Infections In Immunocompromised Hosts Research Articles

The Impact of Enterococcus spp. in the Immunocompromised Host: A Comprehensive Review.

The immunocompromised host is usually vulnerable to infectious diseases due to broad-spectrum treatments and immunological dysregulation. The Enterococcus genus consists of normal gut commensals, which acquire a leading role in infective processes among individuals with compromised immune systems. These microorganisms may express a potential virulence and resistance spectrum, enabling their function as severe pathogens. The Enterococcus spp. infections in immunocompromised hosts appear to be difficult to resolve due to the immunological response impairment and the possibility of facing antimicrobial-resistant strains. As regards the related risk factors, several data demonstrated that prior antibiotic exposure, medical device insertion, prolonged hospitalization and surgical interventions may lead to Enterococcus overgrowth, antibiotic resistance and spread among critical healthcare settings. Herein, we present a comprehensive review of Enterococcus spp. in the immunocompromised host, summarizing the available knowledge about virulence factors, antimicrobial-resistance mechanisms and host-pathogen interaction. The review ultimately yearns for more substantial support to further investigations about enterococcal infections and immunocompromised host response.

Chagas disease in immunocompromised patients.

SUMMARYAs Chagas disease remains prevalent in the Americas, it is important that healthcare professionals and researchers are aware of the screening, diagnosis, monitoring, and treatment recommendations for the populations of patients they care for and study. Management of Trypanosoma cruzi infection in immunocompromised hosts is challenging, particularly because, regardless of antitrypanosomal treatment status, immunocompromised patients with Chagas disease are at risk for T. cruzi reactivation, which can be lethal. Evidence-based practices to prevent and manage T. cruzi reactivation vary depending on the type of immunocompromise. Here, we review available data describing Chagas disease epidemiology, testing, and management practices for various populations of immunocompromised individuals, including people with HIV and patients undergoing solid organ and hematopoietic stem cell transplantation.

Genomic revisitation and reclassification of the genus Providencia.

The Providencia genus, known to harbor opportunistic pathogens, has been a subject of interest due to its potential to cause severe infections, particularly in vulnerable individuals. Our research offers groundbreaking insights into this genus, unveiling a novel species, Providencia zhijiangensis sp. nov., and highlighting the need for a re-evaluation of existing classifications. Our comprehensive genomic assessment offers a detailed classification of 545 genomes into distinct species and lineages, revealing the rich biodiversity and intricate species diversity within the genus. The substantial presence of antibiotic-resistance genes in the Providencia genus underscores potential challenges for public health and clinical treatments. Our study highlights the pressing need for increased surveillance and research, enriching our understanding of antibiotic resistance in this realm.

Trends in the Incidence of Disseminated Cryptococcosis in Japan: A Nationwide Observational Study, 2015–2021

BackgroundCryptococcus species can cause severe disseminated infections in immunocompromised hosts. This study investigated the epidemiological features and trends in disseminated cryptococcosis in Japan.MethodsWe used publicly available Infectious Diseases Weekly Reports to obtain data on the incidence of disseminated cryptococcosis in Japan from 2015 to 2021. Patient information, including age, sex, and regional and seasonal data, were extracted. The Joinpoint regression program was used to determine the age-adjusted incidence rate (AAR) per 100,000 population, annual percentage change (APC), and average APC (AAPC).ResultsA total of 1047 cases of disseminated cryptococcosis were reported, of which those aged ≥ 70 years accounted for 68.8%. The AAR in men was significantly higher than that in women (median: 0.13 vs. 0.09: p = 0.0024). APC for the overall cases increased by 9.9% (95% confidence interval [95% CI] − 5.4–27.7) from 2015 to 2018 and then decreased by 3.3% (95% CI − 15.5–10.7) from 2018 to 2021. AAPC for the entire study period was 3.1% (95% CI − 1.5–8.0), indicating a possible increase in its number, although not statistically significant. In terms of regional distribution, the average AAR was highest in Shikoku District (0.17) and lowest in Hokkaido District (0.04). Northern Japan exhibited a significantly lower median AAR (median [interquartile range]: 0.06 [0.05, 0.08]) than the Eastern (0.12 [0.12, 0.13]), Western (0.11 [0.10, 0.13]), and Southern (0.14 [0.12, 0.15]) regions. No seasonal variation in incidence was observed.ConclusionThe prevalence of disseminated cryptococcosis has not increased in Japan. Geographically, the incidence is lower in Northern Japan. Further investigations that incorporate detailed clinical data are required.

