Cause Of Infection-related Mortality Research Articles

Multidrug-resistant tuberculosis: Successes, challenges, and the road ahead

Tuberculosis (TB) is a leading cause of infection-related mortality globally and imposes a significant burden on morbidity among survivors. While progress has been achieved toward the World Health Organization’s End TB goal, it has been slower than anticipated and, in part, reversed by the impact of the severe acute respiratory syndrome coronavirus 2 pandemic. Multidrug-resistant TB (MDR-TB) presents a formidable challenge, characterized by catastrophic costs, reduced treatment success rates, and increased loss to follow-up, leading to its perpetuation in local communities and the risk of onward transmission. Given this, the need to reshape services and refine management in a cost-effective manner is of paramount importance, particularly in developing countries where the majority of cases reside. In this short piece, we discuss the economic impact of MDR-TB and how this impact can be mitigated through several methods, including decentralized models of care.

The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Cold abscess as a primary manifestation of thyroid tuberculosis

Tuberculosis remains the highest cause of infection-related mortality in low- and middle-income countries. Extra-pulmonary tuberculosis is often misdiagnosed because of the nonspecific clinical presentations and gaps in the laboratory assessment. Delayed and misdiagnosis can cause increased risks of morbidity and potential community transmission. Primary thyroid tuberculosis is very rare presentation even in the endemic area. We presented a Case Illustrated of a patient with cold abscess as a primary presentation of thyroid tuberculosis. Difficulty in the diagnosis and treatment were described. Although very rare, atypical presentation of extra-pulmonary tuberculosis in the thyroid gland requires thorough anamnesis and in-depth examination. Clinicians should put high-index suspicion on high-risk patients from endemic areas with medical comorbidity including immunocompromised disease and poor nutritional status. Our report underlines the importance of thorough medical assessment for unusual presentation of thyroid tuberculosis.

1484. Microbial Etiology of Community-acquired Pneumonia in Immunocompromised Patients

BackgroundCommunity-acquired pneumonia (CAP) is a leading cause of infection related mortality. Few studies have specifically evaluated the microbial etiology of CAP in immunocompromised patients. Using a large national inpatient database, we compared the microbial etiology of CAP in immunocompromised patients compared to immunocompetent patients.MethodsWe included adult patients admitted with pneumonia from 2010-2015 to 176 US hospitals participating in Premier. Patients were identified as having CAP if they had a chest X-ray and were on antimicrobials on the first day. Immunocompromised was defined by the receipt of immunosuppressive medications or ICD-9 codes for neutropenia/ hematological malignancy/ organ transplantation or comorbidities with AIDS. For microbial etiology, patients were included if they had a positive culture or test collected by hospital day 0 through 3. Patients with identical bacteria in blood and urine were excluded.ResultsA total of 168,159 patients had a diagnosis of CAP with a culture/test performed on first 3 days. A pathogen was detected in 18.8% of patients. Among pathogen positive patients, 4,851 patients were identified as immunocompromised and 26,752 as immunocompetent. Almost all patients (99%) had at least one culture, blood (96%) and respiratory (51%). Among patients who were immunocompromised, the most common bacterial pathogens (compared to immunocompetent patients) were, S. pneumoniae (17.7% vs 19.0%), MRSA (13.1% vs 14.4%), MSSA (12.0% vs 11.8%), P. aeruginosa (12.0% vs 9.9%), E. coli (7.4% vs 6.4%), K. pneumoniae (5.8% vs 4.9%), H. influenzae (5.5% vs 5.5%), M. pneumoniae (3.0% vs 3.0%) and L. pneumophila (0.93% vs 1.2%). Among viral pathogens, while the most common were influenza virus (12.9% vs 14.1%) followed by rhinovirus (1.5% vs 0.89%), immunocompromised patients has a higher prevalence of noninfluennza viruses (3.42% vs 2.43%).ConclusionIn a large US inpatient sample, the causative organisms in immunocompromised patients did not differ much from those in immunocompetent patients. CAP pathogens in immunocompromised patients were more likely to involve gram-negative bacilli such as P.aeruginosa and E.coli, than gram-positive cocci. These findings may have implications when deciding on empiric therapy in these patients.DisclosuresAbhishek Deshpande, MD, PhD, Ferring Pharmaceuticals (Advisor or Review Panel member)Merck (Consultant)

Communication is the key: biofilms, quorum sensing, formation and prevention.

