Eculizumab in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome: a systematic review.

BACKGROUND: Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS. METHODS: PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively. RESULTS: A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations. DISCUSSION: Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients. SYSTEMATIC REVIEW REGISTRATION NUMBER: OSF Registries, MSZY4, Registration DOI https://doi.org/10.17605/OSF.IO/MSZY4 .

Multifunctional biomimetic hydrogel dressing provides anti-infection treatment and improves immunotherapy by reprogramming the infection-related wound microenvironment.

The advancement of biomaterials with antimicrobial and wound healing properties continues to present challenges. Macrophages are recognized for their significant role in the repair of infection-related wounds. However, the interaction between biomaterials and macrophages remains complex and requires further investigation. In this research, we propose a new sequential immunomodulation method to enhance and expedite wound healing by leveraging the immune properties of bacteria-related wounds, utilizing a novel mixed hydrogel dressing. The hydrogel matrix is derived from porcine acellular dermal matrix (PADM) and is loaded with a new type of bioactive glass nanoparticles (MBG) doped with magnesium (Mg-MBG) and loaded with Curcumin (Cur). This hybrid hydrogel demonstrates controlled release of Cur, effectively eradicating bacterial infection in the early stage of wound infection, and the subsequent release of Mg ions (Mg2+) synergistically inhibits the activation of inflammation-related pathways (such as MAPK pathway, NF-κB pathway, TNF-α pathway, etc.), suppressing the inflammatory response caused by infection. Therefore, this innovative hydrogel can safely and effectively expedite wound healing during infection. Our design strategy explores novel immunomodulatory biomaterials, offering a fresh approach to tackle current clinical challenges associated with wound infection treatment.

Murine Models of Secondary Cytokine Storm Syndromes.

Hemophagocytic lymphohistiocytosis (HLH) comprises a broad spectrum of life-threatening cytokine storm syndromes, classified into primary (genetic) or secondary (acquired) HLH. The latter occurs in a variety of medical conditions, including infections, malignancies, autoimmune and autoinflammatory diseases, acquired immunodeficiency, and metabolic disorders. Despite recent advances in the field, the pathogenesis of secondary HLH remains incompletely understood. Considering the heterogeneity of triggering factors and underlying diseases in secondary HLH, a large diversity of animal models has been developed to explore pivotal disease mechanisms. To date, over 20 animal models have been described that each recapitulates certain aspects of secondary HLH. This review provides a comprehensive overview of the existing models, highlighting relevant findings, discussing the involvement of different cell types and cytokines in disease development and progression, and considering points of interest toward future therapeutic strategies.

Anti-Interferon-γ Therapy for Cytokine Storm Syndromes.

A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.

Etoposide Therapy of Cytokine Storm Syndromes.

Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.

Co-amorphous Systems of Sinomenine with Platensimycin or Sulfasalazine: Physical Stability and Excipient-Adjusted Release Behavior.

There is strong interest to develop affordable treatments for the infection-associated rheumatoid arthritis (RA). Here, we present a drug-drug co-amorphous strategy against RA and the associated bacterial infection by the preparation and characterization of two co-amorphous systems of sinomenine (SIN) with platensimycin (PTM) or sulfasalazine (SULF), two potent antibiotics. Both of them were comprehensively characterized using powder X-ray diffraction, temperature-modulated differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The co-amorphous forms of SIN-PTM and SIN-SULF exhibited high Tgs at 139.10 ± 1.0 and 153.3 ± 0.2 °C, respectively. After 6 months of accelerated tests and 1 month of drug-excipient compatibility experiments, two co-amorphous systems displayed satisfactory physical stability. The formation of salt and strong intermolecular interactions between SIN and PTM or SULF, as well as the decreased molecular mobility in co-amorphous systems, may be the intrinsic mechanisms underlying the excellent physical stability of both co-amorphous systems. In dissolution tests, two co-amorphous systems displayed distinct reduced SIN-accumulative releases (below 20% after 6 h of release experiments), which may lead to its poor therapeutic effect. Hence, we demonstrated a controlled release strategy for SIN by the addition of a small percentage of polymers and a small-molecule surfactant to these two co-amorphous samples as convenient drug excipients, which may also be used to improve the unsatisfactory dissolution behaviors of the previously reported SIN co-amorphous systems. Several hydrogen bonding interactions between SIN and PTM or SULF could be identified in NMR experiments in DMSO-d6, which may be underlying reasons of decreased dissolution behaviors of both co-amorphous forms. These drug-drug co-amorphous systems could be a potential strategy for the treatment of infection-associated RA.

