Fungal Sepsis Research Articles

Recent advances in prevention of sepsis in the premature neonates in NICU

Sepsis-related morbidity and mortality are major problems in NICU. Preterm neonates display clinical characteristics that make them prone to infections. Due to the high frequency of severe neurodevelopmental sequelae in survivors, the best possible strategy to manage sepsis in NICU is to prevent them. Hygiene, cohorting, stewardship on use of H2-blockers, steroids and broad-spectrum antibiotic are mandatory, as well as proper management of central venous accesses and surgical devices. In addition, clinical research offers the opportunity of adopting pharmacological preventative strategies such as use of palivizumab to prevent RSV infection, use of fluconazole to prevent fungal sepsis, use of probiotics and lactoferrin to enhance the innate immunity, and use of pagibaximab to prevent staphylococcal sepsis.

Antifungal prophylaxis in neonates

Fungal-related morbidity and mortality is a major concern for most neonatal intensive care units (NICUs) worldwide. Incidence rates are increasing and might be higher than reported due to the challenges associated with diagnosing fungal infections. As preterm neonates display clinical characteristics that make them prone to Candida spp infections, and there is a high frequency of severe neurodevelopmental sequelae in those who survive neonatal fungal infections, specific prevention – rather than empiric or pre-emptive treatment – should be the optimal strategy. Besides stewardship of drug use and efforts to minimize invasive cares, pharmacological prevention with use of fluconazole has proved highly effective in decreasing the rates of fungal sepsis in very low birth weight (VLBW) neonates. Alternative options needing further and more conclusive assessments include use of nystatin, bovine lactoferrin or probiotics.

Trends in Epidemiology of Neonatal Sepsis in a Tertiary Center in Korea: A 26-Year Longitudinal Analysis, 1980-2005

There were many reports of longitudinal changes in the causative organisms of neonatal sepsis in Western countries but few in Asia. We aimed to study longitudinal trends in the epidemiology of neonatal sepsis at Seoul National University Children's Hospital (SNUCH), a tertiary center in Korea, and compared the results to previous studies of Western countries. The medical records of all of the neonates who were hospitalized at SNUCH from 1996 to 2005 with positive blood cultures were reviewed. We also compared the findings to previous 16-yr (1980-1995). One hundred and forty-nine organisms were identified in 147 episodes from 134 infants. In comparison with the previous 16-yr studies, there was a decrease in the number of Escherichia coli infections (16.2% vs 8.7%: odds ratio [OR] 0.495; 95% confidence interval [CI], 0.255-0.962; P = 0.035), but an increase in Staphylococcus aureus (16.6% vs 25.5%: OR 1.720; 95% CI, 1.043-2.839; P = 0.033) and fungal infections (3.3% vs 18.7%: OR 6.740; 95% CI, 2.981-15.239; P < 0.001), predominantly caused by Candida species. In conclusion, the incidence of sepsis caused by E. coli decreases, but S. aureus and fungal sepsis increases significantly. Compared with Western studies, the incidence of sepsis caused by S. aureus and fungus has remarkably increased.

A Pilot Study of Reduced Toxicity Conditioning (RTC) with Busulfan (Bu), Fludarabine (Flu), and Alemtuzumab Followed by Allogeneic Stem Cell Transplantation (AlloSCT) to Induce Sustained Mixed Donor Chimerism In Patients with Symptomatic Sickle Cell Disease (SCD)