A Novel Inhibitor against the Biofilms of Non-Tuberculous Mycobacteria.

Non-tuberculous Mycobacteria (NTM), previously classified as environmental microbes, have emerged as opportunistic pathogens causing pulmonary infections in immunocompromised hosts. The formation of the biofilm empowers NTM pathogens to escape from the immune response and antibiotic action, leading to treatment failures. NF1001 is a novel thiopeptide antibiotic first-in-class compound with potent activity against planktonic/replicating and biofilm forms of various NTM species. It is potent against both drug-sensitive and -resistant NTM. It has demonstrated a concentration-dependent killing of replicating and intracellularly growing NTM, and has inhibited and reduced the viability of NTM in biofilms. Combination studies using standard-of-care (SoC) drugs for NTM exhibited synergetic/additive effects, but no antagonism against both planktonic and biofilm populations of Mycobacterium abscessus and Mycobacterium avium. In summary, the activity of NF1001 alone or in combination with SoC drugs projects NF1001 as a promising candidate for the treatment of difficult-to-treat NTM pulmonary diseases (NTM-PD) and cystic fibrosis (CF) in patients.

Analytical and clinical validation of multiplex droplet digital PCR assay for detecting pathogenic fungal infection in lungs

ABSTRACT Pulmonary invasive fungal infection in immunocompromised hosts is difficult to diagnose, and current tools for diagnosis or monitoring of response to antifungal treatments have inherent limitations. Droplet digital PCR (ddPCR) has emerged as a promising tool for pulmonary pathogen detection with high sensitivity. This study presents a novel ddPCR panel for rapid and sensitive identification of pulmonary fungal pathogens. First, a ddPCR method for detecting three fungal genera, including Pneumocystis, Aspergillus, and Cryptococcus, was established and evaluated. Then, the clinical validation performance of ddPCR was compared with that of qPCR using 170 specimens, and the 6 specimens with inconsistent results were further verified by metagenomics next-generation sequencing, which yielded results consistent with the ddPCR findings. Finally, the area under the ROC curve (AUC) was used to evaluate the efficiency of ddPCR. While the qPCR identified 16 (9.41%) cases of Aspergillus and 6 (3.53%) cases of Pneumocystis, ddPCR detected 20 (11.76%) Aspergillus cases and 8 (4.71%) Pneumocystis cases. The AUC for Aspergillus, Cryptococcus, and Pneumocystis was 0.974, 0.998, and 0.975, respectively. These findings demonstrated that the ddPCR assay is a highly sensitive method for identifying pathogens responsible for invasive fungal pulmonary infections, and is a promising tool for early diagnosis.

668. The clinical effectiveness of Fidaxomicin compared to Vancomycin in the treatment of Clostridioides difficile infection in immunocompromised hosts, a single center study

Abstract Background Patients with immunocompromising conditions are at increased risk of C.difficile infection (CDI) and recurrence. Fidaxomicin reduces the risk of recurrence in immunocompetent hosts. However, there is limited data on fidaxomicin effectiveness in hosts with immunocompromising conditions. Methods We retrospectively assessed the treatment of CDI among patients with immunocompromising conditions who were diagnosed between 2011 and 2021 at Tufts Medical Center. Patients were considered to be treated by fidaxomicin or vancomycin if they received ≥72 hours of the agent. Patients less than 18 years, those who did not receive treatment for CDI, and those treated with metronidazole only were excluded. The study outcome was a composite of failure to achieve clinical cure within 72 hours of treatment initiation, relapse within 30 days following completion of initial treatment and death due to CDI. Time to event analysis used a cause specific Cox proportional hazards to compare the rate of the composite outcome in the two groups, accounting for the competing risk of death from other causes. Multiple imputation was used for missing variables but not the outcome. Results A total of 238 patients with immunocompromising conditions received vancomycin (n= 38) or fidaxomicin (n= 200) for treatment of CDI. Patients who received vancomycin were significantly more likely to be male (51.5% vs 26.2%, p 0.005) and to have had community acquired infection (31.1% vs 9.5%, p 0.03) compared to fidaxomicin (Table 1). The composite outcome occurred in 48 (24%) patients in the vancomycin group compared to 5 (13.2%) in the fidaxomicin group. In the multivariable model adjusted for sex, number of antecedent antibiotics, antibiotics during treatment, severity and type of immunosuppression, fidaxomicin was associated with 65% reduction in the hazard of the composite outcome compared with vancomycin (HR 0.35, 95% CI 0.12-0.99) (Table 2). Conclusion The use of fidaxomicin was more effective than vancomycin in preventing poor CDI outcomes among patients with immunocompromising conditions. The study may have residual confounding by indication and limited generalizability based on a single site. Future studies should confirm our findings. Disclosures Jennifer K. Chow, MD, MS, Kamada: Grant/Research Support|Merck: Grant/Research Support|Moderna: DSMB David Kent, MD, W.L. Gore: Grant/Research Support David R. Snydman, MD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Prolacta: Advisor/Consultant|Prolacta: Grant/Research Support|Seres therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit Therapeutics: Grant/Research Support

