Fulminant Bacterial Infection Research Articles

Structural dynamics of the CROPs domain control stability and toxicity of Paeniclostridium sordellii lethal toxin

Paeniclostridium sordellii lethal toxin (TcsL) is a potent exotoxin that causes lethal toxic shock syndrome associated with fulminant bacterial infections. TcsL belongs to the large clostridial toxin (LCT) family. Here, we report that TcsL with varied lengths of combined repetitive oligopeptides (CROPs) deleted show increased autoproteolysis as well as higher cytotoxicity. We next present cryo-EM structures of full-length TcsL, at neutral (pH 7.4) and acidic (pH 5.0) conditions. The TcsL at neutral pH exhibits in the open conformation, which resembles reported TcdB structures. Low pH induces the conformational change of partial TcsL to the closed form. Two intracellular interfaces are observed in the closed conformation, which possibly locks the cysteine protease domain and hinders the binding of the host receptor. Our findings provide insights into the structure and function of TcsL and reveal mechanisms for CROPs-mediated modulation of autoproteolysis and cytotoxicity, which could be common across the LCT family.

Comparisons of deep learning algorithms for diagnosing bacterial keratitis via external eye photographs

Bacterial keratitis (BK), a painful and fulminant bacterial infection of the cornea, is the most common type of vision-threatening infectious keratitis (IK). A rapid clinical diagnosis by an ophthalmologist may often help prevent BK patients from progression to corneal melting or even perforation, but many rural areas cannot afford an ophthalmologist. Thanks to the rapid development of deep learning (DL) algorithms, artificial intelligence via image could provide an immediate screening and recommendation for patients with red and painful eyes. Therefore, this study aims to elucidate the potentials of different DL algorithms for diagnosing BK via external eye photos. External eye photos of clinically suspected IK were consecutively collected from five referral centers. The candidate DL frameworks, including ResNet50, ResNeXt50, DenseNet121, SE-ResNet50, EfficientNets B0, B1, B2, and B3, were trained to recognize BK from the photo toward the target with the greatest area under the receiver operating characteristic curve (AUROC). Via five-cross validation, EfficientNet B3 showed the most excellent average AUROC, in which the average percentage of sensitivity, specificity, positive predictive value, and negative predictive value was 74, 64, 77, and 61. There was no statistical difference in diagnostic accuracy and AUROC between any two of these DL frameworks. The diagnostic accuracy of these models (ranged from 69 to 72%) is comparable to that of the ophthalmologist (66% to 74%). Therefore, all these models are promising tools for diagnosing BK in first-line medical care units without ophthalmologists.

Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID-19 pandemic.

SummaryWith the developing COVID‐19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self‐isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life‐saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID‐19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID‐19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID‐19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.

Successful cure of C1q deficiency in human subjects treated with hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is used to cure a number of primary immunodeficiency diseases but has never been attempted for patients with complement deficiencies because most complement factors are produced in the liver rather than the bone marrow. Inherited deficiency of the C1q component of the classical complement pathway is a severe autosomal recessive immunodeficiency disease associated with a high risk of death from either fulminant bacterial infections or systemic lupus erythematosus–like autoimmunity.

Autopsy cases of fulminant bacterial infection in adults: clinical onset depends on the virulence of bacteria and patient immune status

To assist physicians in recognizing the potentially fatal onset of symptoms in cases of fulminant bacterial infection, we analyzed 11 autopsy cases of such infection (four caused by Streptococcus pneumoniae, four by S. pyogenes, one by S. dysgalactiae subsp. equisimilis, one by Staphylococcus aureus, and one by Vibrio vulnificus). Clinicohistopathologic features were evaluated. All patients experienced sudden onset of hypotension and multiple organ failure, leading to unexpected death. Blood culture confirmed bacteremia. The main chief complaints were gastrointestinal symptoms (45%) and limb pain (36%). All had an underlying chronic illness (82%), e.g., a hematologic disorder (36.3%) or liver cirrhosis (27.2%). Necrotizing fasciitis occurred in only 55% of cases, with none involving pneumococcal infection. Laboratory tests typically showed C-reactive protein elevation but without leukocytosis, indicating a high-level inflammatory state. In ten cases, death was attributed to circulatory collapse due to sepsis; severe pulmonary congestion and hemorrhage were present in these cases. The onset of fulminant bacterial infection depends on both virulence of the bacterium and status of the host defense system.