AbstractAbstract 3504The only known curative therapy for patients with SCD is a matched family donor AlloSCT (Walters et al, NEJM, 1996). Complications after myeloablative AlloSCT are numerous and include death, graft versus host disease (GVHD), and infections, making reduced toxicity conditioning regimens more appealing. A major obstacle allowing most SCD patients to undergo SCT is the lack of an unaffected, HLA-matched identical sibling (Bhatia et al, BMT, 2008). Umbilical cord blood (UCB) has been proven to be an excellent alternate donor source that can safely reconstitute hematopoiesis after AlloSCT in pediatric recipients with non-malignant conditions (Cairo et al, BBMT, 2008). In this study, we report the results of a RTC regimen followed by an AlloSCT from matched family and unrelated UCB donors in selected patients with symptomatic SCD. Between August 27, 2004 and March 2, 2010, 18 patients (14M:2F) with symptomatic SCD (HbSS=10, HbSC=4, HbSßThal=4) underwent an AlloSCT. Indications for SCT included: ACS (n=8), CVA (n=2), multiple VOC (n=9), splenic sequestration (n=6) and retinopathy (n=1). Conditioning was Bu (4mg/kg × 4d < 4 yrs and 12.8mg/kg × 4d > 4 yrs), Flu (30mg/m2 × 6d), and Alemtuzumab (2mg/m2 × 1d, 6mg/m2 × 2d, and 20mg/m2 × 2d). Median age was 6.29 yrs(1.3–19.2). Median follow-up was 26 months. Donor sources: 8-6/6 HLA-matched sibling bone marrow (BM), 2–6/6 sibling UCB, 1–6/6, 4–5/6 and 3–4/6 unrelated UCB. Donors were HbAA (n=13), HbAC (n=1), HbAS(n=3), or ßThal trait (n=1). Sibling BM recipients received a median total nucleated cell (TNC) dose/kg of 7.16 × 108 (range 2.27–11.31) and a median CD34 cell dose/kg of 5.38 × 106 (range 1.50–6.83). Recipients of related or unrelated UCB received a median TNC dose/kg of 4.35 × 107 (range 3.40–9.10) and a median CD34 cell dose/kg of 2.21 × 105 (range 0.60–7.94). All received tacrolimus and mycophenolate mofetil as GVHD prophylaxis (Bhatia/Cairo et al, BBMT, 2009) and phenytoin or keppra as seizure prophylaxis for 180 days post SCT. Patients receiving sibling donor AlloSCT had a median time to neutrophil engraftment of 16 days (range 13–41). Among evaluable unrelated UCBT recipients, median time to neutrophil engraftment was 34 days (range 27–47). Four patients (all unrelated UCBT) experienced primary graft failure at day +60 post-SCT secondary to CMV (n=2), adenovirus, and low Bu Css levels with early withdrawal of MMF. Patients with sibling donors had a median time to platelet engraftment of 26 days (range 17–75). Of evaluable unrelated UCB recipients, median time to platelet engraftment was 54 days (range 43–70). Patients achieved mean whole blood donor chimerism of 71.0, 79.6, 85.7, 92.9, 90.7% and 93.2% at days 30, 60, 100, 180, 365 and 730 post-transplant, respectively. Mean erythroid (CD71) donor chimerism at these time points was 78.1, 81.1, 86.6, 90.5, 87.9% and 94.0%, respectively. Patients with non-sickle cell trait donors had median HbS levels of 0% at 1 yr (n=8) and 2 yrs (n=3) post-SCT; those with sickle cell trait donors had median HbS levels of 38.3% at 1 yr (n=3) and 39% at 2yrs (n=3) post-SCT. Among evaluable patients, the Kaplan-Meier probability of grade II-IV acute GVHD is 33.3% and of chronic GVHD is 8.3%. Among the ten donor-recipient pairs in which at least one member of the pair had CMV positivity, four experienced CMV reactivation on days +13, +26, +30 and +32 (BM: n=2, unrelated UCB: n=2). Of the four patients with primary graft failure (all unrelated UCBT recipients), one resumed chronic transfusions, two died of complications from disseminated CMV and adenoviral infections, and one received a second myeloablative SCT 1 yr after initial SCT and died of fungal sepsis. Among all patients, the Kaplan-Meier probability of OS is 81.8% (100% with sibling donors, 62.5% with UCB donors) and of EFS is 77.8% (100% with sibling donors, 50% with UCB donors) with none of these patients showing any evidence of SCD symptomatology post-SCT. The longest follow-up is 2134 days. In summary, we report the largest experience of RTC and matched family AlloSCT in selected children with symptomatic SCD with persistent long-term donor chimerism and absence of SCD symptoms or progression of disease. However, with the high incidence of viral infections and toxic deaths following unrelated UCBT, it is too premature to extend this treatment option to those SCD patients lacking a sibling donor. Disclosures:No relevant conflicts of interest to declare.

1395 Invasive Fungal Sepsis Before and After Institution of Antifungal Prophylaxis in a Tertiary Neonatal Unit - 10 Year Observational Study

Background and aims: Fungal sepsis (FS) is an important cause of morbidity and mortality in very low birth weight(VLBW) babies. The objective of our study was to review the cases of invasive fungal infection before and after starting antifungal prophylaxis (AFP) over a 10 year period.Methods: Retrospective review of all cases of blood culture-positive fungal sepsis before AFP (January 1999 to December 2006) and after AFP (Jan 2007 to current).Results: There were 12 cases of blood culturepositive fungal sepsis in the 7 year period before AFP. Age at diagnosis was < 14 days in 75% of cases. Fungi isolated were Candida albicans(75%), Candida parapsilosis(17%) and Candida glabrata(8%). Major risk factors for FS were gestational age < 27 weeks, weight < 750g and preterm babies undergoing abdominal surgery for necrotising enterocolitis with the need for prolonged presence of central line.AFP with fluconazole 3 mg/kg intravenously was commenced from Jan 2007 targeting high risk groups as above. In this period, there was expansion in cot capacity with 2614 admissions to our unit, of which 183 babies were either < 27 weeks or < 750g. Until now there have been no cases of FS in babies with strict adherence to the protocol. The only case of FS (Candida albicans) occurred on day 10 in a VLBW baby where fluconazole had not been administered as recommended.Conclusion: AFP significantly reduces the incidence of invasive fungal infection in VLBW babies. We recommend their rational use targeting high risk babies as above.

