Neoformans Infection Research Articles

Patterns of Amphotericin B Use and Factors Related to Mortality in a Low-Middle Income Country: An Observational and Longitudinal Study

Background/Objectives: Amphotericin B is indicated in deep systemic fungal infections. The aim was to determine the sociodemographic, clinical and pharmacological variables of a group of Colombian patients treated with amphotericin B and factors associated with mo rtality. Methods: A longitudinal observational retrospective study on the use of amphotericin B in Colombia was conducted between January 2015 and December 2022. The multivariate analysis sought to identify variables related to mortality. Results: A total of 310 patients were identified, with a median age of 44.0 years, and 71.0% were women. Conventional amphotericin B was the most used (74.8%). The main uses were cryptococcosis (38.7%), histoplasmosis (31.9%) and candidiasis (29.4%). More than a third of patients died during hospitalization (40.3%). An increase in the Charlson Comorbidity Index score (HR: 1.13; 95% CI: 1.05–1.22) and in the qSOFA score (HR: 1.34; 95% CI: 1.04–1.73), coinfection by Mycobacterium tuberculosis (HR: 2.09; 95% CI: 1.32–3.31) and the requirement of vasopressors (HR: 4.20; 95% CI: 2.16–8.15) or invasive mechanical ventilation (HR: 2.73; 95% CI: 1.40–5.33) increased the probability of in-hospital death. In contrast, those who received systemic corticosteroids (HR: 0.43; 95% CI: 0.26–0.70) had a lower risk. Conventional amphotericin B is the most used drug mainly treating Cryptococcus neoformans infections. Conclusions: The use of amphotericin B was consistent with clinical practice guideline recommendations. In-hospital mortality was common, and factors such as increased comorbidities, higher qSOFA scores, coinfection with Mycobacterium tuberculosis and invasive procedures like mechanical ventilation were linked to increased mortality.

Cryptococcus neoformans infections: aspartyl protease potential to improve outcome in susceptible hosts.

Vaccination and immunotherapies against fungal pathogens still remain a challenge. Here, we show using an in vivo model based on outbred mice that development of antibodies against Pep1p, an antigenic protein of the fungal pathogen Cryptococcus neoformans, confers resistance to this fungal infection. In support of this observation, prophylactic or therapeutic immunization of the mice with recombinant Pep1p could improve their survival when infected with a lethal dose of C. neoformans. Moreover, passive therapy with monoclonal anti-Pep1p antibodies also enhanced survival of the mice from C. neoformans infection. The associated antifungal mechanisms were mounting of a protective immune response and the development of fungal specific antibodies that decrease the fungal burden due to an increase in their phagocytosis and/or inhibit the fungal multiplication. Together, our study demonstrates (a) the mode of host-fungal interaction and the immune response developed thereby play a crucial role in developing resistance against C. neoformans; (b) Pep1p, an aspartic protease as well as an antigenic protein secreted by C. neoformans, can be exploited for vaccination (both prophylactic and therapeutic) or immunotherapy to improve the host defense during this fungal infection.

Dietary L-3,4-dihydroxyphenylalanine (L-DOPA) augments cuticular melanization in Anopheles mosquitos while reducing their lifespan and malaria parasite burden.

L-3,4-dihydroxyphenylalanine (L-DOPA), a naturally occurring tyrosine derivative, is prevalent in environments that include mosquito habitats, potentially serving as part of their diet. Given its role as a precursor for melanin synthesis we investigated the effect of dietary L-DOPA on mosquito physiology and immunity to Plasmodium falciparum and Cryptococcus neoformans infection. Dietary L-DOPA was incorporated into mosquito melanin via a non-canonical pathway and had profound transcriptional effects that were associated with enhanced immunity, increased pigmentation, and reduced lifespan. Increased melanization resulted in an enhanced capacity to absorb electromagnetic radiation that affected mosquito temperatures. Bacteria in the mosquito microbiome were sources of dopamine, which is a substrate for melanization. Our results illustrate how an environmentally abundant amino acid analogue can affect mosquito physiology and suggest its potential usefulness as an environmentally friendly vector control agent to reduce malaria transmission, warranting further research and field studies.