239. Comparing Alternative Treatment Options for Stenotrophomonas maltophilia bacteremia

Abstract Background Stenotrophomonas maltophilia can cause nosocomial infections in immunocompromised hosts and patients with indwelling devices or broad-spectrum antibiotic exposure. Treatment of S maltophilia infections poses a challenge due to intrinsic resistance mechanisms, including inducible L1 metallo and L2 cephalosporinase beta-lactamases. Trimethoprim-sulfamethoxazole (SXT) is recognized as the agent of choice for S maltophilia infections. Outcomes with alternative antimicrobials are not well described. Methods We conducted a retrospective study of adults with positive blood cultures with S maltophilia who received ≥48h of directed antimicrobials at our institution between 3/2013 and 6/2022. Patients were stratified by their antimicrobial treatment, including levofloxacin, SXT, minocycline, ceftazidime, or combination therapy. The primary outcome was 30d all-cause mortality. Secondary outcomes were microbiological and clinical cure. Microbiological failure was defined as blood cultures growing S maltophilia during or within 7d of discontinuing therapy. Clinical failure was defined as a lack of resolution of signs or symptoms of infection requiring therapy adjustment. Results Of 67 patients with positive S maltophilia blood cultures, 53 patients treated with levofloxacin (n = 27), SXT (n = 10), minocycline (n = 8), combination (n = 5) or ceftazidime (n = 3) were included. The remaining 14 patients were excluded for receiving < 48h of therapy. The median Charlson comorbidity index was 4 [IQR 3-6]. The most common source of bacteremia was catheter-related (n = 27). Overall, 30d mortality was 26.4%. There was no significant difference in 30d mortality among patients treated with levofloxacin, SXT, minocycline, combination or ceftazidime (p = 0.23). Interestingly, patients with monomicrobial S maltophilia bacteremia had statistically higher 30d mortality (35.3% versus 11.8%, p < 0.05). Microbiological and clinical cure rates were similar between treatment groups (p = 0.06 and p = 0.16, respectively). Conclusion Treatment options for S maltophilia bacteremia resulted in similar 30d mortality; however, findings were limited by the small sample size. Larger, prospective studies are warranted to detect differences in treatment alternatives. Disclosures All Authors: No reported disclosures

Investigational non-antibiotic therapeutics for infections in hematopoietic cell transplant recipients and patients with hematologic malignancies receiving cellular therapies.

In the age of progressive antimicrobial resistance and increased difficulty combating infections in immunocompromised hosts, there has been renewed interest in the use of nontraditional therapeutics for infections. Herein, we review the use of investigational non-pharmaceutical anti-infective agents targeting fungal, bacterial, and viral infections in patients with hematologic malignancies, focusing on those receiving hematopoietic cell transplantation or cellular therapies. We discuss immune checkpoint inhibitors, granulocyte transfusions, bone marrow colony-stimulating factors, bacteriophages, fecal microbiota transplantation, and virus specific T-cell therapy. Although there is promising early experience with many of these treatments, further studies will be required to define their optimal role in the therapeutic armamentarium against infections in immunocompromised hosts.