The first case of Streptococcus intermedius brain abscess with hemophagocytic histiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening immune syndrome associated with an excessive systemic inflammatory response. Viral infection caused HLH is the most common secondary HLH, but there are relatively few reports of HLH caused by bacterial infection. The present study is the first case of HLH caused by Streptococcus intermedia meningitis. CASE PRESENTATION: The patient is an 11-year-old and 9-month-old boy. The main symptoms are fever, headache, and vomiting. The imaging finding of the brain is cerebritis and brain abscess. The cerebrospinal fluid (CSF) routine test showed increased nucleated cells, but the smear and culture of CSF were negative. The metagenomics next-generation sequencing (mNGS) of CSF detected Streptococcus intermedius, and the body temperature of the children returned to normal after antibiotic treatment according to etiology. One week later, the child developed fever again, with Kawasaki disease-like manifestations. After high-dose immunoglobulin therapy, the body temperature returned to normal again. The routine blood test showed a progressive decrease in leukocytes and platelets, and bone marrow biopsy detected histiocytes phagocytosed blood cells. Then infection-associated hemophagocytic syndrome (IAHS) was diagnosed, high-dose methylprednisolone and sequential therapy were given and the patient's recovery was encouraging. CONCLUSIONS: Our case shows that HLH can also be secondary to Streptococcus intermediate infection, and early bone marrow biopsy is the golden standard for HLH diagnosis. mNGS can improve the detection sensitivity for pathogens when traditional pathogenic tests are negative. Conventional chemotherapy regimens may not be required for IAHS when high-dose glucocorticoids and immunoglobulin therapy are effective.

IgA-dominant infection-associated glomerulonephritis in the pediatric population.

BACKGROUND: IgA-dominant infection-associated glomerulonephritis is well-documented in adults but has not been studied in depth in children. We assessed the incidence of pediatric IgA-dominant infection-associated glomerulonephritis and clinical and kidney biopsy findings. METHODS: Pediatric native kidney biopsies over a 10-year period with IgA dominance, strong C3, and findings indicative of infection-associated etiology were identified. RESULTS: We identified 9 cases of IgA-dominant infection-associated glomerulonephritis, 0.8% of pediatric native kidney biopsies. Seven patients presented with elevated creatinine. All had hematuria and proteinuria. Eight patients had clinical evidence of infection: one each with central port infection by methicillin-sensitive Staphylococcus aureus, recurrent streptococcal pharyngitis and recent otitis media, streptococcal pharyngitis demonstrated 8 months after biopsy, suspected streptococcal scalded skin syndrome, and viral gastroenteritis, and three with serologic evidence of Streptococcal infection but no identified site of infection. All but one patient experienced short-term normalization of creatinine and resolution of proteinuria, though two eventually progressed to kidney failure: one 3 years later due to progressive disease and one 11 years later due to focal segmental glomerulosclerosis without concurrent immune deposits. CONCLUSIONS: Pediatric IgA-dominant infection-associated glomerulonephritis is rare, and generally has a favorable prognosis, contrasting that seen in adults with severe comorbidities. A higher resolution version of the Graphical abstract is available as Supplementary.

In Vitro Selection of Lactobacillus and Bifidobacterium Probiotic Strains for the Management of Oral Pathobiont Infections Associated to Systemic Diseases.