Primary Cutaneous Cryptococcus Following Traumatic Exposure: A Case Report and Retrospective Analysis

Primary cutaneous cryptococcus (PCC) is a form of Cryptococcal neoformans infection characterized by localized cutaneous colonization and proliferation. In this case study, we present PCC occurring following a previous trauma in a 77-year-old male with a history of renal organ transplant maintained by immunosuppressive therapy. Colonies of C. neoformans were successfully identified during a secondary workup after the patient had been misdiagnosed. Despite the delay in treatment, complete remission was achieved through aggressive antifungal therapy. Our case highlights common clinical pitfalls that contribute to the prolonged diagnosis of PCC. Our findings and retrospective analysis underscore commonalities in disease presentation, such as high-risk patient populations, transmission routes, and associated symptoms. Integrating these insights into clinical practice may heighten provider suspicion and enhance patient outcomes.

A case of primary cutaneous Cryptococcus neoformans infection

BackgroundCryptococcosis is an infectious disease caused by encapsulated heterobasidiomycete yeasts. As an opportunistic pathogen, cryptococcal inhalation infection is the most common. While Primary cutaneous cryptococcosis is extremely uncommon.Case presentationA 61-year-old woman with a history of rheumatoid arthritis on long-term prednisone developed a red plaque on her left thigh. Despite initial antibiotic treatment, the erythema worsened, leading to rupture and fever. Microbiological analysis of the lesion’s secretion revealed Candida albicans, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus epidermidis. Skin biopsy showed thick-walled spores, and culture confirmed primary cutaneous infection with Cryptococcus neoformans. Histopathological stains were positive, and mass spectrometry identified serotype A of the pathogen. The patient was treated with oral fluconazole and topical nystatin, resulting in significant improvement and near-complete healing of the skin lesion within 2.5 months.ConclusionsPrimary cutaneous cryptococcosis was a primary skin infection exclusively located on the skin. It has no typical clinical manifestation of cutaneous infection of Cryptococcus, and culture and histopathology remain the gold standard for diagnosing. The recommended medication for Primary cutaneous cryptococcosis is fluconazole. When patients at risk for opportunistic infections develop skin ulcers that are unresponsive to antibiotic, the possibility of primary cutaneous cryptococcosis needs to be considered.

Disseminated Cryptococcus neoformans infection involving multiple bones and lung in an immunocompetent patient: a case report

BackgroundCryptococcal osteomyelitis is a rare and potentially serious condition, typically encountered in individuals with compromised immune systems. This case underscores the unusual occurrence of disseminated Cryptococcosis in an immunocompetent person, involving multiple bones and lungs, with Cryptococcus neoformans identified as the causative agent.Case presentationAn Indonesian man, previously in good health, presented with a chief complaint of successive multiple bone pain lasting for more one month, without any prior history of trauma. Additionally, he reported a recent onset of fever. On physical examination, tenderness was observed in the left lateral chest wall and right iliac crest. Laboratory findings indicated mildly elevated inflammatory markers. A computed tomography (CT) scan of the chest revealed an ovoid solid nodule in the right lower lung and multifocal osteolytic lesions in the sternum, ribs, and humeral head. A magnetic resonance imaging (MRI) study of the sacrum showed multiple lesions in the bilateral iliac bone and the lower L4 vertebral body. Confirmation of Cryptococcal osteomyelitis involved a fine-needle biopsy and culture, identifying Cryptococcus neoformans in the aspirate. The patient responded positively to targeted antifungal treatments, leading to a gradual improvement in his condition.ConclusionsThis case emphasizes the need to consider Cryptococcus neoformans osteomyelitis in immunocompetent patients with bone pain. A definitive diagnosis involves a fine-needle biopsy for pathology and culture, and prompt initiation of appropriate antifungal treatment has proven effective in preventing mortality.

