Recurrent Fungal Infections Research Articles

Utilizing a sutureless valve for prosthetic valve endocarditis after aortic root replacement

BackgroundReoperation following aortic root replacement is associated with significantly high operative mortality. Etiologies related to infection are known to increase the operative mortality rate more than other etiologies. In such a clinical setting, a sutureless valve could lower the operative mortality by shortening the cardiac arrest and the operative time.Case presentationA 61-year-old male underwent emergent aortic root and total arch replacement with an open stent graft for acute type-A aortic dissection. A bioprosthetic valve was employed for aortic root replacement using the double-sewing ring technique. A fungal infection by Candida parapsilosis was postoperatively detected and improved with intravenous antifungal drug administration. However, he developed congestive heart failure one year later, and the blood cultures turned positive repeatedly for Candida parapsilosis. The prosthetic valve infection was suspected upon identifying vegetation on the bioprosthetic valve through transthoracic echocardiography. The computed tomography scan and operative findings confirmed that the infection was localized on the prosthetic valve. Consequently, the infected valve was removed without a vascular conduit, and a sutureless valve was implanted. The postoperative course was uneventful, without any evidence of recurrent fungal infection, and the patient was discharged on postoperative day 28.ConclusionsDeploying a sutureless valve can facilitate a more straightforward and minimally invasive redo procedure. Preoperative computed tomography can predict the valve size, which is the key to implanting a sutureless valve successfully after the modified Bentall procedure.

A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review.

Inborn errors of the CARD11-BCL10-MALT1 (CBM) signalosome have recently been shown to underlie severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) with variable immunological and clinical phenotypes, and patients usually present with recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. In the present study, we describe the clinical and immunological characteristics of an Egyptian patient with a mutation in the MALT1 gene. The patient suffered from an itchy exfoliative skin rash and eczematous lesions over his face and flexural surface of the limbs. He also had dental enamel erosion, repeated attacks of diarrhea, and pneumonia. He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation. DOCK8 expression on the lymphocytes by flow cytometry was normal. Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12). Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency. Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases. Early diagnosis will also enable the proper patient management by hematopoietic stem cell transplantation (HSCT) prior to the establishment of infections and pulmonary damage leading to a better outcome.

Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort

AbstractNeutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2

Essential for reactive oxygen species (EROS) protein is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in EROS is a recently identified cause for chronic granulomatous disease, a genetic disorder with recurrent bacterial and fungal infections. Here, we report a cryo-EM structure of the EROS-NOX2-p22phox heterotrimeric complex at an overall resolution of 3.56Å. EROS and p22phox are situated on the opposite sides of NOX2, and there is no direct contact between them. EROS associates with NOX2 through two antiparallel transmembrane (TM) α-helices and multiple β-strands that form hydrogen bonds with the cytoplasmic domain of NOX2. EROS binding induces a 79° upward bend of TM2 and a 48° backward rotation of the lower part of TM6 in NOX2, resulting in an increase in the distance between the two hemes and a shift of the binding site for flavin adenine dinucleotide (FAD). These conformational changes are expected to compromise superoxide production by NOX2, suggesting that the EROS-bound NOX2 is in a protected state against activation. Phorbol myristate acetate, an activator of NOX2 in vitro, is able to induce dissociation of NOX2 from EROS with concurrent increase in FAD binding and superoxide production in a transfected COS-7 model. In differentiated neutrophil-like HL-60, the majority of NOX2 on the cell surface is dissociated with EROS. Further studies are required to delineate how EROS dissociates from NOX2 during its transport to cell surface, which may be a potential mechanism for regulation of NOX2 activation.

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

Antifungal activity of silver nanoparticles loaded oregano oil nano-emulsion for topical treatment of mucocutaneous candidiasis

Oregano essential oil (OEO) possesses antimicrobial, antioxidant, and preservative properties, making it a promising candidate for various biotechnological and biomedical applications. However, the inherent volatility, hydrophobicity, and susceptibility to external factors such as light, heat, and oxygen can compromise its stability and bioactivity. To overcome these limitations, silver nanoparticles (AgNPs) were incorporated into an oregano oil nanoemulsion, enhancing both its antimicrobial efficacy and mechanical properties. Chronic Mucocutaneous candidiasis, often associated with recurrent unexplained fungal infections, is characterized by inherited T-cell defects and typically requires prolonged antifungal treatment. The approved oral imidazole derivative, ketoconazole, is commonly used for the treatment of candidiasis, chronic Mucocutaneous candidiasis, and oral thrush. However, non-compliance, therapy failure, and systemic side effects have been reported with prolonged use of ketoconazole. In this study, we developed a silver nanoparticle-loaded oregano oil nanoemulsion as a potential alternative. Our results demonstrated that the prepared nanoemulsion exhibited enhanced antimicrobial activity, as indicated by larger zones of inhibition compared to the standard ketoconazole and oregano oil combination, as confirmed by the disc diffusion method. This novel formulation holds great promise for the treatment of Mucocutaneous candidiasis, providing an effective and potentially safer alternative to current therapies.