DIFFERENTIAL EFFECTS OF IL-17 PATHWAY IN DISSEMINATED CANDIDIASIS AND ZYMOSAN-INDUCED MULTIPLE ORGAN FAILURE

The role of the IL-17 pathway in antifungal host defense is controversial. Several studies suggested that IL-17 is crucial for the protection against Candida infection, whereas other studies reported that IL-17 may contribute to inflammatory pathology and worsening of fungal disease. To address these discrepancies, we assessed the differential role of IL-17 pathway in two models of fungal sepsis: intravenous infection with live Candida albicans, in which fungal growth is the main cause of mortality, and zymosan-induced multiple organ failure, in which the inflammatory pathology drives the mortality. First, IL-17 receptor-deficient (IL-17RA) mice showed increased mortality and higher fungal loads in the kidneys in the model of disseminated candidiasis, partly caused by lower neutrophil recruitment in the IL-17RA mice. Second, IL-17RA mice were not protected against the multiorgan failure induced by zymosan. These data demonstrate that IL-17 does not have a major contribution to the inflammatory pathology leading to organ failure in fungal sepsis and support the concept that the IL-17 pathway is protective in antifungal host defense.

Fatal Strongyloides stercoralis hyper-infection in a patient with multiple myeloma

Strongyloides stercoralis (S.S.) is a human intestinal parasite, which may lead to complicated strongyloidiasis. We report a case of disseminated strongyloidiasis following the treatment of myeloma. The patient developed skin lesions, respiratory distress, aseptic meningitis and bacterial and fungal sepsis. The diagnosis of strongyloidiasis was established through endotracheal tube secretions. Despite the treatment with Ivermectin and Albendazole, the outcome was fatal. The value of screening for strongyloidiasis is unclear but may be of benefit in patients with hematological malignancies from high endemic areas

WHAT'S NEW IN SHOCK, OCTOBER 2010?

WHAT'S NEW IN SHOCK, OCTOBER 2010?

Giant Mycotic Right Atrial Thrombus Due to Candida dubliniensis Septicemia in a Premature Infant

To the Editors: Invasive candidal infections are increasing in incidence and have become the third most common cause of late-onset infection among premature infants. Candida endocarditis has been found in 5.5% to 15.2% of cases of fungal sepsis and can be associated with higher mortality than fungemia alone.1–3 Candida species other than C. albicans have been rarely isolated.1 We report a premature infant, successfully treated for a large mycotic vegetation in the right atrium (RA) secondary to C. dubliniensis sepsis refractory to antimycotic treatment. This is a second report of C. dubliniensis as a cause of neonatal endocarditis.4 A 1400-g female was delivered at 33 weeks gestation with gastroschisis and apple-peel intestinal atresia accompanied with a short gut and atretic microcolon originating from the splenic flexure. Prophylactic antibiotic treatment and total parenteral nutrition were started through a catheter placed at the RA/inferior vena cava junction. Initially, necrotic parts of intestine were removed, and enterostomy with temporary abdominal closure was performed. She subsequently developed ileus with an enterocutaneous fistula, and additional intestinal resection was done. The proximal 30 cm of the intestines were preserved only. At the age of 10 days, she deteriorated with apnea, bradycardia, hypotension, lethargy, and fever. Complete blood count revealed thrombocytopenia (T 5 × 109/L), leukopenia with a left shift (L 5.9 × 109/L, immature/mature neutrophil ratio 0.56), and elevated C-reactive protein (216 mg/L). Blood cultures grew C. dubliniensis susceptible to amphotericin B and fluconazole. The catheter was withdrawn, and treatment with liposomal amphotericin B (5 mg/kg/d) was started because of impaired renal function (BUN 131 mg/dl and creatinine 1.7 mg/dl). Despite therapy, the infant remained thrombocytopenic and blood cultures continued to grow C. dubliniensis. Echocardiogram revealed a gigantic floating polypoid thrombus in the RA measuring 20 × 10 mm (Fig. 1), originating from the inferolateral RA wall next to the inferior vena cava orifice intermittently reaching the right ventricular cavity (see Video, Supplemental Digital Content 1, https://links.lww.com/INF/A474, which represents echocardiogram in subcostal 4 chamber view). Candidal involvement of other organs was excluded. Therapy was modified to liposomal amphotericin B (20 mg/kg/d) with fluconazole (12 mg/kg/d).FIGURE 1.: Echocardiographic image showing the large mycotic thrombus in the right atrium measuring 20 × 10 mm.Because antifungal therapy after 9-week duration failed to obtain sterilization and regression of the thrombus, the infant was referred for surgery. Her body weight was 2300 g, at that time. After successful thrombectomy, blood cultures become negative. Diagnosis was verified by the clinical pathologist and microbiology tests. Antimycotic therapy was discontinued 8 weeks after negative cultures were achieved. Two more operations were required to reestablish intestinal continuity. On 18 months follow-up, she has no neurodevelopmental abnormalities, she is gaining weight on full enteral feeding, and there has been no recurrence of Candida infection. The small number of cases reported so far precludes a definitive recommendation about the optimal treatment concerning infected intracardiac thrombi. Current options include antifungal chemotherapy, thrombolysis, and surgical intervention.5 We believe that the excellent outcome in our case validates the strategy that infected atrial thrombus refractory to medical treatment can be safely removed by cardiotomy even in preterm infants and that surgery could be potentially lifesaving in such cases. Ruža Grizelj, MD Jurica Vuković, MD, PhD Dalibor Šarić, MD Department of Pediatrics University of Zagreb Medical School Tomislav Luetić, MD, PhD Department of Pediatric Surgery University of Zagreb Medical School University Hospital Zagreb, Croatia