An Augmented Passive Immune Therapy to Treat Fulminant Bacterial Infections

In the early 1900s, passive immunization/antibody therapy was used to treat a variety of human ailments such as hypoimmunoglobulinemia, cancer and infectious disease. The advent of antibiotic therapy had relegated this type of therapy obsolete for treatment of infectious diseases. Emergence of multi-drug resistant pathogens along with novel monoclonal antibody production techniques has rekindled the interest in passive immunization (PI). An increase in the number of monoclonal antibody patent applications in the recent past suggests a renewed commercial interest in PI. Despite these developments, antibody therapy for infectious diseases has limitations including the need for large or frequent dosages. P4, a 28-amino acid peptide is a multi-lineage cellular activator. P4, along with infectious disease (i.e. Pathogen) specific immunoglobulin, has been shown in vitro and in vivo in mice to potentiate innate immunity. This review will discuss the progress made in passive antibody therapy, the challenges still to be surmounted, and the potential expanded role of an immune-potentiating peptide (bio-molecule) in the quest to utilize and revitalize passive immunization.

Bistability and bacterial infections.

Bacterial infections occur when the natural host defenses are overwhelmed by invading bacteria. The main component of the host defense is impaired when neutrophil count or function is too low, putting the host at great risk of developing an acute infection. In people with intact immune systems, neutrophil count increases during bacterial infection. However, there are two important clinical cases in which they remain constant: a) in patients with neutropenic-associated conditions, such as those undergoing chemotherapy at the nadir (the minimum clinically observable neutrophil level); b) in ex vivo examination of the patient's neutrophil bactericidal activity. Here we study bacterial population dynamics under fixed neutrophil levels by mathematical modelling. We show that under reasonable biological assumptions, there are only two possible scenarios: 1) Bacterial behavior is monostable: it always converges to a stable equilibrium of bacterial concentration which only depends, in a gradual manner, on the neutrophil level (and not on the initial bacterial level). We call such a behavior type I dynamics. 2) The bacterial dynamics is bistable for some range of neutrophil levels. We call such a behavior type II dynamics. In the bistable case (type II), one equilibrium corresponds to a healthy state whereas the other corresponds to a fulminant bacterial infection. We demonstrate that published data of in vitro Staphylococcus epidermidis bactericidal experiments are inconsistent with both the type I dynamics and the commonly used linear model and are consistent with type II dynamics. We argue that type II dynamics is a plausible mechanism for the development of a fulminant infection.

Asplenia congénita y purpura fulminans neumocóccico en paciente pediátrico: Reporte de caso con necropsia y revisión del tema

Absent or defective splenic function is associated with a high risk of fulminant bacterial infections, especially due to encapsulated bacteria. Not knowing this condition may delay medical treatment. Streptococcus pneumoniae is the leading cause of sepsis in these patients. Asplenic patients are at high risk for septic shock and eventually purpura fulminans, a life-threatening condition. We report the case of a 3 years oíd girl, with mitral stenosis and recurrent pneumonía that was admitted due to fever but in the next few hours presented hypotension, purpura and livedo reticularis. Laboratory test showed leucopenia (3.400/mm(3)), bandemia (43% of immature forms), thrombocytopenia, hypoprothombinemia and severe lactic acidosis (ph: 7.0 and lactic acid 11 mmol/1). The patient developed septic shock and multiorganic failure. Mechanical ventilation, volume resuscitation, vasoactive drugs and antibiotic therapy was initiated. Ultrasound was performed on the second day, demostrating asplenia. Peripheral blood smear showed Howell-Jolly bodies. Patient had a positive blood culture for penicillin-resistant Streptococcus pneumoniae (serotype 19F). Patient died of intracerebral hemorrhage after 8 days of admission. Necropsy confirmed asplenia and bilateral suprarenal haemorrhage. Absence of spleen can lead to life threatening infections, it is important to recognize it because vaccination and antibiotic prophylaxis can provide life-saving protection. This case provides a reminder to pursue asplenia as a potential underlying mechanism for invasive bacterial infection in children.