Rise and fall of Caspofungin: the current status of Caspofungin as a treatment for Cryptococcus neoformans infection.

Antifungal infections are becoming a major concern to human health due to antimicrobial resistance. Echinocandins have been promising agents against resistant fungal infections, primarily caspofungin, which has a more effective mechanism of action than azoles and polyenes. However, fungi such as Cryptococcus neoformans appear to be inheritably resistant to these drugs, which is concerning due to the high clinical importance of C. neoformans. In this review, we review the history of C. neoformans and the treatments used to treat antifungals over the years, focusing on caspofungin, while highlighting the C. neoformans problem and possible explanations for its inherent resistance.

Activation of leukotriene B4 receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils.

Invasive fungal infections are life-threatening, and neutrophils are vital cells of the innate immune system that defend against them. The role of LTA4H-LTB4-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly understood. Here, we demonstrated that the LTA4H-LTB4-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus, but not Cryptococcus neoformans infection, by regulating the antifungal activity of neutrophils. Our results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of neutrophils. Moreover, defective activation of the spleen tyrosine kinase (Syk) and extracellular signal-related kinase (ERK1/2) pathways in neutrophils accompanies this impairment. Mechanistically, BLT1 regulates CR3-mediated, β-1,3-glucan-induced neutrophil phagocytosis, while a physical interaction with CR3 with slight influence on its dynamics is observed. Our findings thus demonstrate that the LTA4H-LTB4-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.

Proteomic Profiling of Samples Derived from a Murine Model Following Cryptococcus neoformans Infection.

Proteomic profiling provides in-depth information about the regulation of diverse biological processes, activation of and communication across signaling networks, and alterations to protein production, modifications, and interactions. For infectious disease research, mass spectrometry-based proteomics enables detection of host defenses against infection and mechanisms used by the pathogen to evade such responses. In this chapter, we outline protein extraction from organs, tissues, and fluids collected following intranasal inoculation of a murine model with the human fungal pathogen Cryptococcus neoformans. We describe sample preparation, followed by purification, processing on the mass spectrometer, and a robust bioinformatics analysis. The information gleaned from proteomic profiling of fungal infections supports the detection of novel biomarkers for diagnostic and prognostic purposes.

Vaccine Strategies for Cryptococcus neoformans.

Cryptococcus neoformans infections are a major worldwide concern as current treatment strategies are becoming less effective in alleviating the infection. The most extreme and fatal cases are those of immunocompromised individuals. Clinical treatments for cryptococcosis are limited to a few classes of approved drugs, and due to a rise in drug resistance, these drugs are becoming less effective. Therefore, it is essential to develop innovative ways to control this infection. Vaccinations have emerged as a safe, viable, and cost-effective solution to treat a number of diseases over the years. Currently, there are no clinically available vaccines to treat cryptococcal infections, but a number of studies have shown promising results in animal models. Here, we present step-by-step experimental protocols using live-attenuated or heat-killed C. neoformans cells as a vaccination strategy in a preventive or in a therapeutic murine model of cryptococcosis.

Assessing the In Vitro Potential of Glatiramer Acetate (Copaxone®) as a Chemotherapeutic Candidate for the Treatment of Cryptococcus neoformans Infection.

