Life-threatening Infections Research Articles

Daily functioning and (health-related) quality of life of young adult survivors of childhood bacterial meningitis.

Young adult survivors of childhood BM reported similar and even better levels of daily functioning, HRQoL, and overall QoL than age-matched Dutch reference scores. However, clinicians and healthcare workers should be mindful of poor mental and physical health of some survivors of childhood BM because these survivors also face problems with functioning in daily life. • Acute bacterial meningitis is a life-threatening infection which may lead to devastating lifelong disabilities. • Health-related quality of life is decreased in school-age survivors of bacterial meningitis. • The present study shows that HRQoL in survivors of childhood BM improves over time • However, especially poor mental health in adolescent and young adult survivors is associated with impaired functioning in daily life.

Synergistic wall digestion and cuproptosis against fungal infections using lywallzyme-induced self-assembly of metal-phenolic nanoflowers

Fungi are very common infectious pathogens, which may cause invasive and potentially life-threatening infections. However, the efficacy of antifungal medications remains limited. Herein, a Cu2+-phenolic nanoflower is designed to combat fungal infections by combining cuproptosis and cell wall digestion. Firstly, protocatechuic acid (PA)-Cu2+ (PC) nanopetals are prepared by coordination interaction. Lywallzyme (Lyw) is then added to induce the self-assembly of PC to form Lyw loaded PC (PCW) nanoflowers. PCW nanoflowers can effectively adhere to fungal surface and Lyw can digest fungal cell walls to facilitate Cu2+ to penetrate into fungal interior, thereby exerting a synergistic fungicidal effect. PCW nanoflowers exhibit excellent fungicidal activity even in protein-rich and high-salt conditions, where dissociative Cu2+ completely loses fungicidal activity. Transcriptome sequencing analysis reveals that PCW can lead to fungal cuproptosis. The in vivo fungicidal effect of PCW nanoflowers is confirmed on a murine skin fungal infection model and a murine fungal keratitis model.

Inborn Errors of Immunity in Pediatric Intensive Care: Prevalence, Characteristics, and Prognosis.

Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases characterized by impaired immune system function. This prospective study aimed to determine the frequency, characteristics, and clinical course of IEI patients admitted to the pediatric intensive care unit (PICU) and identify mortality-related factors. Using a comprehensive immunological evaluation protocol, we screened 753 PICU admissions for potential IEIs during three years. Patients with pre-existing IEI diagnoses, chronic diseases, ongoing chronic medication regimens, other known comorbidities, trauma cases, post-surgical cases, and poisonings were excluded. Thirty-three patients were newly diagnosed with IEIs during or as a result of their PICU stay, representing an incidence of 4.39%. The most common disorders were immunodeficiencies with immune dysregulation (48.5%), followed by combined immunodeficiencies (24.2%). Severe viral infections (61%) and life-threatening infections (51.7%) were the most frequent warning signs. Only 31% of patients exhibited at least two Jeffrey Modell Foundation warning signs. The mortality rate was 58%, highlighting the need for early diagnosis and treatment. Newborn screening and family segregation studies are crucial to improving outcomes for IEI patients in intensive care settings.

Protective innate immunity against Pneumocystis does not require Stat6-dependent macrophage polarization.

Pneumocystis species are respiratory fungal pathogens that cause life-threatening opportunistic infections in immunocompromised hosts. Pneumocystis typically evade pulmonary innate immunity but are efficiently eradicated by a functional adaptive immune response. FVB/NJ mice are unique in that they display protective alveolar macrophage-dependent innate immunity against Pneumocystis, and remain resistant to infection even in the absence of CD4+ T lymphocyte function. FVB/NJ alveolar macrophages (AMs) were found to display an M2-biased phenotype at baseline, which was potentiated after stimulation with Pneumocystis, suggesting that macrophage polarization may dictate the outcome of the Pneumocystis-macrophage interaction. To determine whether Stat6, a key global regulator of M2 polarization, was required for FVB/NJ innate immunity, FVB Stat6-/- mice were generated. FVB Stat6-deficient AMs were markedly impaired in their ability to polarize to an M2 phenotype when stimulated with Th2 cytokines. However, FVB Stat6-/- mice remained highly resistant to infection, indicating that Stat6 signaling is dispensable for innate FVB/NJ resistance. Despite the loss of Stat6 signaling, primary AMs from FVB Stat6-/- mice maintained baseline expression of M2 markers, and also strongly upregulated M2-associated genes following direct stimulation with Pneumocystis. Additional FVB/NJ knockout strains were generated, but only FVB MerTK-/- mice showed a marginally increased susceptibility to Pneumocystis infection. Together, these findings demonstrate that effective FVB/NJ innate immunity against Pneumocystis does not require Stat6 signaling and suggest that alternative pathways regulate M2 bias and macrophage-mediated innate resistance in FVB/NJ mice.