Sudden Death Caused by Fulminant Bacterial Infection: Background and Pathogenesis of Japanese Adult Cases

To analyze a risk factor for the onset of fulminant bacterial infection. Nine unexpected acute death cases were clinicopathologically analysed. All cases represented the sudden onset of shock symptom, led to acute death within a few days, and later bacteremia was identified. Pathogens were Streptococcus pneumoniae (S. pneumoniae) (5 cases), group A beta Hemolytic Streptococcus pyogenes (S. pyogenes) (3 cases), and Vibrio vulnificus (V. vulnificus) (1 case). Seven of the nine patients had underlying chronic illness. S. pneumoniae infection was associated with splenic dysfunction, and group A beta Hemolytic S. pyogenes and V. vulnificus infections were associated with alcoholic liver injury. Group A beta hemolytic S. pyogenes and V. vulnificus infections involved necrotizing fasciitis, and alcoholic liver cirrhosis was confirmed in two of the four patients. Despite the different type of bacteria, the onset of fulminant bacterial infection depended upon depressed bacterial phagocytosis in the liver or spleen. Underlying chronic illnesses should be identified as a predisposing common risk factor. It is important to understand the relations between underlying chronic illness and the onset of fulminant infection.

Clinical variability and characteristic autoantibody profile in primary C1q complement deficiency

C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.

Immunization recommendations for adults with cancer.

To review the published literature on immunizing nonbone marrow transplant adult cancer patients, summarize the findings, and make recommendations for the use of vaccines in this population. A search of MEDLINE and CancerLit was conducted (1966-June 2001) to find English-language clinical studies and review articles pertaining to immunization, vaccines, and cancer in humans. Recommendations of the Advisory Committee on Immunization Practices were used extensively. References of each identified article were subsequently reviewed for additional relevant articles. Representative epidemiologic reports, clinical trials, and recommendations of expert panels are summarized in this report. Relevant information was selected to describe the epidemiology of vaccine-preventable diseases, efficacy of the vaccines, and recommendations specific to adults with cancer. In general, adults with cancer are at least at the same risk of infection with vaccine-preventable diseases as are healthy populations. Because of their compromised immune function, many patients who have undergone cancer treatment are specifically at increased risk of morbidity and mortality associated with measles and varicella infections. Asplenic patients with lymphoma are at increased risk of fulminant bacterial infections. Influenza infection is associated with significant morbidity in cancer patients. Although the protection conferred by immunization is lower in immunosuppressed patients with cancer, immunization with inactivated vaccines is indicated. Live vaccines should not be used except in very rare instances. Immunization of adults with cancer is a critical component of their care. Although additional research is necessary, following established recommendations may protect individuals with malignancies from significant morbidity and mortality associated with vaccine-preventable diseases.

Immunization Recommendations for Adults with Cancer

OBJECTIVE:To review the published literature on immunizing nonbone marrow transplant adult cancer patients, summarize the findings, and make recommendations for the use of vaccines in this population.DATA SOURCE:A search of MEDLINE and CancerLit was conducted (1966–June 2001) to find English-language clinical studies and review articles pertaining to immunization, vaccines, and cancer in humans. Recommendations of the Advisory Committee on Immunization Practices were used extensively. References of each identified article were subsequently reviewed for additional relevant articles.STUDY SELECTION AND DATA EXTRACTION:Representative epidemiologic reports, clinical trials, and recommendations of expert panels are summarized in this report. Relevant information was selected to describe the epidemiology of vaccine-preventable diseases, efficacy of the vaccines, and recommendations specific to adults with cancer.DATA SYNTHESIS:In general, adults with cancer are at least at the same risk of infection with vaccine-preventable diseases as are healthy populations. Because of their compromised immune function, many patients who have undergone cancer treatment are specifically at increased risk of morbidity and mortality associated with measles and varicella infections. Asplenic patients with lymphoma are at increased risk of fulminant bacterial infections. Influenza infection is associated with significant morbidity in cancer patients. Although the protection conferred by immunization is lower in immunosuppressed patients with cancer, immunization with inactivated vaccines is indicated. Live vaccines should not be used except in very rare instances.CONCLUSIONS:Immunization of adults with cancer is a critical component of their care. Although additional research is necessary, following established recommendations may protect individuals with malignancies from significant morbidity and mortality associated with vaccine-preventable diseases.

A hampered chemoattractant-induced cytoskeletal rearrangement in granulocytes of patients with unexplained severe chronic and relapsing infections of the upper and lower airways. In vitro restoration by G-CSF exposure.