Analysis of clinical characteristics and antimicrobial susceptibilities in very low birth weight infants and extremely low birth weight infants with neonatal sepsis

Objective To review the basic clinical characteristics and the pathogens and their antimicrobial susceptibilities to neonatal sepsis in very low birth weight infants (VLBWI) and extremely low birth weight infants ( ELBWI) for selection of appropriate antibiotics. Methods A retrospective chart review of 56 cases with neonatal sepsis(early onset neonatal sepsis 3 cases, late onset 53 cases) in VLBWI and ELBWI admitted to the neonatal intensive care unit of Yuying Children's Hospital of Wenzhou Medical College from January 1, 1999 to December 31, 2008 was conducted. The basic clinical characteristics and the results of blood culture and antimicrobial susceptibilities were analyzed. Results Among the 56 cases, the clinical presentations were non-specific. A total of 43 strains of bacteria were isolated, and the most important pathogens responsible for neonatal sepsis in VLBWI and ELBWI were opportunistic pathogenic bacteria. In early onset neonatal sepsis, there was only one culture-proven sepsis that was Chryseobacterium meningosepticum. In the late onset neonatal sepsis cases, the main pathogens of Gram-negative organisms were Klebsiella pneumoniae (33. 3%, 14/42), and the most common Gram-positive organisms were coagulase-negative Staphylococci (26. 2%, 11/42), followed by Enterococcus species (11. 9%,5/42). Furthermore, there were 2 fungal sepsis(4. 8%, 2/42), which were infected by Candida albicans. All of the coagulase-negative Staphylococci were methicillin-resistant coagulase-negative Staphylococci, and they were resistant to common antibiotics and sensitive to vancotnycin and rifampicin. And all of the Klebsiella pneumoniae produced extended-spectrum (Hactamases, which were sensitive only to a few antibiotics such as carbopenems, aminoglycosides and quinolones. Among those 56 cases, 43 patients were cured, 13 died, including six patients who refused any treatments, the mortality rate of neonatal sepsis in VLBWI and ELBWI was 23. 2%. Conclusions The clinical presentations of neonatal sepsis in VLBWI and ELBWI were non-specific, and the most important pathogens were opportunistic pathogenic bacteria, which were multi-drug resistant. Routine blood culture should be taken from infants who are suspected of neonatal sepsis and empirical use of appropriate antibiotics should be initiated as soon as the blood specimen for culture has been drawn. To reduce the occurrence of multi-drug resistant bacteria, we should restrict the use of antibiotics especially the third generation of cephalosporins in neonates as much as possible. Key words: Infant, extremely low birth weight; Sepsis; Drug resistance, bacterial

Association of fungal sepsis and galactosemia

Galactosemia is one of the rare inborn errors of metabolism, which if detected early can be treated effectively. Galactosemic infants have a significant increased risk of developing sepsis. E. coli sepsis is a known entity, and also an important cause of early mortality in these children. But fungal sepsis in these patients is rarely reported. Here is a case of 45 day-old child who presented with fungal sepsis, which on investigation turned out to be galactosemia.