Genetic characterization of Neisseria meningitidis isolates recovered from patients with invasive meningococcal disease in Lithuania.

Neisseria meningitidis is a gram-negative bacterium responsible for life-threatening invasive infections known as invasive meningococcal disease and is associated with high fatality rates and serious lifelong disabilities among survivors. This study aimed to characterize N. meningitidis isolates cultured from blood and cerebrospinal fluid collected between 2009 and 2021 in Lithuania, assess their genomic relationships with European strains, and evaluate the possibility of using a cost-effective method for strain characterization, thus improving the national molecular surveillance of invasive meningococcal disease. In total, 321 N. meningitidis isolates were collected and analyzed using multilocus restriction typing (MLRT). Amplification of the penA gene and restriction fragment length polymorphism analysis were performed to identify the modified penA genes. Based on the MLRT genotyping results, we selected 10 strains for additional analysis using whole-genome sequencing. The sequenced genomes were incorporated into a dataset of publicly available N. meningitidis genomes to evaluate genomic diversity and establish phylogenetic relationships within the Lithuanian and European circulating strains. We identified 83 different strains using MLRT genotyping. Genomic diversity of N. meningitidis genomes analysed revealed 21 different sequence types (STs) circulating in Lithuania. Among these, ST34 was the most prevalent. Notably, three isolates displayed unique combinations of seven housekeeping genes and were identified as novel STs: ST16969, ST16901, and ST16959. The analyzed strains were found to possess virulence factors not commonly found in N. meningitidis. Six distinct penA profiles were identified, each with different frequencies. In the present study, we also identified N. meningitidis strains with new penA, NEIS0123, NEIS1320, NEIS1525, NEIS1600, and NEIS1753 loci variants. In our study, using the cgMLST scheme, Minimum Spanning Tree (MST) analysis did not identify significant geographic relationships between Lithuanian N.meningitidis isolates and strains from Europe. Discussion: To our knowledge, this is the first study to employ whole genome sequencing (WGS) method for a comprehensive genetic characterization of invasive N. meningitidis isolates from Lithuania. This approach provides a more detailed and precise analysis of genomic relationships and diversity compared to prior studies relying on traditional molecular typing methods and antigen analysis.

Chromobacterium violaceum: An incidental finding in a neonate.

Chromobacterium violaceum is a gram-negative saprophytic bacterium causing human infection in tropical and subtropical countries. Such infections are uncommon but cause high mortality when the bacterium enters the bloodstream through an open wound. We present a case of C. violaceum infection isolated from a blood culture sample in a neonate identified at a tertiary care teaching hospital in North East Uttar Pradesh. Timely diagnosis by microbiological methods and antimicrobial treatment led to a successful cure for this life-threatening infection. Thus, such bacteria should be included in the routine spectrum for differential diagnosis of sepsis, to provide a chance of cure.

Immunosenescence: How Aging Increases Susceptibility to Bacterial Infections and Virulence Factors.

