Fungal Sepsis Research Articles

Incidence of thrombocytopenia and changes in various platelet parameters, in blood culture positive neonatal sepsis

Abstract Objective: To assess the incidence of thrombocytopenia and changes in various platelet parameters, in culture positive neonatal sepsis. Methods: This was prospective study conducted over a period of one year from December 2009 to November 2010 in neonatal intensive care unit of DDUH Hospital, a tertiary care hospital in Delhi, North India. All babies who were admitted during this period were evaluated prospectively for evidence of sepsis. Results: sepsis was diagnosed in 560 neonates. Among 560 neonates, 80/560 (14.28%) had Culture positive sepsis. Out of 80 blood culture positive neonates 73 were term neonates and 7 were near term. Gram positive sepsis occurred in 21/80 (26.25%), gram negative sepsis in 54/80 (67.5%), and fungal sepsis in 5/80 (6.25%). Incidence of thrombocytopenia in Gram negative sepsis was (35/54) 64.81%, in gram positive sepsis (15/21) 71.41% and in fungal sepsis was (3/5) 60%. Mean platelet count at the onset of sepsis in all the patients was 123287.5±49428.68. The mean duration of thrombocytopenia in gram positive sepsis was 4.66 ±2.6 days, in gram negative sepsis 4.39 ± 2.22 days and in fungal sepsis 5.2±1.3 days. MPV at the time of onset of sepsis (MPV) was high in gram positive sepsis than in gram negative sepsis (11.57±0.88 Vs 11.29 ± 0.76). The MPV of thrombocytopenic neonates was significantly higher than that of non-thrombocytopenic neonates (p < 0.01).

Fungal sepsis and Indications of antifungal prophylaxis and treatment in neonatal intensive care units : A review

Abstract not availableNorthern International Medical College Journal Vol.6(1) 2014: 6-8

Congenital Chikungunya with Centro-facial Pigmentation and Persistent Thrombocytopenia: A Case Report

Hyperpigmentation over face in a neonate is rare and the differentials for the same are also rare. Congenital chikungunya, fungal and viral infections, drug rash are few differentials. Chikungunya Virus (CHIKV) infection manifesting in neonates is very rare. The prevalence of the entity was described only recently. We describe a neonate with hyperpigmentation on day 3 of life with stormy course thereafter. The distinguishing rash on face helped us in clinching the diagnosis of congenital chikungunya and fungal sepsis. Identification of this entity was based on characteristic skin rash and epidemiological background.

Cytomegalovirus infection and neonatal outcome in extremely preterm infants after freezing of maternal milk.

Cytomegalovirus (CMV) infection acquired from breast milk can cause serious illness in extremely preterm (EPT) infants (<28 weeks). Some neonatal centers freeze maternal milk (MM) to prevent CMV transmission; however, this practice is controversial. In this study, we assessed the CMV transmission rate and neonatal outcome in EPT infants after routine freezing of all MM. EPT infants (n = 140) and their mothers were randomized to the intervention group (only freeze-thawed MM) or the control group (combined fresh and freeze-thawed MM). Freeze-thawed MM was frozen at -20°C for ≥3 days before thawing. Mothers had serological tests for CMV, and MM was analyzed for CMV by polymerase chain reaction and CMV culture. Infants underwent CMV screening with urine analysis by CMV-polymerase chain reaction and CMV culture until 12 weeks of age. Congenital CMV infection was detected in 2% of screened infants. The CMV transmission rate in infants fed with CMV-DNA positive milk was 8% (3 of 37) in the intervention group and 6% (2 of 33) in controls. All infants infected by CMV were asymptomatic. The final per-protocol analysis included 56 infants in the intervention group and 65 controls. Neonatal mortality was comparable between the groups (7% vs. 6%). Neonatal morbidity was similar, except for late onset Candida sepsis, which was more frequent in the controls (12% vs. 0%). Routine freezing of all MM did not affect the rate of CMV transmission but may help to prevent fungal sepsis in EPT infants. This observation merits further investigation.