The human oral pathobionts Aggregatibacter actinomycetemcomitans, Streptococcus mitis and Streptococcus mutans, in dysbiosis-promoting conditions, lead to oral infections, which also represent a threat to human systemic health. This scenario may be worsened by antibiotic misuse, which favours multi-drug resistance, making the research on pathogen containment strategies more than crucial. Therefore, we aimed to in vitro select the most promising probiotic strains against oral pathogen growth, viability, biofilm formation, and co-aggregation capacity, employing both the viable probiotics and their cell-free supernatants (CFSs). Interestingly, we also assessed probiotic efficacy against the three-pathogen co-culture, mimicking an environment similar to that in vivo. Overall, the results showed that Lactobacillus CFSs performed better than the Bifidobacterium, highlighting Limosilactobacillus reuteri LRE11, Lacticaseibacillus rhamnosus LR04, Lacticaseibacillus casei LC04, and Limosilactobacillus fermentum LF26 as the most effective strains, opening the chance to deeper investigation of their action and CFS composition. Altogether, the methodologies presented in this study can be used for probiotic efficacy screenings, in order to better focus the research on a viable probiotic, or on its postbiotics, suitable in case of infections.

Staphylococcus aureus Infection-Related Glomerulonephritis with Dominant IgA Deposition.

Since 1995, when we reported the case of a patient with glomerulonephritis with IgA deposition that occurred after a methicillin-resistant Staphylococcus aureus (MRSA) infection, many reports of MRSA infection-associated glomerulonephritis have accumulated. This disease is being systematized as Staphylococcus infection-associated glomerulonephritis (SAGN) in light of the apparent cause of infection, and as immunoglobulin A-dominant deposition infection-related glomerulonephritis (IgA-IRGN) in light of its histopathology. This glomerulonephritis usually presents as rapidly progressive glomerulonephritis or acute kidney injury with various degrees of proteinuria and microscopic hematuria along with an ongoing infection. Its renal pathology has shown several types of mesangial and/or endocapillary proliferative glomerulonephritis with various degrees of crescent formation and tubulointerstitial nephritis. IgA, IgG, and C3 staining in the mesangium and along the glomerular capillary walls have been observed on immunofluorescence examinations. A marked activation of T cells, an increase in specific variable regions of the T-cell receptor ß-chain-positive cells, hypercytokinemia, and increased polyclonal immune complexes have also been observed in this glomerulonephritis. In the development of this disease, staphylococcal enterotoxin may be involved as a superantigen, but further investigations are needed to clarify the mechanisms underlying this disease. Here, we review 336 cases of IgA-IRGN and 218 cases of SAGN.

Glomerulonephritides associated with infections.

Glomerulonephritides associated with infections constitute an important group of diseases. Their occurrence is shifting from children and young people to elderly people. The rates of acute post-streptococcal glomerulonephritis, a condition with a good prognosis, are decreasing, and the rates of glomerulonephritides associated with various bacterial, viral, or parasitic infections, often with a poor prognosis, are increasing. Renal biopsy plays an important role in the diagnostic process. Manifestations of glomerulonephritis can be the initial sign of an occult infection. When evaluating renal biopsy specimens, certain signs may suggest this option, but it cannot be relied on completely. The search for an active infection is warranted in every patient with newly diagnosed glomerulonephritis. Hepatitis B and C serology is always performed, with other investigations depending on individual risk factors, clinical manifestations, and laboratory and histological findings. Failure to follow this rule may have serious consequences, in part because immunosuppressive therapy for glomerulonephritis can worsen the underlying infection and also because the progressive nature of parainfective glomerulonephritis cannot be reversed without eliminating the causative infection. Distinguishing between parainfective and autoimmune glomerulonephritis can be difficult, as there are no major differences in clinical manifestations, laboratory, and sometimes even histological findings. In the setting of the Czech Republic, important diseases include, in particular, staphylococcus infection-associated glomerulonephritis (SAGN) and, in general, infective endocarditis-associated glomerulonephritis, shunt nephritis, and other cases associated with foreign-material infection, such as catheters or electrodes. Among viral diseases, glomerulonephritides associated with the hepatitis B virus, hepatitis C virus, and the SARS CoV-2 virus are of major significance. The treatment of parainfectious glomerulonephritides involves elimination of the causative infection; only in rare cases, a combination of anti-infective treatment and mild immunosuppression can be indicated.