Antibiotic resistance is a relevant topic nowadays, representing one of the main causes of infection-related mortality and morbidity at a global level. This phenomenon is worrisome and represents an area of interest for both clinical practice and fundamental research. One important mechanism whereby bacteria acquire resistance to antibiotics and evade the immune system is by forming biofilms. It is estimated that ~80% of the bacteria producing chronic infections can form biofilms. During the process of biofilm formation microorganisms have the ability to communicate with each other through quorum sensing. Quorum sensing regulates the metabolic activity of planktonic cells, and it can induce microbial biofilm formation and increased virulence. In this review we describe the biofilm formation process, quorum sensing, quorum quenching, several key infectious bacteria producing biofilm, methods of prevention and their challenges and limitations. Although progress has been made in the prevention and treatment of biofilm-driven infections, new strategies are required and have to be further developed.

Functional and Proteomic Analysis of Streptococcus pyogenes Virulence Upon Loss of Its Native Cas9 Nuclease.

The public health impact of Streptococcus pyogenes (group A Streptococcus, GAS) as a top 10 cause of infection-related mortality in humans contrasts with its benefit to biotechnology as the main natural source of Cas9 nuclease, the key component of the revolutionary CRISPR-Cas9 gene editing platform. Despite widespread knowledge acquired in the last decade on the molecular mechanisms by which GAS Cas9 achieves precise DNA targeting, the functions of Cas9 in the biology and pathogenesis of its native organism remain unknown. In this study, we generated an isogenic serotype M1 GAS mutant deficient in Cas9 protein and compared its behavior and phenotypes to the wild-type parent strain. Absence of Cas9 was linked to reduced GAS epithelial cell adherence, reduced growth in human whole blood ex vivo, and attenuation of virulence in a murine necrotizing skin infection model. Virulence defects of the GAS Δcas9 strain were explored through quantitative proteomic analysis, revealing a significant reduction in the abundance of key GAS virulence determinants. Similarly, deletion of cas9 affected the expression of several known virulence regulatory proteins, indicating that Cas9 impacts the global architecture of GAS gene regulation.

1545. Gram-Negative Bacteremia in Neutropenic Patients: Risk Factors for Mortality in the Era of Multiresistance

BackgroundGram-negative bacteremia (GNB) in neutropenic patients is a major cause of infection-related mortality. Our objective was to identify factors associated with 7-day and 30-day mortality during GNB episodes in neutropenic patients.MethodsProspective multicenter study. Episodes of GNB in adult neutropenic cancer and hematopoietic stem cell transplant (HSCT) patients were included in 10 centers of Argentina, from May 2014 to January 2018. To identify factors associated with 7-day and 30-day mortality, variables with P < 0.05 in univariate analysis were included in a logistic regression model for multivariate analysis.ResultsFour hundred and seventy-six episodes of GNB were included. From these, 68.06% had hematological malignancies, 22.90% HSCT and 9.03% solid tumors. Seven-day and 30-day mortality were 19.53 and 26.47%, respectively. In multivariate analysis, factors independently associated with 7-day mortality were: Meropenem-resistant GNB (OR 8.60, 95% CI 3.06–24.14, P ≤ 0.0001), respiratory source (OR 3.67, 95% CI 1.21–11.10, P = 0.021), skin and soft tissue source (OR 3.89, 95% CI 1.01–14.94, P = 0.048), Charlson score > 4 (OR 2.76, 95% CI 1.06–7.19, P = 0.037) and shock (OR 7.13, 95% CI 2.50–20.33, P ≤ 0.0001). Independent factors for 30-day mortality were: Meropenem-resistant GNB (OR 7.06, 95% CI 2.83–17.64, P ≤ 0.0001), respiratory source (OR 4.41, 95% CI 1.53–12.73, P = 0.006), skin and soft tissue source (OR 3.66, 95% CI 1.00–13.42, P = 0.049), Charlson score > 4 (OR 3.81, 95% CI 1.62–8.91, P = 0.002), intensive care unit requirement (OR 2.46, 95% CI 1.00–6.04, P = 0.049), shock (OR 10.90, 95% CI 4.12–29.85, P ≤ 0.0001) and refractory cancer (OR 4.30, 95% CI 1.57–11.78, P = 0.005).ConclusionThe identification of certain prognostic factors would allow the stratification of neutropenic patients at high risk for mortality during GNB episodes. The appropriate medical intervention of a multidisciplinary team on these factors could improve the outcome of these patients. Since Meropenem-resistant GNB is one of strongest prognostic factors, it is essential to identify the patients at risk and treat them appropriately.Disclosures All authors: No reported disclosures.