The process of aging leads to a progressive decline in the immune system function, known as immunosenescence, which compromises both innate and adaptive responses. This includes impairments in phagocytosis and decreased production, activation, and function of T- and B-lymphocytes, among other effects. Bacteria exploit immunosenescence by using various virulence factors to evade the host's defenses, leading to severe and often life-threatening infections. This manuscript explores the complex relationship between immunosenescence and bacterial virulence, focusing on the underlying mechanisms that increase vulnerability to bacterial infections in the elderly. Additionally, it discusses how machine learning methods can provide accurate modeling of interactions between the weakened immune system and bacterial virulence mechanisms, guiding the development of personalized interventions. The development of vaccines, novel antibiotics, and antivirulence therapies for multidrug-resistant bacteria, as well as the investigation of potential immune-boosting therapies, are promising strategies in this field. Future research should focus on how machine learning approaches can be integrated with immunological, microbiological, and clinical data to develop personalized interventions that improve outcomes for bacterial infections in the growing elderly population.

Green synthesis of silver, starch, and zinc oxide mediated nanoparticles with probiotics and plant extracts, their characterization and anti-bacterial activity

Nanotechnology has various applications in all branches of science, including engineering, medicine, pharmacy, and other related fields. Conventional techniques, such as the chemical reduction approach, which produces nanoparticles (NPs) using various hazardous chemicals, offer several health risks due to their toxicity and raise serious environmental concerns. In contrast, other techniques are expensive and need a lot of energy. More than 70 % of pathogenic bacterial strains have developed resistance to at least one class of antibiotics, leading to an increase in life-threatening bacterial infections that pose a significant health risk. However, the creation of NPs by biogenic synthesis is risk-free for the environment and clean enough for biological use. This study was aimed at synthesis of novel Moringa oleifera mediated starch capped silver-zinc NPs and green synthesis of ZnO nanoparticles from Aloe vera, papaya, and Lactobacillus plantarum. Antimicrobial activity of both NPs was tested against Gram-negative antibiotic-resistant bacteria Pseudomonas aeruginosa, Gram-positive bacteria Staphylococcus aureus (ATCC 6538), and two foodborne pathogens Listeria monocytogenes and Campylobacter jejuni. Ultraviolet–visible spectroscopy, Fourier Transform Infrared Spectroscopy, and Scanning Electron Microscopy were used for characterization. Majority of the research studies stress the flexibility, repeatability, and desirable features of the metals, polymers, and plant components employed in the production of biomedical nanoparticles. Such an intuitive approach provides several advantages, particularly a reasonable total expense, compliance with healthcare and pharmaceutical implementations, and the ability to produce massive volumes for industrial use. The novelty of the presented work lies in the unusual combination of silver, starch, and zinc oxide nanoparticles using Moringa oleifera, which is an eco-friendly alternative to chemical-based methods. This research exhibits the formation of well-defined nanoparticles with strong antibacterial activity against a wide range of pathogens, giving us insights into their potential applications in various biomedical fields.

Modified Laboratory Risk Indicator and Machine Learning in Classifying Necrotizing Fasciitis from Cellulitis Patients

Necrotizing fasciitis (NF) is a severe and life-threatening soft tissue infection that requires timely and accurate diagnosis to improve patient outcomes. The early diagnosis of NF remains challenging due to its similarity to other subcutaneous soft tissue infections like cellulitis. This study aims to employ machine learning techniques to differentiate NF from cellulitis and enhance the diagnostic accuracy of NF by developing a modified LRINEC (MLRINEC) score. These modifications aimed to improve the sensitivity and specificity of NF diagnosis. The study utilized three machine learning classifiers—Logistic Regression, decision tree, and Random Forest—to assess their effectiveness in distinguishing between NF and cellulitis cases. The MLRINEC score was developed by incorporating six key blood test parameters: creatinine, hemoglobin, platelet count, sodium, white blood cell count, and C-reactive protein using laboratory data from Maha Sarakham Hospital in Northeastern Thailand. Our findings indicate that the decision tree classifier demonstrated superior performance, achieving the highest recall, particularly in accurately identifying NF cases. A feature importance analysis revealed that hemoglobin levels and white blood cell counts were the most critical factors influencing the model’s predictions. The platelet count (PT), C-reactive protein (CRP), and creatinine (CT) also played important roles, while sodium levels (NA) were the least influential. The MLRINEC score demonstrates high accuracy in classifying NF and cellulitis patients, paving the way for improved diagnostic protocols in clinical settings.