The Prevalence, Risk Factors, and Clinical Outcome of Balloon Rupture in Balloon-occluded Retrograde Transvenous Obliteration of Gastric Varices

To evaluate the prevalence, risk factors, and clinical outcome after balloon rupture during balloon-occluded retrograde transvenous obliteration (BRTO). Sixty-nine patients who underwent the BRTO procedure from August 1999 to January 2009 were analyzed retrospectively. The occurrence of balloon rupture was recorded by a review of medical records and imaging studies. The chi(2) test was used to analyze risk factors for balloon rupture including balloon type and size, amount of sclerosant, and the use of microcatheters. The influence of balloon rupture on migration of the sclerosant and in-hospital mortality was analyzed with the Fisher exact test. The prevalence of balloon rupture was 8.7% (six of 69 patients). No significant risk factor for balloon rupture was identified because of the small number of balloon rupture cases. Migration of the sclerosant occurred in three patients with early balloon rupture within 1 hour. One of these patients died of recurrent gastric variceal bleeding and another experienced dyspnea and died of fungal sepsis. Among the 63 patients without rupture, no migration of the sclerosant was noted, and one patient died of sepsis caused by liver abscess. Incidences of sclerosant migration and in-hospital mortality were significantly higher in patients with balloon rupture versus patients without balloon rupture (P = .018 and P < .001, respectively). Balloon rupture during BRTO occurred in 8.7% of patients. Balloon rupture may cause rapid migration of sclerosant, pulmonary embolism, and recurrent gastric variceal bleeding.

Left lobe adult-to-adult living donor liver transplantation: Small grafts and hemiportocaval shunts in the prevention of small-for-size syndrome

Adult-to-adult living donor liver transplantation (AA-LDLT) has better outcomes when a graft weight to recipient weight ratio (GW/RW) > 0.8 is selected. A smaller GW/RW may result in small-for-size syndrome (SFSS). Portal inflow modulation seems to effectively prevent SFSS. Donor right hepatectomy is associated with greater morbidity and mortality than left hepatectomy. In an attempt to shift the risk away from the donor, we postulated that left lobe grafts with a GW/RW < 0.8 could be safely used with the construction of a hemiportocaval shunt (HPCS). We combined data from 2 centers and selected suitable left lobe living donor/recipient pairs. Since January 2005, 21 patients underwent AA-LDLT with left lobe grafts. Sixteen patients underwent the creation of an HPCS between the right portal vein and the inferior vena cava. The portocaval gradient (portal pressure - central venous pressure) was measured before the unclamping of the shunt and 10 minutes after unclamping. The median actual graft weight was 413 g (range = 350-670 g), and the median GW/RW was 0.67 (range = 0.5-1.0). The portocaval gradient was reduced from a median of 18 to 5 mmHg. Patient survival and graft survival at 1 year were 87% and 81%, respectively. SFSS developed in 1 patient, who required retransplantation. Two patients died at 3 and 10 months from a bile leak and fungal sepsis, respectively. The median recipient bilirubin level and INR were 1.7 mg/dL and 1.1, respectively, at 4 weeks post-transplant. One donor had a bile leak (cut surface). This is the first US series of small left lobe AA-LDLT demonstrating that the transplantation of small grafts with modulation of the portal inflow by the creation of an HPCS may prevent the development of SFSS while at the same time providing adequate liver volume. As it matures, this technique has the potential for widespread application and could positively effect donor safety, the donor pool, and waiting list times.

Fluconazole plasma concentration measurement by liquid chromatography for drug monitoring of burn patients

Fluconazole (2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol) is a triazole antifungal agent that has been available since 1990. Fluconazole is a broad-spectrum triazole antifungal agent that has emerged as a suitable alternative to amphotericin B in the treatment of a wide variety of superficial and systemic fungal infections.1 Triazole drugs act by inhibiting the enzyme 14-α-demethylase, which belongs to the microsomal CYP system; triazoles also act by blocking the biosynthesis of ergosterol, resulting in the accumulation of 14-α-methyl sterols and producing a fungistatic action. In general, fluconazole is well tolerated, with side effects including nausea, headache, skin rash, vomiting, abdominal pain, and diarrhea occurring during long-term therapy.2 Excellent bioavailability has been reported after oral dosing, and a linear pharmacokinetics has been demonstrated at a dose of 200–800 mg daily. The elimination half-life of fluconazole ranges from 27 to 37 hours, the apparent volume of distribution ranges from 0.5 to 0.7 L/kg, and approximately 80% of unchanged drug is excreted in the urine.3–6 Fluconazole is now used prophylactically in the management of various immune-compromised patient subsets1. High morbidity and mortality in patients with severe thermal injury were associated with fungal sepsis; thus, a study of the efficacy of this drug to prevent fungal sepsis in burn patients is necessary. It is well-known that patients with thermal injuries show many changes in the pharmacokinetics of several drugs, but data on the clinical efficacy of fluconazole related to its kinetics are very limited.7,8 Since changes in the pharmacokinetics of fluconazole are still unknown, it is imperative to investigate burn patients’ drug levels with a controlled clinical protocol. Analytical methods using microbiological, spectrophotometric, and chromatographic techniques have all been shown to determine fluconazole in biological samples. High-performance liquid chromatography (HPLC) is preferred due to its selectivity and the specificity of the assay. Methods for the determination of fluconazole in biological samples by HPLC-UV have been described previously.9–16 The objective of the present study was to develop a simple analytical method to determine fluconazole for plasma drug monitoring in patients with extensive thermal injury. An additional focus is its application to future pharmacokinetic studies. The method was validated as per FDA guidelines.17

Moral Distress: A Growing Problem in the Health Professions?

