Mucormycosis in Liver Allograft Following Transplant for Secondary Biliary Cirrhosis.

Mucormycosis, a group of opportunistic mycoses caused by Mucorales, present a significant threat to immunocompromised patients. In this report, we present the case of a 57-year-old male patient who underwent liver transplant for secondary biliary cirrhosis following inadvertent bile duct injury. Despite initial satisfactory postoperative evolution, the patient developed fever, and imaging revealed a suspicious lesion. Preliminary culture growth suggested a filamentous fungus, leading to initiation of liposomal amphotericin B. However, the lesion progressed, and a surgical debridement was necessary. During surgery, involvement of the liver dome and diaphragm was observed, and a nonanatomical hepatectomy was performed. Despite efforts, the patient's condition deteriorated, ultimately resulting in multiple organ failure and mortality. This case emphasizes the challenging nature of mucormycosis in livertransplant recipients.

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

OBJECTIVES: Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. MATERIALS AND METHODS: Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. RESULTS: BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. CONCLUSIONS: BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Adhesion of Klebsiella oxytoca to bladder or lung epithelial cells is promoted by the presence of other opportunistic pathogens.

The intestinal and respiratory tracts of healthy individuals serve as habitats for a diverse array of microorganisms, among which Klebsiella oxytoca holds significance as a causative agent in numerous community- and hospital-acquired infections, often manifesting in polymicrobial contexts. In specific circumstances, K. oxytoca, alongside other constituents of the gut microbiota, undergoes translocation to distinct physiological niches. In these new environments, it engages in close interactions with other microbial community members. As this interaction may progress to co-infection where the virulence of involved pathogens may be promoted and enhance disease severity, we investigated how K. oxytoca affects the adhesion of commonly co-isolated bacteria and vice versa during co-incubation of different biotic and abiotic surfaces. Co-incubation was beneficial for the adhesion of at least one of the two co-cultured strains. K. oxytoca enhanced the adhesion of other enterobacteria strains to polystyrene and adhered more efficiently to bladder or lung epithelial cell lines in the presence of most enterobacteria strains and S. aureus. This effect was accompanied by bacterial coaggregation mediated by carbohydrate-protein interactions occurring between bacteria. These interactions occur only in sessile, but not planktonic populations, and depend on the features of the surface. The data are of particular importance for the risk assessment of the urinary and respiratory tract infections caused by K. oxytoca, including those device-associated. In this paper, we present the first report on K. oxytoca ability to acquire increased adhesive capacities on epithelial cells through interactions with common causal agents of urinary and respiratory tract infections.

An opportunistic pathogen under stress: how Group B Streptococcus responds to cytotoxic reactive species and conditions of metal ion imbalance to survive.

Group B Streptococcus (GBS; also known as Streptococcus agalactiae) is an opportunistic bacterial pathogen that causes sepsis, meningitis, pneumonia, and skin and soft tissue infections in neonates and healthy or immunocompromised adults. GBS is well-adapted to survive in humans due to a plethora of virulence mechanisms that afford responses to support bacterial survival in dynamic host environments. These mechanisms and responses include counteraction of cell death from exposure to excess metal ions that can cause mismetallation and cytotoxicity, and strategies to combat molecules such as reactive oxygen and nitrogen species that are generated as part of innate host defence. Cytotoxicity from reactive molecules can stem from damage to proteins, DNA, and membrane lipids, potentially leading to bacterial cell death inside phagocytic cells or within extracellular spaces within the host. Deciphering the ways in which GBS responds to the stress of cytotoxic reactive molecules within the host will benefit the development of novel therapeutic and preventative strategies to manage the burden of GBS disease. This review summarizes knowledge of GBS carriage in humans and the mechanisms used by the bacteria to circumvent killing by these important elements of host immune defence: oxidative stress, nitrosative stress, and stress from metal ion intoxication/mismetallation.

A comparison of the prevalence of respiratory pathogens and opportunistic respiratory pathogenic profile of 'clean' and 'unclean' removable dental prostheses.