A cross-sectional study of risk factors of fungal sepsis in paediatric patients at a tertiary care centre in India

A cross-sectional study of risk factors of fungal sepsis in paediatric patients at a tertiary care centre in India

The interplay between inflammasome activation and antifungal host defense.

Fungal infections cause significant morbidity and mortality in humans, and they are a growing problem due to the increased usage of broad-spectrum antibiotics and immunosuppressive therapies. The equilibrium between the commensal microbial flora and the immune system that protects the host against invasive fungal infection is disturbed during disease, and understanding this disturbed balance is important to develop new therapeutic interventions for the treatment of fungal infection. In the context of tolerating fungi during colonization and eliciting a vigorous immune response to eliminate invading fungal pathogens when needed, the inflammasome has been identified as an integral component of antifungal host defense. It contributes to mucosal host defense by regulating T-helper 17 (Th17) cell responses, and contributes to protective responses such as neutrophil influx during fungal sepsis. Several aspects are important for understanding the role of the inflammasome for antifungal host defense, such as the role of fungal cell wall morphology and its components in triggering the inflammasome, the pattern recognition pathways and downstream signaling cascades involved in the activation of the inflammasome, and the effects of inflammasome activation during fungal infection. The future perspectives of inflammasome research in fungal immunology, with emphasis on targeting the inflammasome for the design of future immunotherapies, is also discussed.

Trends in paediatric bloodstream infections at a South African referral hospital.

BackgroundThe epidemiology of paediatric bloodstream infection (BSI) in Sub-Saharan Africa is poorly documented with limited data on hospital-acquired sepsis, impact of HIV infection, BSI trends and antimicrobial resistance.MethodsWe retrospectively reviewed paediatric BSI (0–14 years) at Tygerberg Children’s Hospital between 1 January 2008 and 31 December 2013 (excluding neonatal wards). Laboratory and hospital data were used to determine BSI rates, blood culture contamination, pathogen profile, patient demographics, antimicrobial resistance and factors associated with mortality. Fluconazole resistant Candida species, methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Acinetobacter baumannii and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were classified as antimicrobial resistant pathogens.ResultsOf 17001 blood cultures over 6 years, 935 cultures isolated 979 pathogens (5.5% yield; 95% CI 5.3-5.7%). Contamination rates were high (6.6%, 95% CI 6.4-6.8%), increasing over time (p = 0.003). Discrete BSI episodes were identified (n = 864) with median patient age of 7.5 months, male predominance (57%) and 13% HIV prevalence. BSI rates declined significantly over time (4.6–3.1, overall rate 3.5 per 1000 patient days; 95% CI 3.3–3.7; Chi square for trend p = 0.02). Gram negative pathogens predominated (60% vs 33% Gram positives and 7% fungal); Klebsiella pneumoniae (154; 17%), Staphylococcus aureus (131; 14%) and Escherichia coli (97; 11%) were most prevalent. Crude BSI mortality was 20% (176/864); HIV infection, fungal, Gram negative and hospital-acquired sepsis were significantly associated with mortality on multivariate analysis. Hospital-acquired BSI was common (404/864; 47%). Overall antimicrobial resistance rates were high (70% in hospital vs 25% in community-acquired infections; p < 0.0001); hospital-acquired infection, infancy, HIV-infection and Gram negative sepsis were associated with resistance. S. pneumoniae BSI declined significantly over time (58/465 [12.5%] to 33/399 [8.3%]; p =0.04).ConclusionAlthough BSI rates declined over time, children with BSI had high mortality and pathogens exhibited substantial antimicrobial resistance in both community and hospital-acquired infections. Blood culture sampling technique and local options for empiric antimicrobial therapy require re-evaluation.