Emerging Fungal Infections of the Central Nervous System in the Past Decade: A Literature Review.

Invasive fungal infections affecting the central nervous system (CNS) are a major health concern worldwide associated with high mortality rates. Their increased incidence is largely due to an increase in the vulnerable immunocompromised population, changing environmental factors, and development of more accurate diagnostic methods. The aim of this article is to identify fungal causes of CNS infections that are recently emerging or have the potential to become emerging pathogens in the near future, as well as their clinical characteristics, including: Candida auris, Trichosporon spp., Blastomyces spp., Sporothrix spp., Talaromyces marneffei, Lomentospora prolificans, and Scedosporium spp. A review of the literature in PubMed in the last ten years was conducted to identify central nervous system infections caused by each of these fungi. The review identified 10 cases caused by C. auris, 5 cases by Trichosporon spp., 82 cases by Blastomyces spp., 36 cases by Sporothrix spp., 21 cases by T. marneffei, 22 cases by Lomentospora prolificans, and 42 cases by Scedosporium spp. The exact burden of these diseases remains difficult to ascertain, but their apparent rise underscores the urgent need for improved diagnostic, treatment, and management strategies against CNS fungal pathogens to improve outcomes against these life-threatening infections.

The epidemiology of gram-negative bacteremia in Lebanon: a study in four hospitals

IntroductionGram-negative bacteremia is a life-threatening infection with high morbidity and mortality. Its incidence is rising worldwide, and treatment has become more challenging due to emerging bacterial resistance. Little data is available on the burden and outcome of such infections in Lebanon.MethodsWe conducted this retrospective study in four Lebanese hospitals. Data on medical conditions and demographics of 2400 patients diagnosed with a bloodstream infection based on a positive blood culture were collected between January 2014 and December 2020.ResultsMost bacteremias were caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, with the more resistant organisms being hospital-acquired. Third-generation cephalosporin and quinolone resistance was steady throughout the study, but carbapenem resistance increased. Mortality with such infections is high, but carbapenem resistance or infection with Pseudomonas or Acinetobacter species were significant risk factors for poor outcomes.ConclusionThis is the first multi-center study from Lebanon on gram-negative bacteremia, resistance patterns, and factors associated with a poor outcome. More surveillance is needed to provide data to guide empirical treatment for bacteremia in Lebanon.

Management of Pulmonary Mucormycosis: A Systematic Review

Background Mucormycosis is a life-threatening fungal infection. Rhino-orbito-cerebral mucormycosis (ROCM) and pulmonary mucormycosis (PM) are the most common presentations. This systematic review focuses on the management of PM. Although the mortality from PM has improved over the last few decades, it is still high, at 49.8% (Muthu, Agarwal, et al., 2021). Objective The objective is to identify and map the management of PM. Design This review is designed for knowledge synthesis, with a systematic approach to identifying, synthesizing, and mapping treatment protocols for the management of PM. Methods This systematic review provides a clear, reproducible methodology. It is reported in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Inclusion criteria were defined: peer-reviewed journal articles published in English from 2018 to 2023 relating to treatment protocols for PM, where the full text of the article was available. Exclusion criteria were also defined - articles that focus on limited treatment regimens, such as the use of amphotericin B only, or topics not relevant to the research question, such as fungal infections and pulmonary diseases unrelated to mucormycosis. Results The results span six years, from 2018 to 2023, with 355 articles identified. After removing duplicates, 227 papers remained. Inclusion and exclusion criteria were applied, with 202 articles excluded as a result. The remaining 19 articles were deemed relevant. In addition, seven relevant articles were identified via citation tracking and two articles identified by hand search. Thus, a total of 28 articles thus reviewed. The management of PM was mapped in tabular and diagrammatic form. Conclusion The results indicate that early diagnosis, early and aggressive surgery, and effective antifungals may improve survival. There is a shift away from using Am-B and a clear preference for L-AmB as a first-line antifungal. Posaconazole and Isavuconazole are the drugs of choice for stepdown, maintenance, and salvage therapy, and as alternative therapies. The control of co-morbidities is a crucial aspect of treatment. Cytokines and hyperbaric oxygen may be beneficial. The therapeutic value of iron chelators, zinc, and nebulized amphotericin B (NAB) merit further study.