Discoid lupus erythematosus associated with chronic granulomatous disease

To the Editor, Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder in which a reduced activity of nicotinamide dinucleotide phosphate (NAPDH) oxidase leads to defective reactive oxygen intermediates (ROS) and impairs intracellular killing of microorganisms. Patients have recurrent bacterial and fungal infections as well as granuloma formations, and have a higher risk of autoimmune and inflammatory disorders like lupus erythematosus.1 A 20-year-old caucasian male with a diagnosis of autosomal recessive CGD was referred to our hospital because of a pruritic photosensitive rash on the face and hands, present for more than a year. [...]

Molecular Challenges in the Diagnosis of X-Linked Chronic Granulomatous Disease: CNVs, Intronic Variants, Skewed X-Chromosome Inactivation, and Gonosomal Mosaicism.

Chronic granulomatous disease (CGD) is a prototypical inborn error of immunity affecting phagocytes, in which these cells are unable to produce reactive oxygen species. CGD is caused by defects in genes encoding subunits of the NADPH oxidase enzyme complex (CYBA, CYBB, CYBC1, NCF1, NCF2, NCF4); inflammatory responses are dysregulated, and patients are highly susceptible to recurrent severe bacterial and fungal infections. X-linked CGD (XL-CGD), caused by mutations in the CYBB gene, is the most common and severe form of CGD. In this study, we describe the analytical processes undertaken in 3 families affected with XL-CGD to illustrate several molecular challenges in the genetic diagnosis of this condition: in family 1, a girl with a heterozygous deletion of CYBB exon 13 and skewed X-chromosome inactivation (XCI); in family 2, a boy with a hemizygous deletion of CYBB exon 7, defining its consequences at the mRNA level; and in family 3, 2 boys with the same novel intronic variant in CYBB (c.1151 + 6T > A). The variant affected the splicing process, although a small fraction of wild-type mRNA was produced. Their mother was a heterozygous carrier, while their maternal grandmother was a carrier in form of gonosomal mosaicism. In summary, using a variety of techniques, including an NGS-based targeted gene panel and deep amplicon sequencing, copy number variation calling strategies, microarray-based comparative genomic hybridization, and cDNA analysis to define splicing defects and skewed XCI, we show how to face and solve some uncommon genetic mechanisms in the diagnosis of XL-CGD.

Novel mutations in CYBB Gene Cause X-linked chronic Granulomatous Disease in Pakistani patients

BackgroundChronic Granulomatous Disease (CGD) is a primary immunodeficiency that causes susceptibility to recurrent fungal and bacterial infections. The CYBB gene encodes gp91phox component of the Phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and specifically, X-linked CGD is caused by mutations in the CYBB gene, located on the X chromosome. The aim of the study was to characterize functional and genetic mutations in X-linked CGD.MethodsFunctional analysis was conducted on the whole blood of seventeen male individuals who were suspected to have X-linked chronic granulomatous disease (CGD). Flow cytometry was employed to assess the capacity of NADPH oxidase, measuring both H2O2 production and gp91phox protein expression in neutrophils. Additionally, DNA Sanger sequencing was performed for genetic analysis. The pathogenicity of novel mutations was assessed by pathogenicity prediction tools.ResultAmong the seventeen patients evaluated, five patients (P1, P2, P3, P4, and P5) displayed impaired H2O2 production by their neutrophils upon stimulation with Phorbol myristate acetate (PMA), accompanied by abnormal gp91phox expression. DNA sequencing of the CYBB gene identified specific mutations in each patient. In P1 and P2 (previously reported cases), a hemizygous missense mutation, c.925G > A/p.E309K was identified. In P3 and P4 (novel cases), hemizygous nonsense mutations, c.216T > A/p.C72X were found. Lastly, in P5 (also a novel case), a hemizygous missense mutation, c.732T > G/p.C244W was detected. These mutations reside in exons 9,3 and 7 of the CYBB gene, respectively.ConclusionsThe current study contributes to the understanding of the clinical and genetic spectrum associated with X-linked chronic granulomatous disease (CGD). It highlights the significance of early diagnosis in CGD and emphasizes the importance of lifelong prophylaxis to prevent severe infections.