In the insightful and provocative book Final Exam, noted author and liver transplant surgeon Pauline Chen chronicles her medical education and some of the ethical dilemmas physicians face in practice. (1) describes a hierarchal and often authoritative system of care, reflecting upon the frailties of care providers as well as patients. Though she does not explicitly use the term, Chen implicitly describes the impact of moral distress on health care quality, providers' ability to meet professional and ethical obligations, and subsequent provider satisfaction and retention. Moral distress, as defined by Andrew Jameton in 1984, is the inability of a moral agent to act according to his or her core values and perceived obligations due to internal and external constraints. (2) Others have noted the psychological and physical burdens resulting from moral distress. (3) Today, nurses and their colleagues face ethical issues that seem more complex and more frequent than when Jameton coined the term twenty-five years ago. Although moral distress was originally conceptualized to address ethical issues in nursing, all health care professionals tackle morally relevant questions pertaining to the rightness or wrongness of decisions, treatments, or procedures, while feeling powerless to change situations they perceive to morally wrong. Providers frequently say things like, It's not my job to speak out; no one will listen anyway, or, doesn't make any sense; why are we continuing to do this?, or want to tell the patient to run. A case drawn from practice shows the anger, guilt, and moral compromise that health care professionals may experience in situations of moral distress. A thirty-five-year-old woman, Ms. Adams (all names and identifying details have been changed), had been diagnosed with acute lymphocytic leukemia that proved resistant to all standard and experimental chemotherapy regimens. was divorced, uninsured, and had four young children. Previously hospitalized for fungal pneumonia and sepsis that was compounded by a low white blood cell count from experimental treatment, Ms. Adams returned to the emergency room with abdominal pain, nausea, and vomiting. was readmitted and diagnosed with a pancreatic abscess and small bowel obstruction; she developed intractable pain and pancytopenia--a form of anemia requiring daily transfusions. was not a candidate for surgery at this time because of her debilitation. Ms. Adams and her family met with the team to discuss her options. refused hospice care in lieu of continuing aggressive treatments like experimental chemotherapy, believing that she would be healed and pull through this ordeal. said that after her blood counts recovered, she wanted to go home to spend time with her children. chose to remain a full code rather than agree to a do-not-resuscitate order. Her parents told the oncology fellow, She is a fighter and would want to try anything to save her life. Jane, Ms. Adams's primary nurse, struggled to accept these decisions. had already seen several primary care patients suffer through medically futile chemotherapy. Jane empathized with her patient's desire to keep fighting for her children, but she doubted Ms. Adams would leave the hospital alive. A week later, Ms. Adams again developed sepsis, along with blood in her urine, confusion, rapid breathing, and system failure. Jane asked, Why are we providing false hope to Ms. Adams and her family? This seems senseless. I feel like I'm inflicting unnecessary suffering on her. The fellow agreed, saying he was also troubled and would not choose this type of treatment for himself or his loved ones. He believed hospice would the best option for Ms. Adams, but told Jane that his job was to do everything he could to keep her alive, since he must follow his attending physician's orders and the family's wishes. Ms. Adams died two weeks later in the intensive care unit, never making it home to see her children. …

Human Heme Oxygenase-1 Deficiency Presenting with Hemolysis, Bleeding, Nephritis, Asplenia and Inflammation.