Cryptococcosis is a systemic mycosis affecting immunosuppressed individuals, caused by various Cryptococcus species. The current treatment utilizes a combination of antifungal drugs, but issues such as nephrotoxicity, restricted or limited availability in certain countries, and resistance limit their effectiveness. Repurposing approved drugs presents a viable strategy for developing new antifungal options. This study investigates the potential of glatiramer acetate (Copaxone®) as a chemotherapy candidate for Cryptococcus neoformans infection. Various techniques are employed to evaluate the effects of glatiramer acetate on the fungus, including microdilution, XTT analysis, electron and light microscopy, and physicochemical measurements. The results demonstrate that glatiramer acetate exhibits antifungal properties, with an IC50 of 0.470 mg/mL and a minimum inhibitory concentration (MIC) of 2.5 mg/mL. Furthermore, it promotes enhanced cell aggregation, facilitates biofilm formation, and increases the secretion of fungal polysaccharides. These findings indicate that glatiramer acetate not only shows an antifungal effect but also modulates the key virulence factor-the polysaccharide capsule. In summary, repurposing glatiramer acetate as a potential chemotherapy option offers new prospects for combating C. neoformans infection. It addresses the limitations associated with current antifungal therapies by providing an alternative treatment approach.

Susceptibility to Cryptococcus neoformans Infection with Bruton's Tyrosine Kinase Inhibition.

Patients receiving the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have an increased likelihood of fungal infections. The objectives of this study were to determine if Cryptococcus neoformans infection severity was isolate dependent with BTK inhibition and whether blocking BTK impacted infection severity in a mouse model. We compared four clinical isolates from patients on ibrutinib to virulent (H99) and avirulent (A1-35-8) reference strains. BTK knockout (KO) and wild-type (WT) C57 mice and WT CD1 mice were infected by intranasal (i.n.), oropharyngeal aspiration (OPA), and intravenous (i.v.) routes. Infection severity was assessed by survival and fungal burden (CFU per gram of tissue). Ibrutinib (25 mg/kg) or vehicle was administered daily through intraperitoneal injections. In the BTK KO model, no isolate-dependent effect on fungal burden was observed, and infection severity was not significantly different from that of the WT with i.n., OPA, and i.v. routes. Ibrutinib treatment did not impact infection severity. However, when the four clinical isolates were compared to H99, two of these isolates were less virulent, with significantly longer survival and reduced rates of brain infection. In conclusion, C. neoformans infection severity in the BTK KO model does not appear to be isolate dependent. BTK KO and ibrutinib treatment did not result in significantly different infection severities. However, based on repeated clinical observations of increased susceptibility to fungal infections with BTK inhibitor therapy, further work is needed to optimize a mouse model with BTK inhibition to better understand the role that this pathway plays in susceptibility to C. neoformans infection.

Cryptococcus neoformans osteomyelitis of the tibia: a case report and review of the literature

IntroductionOsteomyelitis is a bone inflammation that can be related to various infectious agents. As with any other type of inflammation, the prevailing symptoms and signs may include redness, swelling, pain, and heat. Fungal osteomyelitis is rare and usually found in immune-compromised patients.Case presentationA non-human immunodeficiency virus immunocompromised Greek female patient, 82 years old, visited the emergency department due to a 3 day pain located mainly over the left tibia’s anterior surface, accompanied by swelling and redness. There was also a subcutaneous lesion of her left breast. Medical history revealed that the patient had an unmasked close contact with pigeons, a main host of the disease. Initial x-ray imaging showed an osteolytic area in the upper third of the tibial diaphysis. The patient was admitted and underwent a computed tomography-guided biopsy. The specimen revealed a Cryptococcus neoformans infection of the bone and the breast. She was treated with 400 mg fluconazole twice a day for 3 weeks while in hospital and 200 mg twice a day upon discharge for 9 months. After that, she underwent surgical debridement because of lasting local irritation. She was closely monitored in our outpatient office, and in her last visit, 1 year after the initial admission, inflammatory signs had regressed vastly.ConclusionsTo our knowledge, this is the ninth cryptococcal osteomyelitis of the tibia to be recorded since 1974, and the most unusual finding was the bifocal nature of the infection, affecting both the tibia and the breast.