OBJECTIVES: To determine and compare the opportunistic respiratory pathogenic index (ORPI) and prevalence of respiratory pathogens between clean and unclean removable prostheses. METHODS: A cross-sectional study was conducted among 97 removable prosthesis wearers at a teaching dental hospital. Participants' prosthesis hygiene was grouped into clean and unclean. After prosthesis plaque samples were sequenced using the Type IIB Restriction-site Associated DNA Sequencing for Microbiome method, the prevalence was assessed for the presence of respiratory pathogens on each sample. The ORPIs for clean and unclean prostheses were quantified based on the sum of the relative abundance of respiratory pathogenic bacteria in a microbiome using a reference database that contains opportunistic respiratory pathogens and disease-associated information. RESULTS: A total of 30 opportunistic respiratory pathogens were identified on the removable prostheses. Eighty-one (83.5 %) removable prostheses harboured respiratory pathogenic bacteria. Stenotrophomonas maltophilia (34.0 %), Pseudomonas aeruginosa (27.8 %), and Streptococcus agalactiae (27.8 %) were the top three prevalent respiratory pathogens detected in plaque samples. There was a significantly higher prevalence of respiratory pathogens residing on unclean than clean prostheses (P = 0.046). However, the ORPIs in both groups showed no statistically significant difference (P = 0.516). CONCLUSIONS: The ORPIs for both clean and unclean prostheses demonstrated a similar abundance of respiratory pathogens. However, the high prevalence of respiratory pathogens residing on unclean prostheses should not be underestimated. Therefore, maintaining good prosthesis hygiene is still important for overall oral and systemic health, even though the direct link between prosthesis cleanliness and reduced abundance of respiratory pathogens has not been established. CLINICAL SIGNIFICANCE: The association between the prevalence of respiratory pathogens and unclean removable prostheses has been demonstrated and might increase the theoretical risk of respiratory disease development.

[Lomentospora prolificans Fungemia in a Patient With T-Cell Large Granular Leukemia: A Rare Pathogen in Türkiye]. / T-hücreli Büyük Granüler Lösemili Bir Hastada Lomentospora prolificans Fungemisi: Türkiye'de Nadir Bir Etken.

Scedosporium/Lomentospora is an opportunistic fungal pathogen found worldwide. While Scedosporium apiospermum and Scedosporium boydii are commonly observed globally, Lomentospora prolificans, which mainly affects immunosuppressed individuals, is rarely encountered and is more prevalent in arid climates, particularly in Australia and Spain. L.prolificans is a fungus commonly found in environmental sources such as contaminated water and soil. This species is known as an opportunistic pathogen that can cause deep-seated fungal infections, especially in immunosuppressed individuals. In this case report, a fatal case of L.prolificans fungemia in a patient with T-cell large granular leukemia during profound neutropenia was presented. The patient admitted to the hospital with prolonged fever, neutropenia, and shortness of breath. Antibiotherapy was administered to the patient for febrile neutropenia, but the fever persisted and his clinical status rapidly deteriorated. L.prolificans was isolated from the blood culture, and considering its antifungal resistance, combination therapy of voriconazole and terbinafine was initiated. However, the patient died of septic shock and multiple organ failure. In conclusion, although L.prolificans infections are rare, they can be life-threatening, especially in immunosuppressed individuals. Diagnosis and treatment of such infections may be difficult, therefore rapid diagnostic methods and appropriate treatment protocols should be developed. Consideration of infections caused by rare fungal pathogens in patients with risk factors may be critical for patient care. The literature review revealed that the first case of L.prolificans fungemia from Türkiye was reported in 2023. This case presentation represents the second reported case. However, in our case, L.prolificans fungemia occurred in 2018, it can be considered that L.prolificans may have been an invasive fungal pathogen of significant concern in Türkiye much earlier than previously documented.

Good girl goes bad: Understanding how gut commensals cause disease.