Resurgence of SARS-CoV-2 Delta after Omicron variant superinfection in an immunocompromised pediatric patient

BackgroundPersistent SARS-CoV-2 infection in immunocompromised hosts is thought to contribute to viral evolution by facilitating long-term natural selection and viral recombination in cases of viral co-infection or superinfection. However, there are limited data on the longitudinal intra-host population dynamics of SARS-CoV-2 co-infection/superinfection, especially in pediatric populations. Here, we report a case of Delta-Omicron superinfection in a hospitalized, immunocompromised pediatric patient.MethodsWe conducted Illumina whole genome sequencing (WGS) for longitudinal specimens to investigate intra-host dynamics of SARS-CoV-2 strains. Topoisomerase PCR cloning of Spike open-reading frame and Sanger sequencing of samples was performed for four specimens to validate the findings. Analysis of publicly available SARS-CoV-2 sequence data was performed to investigate the co-circulation and persistence of SARS-CoV-2 variants.ResultsResults of WGS indicate the patient was initially infected with the SARS-CoV-2 Delta variant before developing a SARS-CoV-2 Omicron variant superinfection, which became predominant. Shortly thereafter, viral loads decreased below the level of detection before resurgence of the original Delta variant with no residual trace of Omicron. After 54 days of persistent infection, the patient tested negative for SARS-CoV-2 but ultimately succumbed to a COVID-19-related death. Despite protracted treatment with remdesivir, no antiviral resistance mutations emerged. These results indicate a unique case of persistent SARS-CoV-2 infection with the Delta variant interposed by a transient superinfection with the Omicron variant. Analysis of publicly available sequence data suggests the persistence and ongoing evolution of Delta subvariants despite the global predominance of Omicron, potentially indicative of continued transmission in an unknown population or niche.ConclusionA better understanding of SARS-CoV-2 intra-host population dynamics, persistence, and evolution during co-infections and/or superinfections will be required to continue optimizing patient care and to better predict the emergence of new variants of concern.

Role of Macrophage Colony-Stimulating Factor for Staphylococcal Infection in the Oral Cavity.

There are few valid indicators of oral infection owing to the complexity of pathogenic factors in oral diseases. Salivary markers are very useful for scrutinizing the symptoms of disease. To provide a reliable and useful predictive indicator of infection for opportunistic pathogens in individuals with compromised immune systems, such as those with periodontal diseases and Human Immunodeficiency Virus (HIV), this study examines opportunistic pathogens such as C. albicans and staphylococci and macrophage colony-stimulating factor (M-CSF) and CA125/MUC16 in saliva. The aim was to explore the correlations investigated among these factors. Samples were divided into two groups (based on patient sex, the absence and presence of dentures in elderly, or HIV-positive patients and healthy subjects), and the correlation was analyzed in two groups of elderly patients with periodontal disease (64.5 ± 11.2 years old) and HIV-infected patients (41.9 ± 8.4 years old). Healthy subjects (33.8 ± 9.1 years old) were also analyzed as a control. Levels of C. albicans, staphylococci, and M-CSF, which is an immunological factor for the differentiation of macrophage, and CA125/MUC16, which provides a protective lubricating barrier against infection, were investigated. A significant and positive correlation between the levels of M-CSF and staphylococci was found in elderly individuals and HIV-positive patients treated with antiretroviral therapy. A significant and positive correlation between the levels of M-CSF and CD125/MUC16 was also found in both patients. These correlations were enhanced in both patients as compared with healthy subjects. Salivary M-CSF might be useful as a new indicator of opportunistic infection caused by staphylococci and a defense against infection in immunocompromised hosts.

Within-Host Rhinovirus Evolution in Upper and Lower Respiratory Tract Highlights Capsid Variability and Mutation-Independent Compartmentalization.