Fournier’s gangrene in voluminous inguinoscrotal herniation: Case report and review of literature

Introduction: Fournier’s gangrene (FG) is a polymicrobial life-threatening infection that affects perineal region and may extend to genitalia and abdominal wall. Necrotizing fasciitis is a rare condition and its association with large inguinoscrotal hernia even rarer. With high mortality rate, some predisposing factors are diabetes and immunodeficiency. Case presentation: We report a case of a 48-year-old man with Fournier’s gangrene associated with voluminous inguinoscrotal herniation which evolved to hernia sac exposure after debridement. Discussion: FG pathophysiology initiates with a localized infection by a combination of gram positive, gram negative and anaerobic bacteria, and its advancing leads to local inflammatory response, thrombosis, blood flow reduction and ischemia. Diagnosis depends on clinical presentation and image evaluation. Conclusion: FG management has been standard in the literature, however its association with inguinoscrotal hernias have not been considered in guidelines. Early diagnosis and proper clinical and surgical treatment are fundamental to avoid life-threatening complications and morbidities.

The development of single-domain VHH nanobodies that target the Candida albicans cell surface.

Candida albicans causes life-threatening invasive infections that are hard to diagnose and treat, with drug resistance leading to treatment failure. The goal of this study was to develop VHH (single variable domain on a heavy chain) nanobodies to detect drug-resistant infections. Llamas were immunized with a mixture of heat killed and fixed C. albicans cells of different morphologies. Llama lymphocyte RNA was used to generate phage display libraries that were tested for binding to C. albicans cells or cell wall fractions, and single antibody domains were isolated. The libraries were panned against echinocandin-resistant C. albicans isolates and counter-selected against echinocandin-susceptible isolates with the aim of isolating binding domains specific for antigens on drug-resistant cells. Thirty diverse VHH nanobodies were selected, and binding characteristics were assessed via dose-response ELISA. Binding was tested against a variety of C. albicans isolates and other Candida species, indicating that the VHHs were specific for C. albicans. The VHH nanobodies were sorted into four distinct groups based on their binding patterns. Two of the groups bound preferentially to the yeast cell poles and hyphae, respectively. Nanobody binding to C. albicans deletion mutants was tested by fluorescence microscopy and ELISA to identify the antigen targets. VHH19 nanobody, belonging to the largest group, recognized the Als4 adhesin. VHH14 antibody in the hyphae-specific group recognized Als3. None of the isolated VHH nanobodies was selective for drug-resistant clinical isolates. Our data indicate that this approach can generate valuable single-domain antibodies specific to C. albicans proteins.IMPORTANCEThe human fungal pathogen Candida albicans causes a range of diseases from superficial mucosal infections such as oral and vaginal thrush to life-threatening, systemic infections. Accurate and rapid diagnosis of these infections remains challenging, and currently, there are no rapid ways to diagnose drug-resistant infections without performing drug susceptibility testing from blood culture, which can take several days. In this proof-of-concept study, we have generated a diverse set of single domain VHH antibodies (nanobodies) from llamas that recognize and bind specifically to C. albicans cell surface. The nanobodies were classified into four groups based on their binding patterns, for example, cell poles or hyphae. Specific nanobodies were verified as recognizing the important adhesin Als4 or the hyphae associated invasin Als3, respectively. The data validate the approach that small VHH antibody domains hold future promise for diagnostic applications and as probes to study the fungal cell surface.

Directly Isolated Allogeneic Virus–Specific T Cells in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus-specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. Fresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

Gas gangrene with Clostridium septicum in a neutropenic patient.