This review examines the complex connection between commensal microbiota and the development of opportunistic infections. Several underlying conditions, such as metabolic diseases and weakened immune systems, increase the vulnerability of patients to opportunistic infections. The increasing antibiotic resistance adds significant complexity to the management of infectious diseases. Although commensals have long been considered beneficial, recent research contradicts this notion by uncovering chronic illnesses linked to atypical pathogens or commensal bacteria. This review examines conditions in which commensal bacteria, which are usually beneficial, contribute to developing diseases. Commensals' support for opportunistic infections can be categorized based on factors such as colonization fitness, pathoadaptive mutation, and evasion of host immune response. Individuals with weakened immune systems are especially susceptible, highlighting the importance of mucosal host-microbiota interaction in promoting infection when conditions are inappropriate. Dysregulation of gut microbial homeostasis, immunological modulation, and microbial interactions are caused by several factors that contribute to the development of chronic illnesses. Knowledge about these mechanisms is essential for developing preventive measures, particularly for susceptible populations, and emphasizes the importance of maintaining a balanced gut microbiota in reducing the impact of opportunistic infections.

Riesgo de mortalidad en infecciones invasivas por Mucor SPP. en niños con enfermedades hemato-oncológicas: revisión sistemática / Mortality risk of invasive Mucor spp. infections in children with cancer: A systematic review

Los estudios sobre la infección fúngica invasiva (IFI) por Mucor spp. en pacientes pediátricos con patología hematooncológica, son de baja solidez científica, lo que dificulta conocer en profundidad sus características y evolución. Con el objetivo de analizar la evolución fatal de esos pacientes, se llevó a cabo esta revisión sistemática (RS). Material y métodos: La búsqueda bibliográfica se realizó con fecha 23 de marzo de 2023, en las principales bases de datos (Medline (a través de Pubmed), Embase (a través de Embase-Elsevier), The Cochrane Library (a través de Wiley), Cinahl (a través de Ebsco HOST), SCI-EXPANDED, SciELO (a través de la WOS) y Scopus (a través de Scopus-Elsevier), libre (mediante el motor Google) y revisando las citas de los artículos incluidos. Resultados: Se rescataron 1393 artículos, de los cuales se descartaron 1386 por diversas razones. Mediante el análisis de los textos completos, finalmente se incluyeron 7 estudios. Todos los estudios eran series de casos (nivel 4). La mediana de la frecuencia de muerte observada fue de 36,6% (Q1 20% - Q347%). Conclusiones: Esta RS mostró en niños con patología hemato-oncológica, que la mortalidad por IFI por Mucor spp. alcanzó a casi un tercio de los pacientes (AU)

Studies on invasive fungal infection (IFI) by Mucor spp. in pediatric patients with cancer have a low level of evidence, which makes it difficult to elucidate its characteristics and progression. To analyze the fatal outcome of these patients, this systematic review (SR) was conducted. Material and methods: A literature search was carried out on March 23, 2023, in the following main databases (Medline (via Pubmed), Embase (via Embase-Elsevier), The Cochrane Library (via Wiley), Cinahl (via Ebsco HOST), SCI-EXPANDED, SciELO (via the WOS) and Scopus (via Scopus-Elsevier). Additionally, a complementary search was carried out using free search engines (such as Google) and by reviewing the references of the included articles. Results: A total of 1393 articles were retrieved, of which 1386 were excluded for various reasons. After a thorough analysis of the full-text articles, 7 studies were ultimately included in the review. All studies were case series (level 4). The median observed death rate was 36.6% (IQR, 20% - 47%). Conclusions: This SR showed that in children with hematological-oncological disease, mortality due to IFI by Mucor spp. affected almost one third of the patients (AU)

If You're Not Confused, You're Not Paying Attention: Ochrobactrum Is Not Brucella.

