁻20 and 0⁻24 h were independent outcome predictors. We did not find blood lactate clearance to be related to survival. Thus, in critically ill septic patients, elevated tissue (but not blood) lactate clearance, was associated with a favorable clinical outcome.

Microdialysis-Assessed Adipose Tissue Metabolism in Critically Ill Patients.

BACKGROUND: Microdialysis is a minimally invasive technique that allows direct in situ and in vivo sampling, studies and manipulations of the interstitial/extracellular fluid/space. It has been shown to be of use mainly in acute brain injury/neurocritical care. METHODS: Microdialysis has been used to study obesity, diabetes mellitus, inflammation and pharmacokinetics at the adipose tissue level. In critically ill patients (and particularly in those with sepsis or septic shock), within days to weeks, adipose tissue shows profound alterations; under such conditions, the implementation of microdialysis can provide researchers with interesting findings. RESULTS: The well-known association between lipolysis and cortisol has been verified at the tissue level with microdialysis. Specific metabolic aberrations in critically ill patients with septic shock have been noted in adipose tissue - assessed with microdialysis before becoming evident in the systemic circulation. Measurement of the lactate to pyruvate ratio in adipose tissue - also assessed with microdialysis - in patients with septic shock has prognostic value equal to that of universally accepted clinical severity scores. CONCLUSION: Microneedle arrays have been already used to assess interstitial fluid glucose. Possibly, the implementation of microneedle and lab-on-a-chip technology, might complement the current use of microdialysis in the study of the interstitial space/adipose tissue metabolism in health and disease.

Evidence of Subcutaneous Tissue Lipolysis Enhancement by Endogenous Cortisol in Critically Ill Patients Without Shock.

BACKGROUND/AIM: Cortisol is involved in in many aspects of adipose tissue metabolism. A positive association between plasma cortisol and lipolysis has been observed. Critically ill patients exhibit 'lipemia of sepsis'. The aim of the present study was to study, in septic ICU patients, adipose tissue lipolysis in relation to tissue cortisol using microdialysis (MD). PATIENTS AND METHODS: We studied 17 mechanically-ventilated patients (9 men; mean±SD age=63±19 years) with a diagnosis of severe sepsis. Upon ICU admission, an MD catheter was inserted under sterile conditions into the subcutaneous adipose tissue of the upper thigh. On days 2, 3 and 4, MD samples were collected six times per day for glycerol (used as an index of lipolysis) and tissue cortisol determinations. The mean of these six collections was used for analysis (normal values for adipose tissue glycerol <200 µmol/l). Statistics were carried-out with analysis of covariance (ANCOVA) and linear regression. RESULTS: More than half of the samplings (19/31) indicated accentuated lipolysis with above-normal MD glycerol levels. By ANCOVA, MD glycerol (log values) was associated with MD cortisol (log values) (p=0.012) and was not associated with age or day of sampling. Furthermore, MD glycerol (log values) was positively correlated to MD cortisol (log values) (r=0.490, p=0.012). DISCUSSION: Changes in interstitial/tissue cortisol may not be reflected in (total) plasma cortisol concentration. Thus, it is interesting that we observed, albeit weak, an association between tissue lipolysis (via MD glycerol levels) and MD cortisol, verifying (although modestly so) the well-known association between lipolysis and cortisol.

Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers.

PURPOSE: Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect "immunocompetent" seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. METHODS: This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ, interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. RESULTS: During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. CONCLUSIONS: Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome.

Coronary flow reserve is associated with tissue ischemia and is an additive predictor of intensive care unit mortality to traditional risk scores in septic shock.

BACKGROUND: Reduced coronary velocity flow reserve (CFR) is associated with poor outcome in patients with cardiovascular disease. We investigated whether CFR is associated with tissue ischemia and acidosis, impaired myocardial deformation and adverse outcome in patients with septic shock. METHODS: In 70 mechanically-ventilated patients with septic shock, we examined: a) S' and E' mitral annular velocities using tissue Doppler imaging (TDI), b) CFR of the left anterior descending artery after adenosine infusion using transesophageal Doppler echocardiography and c) lactate, pyruvate and glycerol in tissue by means of a microdialysis (MD) catheter inserted into the subcutaneous adipose tissue as markers of tissue ischemia and acidosis. SOFA and APACHE II prognostic scores and mortality in the intensive care unit (ICU) were recorded. RESULTS: Reduced CFR, S' and E' as well as increased E/E' correlated with increased SOFA, APACHE II and MD lactate to pyruvate ratio (p<0.05 for all correlations). Impaired TDI markers also correlated with increased MD glycerol (p<0.05). Reduced CFR correlated with decreased E' (p<0.05). CFR was 1.8 ± 0.42 in non-survivors (n=34) versus 2.08 ± 0.44 in survivors (p=0.007). A CFR<1.90 predicted mortality with sensitivity of 70% and specificity of 69% (area under the curve 77%; p=0.003). CFR had an additive value to APACHE (chi-square change: 4.358, p=0.03) and SOFA (chi-square change: 3.692, p=0.04) for the prediction of mortality. CONCLUSION: Tissue ischemia and acidosis is a common pathophysiological link between decreased CFR and impaired LV myocardial deformation in septic shock. CFR is an additive predictor of ICU mortality to traditional risk scores in septic shock.

Yeast central nervous system infection in a critically ill patient: a case report.

INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.