Hematopoietic stem cell transplantation for CYBB heterozygous mutation resulting in very early onset inflammatory bowel disease in children: a case report

BackgroundInflammatory bowel disease (IBD) is a heterogeneous group of disorders associated with environmental triggers and dysregulated immune responses resulting in chronic, recurrent intestinal inflammation. Very early-onset IBD (VEO-IBD) refers to patients with symptoms or diagnosis before the age of 6 years and is widely thought to be associated with monogenic mutations. Traditional drug therapy is often ineffective in this patient population, while hematopoietic stem cell transplantation (HSCT) represents the definitive cure for patients with gene mutations.Case presentationWe report a case of VEO-IBD associated with a monogenic mutation in a 2-year-old girl presenting mainly with gastrointestinal symptoms, including recurrent hematochezia and abdominal pain for more than 3 months. A gastroscopy revealed erosive gastritis and bulbar duodenitis, while a colonoscopy indicated erosive colitis. Abnormal results were obtained from the dihydrohodamine (DHR) assay and immunoglobulin testing. Whole-exome sequencing identified a heterozygous and de novo nonsense mutation (c.388 C > T; p.R130X) in the CYBB gene leading to deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) (encoded by CYBB), a critical component of phagocytes. HSCT was performed successfully, and the DHR assay showed that normal neutrophil function was restored. Six months after HSCT, clinical remission was observed, and a repeat colonoscopy revealed intestinal mucosal healing was attained.ConclusionsPatients with CYBB mutations often develop recurrent or severe bacterial or fungal infections, mostly in the lungs, skin, lymph nodes, and liver. Here, we report on a young female child with CYBB mutations presenting predominantly with gastrointestinal symptoms. This study explores the mechanisms of inflammatory bowel disease caused by a monogenic mutation in CYBB to improve early diagnosis and effective treatment rates of this patient population.

Chronic Granulomatous Disease: a Cohort of 173 Patients—10-Years Single Center Experience from Egypt

PurposeChronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder of phagocytes, characterized by recurrent fungal and bacterial infections. Our aim is to describe the different clinical presentations, non-infectious auto-inflammatory features, types and sites of infections, and to estimate the mortality among our large cohort.MethodsThis is a retrospective study conducted at the Pediatric Department of Cairo University Children’s Hospital in Egypt, including cases with a confirmed CGD diagnosis.ResultsOne hundred seventy-three confirmed CGD patients were included. AR-CGD was diagnosed in 132 patients (76.3%) including 83 patients (48%) with p47phox defect, 44 patients (25.4%) with p22phox defect, and 5 patients (2.9%) with p67phox defect. XL-CGD was diagnosed in 25 patients (14.4%). The most common recorded clinical manifestations were deep-seated abscesses and pneumonia. Gram-negative bacteria and Aspergillus were the most frequently isolated species. Regarding the outcome, 36 patients (20.8%) were lost from follow-up. Among patients with known outcome, 94/137 patients (68.6%) are living, while 43/137 patients (31.4%) died.ConclusionAR-CGD is predominant in Egypt; CGD must always be ruled out in any patient presenting with typical or atypical mycobacterial or BCG-disease.

ORCHITIS and Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder, which is almost always characterized by impairment of the function of leukocytes and generally presents with recurrent chronic relapsing bacterial or fungal infection. This study reported a three-year-old boy who was referred to the Pediatric Hematology and Oncology Center of Shohada Khalij-e-Fars general hospital, Bushehr with recurrent lymphadenitis, and orchitis, who suffered from this disease. Since confirmation of diagnosis, he is receiving Co-trimoxazole three times per week as prophylaxis, and the plan for him is hematopoietic stem cell transplantation (HSCT).

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.

New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.