Bacteria of the genus Brucella are facultative intracellular parasites that cause brucellosis, a severe animal and human disease. Recently, a group of taxonomists merged the brucellae with the primarily free-living, phylogenetically related Ochrobactrum spp. in the genus Brucella. This change, founded only on global genomic analysis and the fortuitous isolation of some opportunistic Ochrobactrum spp. from medically compromised patients, has been automatically included in culture collections and databases. We argue that clinical and environmental microbiologists should not accept this nomenclature, and we advise against its use because (i) it was presented without in-depth phylogenetic analyses and did not consider alternative taxonomic solutions; (ii) it was launched without the input of experts in brucellosis or Ochrobactrum; (iii) it applies a non-consensus genus concept that disregards taxonomically relevant differences in structure, physiology, population structure, core-pangenome assemblies, genome structure, genomic traits, clinical features, treatment, prevention, diagnosis, genus description rules, and, above all, pathogenicity; and (iv) placing these two bacterial groups in the same genus creates risks for veterinarians, medical doctors, clinical laboratories, health authorities, and legislators who deal with brucellosis, a disease that is particularly relevant in low- and middle-income countries. Based on all this information, we urge microbiologists, bacterial collections, genomic databases, journals, and public health boards to keep the Brucella and Ochrobactrum genera separate to avoid further bewilderment and harm.

Emerging subcutaneous mycoses by opportunistic filamentous fungi: A retrospective study in Northwest Spain.

BACKGROUND: Subcutaneous mycoses caused by opportunistic filamentous fungi are emerging infections in developed countries due to the longer survival of immunocompromised patients. The evidence published in relation to subcutaneous mycoses is fundamentally based on case reports and small case series. METHODS: We performed an observational retrospective study of subcutaneous mycoses caused by opportunistic filamentous fungi diagnosed at our institution between 2017 and 2022. This study aims to estimate the incidence rate of subcutaneous mycoses, identify which fungal species are involved, and analyse which clinical variables predispose to infection and if any are associated with mortality. RESULTS: Fifteen patients met the inclusion criteria. The median age was 61 years (range 27-84), and 80% of them were males. Alternaria spp. were the most common fungi. Two other organisms were frequently isolated: Scedosporium apiospermum and Fusarium solani. Among patients infected with F. solani, 66.7% died. The most common clinical presentation was suppurative nodules in the lower limbs and the main risk factors for infection were immunosuppressants, corticosteroids, previous trauma and transplantation, but they were not particularly associated with increased mortality. A statistically significant association with mortality was only found in the case of positive blood culture (p = <.001). CONCLUSIONS: Phaeohyphomycosis has a lower risk of dissemination, especially when compared to subcutaneous mycoses caused by hyalohyphomycetes. It is important to convey the severity of these skin infections to the physicians involved in the treatment and follow-up of susceptible patients to avoid misdiagnosis and delays in the treatment, especially in the case of hyalohyphomycosis.

Expansion of Opportunistic Enteric Fungal Pathogens and Occurrence of Gut Inflammation in Human Liver Echinococcosis.

Increasing evidence shows that the gut fungal mycobiota is implicated in human disease. However, its relationship with chronic helminth infections, which cause immunosuppression and affect over 1 billion people worldwide, remains unexplored. In this study, we investigated the gut mycobiome and its associations with gut homeostasis in a severe helminth disease worldwide: liver echinococcosis. Fecal samples from 63 patients and 42 healthy controls were collected to characterize the fungal signatures using ITS1 sequencing, QIIME pipeline, and machine learning analysis. The levels of fecal calprotectin and serological anti-Saccharomyces cerevisiae antibodies (ASCA) in these subjects were experimentally measured. We found that fungal microbiota was significantly skewed in disease, with an overrepresentation of Aspergillus, Candida, Geotrichum, Kazachstania, and Penicillium and a decrease of Fusarium. Machine learning analysis revealed that the altered fungal features could efficiently predict infection with high sensitivity and specificity (area under the curve [AUC] = 0.93). The dysbiosis was characterized by expansions of multiple opportunistic pathogens (Aspergillus spp. and Candida spp.). Clinical association analysis revealed that host immunity might link to the expansions of the invasive fungi. Accompanying the opportunistic pathogen expansion, the levels of fungi-associated fecal calprotectin and serological ASCA in the patients were elevated, suggesting that gut inflammation and microbiota translocation occurred in this generally assumed extraintestinal disease. This study highlights enteric fungal pathogen expansions and increased levels of markers for fungi-associated mucosal inflammation and intestinal permeability as hallmarks of liver echinococcosis. IMPORTANCE Helminth infection affects over 1 billion people worldwide. However, its relationship with the gut mycobiome remains unknown. Among the most prevalent helminth diseases, human hydatid disease (echinococcosis) is highlighted as one of the most important (second/third for alveolar/cystic echinococcosis) foodborne parasitic diseases at the global level. Herein, we investigated the mycobiome and gut homeostasis (i.e., inflammation and permeability) in human echinococcosis. Our results revealed that fungal dysbiosis with an expansion of opportunistic pathogens and increased levels of fecal calprotectin and serum ASCA are hallmarks of human liver echinococcosis. Host immunity is associated with enteric fungal expansions. These findings suggest that an extraintestinal helminth infection is able to alter gut fungal microbiota and impair gut homeostasis, which resembles concomitant gut symptoms in inflammatory gut-related diseases (e.g., AIDS). In clinical practice, physicians need to take cautious medical consideration of gut health for nonintestinal helminth diseases.