1469. Microbial Etiology of Community-Acquired Pneumonia Requiring Hospitalization Among US Adults

BackgroundCommunity-acquired pneumonia (CAP) continues to be the leading cause of infection-related mortality in the United States. Epidemiological studies of CAP are usually based on single-center studies and there is a need for large population based studies. We evaluated the microbial etiology of CAP among patients requiring hospitalization using a large US database.MethodsWe included adult patients admitted with pneumonia from 2010 to 2015 to 175 US hospitals participating in Premier and providing administrative and microbacteriological data. Patients were identified as having CAP if they had a radiographic evidence of pneumonia (X-ray) on the first day and if they were on antimicrobials on the first day for 3 consecutive days. For studying the microbial etiology, patients were included if they had a positive culture or test collected by hospital Day 0 or 1. Patients with identical Gram negative organisms in blood and urine were excluded. We also excluded patients with a present on admission secondary diagnosis of cholecystitis, appendicitis, peritonitis or abdominal infections.ResultsA total of 95,169 patients had a diagnosis of CAP with a culture or other test performed on the first day. A pathogen was detected in 15.4% of the patients. Among the pathogen positive patients, the mean age was 67 ± 16 years (range 18–89) and 52% were male. Thirty-four percent required ICU care and 8.4% died in the hospital. Almost all patients (99%) had at least one culture drawn, including blood (96%) and respiratory (51%) specimens. Bacteria were the most commonly detected pathogens. Among the Gram-positive bacteria, Streptococcus pneumoniae accounted for 22.2% followed by methicillin sensitive Staphylococcus aureus (MSSA) (14.8%) and methicillin-resistant S. aureus (7.9%). Among the Gram-negative bacteria, the most common organisms reported were Pseudomonas aeruginosa (5.9%), Escherichia coli (5.2%) and Hemophilus influenzae (5.3%). Mycoplasma pneumoniae was identified in 2.2%. Among viral pathogens, the most common were influenza virus (2.6%) and human rhinovirus (0.71%).ConclusionIn a large US inpatient sample, a majority of patients with CAP had no microbial etiology identified by laboratory testing. Among the test positive patients, S. pneumoniae was the most common bacteria reported followed by MSSA and MRSA.Disclosures A. Deshpande, 3M: Investigator, Research support; Clorox: Investigator and Speaker’s Bureau, Research grant and Speaker honorarium; Merck: Investigator and Speaker’s Bureau, Research support. S. S. Richter, bioMerieux: Grant Investigator, Research grant; BD Diagnostics: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant; Hologic: Grant Investigator, Research grant; Diasorin: Grant Investigator, Research grant; Accelerate: Grant Investigator, Research grant; Biofire: Grant Investigator, Research grant.

Secular Trends in Infection-Related Mortality after Kidney Transplantation.