Granulocytes play a major role in host defense against bacterial infections. Severe inborn defects in granulocyte function are associated with fulminant bacterial infections in early childhood. Subtle disturbances in granulocyte function might contribute to an enhanced susceptibility to bacterial infections in adulthood. We investigated chemoattractant (N-formyl-methionyl-leucyl-phenylalanine, fMLP and casein) induced cytoskeletal rearrangements (polarization) of blood granulocytes in 77 adults with chronic and recurrent therapy-resistant infections of the upper and lower airways. These infections could not be explained by B- and/or T-cell defects or local anatomic abnormalities. Besides polarization, chemotaxis of blood granulocytes was measured in 33 patients, as well as granulocyte superoxide production in eight patients. The chemoattractant-induced cytoskeletal rearrangement in patient blood granulocytes was significantly lower as compared to healthy control values with both fMLP and casein as stimuli. About two-thirds of the patients showed a defective polarization response to fMLP. Granulocyte colony-stimulating factor (G-CSF) when added in vitro corrected the defective polarization responses; responses in the normal range were not enhanced. The chemotactic motility of patient blood granulocytes was also slightly, but significantly lowered. However, it did not correlate to the lowered polarization. Granulocyte superoxide production was comparable in patients and in healthy controls. Our data thus show that subtle abnormalities in chemoattractant-induced cytoskeletal and motile function of blood granulocytes are frequent in patients with severe therapy-refractory bacterial infections of the upper and lower airways.

Postoperative Necrotizing Chest-wall Infection: Case Report of a Rare Complication after Elective Lung Surgery

Necrotizing fasciitis, an uncommon, often fulminant bacterial infection, rarely originates in the chest wall. In a 67-year-old woman, elective lower lobectomy of the right lung was followed by fatal necrotizing fasciitis of the chest wall. Tissue necrosis and overwhelming sepsis were due to synergistic infection by Staphylococcus aureus and Streptococcus microaerophilica. As the early appearance of necrotizing fasciitis is deceptively benign, the diagnosis is extremely difficult and is reliant on a high index of suspicion. Prompt surgical intervention is essential.

ECHO THERAPY FOR INFANTS WITH OVERWHELMING SEPSIS

Neonates with fulminant bacterial infections can die in septic shock despite aggressive medical therapy. From 6/84 to 11/86, 10 infants with septic shock were treated at CHNMC with veno- arterial extracorporeal membrane oxygenation (ECMO). All infants had failed to respond to conventional intensive medical management and met ECMO entry criteria predictive of > 80% mortality risk. Diagnosis was by positive blood cultures in 7 infants. One infant had negative blood cultures but Wellcogens were positive for GBS antigen. Two infants had negative cultures, but perinatal hx's were compatible with septic shock. Eight infants had total WBC's <6,600 prior to ECMO. All ten infants survived with ECMO therapy. Morbidity among these infants included: (1) ICH in 4 infants, 2 which were severe; (2) oxygen dependence beyond one month in 3 infants. The risk of ICH was higher in the septic shock infants than in our ECMO population in general (40% vs 26%). Likewise, the risk for chronic lung disease was higher in the septic shock infants than in our ECMO population (30% vs 15%). In our experience ECMO is a valid therapy for infants with septic shock unresponsive to other therapies.

Fulminant Meningococcemia After Splenectomy

FULMINANT bacterial infections complicated by shock and disseminated intravascular coagulation have been reported after splenectomy for trauma.^1-3The majority of these infections are caused by bacteria with polysaccharide capsules; pneumococci are demonstrated in half of the cases.⁴We report two cases of atypical Waterhouse-Friderichsen syndrome from meningococcemia in asplenic young women who did not manifest skin lesions. <h3>Report of Cases</h3><h3>Case 1.—</h3> A 17-year-old girl came to a small hospital emergency room with a one-day history of fever. Malaise and transient blurred vision were noted. About eight hours previously her roommate noted her to be confused. Medical history included a splenectomy after abdominal trauma at age 13 years. She was cyanotic and unresponsive in the emergency room. No skin lesions were present. Shortly after arrival she had a cardiac arrest, and resuscitation measures were unsuccessful. Autopsy showed purulent meningitis, splenosis, and scleral, pulmonary, and bilateral adrenal hemorrhage. Typing