Clinical characteristics and prognostic factors of 60 patients with acquired immune deficiency syndrome combined with Cryptococcus neoformans

ObjectiveCryptococcal meningitis (CM) threatens people’s health and is the main cause of opportunistic fungus-related death in acquired immune deficiency syndrome (AIDS) patients. Herein, we investigate the clinical characteristics and prognostic factors of AIDS patients with Cryptococcus neoformans in Wenzhou, Zhejiang Province, China.MethodsOur study enrolled AIDS patients diagnosed with Cryptococcus neoformans infection who were hospitalised in our hospital. They were divided into Group A (32 patients with CM) and Group B (28 patients without CM) according to their diagnosis. The differences between the two groups of patients’ clinical symptoms, imaging examinations and laboratory examinations were observed. Statistical methods were used to analyse the difference in prognosis between the two groups.ResultsHeadache and fever were the most common clinical characteristics for patients with CM, while respiratory symptoms and fever were the most common clinical characteristics for patients without CM. The positive rate of cryptococcal capsular antigen, India ink staining and culture in the cerebrospinal fluid examination was higher in the CM patients than in the non-CM patients. The overall morbidity and mortality rate after systemic antifungal therapy was higher in the CM patients than in the non-CM patients. A higher incidence of headache, impaired consciousness, nuchal rigidity, first intracranial pressure > 200 mmH2O and mortality was observed in the CM patients than in the non-CM patients. Multifactorial logistic regression analysis showed that headache risk factors affecting the patient’s prognosis at 12 weeks.ConclusionPatients with AIDS diagnosed with Cryptococcus neoformans infection have insidious clinical symptoms in the early stage, and their manifestation is often non-specific, resulting in poor prognosis and high mortality among CM patients compared to patients without CM. Therefore, early identification and timely antifungal therapy before the disease progresses to meningitis are of great value in improving the survival rate of patients.

Isolated cryptococcal osteomyelitis of the sacrum in an immunocompetent patient: a case report and literature review

BackgroundCryptococcus neoformans, an opportunistic fungal pathogen, seldom causes infection in immunocompetent people. Cryptococcal osteomyelitis is an uncommon condition in which Cryptococcus invades the bone. It usually occurs as part of a disseminated infection and rarely in isolation. The spine has been reported as the most common site of cryptococcal osteomyelitis; however, isolated case of sacrum involvement in immunocompetent patients has never been reported.Case presentationWe report the case of a 37-year-old man without underlying disease who presented with progressive low back and sacrococcygeal pain. The patient was initially diagnosed with sacral tumour by a local doctor, and subsequently, after admission, was diagnosed with sacral tuberculosis. He was empirically treated with antitubercular drugs. The patient failed to respond to antitubercular drugs and complained of worsening low back pain. Additionally, he developed persistent radiating pain and numbness in his legs. For further diagnosis, we performed a computed tomography-guided puncture biopsy of the sacrum, which revealed granulomatous inflammation with massive macrophage infiltration and special staining revealed a fungal infection. We performed sacral debridement and drainage and obtained purulent specimens for pathological examination and microbial culture. Microbial identification and drug susceptibility tests revealed a Cryptococcus neoformans infection sensitive to fluconazole. Postoperatively, the persistent radiating pain and numbness in the legs resolved. After 12 consecutive weeks of antifungal therapy, all his symptoms resolved. The patient remained without any signs of recurrence at the 8-month follow-up.ConclusionWe reported a rare case of isolated sacrum cryptococcal osteomyelitis in an immunocompetent patient. Furthermore, we identified and reviewed 18 published cases of spine cryptococcal osteomyelitis. Immunocompetent individuals are also at risk for cryptococcal osteomyelitis. Clinical manifestation and imaging are insufficient to diagnose cryptococcal osteomyelitis of the spine, and invasive examinations, such as puncture biopsy and fungal examinations, are needed. Antifungal therapy yields satisfactory results for the treatment of cryptococcal osteomyelitis of the spine, however, if the infective lesion is large, especially when it compresses the spinal cord and nerves, a regimen combining aggressive surgery with antifungal therapy is indispensable.