Comparative Study of Platelet count and C-Reactive Protein among Gram Positive, Gram Negative and Fungal Sepsis in Newborns

Introduction: Septicemia is characterized by positive blood culture, thrombocytopenia & elevated C-reactive protein. Objective: To compare platelet indices and CRP among gram-positive, gram negative and fungal sepsis in newborns. Methods: This is a retrospective case analysis of 52 blood culture positive patients between January-2012 to December-2014. The parameters examined were Baseline Platelet Count, Change In Platelet Count, (Baseline Platelet count- Change in Platelet count)/ Baseline Platelet Count , Platelet nadir, incidence, duration & severity of Thrombocytopenia, baseline CRP, change in CRP, (baseline CRP- change in CRP)/ baseline CRP, CRP peak, incidence & duration of raised crp. Statistical analysis: All data were collected in validated preformatted proforma sheet & analysed using appropriate statistical methods. Results: Majority (61.53%) had gram negative sepsis. Klebsiella was the commonest organism & was isolated in 21.15% of babies. Weight of the baby (p= 0.014), CRP Peak (p= 0.034), incidence of high CRP (p = 0.003), duration of high CRP (p= 0.004) & duration of thrombocytopenia (p = 0.001) differed significantly among gram-positive, gram negative & fungal sepsis. Conclusion: We noted higher rise in CRP with prolonged duration following Gram negative sepsis. However the incidence of both raised CRP and thrombocytopenia were more among fungal sepsis. Though the onset was delayed, lower platelet nadir, more severe thrombocytopenia with prolonged duration was noted among fungal sepsis.

English

Introduction: Septicemia is characterized by positive blood culture, thrombocytopenia & elevated C-reactive protein. Objective: To compare platelet indices and CRP among gram-positive, gram negative and fungal sepsis in newborns. Methods: This is a retrospective case analysis of 52 blood culture positive patients between January-2012 to December-2014. The parameters examined were Baseline Platelet Count, Change In Platelet Count, (Baseline Platelet count- Change in Platelet count)/ Baseline Platelet Count , Platelet nadir, incidence, duration & severity of Thrombocytopenia, baseline CRP, change in CRP, (baseline CRP- change in CRP)/ baseline CRP, CRP peak, incidence & duration of raised crp. Statistical analysis: All data were collected in validated preformatted proforma sheet & analysed using appropriate statistical methods. Results: Majority (61.53%) had gram negative sepsis. Klebsiella was the commonest organism & was isolated in 21.15% of babies. Weight of the baby (p= 0.014), CRP Peak (p= 0.034), incidence of high CRP (p = 0.003), duration of high CRP (p= 0.004) & duration of thrombocytopenia (p = 0.001) differed significantly among gram-positive, gram negative & fungal sepsis. Conclusion: We noted higher rise in CRP with prolonged duration following Gram negative sepsis. However the incidence of both raised CRP and thrombocytopenia were more among fungal sepsis. Though the onset was delayed, lower platelet nadir, more severe thrombocytopenia with prolonged duration was noted among fungal sepsis.

Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants.

Lactoferrin, a normal component of human colostrum and milk, can enhance host defense and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. Primary objective To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC in preterm neonates. Secondary objectives1. To determine the effects of oral lactoferrin used to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later.2. To determine the adverse effects of oral lactoferrin in the prophylaxis of neonatal sepsis and/or NEC.When data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks.2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants).3. Type of feeding: breast milk versus formula milk. We used the search strategy of the Cochrane Neonatal Review Group (CNRG) and updated our search in July 2014. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, EMBASE, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trials registries and conference proceedings. Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. Review authors used standard methods of the CNRG. Four RCTs are included in this review. Oral lactoferrin supplementation decreased late-onset sepsis (typical risk ratio (RR) 0.49, 95% confidence interval (CI) 0.32 to 0.73; typical risk difference (RD) -0.09, 95% CI -0.14 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 7 to 25; four trials, 678 participants, moderate-quality evidence), NEC stage II or greater (typical RR 0.30, 95% CI 0.12 to 0.76; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence), and "all-cause mortality" (typical RR 0.30, 95% CI 0.12 to 0.75; typical RD -0.05, 95% CI -0.08 to -0.01; NNTB 20, 95% CI 12.5 to 100; two studies, 505 participants, low-quality evidence).Oral lactoferrin supplementation with a probiotic decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants, low-quality evidence) and NEC stage II or greater (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants, low-quality evidence), but not "all-cause mortality."Oral lactoferrin with or without probiotics decreased fungal sepsis but not chronic lung disease or length of hospital stay (from one study, low-quality evidence). No adverse effects were reported. Long-term neurological outcomes or periventricular leukomalacia was not evaluated. Evidence of moderate to low quality suggests that oral lactoferrin prophylaxis with or without probiotics decreases late-onset sepsis and NEC stage II or greater in preterm infants without adverse effects. Completion of ongoing trials will provide evidence from more than 6000 preterm neonates and may enhance the quality of the evidence. Clarifications regarding optimum dosing regimens, type of lactoferrin (human or bovine), and long-term outcomes are still needed.