Gas gangrene is a rare presentation of a necrotizing fasciitis, caused by Clostridium perfringens, C. septicum and other clostridial species. With its rapid progression it is a potentially life-threatening infection, that poses as a challenge in the clinical management requiring an interdisciplinary approach.Here we present a 62-year-old woman, who developed neutropenic fever while undergoing chemotherapy for triple negative breast cancer. She presented with a high fever, reporting little pain in her left thigh accompanied by redness and induration locally. Subsequently the patient developed pain and redness of the back of the left hand. The initial findings suggested cellulitis and immediate empiric treatment with intravenous meropenem was started. Despite the antibiotic treatment the patient rapidly developed septic shock along with progression of the local infection. Emergency surgical debridement revealed extensive necrosis of the soft tissues including extensive myonecrosis of the thigh. On the left hand an extensive debridement was performed, the left lower limb could not be preserved and exarticulation of the left hip was required. Microbiologically C. septicum was isolated in different samples, confirming gas gangrene. As there was no local entry portal on the skin, hematogenous seeding from intestinal translocation in this neutropenic patient was suspected. The empiric antibiotic treatment was tailored to intravenous penicillin and complemented with clindamycin for toxin inhibition. Following radical debridement and antibiotic treatment, the patient could be stabilized. After repetitive debridement wound closure was achieved and the patient was discharged for rehabilitation. Antibiotic treatment was continued for four weeks.This rare case of gas gangrene in a neutropenic patient shows the complexity in the diagnostic and therapeutic management of necrotizing soft tissue infections in immunocompromised patients. It particularly highlights the importance of an interdisciplinary management with fast recognition of the disease and rapid, if needed radical, surgical debridement as well as tailored antibiotic treatment for a successful outcome.

Rapid design of bacteriophage cocktails to suppress the burden and virulence of gut-resident carbapenem-resistant Klebsiella pneumoniae

Antibiotic use can lead to the expansion of multi-drug-resistant pathobionts within the gut microbiome that can cause life-threatening infections. Selective alternatives to conventional antibiotics are in dire need. Here, we describe a Klebsiella PhageBank for the tailored design of bacteriophage cocktails to treat multi-drug-resistant Klebsiella pneumoniae. Using a transposon library in carbapenem-resistant K.pneumoniae, we identify host factors required for phage infection in major Klebsiella phage families. Leveraging the diversity of the PhageBank, we formulate phage combinations that eliminate K.pneumoniae with minimal phage resistance. Optimized cocktails selectively suppress the burden of K.pneumoniae in the mouse gut and drive the loss of key virulence factors that act as phage receptors. Phage-mediated diversification of bacterial populations in the gut leads to co-evolution of phage variants with higher virulence and broader host range. Altogether, the Klebsiella PhageBank charts a roadmap for phage therapy against a critical multidrug-resistant human pathogen.

Hemophagocytosis of the Hilar Pulmonary Lymph Nodes Is a More Sensitive Indicator of the Severity of COVID-19 Disease than Bone Marrow Hemophagocytosis.

In systemic hyper-inflammation, as in severe COVID-19 disease, there are pronounced disorders of the hematological and lymphatic systems with prognostically relevant hemophagocytosis of the bone marrow. The current work aimed to address the importance of hemophagocytosis in the lymph nodes of patients with severe COVID-19 disease. From 28 patients who died of severe COVID-19 infection, samples of the vertebral bone marrow and lymph nodes from the cervical, hilar, para-aortic, mesenteric and inguinal locations were morphologically and immunohistologically (CD163, CD68, CD61, CD71, CD3, CD20, CD138) examined for the possible presence of hemophagocytosis. In the single-center study at the University Hospital Jena, a total of 191 hemophagocytes were found in the bone marrow and a total of 780 hemophagocytes in the lymph nodes in a standardized area of 21,924 mm2 per tissue sample. With 370 hemophagocytes, hilar lymph nodes were most frequently affected (370/780; 47.44%; 95%-CI: [43.94, 50.95]), followed by cervical lymph nodes (206/780; 26.41%; 95%-CI: [23.41, 29.59]), para-aortic lymph nodes (125/780; 16.03%; 95%-CI: [13.58, 18.73]) and inguinal/mesenteric lymph nodes (79/780; 10.13%; 95%-CI: [8.155, 12.4]). Based on the standard area (21,924 mm2), the difference in the number of hemophagocytes in the bone marrow and in the hilar lymph nodes was statistically significant (p < 0.05), while this did not apply to the lymph nodes from the other locations. In fatal COVID-19 disease, hemophagocytosis is particularly found in the hilar lymph nodes and is therefore a better indicator of the severity of the disease than hemophagocytosis in the bone marrow. The findings provide some evidence for the concept of compartmentalized human host responses to life-threatening infections.