Father and son are carriers of two different types of human inborn errors of immunity: a case report

IntroductionChronic granulomatous disease (CGD) is an inborn error of immunity (IEI) characterized by recurrent bacterial and fungal infections of skin, airways, liver, brain and bones with the estimated prevalence of 1 in 250,000 live births. CGD can inherited either in an X-linked (allelic variants in the CYBB gene) or autosomal recessive mode (allelic variants in the CYBA, NCF1, NCF2, NCF4, and CYBC1 genes). Wiskott-Aldrich syndrome is an X-linked disorder with an estimated incidence of 1 in 100 000 live male births caused by variants in the WAS gene, characterized by microthrombocytopenia, eczema, recurrent infections, increased risk for autoimmune disease and malignancy. Materials and MethodsIn this case report, we present our experience about two cases of blood relatives diagnosed with different types of human inborn errors of immunity. Genetic analysis of CYBB gene in 2007 was performed by Sanger sequencing and of WAS gene in 2022 by next generation amplicon sequencing. All subjects consented to the study. ResultsThe first case was a 15-year-old male (1992 y.o.b., proband) who was diagnosed as X-linked CGD patient in 2007 due to his clinical history and hemizygote allelic variant in the CYBB gene (NM_000397.4: c.484–1G>T, COSV101059810). The second case was a 2-month-old boy (biological son of proband) who was hospitalized in 2022 due to microthrombocytopenia, low platelet volume, cytomegalovirus infection, mild anemia. Genetic analysis revealed in the DNA sample of the second case the hemizygote allelic variant in the WAS gene (NM_000377.3: c.777 +3_777+6del GAGT). Genetic testing didn’t reveal such variant in the DNA sample of the proband's wife, that's why this variant was classified as “de novo”. ConclusionInborn errors of immunity (IEI) present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. There are now a total of 485 IEI, which are segregating to 10 groups of disorders into overlapping phenotypes. Despite the fact that IEI are rare diseases, we have shown that even in one family two different types of disorders can occur. In our case the second IEI was occur due to spontaneously alterations during the process of DNA replication during cell division.

X-Linked Chronic Granulomatous Disease in a Female Carrier: A Management Challenge

Abstract Chronic granulomatous disease (CGD) is characterized by recurrent bacterial and fungal infections due to reduced nicotinamide adenine dinucleotide phosphate oxidase resulting in impaired production of reactive oxidant species, and aberrant inflammation. X-linked CGD (XL-CGD) is associated with a mutation in the CYBB gene. XL-CGD affects more males, although some females are affected affected due to skewed X-inactivation. Though management guidelines for CGD patients exist, they remain lacking for clinically affected XL-CGD female carriers. A 3 year old female with history of hematochezia, oral ulcers, and recurrent skin infections who presented with fevers and skin pustules. Pustule cultures were positive for B. cepacian, and colonoscopy was non-acute. Immunology had concern for XL-CGD with recent atypical infections and dihydrorhodamine (DHR) flow cytometry was abnormal, 17.7% (normal greater than 95%). DHR 2 months later showed 13% activation. Genetic testing showed a CYBB, c.45+2dup (intronic), heterozygous, VUS, gene mutation affecting the splice site, associated with XL-CGD, and a NOD2, c.3019dup, heterozygous, with a 2–4 fold increased risk for Crohn’s disease. She was started on bacterial prophylaxis only. She is awaiting gp91phox expression for gene sequencing. XL-CGD carriers can be at higher risk for infections, and risk is inversely correlated with %DHR neutrophil counts, but only clinically apparent with %DHR less than 20%, and more as levels are less than 10%. Though our patient was started on Bactrim prophylaxis with her %DHR less than 20%, there remains the question of when and if she should be started on anti-fungal prophylaxis. There remain no clear guidelines on the management of XL-CGD carriers.

A rare cause of necrotizing pneumonia in an adult woman: p40phox (NCF4) deficient autosomal recessive Chronic Granulomatous Disease

IntroductionChronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency typically diagnosed during childhood due to recurrent severe bacterial and fungal infections. Bi-allelic neutrophil cytoplasmic factor 4 (NCF4) mutations lead to P40phox deficient CGD which is a rare subtype of CGD. CaseA 37-year-old Pakistani woman with consanguineous parents presented with a left lower lobe necrotizing pneumonia. She reported tuberculosis as a child, but did not have a personal or family history of recurrent infections, colitis or other major health issues. Bronchoscopy with lung biopsy and bronchoalveolar lavage grew Burkholderia multivorans, and subsequent sputum culture grew Pseudomonas aeruginosa. Mycobacterium avium complex grew in 1 of 2 acid-fast bacillus cultures. Immune gene panel testing revealed homozygous pathologic mutations (c.118–1G > A-Splice acceptor) in NCF4 which encodes the p40phox subunit of the NADPH oxidase complex. Evaluation of her neutrophils by DHR oxidation revealed a slightly diminished response to PMA, but markedly reduced responses to multiple doses of opsonized, heat-killed S. aureus. PMN production of reactive oxygen species by luminol-enhanced chemiluminescence was also diminished after treatment with either opsonized zymosan or heat-killed S. aureus. Her neutrophils completely lacked p40phox by immunoblotting. Patient was treated with meropenem and levofloxacin. Interferon-gamma was added to her regimen following identification of her p40phox deficiency. After 10 weeks of therapy, computed tomography imaging showed improvement. Discussionp40phox is a regulatory component of the NADPH oxidase complex and impaired p40phox expression in phagocytes is associated with atypical presentations of CGD. Less than 30 cases have been described worldwide. NCF4-related CGD has fewer infections than other forms of CGD and is typically marked by granulomatous inflammation of the GI tract and skin. No adults previously identified have been asymptomatic past the second decade of life. All reported cases have had normal or only mildly impaired levels of DHR oxidation. This case report expands the clinical phenotype of NCF4-related CGD and illustrates the necessity of genetic testing for diagnosis, especially with near-normal DHR testing in the setting of opportunistic infection. Further studies are being pursued to identify why this patient presented so late in life with this infection and without colitis.