The Cause of Acute Respiratory Failure Predicts the Outcome of Noninvasive Ventilation in Immunocompromised Children.

Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure. Mortality, success rate, prognostic factors and side effects of NIV for acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease. In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes. The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.

A case of Candida famata sepsis in a very low birth weight infant successfully treated with fluconazole following antifungal susceptibility testing

Late onset of fungal sepsis in very low birth weight (VLBW) infants is common and has a high mortality and morbidity. Many of these infants were also receiving fluconazole prophylaxis. Amphotericin is often started when invasive neonatal candidiasis is suspected and has significant side effects. Antifungal susceptibility testing can be extremely useful in deciding optimal antifungal therapy. We report a case of successful treatment of fungal sepsis due to Candida famata in a VLBW infant where fluconazole was continued in therapeutic dose following sensitivity testing. This case report highlights the growing number of cases arising due to nonalbicans Candida infections in the neonatal intensive care units and the usefulness of antifungal susceptibility testing in deciding optimal antifungal therapy and preventing the emergence of drug resistance.

Successful Haploidentical Hematopoietic Stem Cell Transplant for GATA2 Deficiency

▪Background: GATA2 deficiency results in a clinical syndrome known variably as: MonoMAC for the lack of monocytes and atypical mycobacterial infections (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger’s syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Reconstitution of the deficient cell compartments in GATA2 deficiency with allogeneic hematopoietic stem cell transplant (HSCT) results in reversal of the infection susceptibility and represents the only curative therapy for both the myeloid disease and the virally driven malignancies seen in this disorder. However, only about one-half of patients that require HSCT will have an HLA-matched related or unrelated donor. Moreover, the use of umbilical cord blood has been reported to be suboptimal in this cohort of patients in whom infection susceptibility underlies much of the need for a transplant.Methods: We performed haploidentical, related donor HSCT with high dose post-transplant cyclophosphamide (PT/CY) in 3 patients with GATA2 deficiency in whom a suitable HLA matched donor was not available. All three patients had a first degree relative (sibling) who shared at least 1 HLA-haplotype. The first patient, a 21 year-old Chinese woman presented with Hydroa Vacciniforme like T-cell lymphoma involving her lung, bowel (resulting in multiple small bowel resections and ileostomy), and skin (with large ulcerative lesions); multiple thrombotic cerebral events; and macrophage activation syndrome requiring etoposide and high dose prednisone in the intensive care unit (ICU). The second patient, a 20 year-old Hispanic female, presented with myelodysplasia (MDS), profound neutropenia, an invasive fungal sinusits due to Fusarium sp., and recurrent bacteremias. The third patient, a 45 year-old woman, presented with Emberger’s Syndrome, multiple episodes of bacterial and fungal sepsis and hypocellular MDS. All three patients received cyclophosphamide 14.5mg/kg on day’s -6 and-5; fludarabine 30mg/m2 on day’s -6 through -2; 200cGy of total body irradiation (TBI) on day -1. Patients 2 and 3 also received busulfan 3.2 mg/kg on day’s -4 and -3 because of MDS. All 3 patients received high dose PT/CY 50mg/kg on day’s +3 and +4, and mycophenolate mofetil and tacrolimus starting on day +5.Results: All 3 patients engrafted at a mean of 18 days and all are alive at a median follow-up of 9 months (range, 5 to 13 months). All three patients achieved 100% donor myeloid and lymphoid chimerim by day +100 post-transplant. The first patient had complete resolution of her T-cell lymphoma and macrophage activation syndrome, the second patient has had complete reversal of her hematopoietic and infectious phenotype, and the third patient has had resolution of her infectious complications that required continuous IV Daptomycin for 5 years prior to transplant. In addition, all three patients had complete reconstitution of the monocyte, NK cell, and B-lymphocyte compartments that were severely deficient prior to transplant. The main toxicity was mucositis, which required intravenous narcotics in all three patients. Lastly, the first patient developed late grade I liver graft-versus-host disease (GVHD) that was responsive to cyclosporine, the second patient developed grade I acute GVHD of skin that was responsive to topical steroids, and the third patient had no evidence of acute or chronic GVHD.Conclusions: Haploidentical, related donor HSCT represents a safe and effective viable alternative for patients with GATA2 deficiency who lack an HLA-matched donor, including patients such as our first patient who was in the ICU at the time of transplant. DisclosuresNo relevant conflicts of interest to declare.