Rhinovirus (RV) infections can progress from the upper (URT) to lower (LRT) respiratory tract in immunocompromised individuals, causing high rates of fatal pneumonia. Little is known about how RV evolves within hosts during infection. We sequenced RV complete genomes from 12 hematopoietic cell transplant patients with infection for up to 190 days from both URT (nasal wash, NW) and LRT (bronchoalveolar lavage, BAL). Metagenomic and amplicon next-generation sequencing were used to track the emergence and evolution of intrahost single nucleotide variants (iSNVs). Identical RV intrahost populations in matched NW and BAL specimens indicated no genetic adaptation is required for RV to progress from URT to LRT. Coding iSNVs were 2.3-fold more prevalent in capsid over nonstructural genes. iSNVs modeled were significantly more likely to be found in capsid surface residues, but were not preferentially located in known RV-neutralizing antibody epitopes. Newly emergent, genotype-matched iSNV haplotypes from immunocompromised individuals in 2008-2010 could be detected in Seattle-area community RV sequences in 2020-2021. RV infections in immunocompromised hosts can progress from URT to LRT with no specific evolutionary requirement. Capsid proteins carry the highest variability and emergent mutations can be detected in other, including future, RV sequences.

Updates in hematopoietic cell transplant and cellular therapies that enhance the risk for opportunistic infections.

Infectious disease physicians may be asked to evaluate and manage a variety of infections in immunocompromised hosts undergoing hematopoietic cell transplant (HCT) and cellular therapies. Over the last decade, several advances in cellular therapy have occurred, with implications for the types of infectious complications that may be seen. The purpose of this review is to update the infectious disease physician on newer advances in HCT and cellular therapy, including haploidentical transplant, expanding indications for transplant in older individuals and children, and chimeric antigen receptor T-cells. We will review how these advances might influence infectious disease complications following HCT. We will also provide a perspective that infectious disease physicians can use to evaluate the degree of immune suppression in an individual patient to help determine the type of infections that may be encountered.

Metagenomics assists in the diagnosis of a refractory, culture-negative pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with primary agammaglobulinemia

Helicobacter cinaedi is known to cause various infections in immunocompromised hosts ranging from skin lesions to disseminated septicemia. Identification of H. cinaedi is difficult through conventional identification methods due to its fastidious nature. We reported a refractory and culture-negative pyoderma gangrenosum-like ulcer caused by H. cinaedi in a patient with primary agammaglobulinemia. Metagenomic next-generation sequencing (mNGS) was applied for the identification of H. cinaedi and prolonged minocycline and amoxicillin-clavulanate potassium was used to eradicate the infection. Given the difficulties in culturing this organism, it's highly possible that H cinaedi infections have been overlooked. We suggest that early consideration of H. cinaedi infection should be suspected in immunocompromised patients presenting with unexplained skin lesions as the appropriate antibiotic choice plus a prolonged treatment course is essential for the prognosis. Application of mNGS could contribute to the early identification of rare and cryptogenic pathogens.

Sulfated motifs in heparan sulfate inhibit Streptococcus pneumoniae adhesion onto fibronectin and attenuate corneal infection

AbstractA large number of bacterial pathogens bind to host extracellular matrix (ECM) components. For example, many Gram‐negative and Gram‐positive pathogens express binding proteins for fibronectin (FN) on their cell surface. Mutagenesis studies of bacterial FN‐binding proteins have demonstrated their importance in pathogenesis in preclinical animal models. However, means to draw on these findings to design therapeutic approaches that specifically target FN‐bacteria interactions have not been successful because bacterial pathogens can elaborate several FN‐binding proteins and also because FN is an essential protein and likely a nondruggable target. Here we report that select heparan compounds potently inhibit Streptococcus pneumoniae infection of injured corneas in mice. Using intact heparan sulfate (HS) and heparin (HP), heparinase‐digested fragments of HS, HP oligosaccharides, and chemically or chemoenzymatically modified heparan compounds, we found that inhibition of S. pneumoniae corneal infection by heparan compounds is not mediated by simple charge effects but by a selective sulfate group. Removal of 2‐O‐sulfates significantly inhibited the ability of HP to inhibit S. pneumoniae corneal infection, whereas the addition of 2‐O‐sulfates to heparosan (H) significantly increased H's ability to inhibit bacterial corneal infection. Proximity ligation assays indicated that S. pneumoniae attaches directly to FN fibrils in the corneal epithelial ECM and that HS and HP specifically inhibit this binding interaction in a 2‐O‐sulfate‐dependent manner. These data suggest that heparan compounds containing 2‐O‐sulfate groups protect against S. pneumoniae corneal infection by inhibiting bacterial attachment to FN fibrils in the subepithelial ECM of injured corneas. Moreover, 2‐O‐sulfated heparan compounds significantly inhibited corneal infection in immunocompromised hosts, by a clinical keratitis isolate of S. pneumoniae, and also when topically administered in a therapeutic manner. These findings suggest that the administration of nonanticoagulant 2‐O‐sulfated heparan compounds may represent a plausible approach to the treatment of S. pneumoniae keratitis.