Review on Stenotrophomonas maltophilia: An Emerging Multidrug- resistant Opportunistic Pathogen.

Stenotrophomonas maltophilia is an opportunistic pathogen that results in nosocomial infections in immunocompromised individuals. These bacteria colonize on the surface of medical devices and therapeutic equipment like urinary catheters, endoscopes, and ventilators, causing respiratory and urinary tract infections. The low outer membrane permeability of multidrug-resistance efflux systems and the two chromosomally encoded ß- lactamases present in S. maltophilia are challenging for arsenal control. The cell-associated and extracellular virulence factors in S. maltophilia are involved in colonization and biofilm formation on the host surfaces. The spread of antibiotic-resistant genes in the pathogenic S. maltophilia attributes to bacterial resistance against a wide range of antibiotics, including penicillin, quinolones, and carbapenems. So far, tetracycline derivatives, fluoroquinolones, and trimethoprim-sulfamethoxazole (TMP-SMX) are considered promising antibiotics against S. maltophilia. Due to the adaptive nature of the intrinsically resistant mechanism towards the number of antibiotics and its ability to acquire new resistance via mutation and horizontal gene transfer, it is quite tricky for medicinal contribution against S. maltophilia. The current review summarizes the literary data on pathogenicity, quorum sensing, biofilm formation, virulence factors, and antibiotic resistance of S. maltophilia.

A Wide Database for a Multicenter Study on Pneumocystis jirovecii Pneumonia in Intensive Care Units.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that may affect patients with immunosuppression. In order to improve the diagnosis accuracy for PJP, facilitating the collection of data across Europe to reliably assess the performance of diagnostic tests for PJP is essential to improve the care of critically ill patients developing this severe condition. Such large data can be collected thanks to the contribution of several European hospitals in the compilation of a dedicated electronic Case Report Form (eCRF). The main focus of this work is to create an interface with high ergonomics both in the compilation and in the subsequent validation of the records.

COVID-19-associated-mucormycosis: possible role of free iron uptake and immunosuppression.

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.

NLRP3 Inflammasome Contributes to Host Defense Against Talaromyces marneffei Infection.

Talaromyce marneffei is an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous studies have suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense against T. marneffei remains unclear. We show that T. marneffei yeasts but not conidia induce potent IL-1ß production. The IL-1ß response to T. marneffei yeasts is differently regulated in different cell types; T. marneffei yeasts alone are able to induce IL-1ß production in human PBMCs and monocytes, whereas LPS priming is essential for IL-1ß response to yeasts. We also find that Dectin-1/Syk signaling pathway mediates pro-IL-1ß production, and NLRP3-ASC-caspase-1 inflammasome is assembled to trigger the processing of pro-IL-1ß into IL-1ß. In vivo, mice deficient in NLRP3 or caspase-1 exhibit higher mortality rate and fungal load compared to wild-type mice after systemic T. marneffei infection, which correlates with the diminished recruitment of CD4 T cells into granulomas in knockout mice. Thus, our study first demonstrates that NLRP3 inflammasome contributes to host defense against T. marneffei infection.