Final Results from a Phase 4 Open-Label 3-Year Study Evaluating Changes in Bone Marrow (Bm) Morphology in Adult Immune Thrombocytopenia (ITP) Patients (Pts) Receiving the Thrombopoietin Mimetic Romiplostim

Introduction: Normal bm may contain reticulin, which is of unknown clinical relevance. An analysis of romiplostim ITP trials as of 2011 showed 17 reticulin cases and one collagen case; however, biopsies were not performed systematically. Reported here are final results from a prospective 3-year (y) study evaluating bm biopsies for reticulin and collagen before and after treatment with romiplostim in adult ITP pts. Methods: Eligible ITP pts had platelets Results: All pts received romiplostim and had evaluable baseline bm biopsies. Of the 50 pts in Cohort 1 [54% female, mean age 55.5 y, range 20–86 y, mean (SD) dose 4.0 (2.8) µg/kg], 39 had post-baseline bm biopsies (Table). No pts with evaluable results developed collagen or had an increase ≥2 grades from baseline in reticulin. Of the 50 pts in Cohort 2 [76% female, mean age 48.6 y, range 19–83 y, mean (SD) dose 4.3 (3.1) µg/kg], 40 had post-baseline bm biopsies. There was no evidence of collagen; 2 pts had a 2-grade increase in reticulin. Of the 69 pts in Cohort 3 [71% female, mean age 46.6 y, range 18-81 y, mean (SD) dose 4.1 (2.9) µg/kg], 58 had post-baseline bm biopsies; 7 pts had a 2-grade increase in modified Bauermeister score, with 2 of the 7 showing collagen. Of those 2, 1 had no evidence of collagen on follow-up biopsy 12 weeks later; the other refused a follow-up biopsy. The safety profile was similar to that in past trials. In Cohort 1, 4 pts died; causes were fungal sepsis in a pt with longstanding corticosteroid use, cerebral hemorrhage, pulmonary hemorrhage in a pt with pulmonary thrombosis treated with acenocoumarol, and subdural hematoma that occurred after the pt fell and sustained a head injury. In Cohort 2, 2 pts died; causes were acute renal failure in a pt with a history of chronic renal insufficiency and suicide. In Cohort 3, 1 pt died of multiple thromboses of microcirculation and failure of the heart, kidneys, and lungs. No deaths were attributed to romiplostim. One pt in Cohort 3 tested positive for neutralizing antibodies (Ab) to romiplostim at Week 30 through the Year 1 visit, but was Ab negative on a subsequent test; the last romiplostim dose was at Week 36, but the pt maintained platelet response throughout. Summary/Conclusion: An increase in modified Bauermeister score by ≥2 grades occurred in 9 of 131 pts (6.9%) treated with romiplostim; 7 had increased reticulin only and 2 also had collagen. The low incidence of both collagen and increased reticulin is consistent with results of past romiplostim studies. Table Biopsy Results 1 3 pts in cohort 1, 3 in cohort 2, and 10 in cohort 3 had biopsies at end of treatment due to early discontinuation. 2 Trichrome and silver staining results could not be obtained for all biopsies due to inadequate samples. 3 Duration-adjusted, per 100 pt-y 4 1 case: grade 0 to 2; 1 case: grade 1 to 3 5 1 case: grade 4 after 25 weeks in a pt with atypical ITP, no evidence of collagen on follow-up biopsy 12 weeks later; 1 case: grade 4 at end of treatment, pt refused follow-up biopsy 6 2 cases: collagen (as above in 5); 2 cases: grade 0 to 2; 3 cases: grade 1 to 3 Disclosures Janssens:Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:GSK: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Chong:Amgen Inc.: Research Funding; GSK: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cervinek:Alexion: Consultancy; GSK: Consultancy; Amgen Inc.: Consultancy. Wang:Amgen Inc.: Employment, Equity Ownership. Lopez:Amgen Inc.: Employment, Equity Ownership.