Recurrent Campylobacter jejuni Infections with In Vivo Selection of Resistance to Macrolides and Carbapenems: Molecular Characterization of Resistance Determinants.

We present two independent cases of recurrent multidrug-resistant Campylobacter jejuni infection in immunocompromised hosts and the clinical challenges encountered due to the development of high-level carbapenem resistance. The mechanisms associated with this unusual resistance for Campylobacters were characterized. Initial macrolide and carbapenem-susceptible strains acquired resistance to erythromycin (MIC > 256mg/L), ertapenem (MIC > 32mg/L), and meropenem (MIC > 32mg/L) during treatment. Carbapenem-resistant isolates developed an in-frame insertion resulting in an extra Asp residue in the major outer membrane protein PorA, within the extracellular loop L3 that connects β-strands 5 and 6 and forms a constriction zone involved in Ca2+ binding. The isolates presenting the highest MIC to ertapenem exhibited an extra nonsynonymous mutation (G167A|Gly56Asp) at PorA's extracellular loop L1. IMPORTANCE Carbapenem susceptibility patterns suggest drug impermeability, related to either insertion and/or single nucleotide polymorphism (SNP) within porA. Similar molecular events occurring in two independent cases support the association of these mechanisms with carbapenem resistance in Campylobacter spp.

Development of loop-mediated isothermal amplification for rapid detection of sporotrichosis caused by Sporothrix schenckii.

Sporothrix schenckii is the causative agent of sporotrichosis, which most commonly causes lymphocutaneous infections in immunocompromised hosts. This pathogen infects dogs, cats, cattle, and buffaloes and can potentially infect humans. Diagnosis by fungal culture is lengthy, and although there are several clinical diagnoses and molecular methods, these are complicated and time-consuming for veterinarians. This study aimed to develop a visual diagnostic assay that is less time-consuming and can be used by veterinarians to screen for sporotrichosis. To develop a loop-mediated isothermal amplification (LAMP) assay for sporotrichosis, primers specific for fragments of the 18S rRNA gene of S. schenckii were designed. Then, the time and temperature were optimized to successfully achieve LAMP. Ten-fold serial dilutions of DNA were used to determine the detection limit using both LAMP and nested polymerase chain reaction (nPCR) assays. The optimal LAMP conditions were incubation at 73°C for 30 min. Agarose gel electrophoresis revealed a ladder-like pattern of the LAMP product, and a sky-blue color indicated a positive result. A comparison of the LAMP assay with nPCR revealed that it was 10 times more sensitive than nPCR, with a detection limit of 10 pg. The use of a heat box compared with a thermocycler gave the same results. Loop-mediated isothermal amplification gives good results and may represent a future alternative diagnostic tool for screening fungal pathogens before the results of conventional fungal cultures are received. However, this method should be further studied to clarify its use with clinical samples.

Fecal microbiota transplant from common variable immunodeficiency patients to germ-free mice recapitulates gut dysbiosis