Infections are the most common noncardiovascular causes of death after kidney transplantation. We analyzed the current infection-related mortality among kidney transplant recipients in a nationwide cohort in Finland. Altogether, 3249 adult recipients of a first kidney transplant from 1990 to 2012 were included. Infectious causes of death were analyzed, and the mortality rates for infections were compared between two eras (1990-1999 and 2000-2012). Risk factors for infectious deaths were analyzed with Cox regression and competing risk analyses. Altogether, 953 patients (29%) died during the follow-up, with 204 infection-related deaths. Mortality rate (per 1000 patient-years) due to infections was lower in the more recent cohort (4.6; 95% confidence interval, 3.5 to 6.1) compared with the older cohort (9.1; 95% confidence interval, 7.6 to 10.7); the incidence rate ratio of infectious mortality was 0.51 (95% confidence interval, 0.30 to 0.68). The main causes of infectious deaths were common bacterial infections: septicemia in 38% and pulmonary infections in 45%. Viral and fungal infections caused only 2% and 3% of infectious deaths, respectively (such as individual patients with Cytomegalovirus pneumonia, Herpes simplex virus meningoencephalitis, Varicella zoster virus encephalitis, and Pneumocystis jirovecii infection). Similarly, opportunistic bacterial infections rarely caused death; only one death was caused by Listeria monocytogenes, and two were caused by Mycobacterium tuberculosis. Only 23 (11%) of infection-related deaths occurred during the first post-transplant year. Older recipient age, higher plasma creatinine concentration at the end of the first post-transplant year, diabetes as a cause of ESKD, longer pretransplant dialysis duration, acute rejection, low albumin level, and earlier era of transplantation were associated with increased risk of infectious death in multivariable analysis. The risk of death due to infectious causes after kidney transplantation in Finland dropped by one half since the 1990s. Common bacterial infections remained the most frequent cause of infection-related mortality, whereas opportunistic viral, fungal, or unconventional bacterial infections rarely caused deaths after kidney transplantation.

Group A streptococcal M protein activates the NLRP3 inflammasome

Group A Streptococcus (GAS) is among the top ten causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections, including necrotizing fasciitis and toxic shock syndrome. Here, we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine interleukin-1β (IL-1β) and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K+ efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.

RtfA controls development, secondary metabolism, and virulence in Aspergillus fumigatus.

Invasive aspergillosis by Aspergillus fumigatus is a leading cause of infection-related mortality in immune-compromised patients. In order to discover potential genetic targets to control A. fumigatus infections we characterized rtfA, a gene encoding a putative RNA polymerase II transcription elongation factor-like protein. Our recent work has shown that the rtfA ortholog in the model fungus Aspergillus nidulans regulates morphogenesis and secondary metabolism. The present study on the opportunistic pathogen A. fumigatus rtfA gene revealed that this gene influences fungal growth and conidiation, as well as production of the secondary metabolites tryptoquivaline F, pseurotin A, fumiquinazoline C, festuclavine, and fumigaclavines A, B and C. Additionally, rtfA influences protease activity levels, the sensitivity to oxidative stress and adhesion capacity, all factors important in pathogenicity. Furthermore, rtfA was shown to be indispensable for normal virulence using Galleria mellonella as well as murine infection model systems.

Serum Alkaline Phosphatase Levels Predict Infection-Related Mortality and Hospitalization in Peritoneal Dialysis Patients.

BackgroundSerum alkaline phosphatase (ALP) levels have been reported to be associated with all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. However, it is unclear whether serum ALP levels predict infection-related clinical outcomes in PD patients. The aim of this study was to determine the relationships between serum ALP levels, infection-related mortality and hospitalization in PD patients.MethodsPD patients from the Clinical Research Center registry for end-stage renal disease, a multicenter prospective observational cohort study in Korea, were included in the present study. Patients were categorized into three groups by serum ALP tertiles as follows: Tertile 1, ALP <78 U/L; Tertile 2, ALP = 78–155 U/L; Tertile 3, ALP >155 U/L. Tertile 1 was used as the reference category. The primary outcomes were infection-related mortality and hospitalization.ResultsA total of 1,455 PD patients were included. The median follow-up period was 32 months. The most common cause of infection-related mortality and hospitalization was PD-related peritonitis. Multivariate Cox regression analyses showed that patients in the highest tertiles of serum ALP levels were at higher risk of infection-related mortality (HR 2.29, 95% CI, 1.42–5.21, P = 0.008) after adjustment for clinical variables. Higher tertiles of serum ALP levels were associated with higher risk of infection-related hospitalization (Tertile 2: HR 1.56, 95% CI, 1.18–2.19, P = 0.009, tertile 3: HR 1.34, 95% CI, 1.03–2.62, P = 0.031).ConclusionsOur data showed that elevated serum ALP levels were independently associated with a higher risk of infection-related mortality and hospitalization in PD patients.

A Fluorescence-Based High-Throughput Screening Assay to Identify Growth Inhibitors of the Pathogenic Fungus Aspergillus fumigatus.