The non-receptor tyrosine kinase Tec controls assembly and activity of the noncanonical caspase-8 inflammasome.

Tec family kinases are intracellular non-receptor tyrosine kinases implicated in numerous functions, including T cell and B cell regulation. However, a role in microbial pathogenesis has not been described. Here, we identified Tec kinase as a novel key mediator of the inflammatory immune response in macrophages invaded by the human fungal pathogen C. albicans. Tec is required for both activation and assembly of the noncanonical caspase-8, but not of the caspase-1 inflammasome, during infections with fungal but not bacterial pathogens, triggering the antifungal response through IL-1β. Furthermore, we identify dectin-1 as the pathogen recognition receptor being required for Syk-dependent Tec activation. Hence, Tec is a novel innate-specific inflammatory kinase, whose genetic ablation or inhibition by small molecule drugs strongly protects mice from fungal sepsis. These data demonstrate a therapeutic potential for Tec kinase inhibition to combat invasive microbial infections by attenuating the host inflammatory response.

Organism Specific Response of Platelet Count in Neonatal Sepsis

Background: Neonatal sepsis is one of the major causes of neonatal morbidity and mortality, particularly in developing countries and it is caused by Gram positive bacteria, Gram negative bacteria and fungi. Thrombocytopenia has been used as an early but nonspecific marker for sepsis. About 75% of culture positive neonates have thrombocytopenia. The severity and duration of thrombocytopenia varies in different types of organism. So, the objectives of this study were to examine platelet counts and platelet indices in neonates with culture proven sepsis and to determine if there was an organism specific platelet response.Methods: This cross- sectional prospective study was carried out in the special care baby unit (SCABU) under department of Paediatrics and Neonatology, BIRDEM General Hospital, Dhaka from November 2008 to September 2009.Results: Total 120 newborn babies with culture positive sepsis were included in this study. Gram positive bacteria was found in 06 (5%), Gram negative bacteria was found in 58(48.3%) and fungi was found in 56 (46.7%) neonates. Thrombocytopenia was found in 95% of culture positive neonates. When compared with neonates with Gram positive sepsis, those with Gram-negative or fungal sepsis had a significantly lower platelet count, platelet nadir and prolonged duration of thrombocytopenia (p=&lt;0.05). Fungal sepsis was also associated with prolonged duration of thrombocytopenia when compared with that of Gram negative sepsis (p=0.03).Conclusion: Neonatal sepsis is frequently associated with thrombocytopenia. However, Gram negative and fungal sepsis is associated with a lower platelet count, platelet nadir and prolonged duration of thrombocytopenia compared with that of Gram positive sepsis.Birdem Med J 2014; 4(2): 79-83