Development of films from natural sources for infections during wound healing.

The skin is the largest organ in the human body, and due to its barrier function, it is susceptible to multiple injuries. The appearance of infections during the wound healing process is a complication that represents a formidable hospital challenge. The presence of opportunistic bacteria with sophisticated resistance mechanisms is difficult to eradicate and compromises patients' lives. Therefore, the search for new efficacious treatments from natural sources that prevent and counteract infections, in addition to promoting the healing process, has increased in recent years. In this respect, films with the capability to protect wounds and release drugs are the presentation that predominates commercially in the hospital environment. Those films can offer several mechanical advantages such as physical protection to prevent opportunistic bacteria's entry, regulation of gas exchange, and capture of exudate through a swelling process. Wound dressings are generally curative materials easily adaptable to different anatomical regions, with high strength and elasticity, and some are even bioabsorbable. Additionally, the components of the films can actively participate in promoting the healing process. Even more, the film can be made up of carriers with other active participants to prevent and eradicate infections. Therefore, the extensive versatility, practicality, and usefulness of films from natural sources to address infectious processes during wound healing are relevant and recurrent themes. This work presents an analysis of the state-of-the-art of films with natural products focused on preventing and eradicating infections in wound healing.

Mucormycotic osteomyelitis of maxilla post-COVID patient: a case report.

Fungal osteomyelitis is a life-threatening and seldom seen opportunistic infection. It is commonly an affectation of the nose and paranasal sinuses within the orofacial region. It is an aggressive infection that needs to be addressed promptly to prevent fatal consequences. The mode of infection is via the inhalation route and infection begins initially in the nose and paranasal sinuses with subsequent invasion into the vascular tissue, eventually leading to thrombosis and necrosis of nearby hard and soft tissues. Here, we report a case of a 31-year-old male who presented with pain over the upper jaw that was sudden in onset, continuous, dull aching, radiating towards forehead and neck of the left side, aggravates on mastication and relives on its own. He had a history of uncontrolled diabetes mellitus. On further investigation, using diagnostic and Interventional aids, a final diagnosis of mucormycotic osteomyelitis of the maxilla was made.

Cryptococcus gattii Species Complex as an Opportunistic Pathogen: Underlying Medical Conditions Associated with the Infection.

The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.

Clinical Application of Metagenomic Next-Generation Sequencing for Suspected Infections in Patients With Primary Immunodeficiency Disease.

Background: Infections are the major cause of morbidity and mortality in patients with primary immunodeficiency disease (PID). Timely and accurate microbiological diagnosis is particularly important in these patients. Metagenomic next-generation sequencing (mNGS) has been used for pathogen detection recently. However, few reports describe the use of mNGS for pathogen identification in patients with PID. Objective: To evaluate the utility of mNGS for detecting pathogens in patients with PID, and to compare it with conventional microbiological tests (CMT). Methods: This single center retrospective study investigated the diagnostic performance of mNGS for pathogens detection in PID patients and compared it with CMT. Sixteen PID patients with suspected infection were enrolled, and medical records were analyzed to extract detailed clinical characteristics such as gene variation, immune status, microbial distribution, time-consuming of mNGS and CMT, treatment, and outcomes. Results: mNGS identified pathogenic microbe in 93.75% samples, compared to 31.25% for culture and 68.75% for conventional methods, and detected an extra 18 pathogenic microorganisms including rare opportunistic pathogens and Mycobacterium tuberculosis. Pathogen identification by mNGS required 48 hours, compared with bacterial culture for 3-7 days and even longer for fungus and Mycobacterium tuberculosis culture. Conclusions: mNGS has marked advantages over conventional methods for pathogenic diagnosis, particularly opportunistic pathogens and mixed infections, in patients with PID. This method might enable clinicians to make more timely and targeted therapeutic decisions, thereby improving the prognosis of these patients.