Gut microbiota associated with cryptococcal meningitis and dysbiosis caused by anti-fungal treatment.

The gut microbiota is a dynamic and highly diverse microbial ecosystem that affects many aspects of the host's physiology. An improved understanding of the gut microbiota could lead to better strategies for the diagnosis and therapy of cryptococcal meningitis (CM), but the impact of Cryptococcus infection and anti-fungal treatment on the gut microbiota has rarely been studied. We characterized the diversity and composition of the gut microbiota in CM patients at diagnosis and healthy controls (HCs) using metagenomic sequencing and determined the effects of anti-fungal drugs. We found that CM patients had distinct bacterial and fungal compositions compared with HCs, with eight differentially abundant fungal and 72 differentially abundant bacterial species identified between the two groups. CM patients showed an increased abundance of Enterococcus avium, Leuconostoc mesenteroides, and Weissella cibaria, and a decreased abundance of Prevotella spp. compared with HCs. However, anti-fungal treatment only led to minor changes in the intestinal microbiota. Moreover, both positive and negative correlations existed in fungal, bacterial, and clinical indicators. Our study suggests that the Cryptococcus neoformans infection caused a distinct dysbiosis of the gut microbiota and contributes valuable information implying potential links between the CM and gut microbiota.

A Young Patient With Lupus Nephritis and Cryptococcemia Lacking Central Nervous System Involvement

There has been a recent increase in the prevalence of cryptococcal infections worldwide due to increased prevalence of immunosuppressed individuals secondary to AIDS, autoimmune disease, or neoplastic disease. Cryptococcus neoformans infection typically presents as a meningoencephalitis; however, there is low incidence of cryptococcemia in the absence of central nervous system and other organ involvement. Here we present a case of a 26-year-old female patient with lupus nephritis on immunosuppressants found to have asymptomatic cryptococcemia in the absence of meningoencephalitis and other organ involvement.

A comparative study of IL-33 and its receptor ST2 in a C57BL/6J mouse model of pulmonary Cryptococcus neoformans infection.

It has been reported that IL-33 receptor ST2 deficiency mitigates Cryptococcus neoformans (C. neoformans) pulmonary infection in BALB/c mice. IL-33 may modulate immune responses in ST2-dependent and ST2-independent manners. The host genetic background (i.e., BALB/c, C57BL/6J) influences immune responses against C. neoformans. In the present study, we aimed to explore the roles of IL-33 and ST2 in pulmonary C. neoformans-infected mice on a C57BL/6J genetic background. C. neoformans infection increased IL-33 expression in lung tissues. IL-33 deficiency but not ST2 deficiency significantly extended the survival time of C. neoformans-infected mice. In contrast, either IL-33 or ST2 deficiency reduced fungal burdens in lung, spleen and brain tissues from the mice following C. neoformans intratracheal inoculation. Similarly, inflammatory responses in the lung tissues were more pronounced in both the IL-33-/- and ST2-/- infected mice. However, mucus production was decreased in IL-33-/- infected mice alone, and the level of IL-5 in bronchoalveolar lavage fluid (BALF) was substantially decreased in the IL-33-/- infected mice but not ST2-/- infected mice. Moreover, IL-33 deficiency but not ST2 deficiency increased iNOS-positive macrophages. At the early stage of infection, the reduced pulmonary fungal burden in the IL-33-/- and ST2-/- mice was accompanied by increased neutrophil infiltration. Collectively, IL-33 regulated pulmonary C. neoformans infection in an ST2-dependent and ST2-independent manner in C57BL/6J mice.

Cryptococcus neoformans Infection in the Central Nervous System: The Battle between Host and Pathogen.

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood–brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

CRYPTIC CRYPTO: PULMONARY CRYPTOCOCCOSIS IN AN IMMUNOCOMPETENT HOST

CRYPTIC CRYPTO: PULMONARY CRYPTOCOCCOSIS IN AN IMMUNOCOMPETENT HOST