Bacterial Diversity Correlates with Overall Survival in Cancers of the Head and Neck, Liver, and Stomach.

One in five cancers is attributed to infectious agents, and the extent of the impact on the initiation, progression, and disease outcomes may be underestimated. Infection-associated cancers are commonly attributed to viral, and to a lesser extent, parasitic and bacterial etiologies. There is growing evidence that microbial community variation rather than a single agent can influence cancer development, progression, response to therapy, and outcome. We evaluated microbial sequences from a subset of infection-associated cancers-namely, head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and stomach adenocarcinoma (STAD) from The Cancer Genome Atlas (TCGA). A total of 470 paired tumor and adjacent normal samples were analyzed. In STAD, concurrent presence of EBV and Selemonas sputigena with a high diversity index were associated with poorer survival (HR: 2.23, 95% CI 1.26-3.94, p = 0.006 and HR: 2.31, 95% CI 1.1-4.9, p = 0.03, respectively). In LIHC, lower microbial diversity was associated with poorer overall survival (HR: 2.57, 95% CI: 1.2, 5.5, p = 0.14). Bacterial within-sample diversity correlates with overall survival in infection-associated cancers in a subset of TCGA cohorts.

Surface sensing and signaling networks in plant pathogenic fungi.

Pathogenic fungi have evolved highly varied and remarkable strategies to invade and infect their plant hosts. Typically, such fungal pathogens utilize highly specialized infection structures, morphologies or cell types produced from conidia or ascospores on the cognate host surfaces to gain entry therein. Such diverse infection strategies require intricate coordination in cell signaling and differentiation in phytopathogenic fungi. Here, we present an overview of our current understanding of cell signaling and infection-associated development that primes host penetration in the top ten plant pathogenic fungi, which utilize specific receptors to sense and respond to different surface cues, such as topographic features, hydrophobicity, hardness, plant lipids, phytohormones, and/or secreted enzymes. Subsequently, diverse signaling components such as G proteins, cyclic AMP/Protein Kinase A and MAP kinases are activated to enable the differentiation of infection structures. Recent studies have also provided fascinating insights into the spatio-temporal dynamics and specialized sequestration and trafficking of signaling moieties required for proper development of infection structures in phytopathogenic fungi. Molecular insight in such infection-related morphogenesis and cell signaling holds promise for identifying novel strategies for intervention of fungal diseases in plants.

Chikungunya Virus-Associated Disease.

PURPOSE OF REVIEW: Chikungunya virus (CHIKV) infection has become increasingly prevalent in the last decade not only across the southern hemisphere but also, because of a recently documented viral mutation, in southern Europe and the USA. With the global spread of CHIKV infection, practitioners should know its epidemiology, pathophysiology and clinical features. RECENT FINDINGS: The acute phase of CHIKV disease is characterised by a fever-arthralgia-rash syndrome. Chronic rheumatic manifestations can persist for months to years with very variable clinical presentations. Some cases mimic inflammatory rheumatism such as rheumatoid arthritis. Several risk factors for persistent joint pain, notably older age, have been identified in cohort studies. Despite a low mortality rate with CHIKV infection, the rate of disability with chronic joint symptoms is high, and effective treatments are lacking. Current research is focusing on the development of vaccines and antiviral drugs, and data on treatment of CHIKV-induced chronic arthritis are needed.

Overview of Infectious Causes of Human Cancers.

Emerging evidence has demonstrated that almost each person is infected at least one potentially cancer-causing organism; however, only a small proportion of infected individual develops cancer. In this review, to elucidate the potential role of infectious organisms in the development and progression of human cancers, we summarize the previous history and current understandings of infection-associated cancers and highlight the common molecular mechanisms of cancers caused by infectious agents and their potential cofactors, which may bring us to effectively prevent and reduce the infection-associated cancers in the future.

Infection-Associated Glomerulonephritis.

The nephritic syndrome has been associated with a wide variety of infections, spanning many organisms and myriad clinical presentations. Infection-associated glomerulonephritis is challenging to diagnose given the many confounding factors linking kidney injury to infection; however, urine microscopy can assist in identifying abnormal cellular elements suggestive of glomerulonephritis. Kidney biopsy remains the gold standard for diagnosing the underlying pathologic lesion. Treatment of infection-associated glomerulonephritis centers around aggressive and complete treatment of the underlying infectious driver. It is often hard to know exactly when immunosuppression may be required in addition to treating the infection.