NADPH oxidase 2 limits amplification of IL-1β-G-CSF axis and animmature neutrophil subset in murine lung inflammation.

The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its antimicrobial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 (LTB4) production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the model fungal particle zymosan. We now identify interleukin-1β (IL-1β) and downstream granulocyte colony-stimulating factor (G-CSF) as critical amplifying signals that augment and sustain neutrophil accrual in CGD mice. Neutrophils, delivered into the lung via LTB4, were the primary source of IL-1β within the airways, and their increased numbers in CGD lungs led to significantly elevated local and plasma G-CSF. Elevated G-CSF simultaneously promoted increased granulopoiesis and mobilized the release of higher numbers of an immature CD101- neutrophil subset from the marrow, which trafficked to the lung and acquired a significantly more proinflammatory transcriptome in CGD mice compared with wild-type mice. Thus, neutrophil-produced IL-1β and downstream G-CSF act sequentially but nonredundantly with LTB4 to deploy neutrophils and amplify inflammation in CGD mice after inhalation of zymosan. NOX2 plays a critical role in dampening multiple components of a feed-forward pipeline for neutrophil recruitment, and these findings highlight NOX2 as a key regulator of neutrophil number, subsets, and function at inflamed sites.

Sexual Dysfunction Evaluation in Candidal Balanoposthitis: A Single Centred Observational Study.

A common genito-urinary infection known as Balanoposthitis presents with mild symptoms like itching or severe complications such as phimosis, ulceration of glans, and foreskin. It can result in four types of sexual dysfunction including Disorder of sexual desire, Disorder of erectile dysfunction, Disorder of satisfaction/premature ejaculation, and Disorder of orgasm. An observational clinic study including 50 patients diagnosed with Candidal Balanoposthitis based on KOH and clinical findings were recruited and evaluated for sexual function using a standardised questionnaire. The results demonstrated that sexual dysfunction in patients with Candidal Balanoposthitis is a common entity encountered in STI clinics and should be addressed properly as any deficiency in any aspect of sexual health of a patient can lead to emotional and psychological disability impacting the overall quality of the life. The factors like advanced age, Diabetes Mellitus, and poor hygiene measures of genitalia can increase the incidence of candidal Balanoposthitis as well as sexual dysfunction. Candidal Balanoposthitis, a common cause of sexual dysfunction in elderly population takes a toll on emotional and psychological health and certain modifiable factors like diabetic control and hygiene can prevent recurrent fungal infections.

Intracranial aspergilloma mimicking metachronous meningioma following transsphenoidal removal of a tuberculum sellae meningioma: illustrative case.

Endoscopic transsphenoidal surgery (eTSS) is a well-established approach for resection of skull-based pathologies such as tuberculum sellae meningiomas; however, central nervous system (CNS) fungal infection is a potential complication, particularly in a patient with concomitant sinusitis. A 58-year-old woman with a tuberculum sellae meningioma causing progressive visual disturbance and concurrent asymptomatic chronic maxillary sinusitis underwent eTSS. Six months later, a de novo dura-based mass with peripheral edema, which was assumed to be an aggressive metachronous meningioma, developed in the middle cranial fossa. The patient underwent frontotemporal craniotomy for complete resection of the lesion, and subsequent histological examination revealed an aspergilloma. She was then treated with an antifungal agent and endoscopic sinus surgery to clear the sinusitis, and no recurrent fungal infection occurred thereafter. CNS fungal infections may appear as a dura-based mass mimicking meningioma. The current case reiterates the importance of the appropriate management of sinusitis prior to eTSS.