Due to the advancements in modern medicine that have resulted in an increased number of immunocompromised individuals, the incidences and the associated mortality of invasive aspergillosis have continued to rise over the past three decades despite appropriate treatment. As a result, invasive aspergillosis has emerged as a leading cause of infection-related mortality in immunocompromised individuals. Utilizing the resazurin to resorufin conversion fluorescence readout to monitor cell viability, herein, we outline a high-throughput screening method amenable to profiling a large pharmaceutical library against the clinically relevant but less frequently screened fungal pathogen Aspergillus fumigatus. This enables the user to conduct high-throughput screening using a disease-relevant fungal growth assay and identify novel antifungal chemotypes as drug leads.

Antibiotic synergy testing for multidrug-resistant Gram-negative pathogens in a Greek ICU

The emergence of multidrug-resistant (MDR) pathogens is a major cause of infection-related mortality among critically ill patients. The synergistic effect between commonly used antibiotics against difficult to treat nosocomial MDR Gram-negative strains, if present, could provide a viable option as an alternative therapy. The aim of this study was to investigate the potential of antibiotic synergy against MDR A. baumannii, K. pneumonia and P. aeruginosa strains, isolated from critically ill patients in a Greek ICU.

The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design.

Group A Streptococcus (GAS) is a leading cause of infection-related mortality in humans. All GAS serotypes express the Lancefield group A carbohydrate (GAC), comprising a polyrhamnose backbone with an immunodominant N-acetylglucosamine (GlcNAc) side chain, which is the basis of rapid diagnostic tests. No biological function has been attributed to this conserved antigen. Here we identify and characterize the GAC biosynthesis genes, gacA through gacL. An isogenic mutant of the glycosyltransferase gacI, which is defective for GlcNAc side-chain addition, is attenuated for virulence in two infection models, in association with increased sensitivity to neutrophil killing, platelet-derived antimicrobials in serum, and the cathelicidin antimicrobial peptide LL-37. Antibodies to GAC lacking the GlcNAc side chain and containing only polyrhamnose promoted opsonophagocytic killing of multiple GAS serotypes and protected against systemic GAS challenge after passive immunization. Thus, the Lancefield antigen plays a functional role in GAS pathogenesis, and a deeper understanding of this unique polysaccharide has implications for vaccine development.

Kalkulierte Antibiotikatherapie bei intraabdominellen Infektionen - Fallbeispiele und evidenzbasierte Therapieempfehlungen

Intra-abdominal infections (IAI) are a common problem in visceral medicine. In Germany more than 150 000 patients are treated each year for IAI with courses ranging from uncomplicated disease to severe life-threatening manifestations. IAI represent the second most common cause of septic shock and the second most common cause of infection-related mortality in intensive care. Due to increasing antimicrobial resistance, changes in pathogen spectra and increasing patient co-morbidities, recommendations for empirical antibiotic therapy have to be continuously updated: Whereas inadequate empirical treatment is associated with poor prognosis, unselected broad-spectrum therapy may increase antimicrobial resistances. Illustrated by clinical cases of typical intra-abdominal infections, this article reviews recommendations for antibiotic therapy based on national and international guidelines under consideration of local resistance rates and patient-specific factors to provide a basis for improved therapy of this common problem.

Prognosis of multi-lobar pneumonia in community-acquired pneumonia: A systematic review and meta-analysis

BackgroundPneumonia is the leading cause of infection related mortality. Multilobar pneumonia (MLP) may have poorer outcomes and is a constituent of some prognostic indices. Our aim was to systematically-review and meta-analyse the impact of multi-lobar involvement in pneumonia. MethodsWe searched PubMed in June 2012 for studies reporting on the association between MLP and clinical outcomes. Potentially relevant studies were cross checked by two independent reviewers before final inclusion. Odds-ratios (OR) for the association between MLP and mortality, unfavourable outcomes, and poor treatment response were pooled using random effects meta-analysis. ResultsTwenty-two studies were included in this report. There were a total of 11,456 pneumonia patients including 2897 (25.3%) patients with MLP. As there was substantial clinical and statistical heterogeneity in the overall dataset, we limited the main meta-analysis to patients with community-acquired pneumonia (CAP). This showed that MLP was associated with increased mortality, OR 2.57 (95% CI: 1.83–3.61), with no statistical heterogeneity (I2=0%). Evidence from other settings suggests that MLP may also be associated with higher likelihood of other poor outcomes such as worsening clinical/radiological status, delayed resolution, and need for mechanical ventilation. ConclusionMLP appears to be an independent risk factor for mortality in CAP. It may be possible to improve commonly used prognostic indices in CAP by addition of MLP as a criterion.