Structural and quantitative comparison of viral infection-associated N-glycans in plasma from humans, pigs, and chickens: Greater similarity between humans and chickens than pigs.

Host N-glycans play an essential role in the attachment, invasion, and infection processes of viruses, including zoonotic infectious diseases. The similarity of N-glycans in the trachea and lungs of humans and pigs facilitates the cross-species transmission of influenza viruses through respiratory tracts. In this study, the structure and quantity of N-glycans in the plasma of humans, pigs, and chickens were analyzed using liquid chromatography-quadrupole-Orbitrap-tandem mass spectrometry. N-glycans in humans (35), pigs (28), and chickens (53) were identified, including the most abundant, species-common, and species-specific N-glycans. Among the N-glycans (relative quantity >0.5%), the sialic acid derivative of N-acetylneuraminic acid was identified in humans (the sum of the relative quantities of each; 64.3%), pigs (45.5%), and chickens (64.4%), whereas N-glycolylneuraminic acid was only identified in pigs (18.1%). Sialylated N-glycan linkage isomers are the influenza virus receptors (α2-6 in humans, α2-3 and α2-6 in pigs, and α2-3 in chickens). Only α2-6 linkages (human, 58.2%; pig, 44.8%; and chicken, 60.6%) were more abundant than α2-3/α2-6 linkages (human, 4.6%; pig, 0.6%; and chicken, 3.4%) and only α2-3 linkages (human, 1.5%; pig, 0.1%; and chicken, 0.4%). Fucosylation, which can promote viral infection through immune modulation, was more abundant in pigs (76.1%) than in humans (36.4%) and chickens (16.7%). Bisecting N-acetylglucosamine, which can suppress viral infection by inhibiting sialylation, was identified in humans (10.3%) and chickens (16.9%), but not in pigs. These results indicate that plasma N-glycans are similar in humans and chickens. This is the first study to compare plasma N-glycans in humans, pigs, and chickens.

Survivorship Struggles: Navigating Etiologies and Clinical Parameters of Febrile Neutropenia During Induction Chemotherapy in Acute Leukemia Patients.

Background Acute leukemia, characterized by the uncontrolled proliferation of immature white blood cell precursors, poses significant challenges during induction chemotherapy, including the elevated risk of febrile neutropenia and its associated complications. Our study aims to explain the clinical and etiological parameters of these patients in a resource-limited setting. Methods This retrospective study focused on a total of 102 adult patients with acute leukemia who developed febrile neutropenia during the induction chemotherapy phase. Patients with disease relapse, prior bone marrow transplantation, and cases of acute promyelocytic leukemia were excluded from the study. Demographical characteristics, symptoms at presentation, diagnoses, infectious causes, and outcomes were systematically reported. Infectious etiologies and detailed culture reports were meticulously tabulated, and subsequent data were analyzed. Results Of the 102 patients, 43 (42.2%) were males, with a mean age of 31.9 ± 6.5 years. During the induction chemotherapy, a total of 31 patients died of complicated febrile neutropenia. Severe vomiting was the most common symptom present in 37 (36.2%), followed by cough in 35 (34.3%) and loose stools in 28 (27.5%). Community-acquired pneumonia, neutropenic sepsis, and neutropenic colitis were among the most common etiologies of febrile neutropenia. A total of 72 (70.6%) patients had culture-proven multidrug-resistant Gram-negative bacteremia that contributed to poor outcomes. Conclusions Acute leukemia patients undergoing induction chemotherapy face high infection-associated mortality due to their immunocompromised state. Inadequate infection control measures and antimicrobial resistance contribute to the emergence of multidrug-resistant organisms. Enhanced infection prevention strategies and evidence-based antibiotic prescription guidelines are need of time in resource-limited settings such as Pakistan to address febrile neutropenia complications and bridge the existing care gap in its management.