Treatment of fungal infections: an update

Fungal infections represent a serious problem in neonatal intensive care units (NICUs) worldwide. Preterm infants are a vulnerable population for major events and adverse sequelae from fungal sepsis. The primary fungus of concern in neonates is C. albicans , whose colonization is associated with devastating complication and high rate of mortality. Among the risk factors responsible for development of invasive fungal infections, previous mucosal and skin colonization are of primary importance. Fungal colonization in neonates may be secondary to either maternal transmission or nosocomial acquisition in the nursery. Antifungal prophylaxis is currently applied in different NICUs and in various patients groups with successful results. Prophylactic drugs can include oral nystatin and oral or intravenous fluconazole. To date, antifungal prophylaxis with fluconazole is the recommended approach for neonates lower than 1,000 g and/or 27 weeks’ gestation or less, manly in NICUs with relatively high frequency of invasive candidiasis. First-line treatment of invasive fungal infections includes amphotericin B deoxycholate, lipid preparations of amphotericin B, fluconazole, or micafungin. However, data on pharmacokinetic, schedule treatment and appropriate dosage of antifungal agents in neonates, mainly in premature, are still limited. Future strategies to reduce neonatal morbidity and mortality derived from invasive fungal infections include new echinocandins not yet approved for neonatal use (caspofungin or anidulafungin) and other adjuvant treatments as intravenous immunoglobulin, lactoferrin or probiotics. Since current therapies for systemic fungal diseases are not universally successful and morbidity remains high, future efforts will be also focused on better prevention of fungal diseases and understanding of appropriate dosing schedule of the available antifungal agents. Proceedings of the 10 th International Workshop on Neonatology · Cagliari (Italy) · October 22 nd -25 th , 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

Monitoring neonatal fungal infection with metabolomics

The objective of our study was to evaluate the capability of the metabolomics approach to identify the variations of urine metabolites over time related to the neonatal fungal septic condition. The study population included a clinical case of a preterm neonate with invasive fungal infection and 13 healthy preterm controls. This study showed a unique urine metabolic profile of the patient affected by fungal sepsis compared to urine of controls and it was also possible to evaluate the efficacy of therapy in improving patient health.

Syk signaling in dendritic cells orchestrates innate resistance to systemic fungal infection.

Host protection from fungal infection is thought to ensue in part from the activity of Syk-coupled C-type lectin receptors and MyD88-coupled toll-like receptors in myeloid cells, including neutrophils, macrophages and dendritic cells (DCs). Given the multitude of cell types and receptors involved, elimination of a single pathway for fungal recognition in a cell type such as DCs, primarily known for their ability to prime T cell responses, would be expected to have little effect on innate resistance to fungal infection. Here we report that this is surprisingly not the case and that selective loss of Syk but not MyD88 in DCs abrogates innate resistance to acute systemic Candida albicans infection in mice. We show that Syk expression by DCs is necessary for IL-23p19 production in response to C. albicans, which is essential to transiently induce GM-CSF secretion by NK cells that are recruited to the site of fungal replication. NK cell-derived-GM-CSF in turn sustains the anti-microbial activity of neutrophils, the main fungicidal effectors. Thus, the activity of a single kinase in a single myeloid cell type orchestrates a complex series of molecular and cellular events that underlies innate resistance to fungal sepsis.

Serum procalcitonin levels in patients with ankylosing spondylitis.

Procalcitonin is a marker of bacterial and fungal infection and sepsis. The present study evaluated the relationship between serum procalcitonin levels and disease activity in patients with ankylosing spondylitis (AS). A total of 61 patients who met the 1984 New York criteria for AS were studied. Twenty-four age- and sex-matched healthy volunteers were recruited to this study as a control group. Disease activity was assessed by the Bath AS Disease Activity Index (BASDAI). The functional status of patients was evaluated by the Bath AS Functional Index (BASFI). Spinal mobility was measured by the Bath AS Metrology Index (BASMI). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum procalcitonin levels were measured. Thirty patients were on anti-tumor necrosis factor-alpha treatment and 31 patients were on conventional treatment. Seventeen (28%) of the AS patients were active (BASDAI >4) and 44 (72%) of the AS patients were in remission. The median ESR was 14 (34-6)mm/h and 4 (7-2)mm/h (P<0.001) for the patient and control groups, respectively. The median CRP level was 0.91 (2.72-0.37) mg/dL and 0.15 (0.25-0.07) mg/dL in the patient and control groups, respectively (P<0.001). Median BASDAI, BASFI and BASMI scores for all AS patients were 3.6 (5.25-2.29), 2.5 (4.22-0.91) and 3 (5-1), respectively. Serum procalcitonin levels were normal (<0.05ng/mL) for all patients and controls. Serum procalcitonin levels were not high in AS patients and controls, and the levels were independent of disease activity and medications. If bacterial or fungal infection is suspected in an AS patient, serum procalcitonin level may be useful for diagnosis.