Fungal infections in stem cell transplantation: epidemiology and therapy

Invasive fungal infections (IFIs) are an increasingly important cause of infection-related mortality in stem cell transplantation (SCT). Mortality from IFIs remains high because of diagnostic limitations and has given rise to the concepts of empiric and pre-emptive, as opposed to targeted, antifungal therapy. Data from the 2010 US TRANSET consortium found that Aspergillus (43%) and Candida (28%) were the two most frequently encountered pathogen groups; Zygomycetes and Pneumocystis comprised 8% and 2%, respectively. The frequency of IFIs varies with SCT type with 12 month cumulative incidences highest for matched unrelated SCT and lowest for autologous SCT. Trends in susceptibility to antifungals have identified increasing azole resistance (with cross-resistance) amongst Candid a spp., ampho-tericin B resistance amongst certain moulds and azole resistance in Aspergillus and other moulds. Recommendations for targeted antifungal therapy of yeasts and mould infections of the Infectious Diseases of Society of American, European, and Australian and New Zealand Mycoses Interest Group are similar. Early intervention strategies include empirical therapy which reduces IFIfrequency but has not been shown to reduce mortality and has high costs and drug toxici-ties. Pre-emptive therapy attempts to harness clinical/radiological features in conjunction with fungal biomarkers to detect early disease but its advantage has not been documented.

VeA Regulates Conidiation, Gliotoxin Production, and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus

Invasive aspergillosis by Aspergillus fumigatus is a leading cause of infection-related mortality in immunocompromised patients. In this study, we show that veA, a major conserved regulatory gene that is unique to fungi, is necessary for normal morphogenesis in this medically relevant fungus. Although deletion of veA results in a strain with reduced conidiation, overexpression of this gene further reduced conidial production, indicating that veA has a major role as a regulator of development in A. fumigatus and that normal conidiation is only sustained in the presence of wild-type VeA levels. Furthermore, our studies revealed that veA is a positive regulator in the production of gliotoxin, a secondary metabolite known to be a virulent factor in A. fumigatus. Deletion of veA resulted in a reduction of gliotoxin production with respect to that of the wild-type control. This reduction in toxin coincided with a decrease in gliZ and gliP expression, which is necessary for gliotoxin biosynthesis. Interestingly, veA also influences protease activity in this organism. Specifically, deletion of veA resulted in a reduction of protease activity; this is the first report of a veA homolog with a role in controlling fungal hydrolytic activity. Although veA affects several cellular processes in A. fumigatus, pathogenicity studies in a neutropenic mouse infection model indicated that veA is dispensable for virulence.

Eradication of Pulmonary Aspergillosis in an Adolescent Patient Undergoing Three Allogeneic Stem Cell Transplantations for Acute Lymphoblastic Leukemia

Systemic fungal infections are a major cause of infection-related mortality in patients with hematologic malignancies. This report addresses the case of an adolescent patient with acute lymphoblastic leukemia who underwent three allogeneic hematopoietic stem cell transplantations and developed pulmonary aspergillosis. Combination therapy with liposomal amphotericin B (L-AmB, 3 mg/kg bw/day) and caspofungin (CAS, 50 mg/day) during the first allogeneic hematopoietic stem cell transplantation (HSCT) improved the pulmonary situation. After shifting the antifungal combination therapy to oral voriconazole (2 × 200 mg/day) and CAS, a new pulmonal lesion occurred alongside the improvements in the existing pulmonary aspergillosis. An antifungal combination during a second HSCT with L-AmB (3 mg/kg bw/day) and CAS showed an improvement in the pulmonary aspergillosis. A combination therapy with CAS and L-AmB (1 mg/kg bw/day) during the third HSCT led once again to progress the pulmonary aspergillosis, after increasing the L-AMB to 3 mg/kg bw/day for recovery. The presented case provides an example of how, despite severe immunosuppression, a combination of antifungal drugs administered intravenously at therapeutic dosages may be more efficient than either intravenous monotherapy or combinations of intravenous and oral antifungals in selecting pediatric and adolescent patients with proven fungal infections.