Abstract 3013Poster Board II-989 Introduction:Heme oxygenase-1 (HO-1) is a stress induced enzyme that catalyses the oxidation of heme to biliverdin and bilirubin. HO-1 is not constitutively produced and has been shown to be an endogenous factor against inflammation. Deficiency of HO-1 in HO-1 knockout mice as well as in one human case has been found to have a pro-inflammatory phenotype. To the best of our knowledge, previously there is only one published case of human HO-1 deficiency in literature. We report a patient who presented with massive hemolysis, bleeding, nephritis and inflammation and was proved to have HO-1 deficiency. Case report:A 15-year-old previously well girl presented with high-grade fever for 2 weeks and cervical and axillary lymphadenopathy. She had an insignificant family history and had no growth or developmental retardation. Initial evaluation was unremarkable except for thrombocytosis noted from first week of fever and asplenia that was noted on CT scan. There was no past history of any major infection or thrombocytosis. She developed intravascular hemolysis from the second week of illness followed by nephritis as evidenced by hematuria, proteinuria (2950 mg over 24 hr), hyaline cast with hypertension. C3 levels were normal. IgA levels were increased to 502 mg/dl. Her blood was agglutinating at room temperature and serum could be separated with great difficulty. Workup for hemolysis showed evidence of cold antibody mediated immune hemolysis. Her direct combs test was positive. LDH was 9262 IU/l. Urine was positive for hemoglobinuria. Her serum ferritin was 4219 ng/ml, ESR was 75mm/1st hr, platelets were increased to 1200,000/ul and interleukin-6 levels were increased to 139 pg/ml. Blood cultures were negative repetitively. However etiology including infections, lymphoreticular malignancies was ruled out. She was started on treatment with methylprednisolone (20 mg/kg x 3 days) followed by oral prednisolone at 2mg/kg/day. A month later, she developed vasculitic skin rash. In renal biopsy, glomeruli showed normal cellularity with mild focal mesangeal prominence, normal basement membrane and open capillary loops compatible with IgA nephropathy or minimal change disease. Immunoflourescence was non-contributory due to absence of any glomerulus. Bone marrow was normal and skin biopsy was non-contributory. Hemolysis persisted despite giving steroids. She developed bleeding diathesis in the form of uncontrolled epistaxis, diffuse alveolar hemorrhage and skin bleeds. Evaluation for coagulopathy showed high platelet count and normal PT (14.9 sec), INR 1.24 and APTT (32 sec). Von Willebrand antigen was raised to 308 %; Fibrinogen was 2.4 g/l and FDP level was increased to 8.0 mg/l by screening method. Epistaxis was controlled with repeated transfusion of fresh plasma. In view of hemolysis and nephritis non-responsive to steroids, she received a pulse of cyclophosphamide (500mg/m2) followed by two doses of Rituximab (375 mg/m2 each). Her condition deteriorated further over the next few weeks. She developed intracranial hemorrhage in right parietal lobe and required Factor VIIa for control of bleeding. She died with fungal sepsis (Trichosporon asahii) after prolonged hospitalization within 5 months from onset of the illness. Atypical features noticed in this case were near normal serum bilirubin despite severe intravascular hemolysis and presence of asplenia. In view of a similar case with hemolysis, asplenia and nephritis reported from Japan as the first case of human HO-1 deficiency, our patient's DNA was sent to the same lab for HO-1 gene mutation. Mutation analysis revealed homozygous mutations in exon 2 (R44X) on chromosome 22q12 which would result in absence of functional protein HO. Renal biopsy for HO-1 immunostaining showed little if any detectable HO-1 in renal tubules, despite the presence of massive hemolysis. Conclusion:HO-1 has been found to have cytoprotective effect against stress mediated organ damage. Inhibition of HO-1 has been shown to increase the vulnerability of an individual to stressful stimuli like infections. Lack of this enzyme might explain the varied clinical features and exaggerated response to stress noted in our patient. However it is not clear whether the entire spectrum of manifestations noted in our patient can be explained solely by HO-1 deficiency. Further cases are required to characterize the clinical and pathological manifestations of HO-1 deficiency. Disclosures:Off Label Use: Use of activated factor VII for control of intracranial hemorrhage.

Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates&lt;subtitle&gt;A Randomized Trial&lt;/subtitle&gt;

Sepsis is a common and severe complication in premature neonates, particularly those with very low birth weight (VLBW) (<1500 g). Whether lactoferrin, a mammalian milk glycoprotein involved in innate immune host defenses, can reduce the incidence of sepsis is unknown. In animal models, the probiotic Lactobacillus rhamnosus GG (LGG) enhances the activity of lactoferrin but has not been studied in human infants. To establish whether bovine lactoferrin (BLF), alone or in combination with LGG, reduces the incidence of late-onset sepsis in VLBW neonates. Prospective, multicenter, double-blind, placebo-controlled, randomized trial conducted in 11 Italian tertiary neonatal intensive care units. Patients were 472 VLBW infants enrolled from October 1, 2007, through July 31, 2008, and assessed until discharge for development of sepsis. Infants were randomly assigned to receive orally administered BLF (100 mg/d) alone (n = 153), BLF plus LGG (6 x 10(9) colony-forming units/d) (n = 151), or placebo (n = 168) from birth until day 30 of life (day 45 for neonates <1000 g at birth). First episode of late-onset sepsis, ie, sepsis occurring more than 72 hours after birth with isolation of any pathogen from blood or from peritoneal or cerebrospinal fluid. Demographic, clinical, and management characteristics of the 3 groups were similar, including type of feeding and intake of maternal milk. Incidence of late-onset sepsis was significantly lower in the BLF and BLF plus LGG groups (9/153 [5.9%] and 7/151 [4.6%], respectively) than in the control group receiving placebo (29/168 [17.3%]) (risk ratio, 0.34; 95% confidence interval, 0.17-0.70; P = .002 for BLF vs control and risk ratio, 0.27; 95% confidence interval, 0.12-0.60; P < .001 for BLF plus LGG vs control). The decrease occurred for both bacterial and fungal sepsis. No adverse effects or intolerances to treatment occurred. Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of a first episode of late-onset sepsis in VLBW neonates. isrctn.org Identifier: ISRCTN53107700.