Ergosterol Biosynthesis and Regulation Impact the Antifungal Resistance and Virulence of Candida spp.

Ergosterol is a key fungal sterol that is mainly found in the plasma membrane and is responsible for the proper membrane structure, rigidity, permeability and activity of membrane proteins. Ergosterol plays a crucial role in the ability of fungi to adapt to environmental stresses. The biosynthesis of ergosterol is also intimately connected with the antifungal resistance and virulence of pathogenic fungi. The most common etiological agents of life-threatening fungal infections are yeasts belonging to the genus Candida. The antifungal agents mostly used to treat Candida spp. infections are azoles, which act as competitive inhibitors of sterol demethylase, a key enzyme in the fungal ergosterol biosynthetic pathway. Although most studies on ergosterol biosynthesis, its regulation and the uptake of sterols are from the baker’s yeast Saccharomyces cerevisiae, the study of ergosterol biosynthesis and its relationship to antifungal drug resistance and virulence in pathogenic fungi is of utmost importance. The increasing antifungal drug resistance of Candida spp. and the limited armamentarium of antimycotics pose a challenge in the development of new therapeutic approaches. This review summarizes the available data on ergosterol biosynthesis and related phenomena in Candida albicans and non-albicans Candida species (Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida auris) with special emphasis on C. albicans and C. glabrata as the most common etiological agents of systemic candidiasis.

Reprint-Necrotizing Fasciitis: A Case Report and A Review of the Literature

Necrotizing fasciitis is a soft-tissue infection characterized by extensive necrosis of subcutaneous fat, neurovascular structures, and fascia. In general, fascial necrosis precedes muscle and skin involvement, hence its namesake. Initially, this uncommon and rapidly progressive disease process can present as a form of cellulitis or superficial abscess. However, the high morbidity and mortality rates associated with necrotizing fasciitis suggest a more serious, ominous condition. Diagnosis may be delayed because of the initial minimal skin cellulitis, even as the subcutaneous tissue suffers extensive necrosis and pronounced systemic toxicity develops. A delay in diagnosis can result in progressive advancement highlighted by widespread infection, multiple-organ involvement, and, ultimately, death. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) might be useful in cases where signs are equivocal or diagnosis is in doubt. Computed tomography scans are estimated to have a sensitivity of 80% for detecting necrotizing soft tissue infections. We present a case of limb salvage in a 52-year-old patient with misunderstood type 2 diabetes mellitus and progressive fascial necrosis. A detailed review of the literature is presented, and current treatment modalities are described. Aggressive surgical debridement, comprehensive medical management of the sepsis and comorbidities, and timely closure of the resultant wound or wounds are essential for a successful outcome. Necrotizing fasciitis is a soft tissue infection characterized by extensive necrosis of subcutaneous fat, neurovascular structures and fascia. Background: the characteristic of this case was aggression and rapid extension. Case presentation: a 59-year-old woman was observed in a very serious condition, with fever and a large necrotic area that smelled of the right inguinal-femoral region in extension to the thigh. No history of illness. Obesity. Diagnosis may be delayed due to minimal initial cutaneous cellulite. A delay in diagnosis can lead to the progression of the disease shown by shock, multiple organ failure and, ultimately, death. Computed tomography and Magnetic Resonance Imaging could be useful in cases where the signs are equivocal or the diagnosis is in doubt. A detailed review of the literature is presented and the current treatment modalities are described. In this case, the aggressive surgical debridement, the complete medical management of sepsis and comorbidities and the timely closure of the wound by dermo-epidermal grafting were essential for a positive result. Conclusions: necrotizing fasciitis is an uncommon life-threatening soft tissue infection, which spreads rapidly and progressively along the deep fascia. The prognosis depends on accurate diagnosis and immediate treatment.