Patients with non-infectious complications (NIC) have worse clinical outcomes in common variable immunodeficiency (CVID) than those with infections-only (INF). NIC are associated with gut microbiome aberrations, but there are no reductionist animal models that emulate CVID, to examine the microbiome’s role in NIC-CVID development. To uncover potential microbiome roles in NIC-CVID development, we examined fecal whole genome shotgun sequencing (mWGS) from patients with NIC-CVID, INF-CVID, and their household controls. Potentially pathogenic microbes Streptococcus parasanguinis and Erysipelatoclostridium ramosum were enriched in the gut microbiomes of NIC-CVID patients. In contrast, Fusicatenibacter saccharivorans and Anaerostipes hadrus, known to suppress inflammation and promote healthy metabolism, were enriched in the gut microbiomes of INF-CVID patients. Fecal microbiota transplant (FMT) from NIC-CVID patients, INF-CVID patients, and their household controls into germ-free (GF) mice treated with anti-CD20 revealed gut dysbiosis patterns in NIC-FMT recipients but not INF-FMT and control-FMT recipients. Similar to what we observed in CVID patients, NIC-FMT recipients had a higher relative abundance of microbes that can potentially cause opportunistic infections in immunocompromised individuals, including Dysgonomonas mossii and Negativebacillus massiliensis. Further, INF-FMT recipients had a higher relative abundance of potentially beneficial microbes, including Clostridium symbiosum, a short-chain fatty acid producer associated with immunomodulatory and anti-inflammatory effects. And Parabacteroides distasonis, a succinate and secondary bile acid producer, can promote gut barrier integrity and reduce inflammation in the gut of obese mice. Inter-group analysis in gut microbiota composition identified dissimilarities between NIC-CVID and their household controls, and between NIC-CVID and INF-CVD. In mice, we noted dissimilarities between FMT recipients, most notably between CVID-FMTand control-FMT recipients.Together, mWGS analysis of fecal matter from CVID patients and FMT-recipient mice revealed a high level of similarity between humans and mice, both in diversity metrics and in potential function. Both NIC-CVID patients and NIC-FMT recipients harbored potential pathogenic microbes associated with opportunistic infections in immunocompromised hosts, whereas INF-CVID patients and INF-FMT recipients harbored microbes with beneficial metabolic functions and potential anti-inflammatory capacity. The gut dysbiosis model provides new insights into the impact of microbiome manipulation on immune responses and test therapeutics to ameliorate immune dysregulation in an immunocompromised host. [Display omitted] [Display omitted]

Oral vaccination with live attenuated pathogenic bacteria protects immunocompromised hosts from lethal colitis

Abstract Enteropathogenic Escherichia coli(EPEC) and enterohemorrhagic E. coli(EHEC) are significant causative agents for diarrheal diseases globally. Vaccination has been deemed as the most effective strategy for preventing EPEC and EHEC caused foodborne illnesses; however, FDA has not yet licensed any vaccine against EPEC or EHEC. Of note, live attenuated bacterial vaccine strategy has been scarcely investigated for against EPEC or EHEC infection, in particular in immunocompromised populations where the infections are associated with severe symptoms and outcomes. Infection with Citrobacter rodentium(CR), the murine equivalent of EPEC and EHEC, in mice has been widely used to develop novel vaccine strategies and evaluate vaccination efficacy. CR infection in immunocompromised mice such as interleukin-22 knockout (Il22−/−) mice leads to severe symptoms and mortality, which mirrors the severe outcomes of EPEC and EHEC infections in immunocompromised populations. We explored whether oral inoculation with live CR mutants with rationally attenuated virulence could protect lethal infection in susceptible Il22−/−mice. We showed that oral administration of live attenuated CR strains elicited efficient systemic and humoral immunity against variant CR virulence proteins, hence protecting otherwise lethal CR infection, in Il22−/−mice. Our findings provide proof of concept evidence for live attenuated vaccination strategy to prevent EPEC/EHEC infections in immunocompromised hosts associated with more severe symptoms and lethality, and reveal novel CR-specific antibody subtypes and virulence determinants that are critical for live attenuated vaccination offered immune protection.

CASE OF DISSEMINATED NOCARDIOSIS PRESENTING IN AN IMMUNOCOMPROMISED PATIENT

Patients with deciencies in cell mediated immunity are at high risk of 1 infection with opportunistic pathogens such as Nocardia . It is challenging to diagnose and can have multisystem manifestations. Failure to diagnose and appropriately treat can result in signicant 2,3 mortality . Nocardiosis is known as an opportunistic infection in immunocompromised hosts, but occasionally it has been reported in 4 immunocompetent patient . Nocardia infects the lungs, skin, central nervous system (CNS) or other organs presenting as localized or disseminated infections. Pulmonary nocardiosis is the main type of 5 nocardiosis. Nocardiosis involves the lung in 60–70% of cases . The data about worldwide incidence of Nocardia infection is limited and unclear. In An American study, Annual incidence of nocardiosis in 6 United State is about 500–1000 cases per year .Patients with the greatest susceptibility to this include those with solid organ transplant, hematopoietic stem cell transplant recipients, human immunodeciency virus (HIV) infected patients, patients taking corticosteroids for a long time or patients with ongoing malignant 7 processes .