Fulminant, Undetected Candida Sepsis After an Apparently Survivable Burn Injury

We report a 20-year-old male who suffered smoke inhalation injury and burns covering 26% of his TBSA, including his face, dorsal chest, and both the arms. The Abbreviated Burn Severity Index was 5 (likelihood of survival 95%). He underwent burn surgery, requiring massive transfusion. Postoperatively, he appeared increasingly hyperthermic, showed respiratory exhaustion, and was neutropenic (lowest white blood cell count was 0.8 Gpt with a normal granulocyte count). He developed acute respiratory distress syndrome, renal failure, and severe inflammatory response syndrome. Aggressive ventilation patterns, intermittent prone positioning, and high-dose catecholamine therapy were performed. Hydrocortisone therapy and antibiotic prophylaxis did not improve his clinical status. He died after 12 days of septic multiple organ failure. Legal medicine autopsy identified aggressive Candida famata mycosis. The organism mainly affected the alimentary canal, and there were multiple pyemic abscesses in tissues of the heart, liver, spleen, kidneys, lungs, and meninges. Histology confirmed gastric ulcers as the source of the Candida infection. Despite the autopsy findings, all intravital specimens collected (blood, urine, and tracheal mucus) and all clinical Candida antigen tests were unsuspicious. Postoperative neutropenia may be a warning sign of severe infection even in survivable burns. Suppression of immune response and possible previous gastric Candida colonization may contribute to hazardous outcomes. However, delayed and unreliable methods to detect fungal infections remain a major problem in burn care. Occult aggressive fungal sepsis resulting in early multiple organ failure should be kept in mind.

Acute Fungal Sinusitis

Acute fungal sinusitis is a life-threatening infection affecting immunocompromised patients. Historically, the most commonly recovered fungi are Aspergillus and Mucor. The extent of potentially disfiguring debridement surgery is grossly determined by the appearance of bleeding at the margins, signifying viable tissue and the absence of fungus. Requests for frozen section may concern the initial diagnosis and the intraoperative verification of margin status. In 12 patients with acute fungal sinusitis, frozen section was used in 8. Routine H&E stains demonstrated fungal hyphae in necrotic debris in 5 cases, often associated with vascular and perineural invasion. All patients underwent extensive sinus debridement, including orbital exenteration in 2 cases. All 12 patients died, 9 of fungal sepsis. Autopsy in 3 patients showed pulmonary involvement (2 cases), intracranial spread (1 case), and no residual fungus (1 case). Inexperience with organism recognition is surmountable. Frozen section has a role in the management of this devastating disease.

Multiplex real-time PCR and blood culture for identification of bloodstream pathogens in patients with suspected sepsis

Severe sepsis is increasingly a cause of death. Rapid and correct initial antimicrobial treatment reduces mortality. The aetiological agent(s) cannot always be found in blood cultures (BCs). A novel multiplex PCR test (SeptiFast (alpha version)) that allows identification of 20 bacterial and fungal species directly from blood was used, comparatively with BC, in a multicentre trial of patients with suspected bacterial or fungal sepsis. Five hundred and fifty-eight paired samples from 359 patients were evaluated. The rate of positivity was 17% for BC and 26% for SeptiFast. Ninety-six microorganisms were isolated with BC, and 186 microorganisms were identified with SeptiFast; 231 microrganisms were found by combining the two tests. Of the 96 isolates identified with BC, 22 isolates were considered to be contaminants. Of the remaining 74 non-contaminant BC isolates available for comparison with SeptiFast, 50 were identified as a species identical to the species identified with SeptiFast in the paired sample. Of the remaining 24 BC isolates for which the species, identified in the BC, could not be detected in the paired SeptiFast sample, 18 BC isolates were identified as a species included in the SeptiFast master list, and six BC isolates were identified as a species not included in the SeptiFast master list. With SeptiFast, 186 microorganisms were identified, 12 of which were considered to be contaminants. Of the 174 clinically relevant microorganisms identified with SeptiFast, 50 (29%) were detected by BC. More than half of the remaining microorganisms identified with SeptiFast (but not isolated after BC) were also found in routine cultures of other relevant samples taken from the patients. Future clinical studies should assess whether the use of SeptiFast is of significant advantage in the detection of bloodstream pathogens.