Unique characteristics of cryptococcosis identified after death in patients with liver cirrhosis: comparison with concurrent cohort diagnosed antemortem
Nina SinghCosti D. SifriFernanda P. SilveiraRachel MillerKevin GreggShirish HuprikarErika D. LeaseAndrea ZimmerJ. Stephen DummerCedric W. SpakChristine KovalDavid BanachMiloni ShroffJade LeDarin OstranderRobin K. AveryAlbert EidRaymund R. RazonableJosé MonteroEmily A. BlumbergAhlaam AlynbiawiMichele I. MorrisHenry B. RandallGeorge AlangadenJeffrey TessierThomas V. CacciarelliMarilyn M. WagenerHsin‐Yun Sun
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Abstract:
Characteristics of cirrhosis-associated cryptococcosis first diagnosed after death are not fully known. In a multicenter study, data generated as standard of care was systematically collected in 113 consecutive patients with cirrhosis and cryptococcosis followed for 80 patient-years. The diagnosis of cryptococcosis was first established after death in 15.9% (18/113) of the patients. Compared to cases diagnosed while alive, these patients had higher MELD score (33 vs. 22, P = .029) and higher rate of cryptococcemia (75.0% vs. 41.9%, P = .027). Cases diagnosed after death, in comparison to those diagnosed during life were more likely to present with shock (OR 3.42, 95% CI 1.18–9.90, P = .023), require mechanical ventilation at admission (OR 8.5, 95% CI 2.74-26.38, P = .001), less likely to undergo testing for serum cryptococcal antigen (OR 0.07, 95% CI 0.02–0.21, P < .001) and have positive antigen when the test was performed (OR 0.07, 95% CI 0.01–0.60, P = .016). In a subset of cirrhotic patients with advanced liver disease cryptococcosis was first recognized after death. These patients had the characteristics of presenting with fulminant fungemia, were less likely to have positive serum cryptococcal antigen and posed a diagnostic challenge for care providers.Keywords:
Fungemia
Fulminant
Liver disease
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Cryptococcosis is an infection that affects humans and animals, the etiology is attributed to Cryptococcus neoformans variety neoformans, C. neoformans var. grubii and Cryptococcus gattii. The infection is common in dogs and cats, causing respiratory, neurological, cutaneous and ocular infections. Aiming to better understand the epidemiology of cryptococcosis in animals in the region, this paper describe the occurrence and characterization of the Cryptococcus species involved in this illness in pet animals at Mato Grosso State, Brazil. Clinical samples of four cases, two in cats and two dogs, were submitted for pathological, microbiological and molecular analysis. Microscopically, in three cases, tissue sections stained with hematoxylin and eosin had absence to severe granulomatous reaction composed by histiocytes, multinucleated cells and lymphocytes infiltration. In one case, citological imprint analysis showed similar inflammatory mainly mononuclear and lymphocyte cells infiltration. All cases had variable amounts of intracellular and extracellular fungal structures compatible with Cryptococcus sp. on Periodic Acid-Schiff (PAS) stain. All clinical samples were positive for culture on Sabouraud Dextrose Agar (SDA) and morphologically classified as Cryptococcus sp. The isolates were PCR positive for C. gatti, being confirmed by sequencing technique. The findings characterize the molecular species involved in animal infections in the region, and may contribute to future studies of the epidemiology of C. gattii.
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Cryptococcus spp is a major cause of opportunistic infections in immunocompromised patients, primarily due to Cryptococcus neoformans and Cryptococcus gattii. There are occasional reports of other Cryptococcus species causing invasive human disease. However, their epidemiology and clinical significance are not fully defined. We sought to describe cases with cultures positive for Cryptococcus species other than C neoformans and C gattii.A retrospective descriptive analysis of clinical and laboratory data of patients with cultures growing Cryptococcus species other than C neoformans and C gattii from November 2011 to February 2019 was performed. Three Mayo Clinic sites in Arizona, Florida, and Minnesota were included.From 176 cases with a culture growing Cryptococcus spp, 54 patients (30%) had a culture for Cryptococcus other than C neoformans and C gattii in the study time frame. The most common species were Cryptococcus magnus, Cryptococcus laurentii, and Cryptococcus ater. The organisms were isolated and identified in culture of bronchoalveolar lavage (11), skin (11), urine (7), oral (4), sinus (3), intraoperative soft tissue (3), sputum (2), synovial fluid (2), cerebrospinal fluid (2), and intravenous catheter (2), among others (7).Only 8 (15%) cases were considered to be potentially pathogenic, with 1 case of invasive disease. Antifungal treatment was fluconazole, itraconazole, and griseofulvin, for a mean systemic antifungal duration of 42 days.This large series of patients with Cryptococcus spp other than C neoformans and C gattii suggests that these species rarely cause clinically significant infection in humans. Only 1 case of invasive disease was found.
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This chapter considers over a century of clinical experience to examine the encapsulated yeast Cryptococcus, to identify the highlights of its maturation in identifying, understanding, diagnosing, and managing this major emerging fungal pathogen. In the areas of pathogenesis, diagnosis, and treatment of cryptococcosis, there are myriad events to report. A study conducted in 1998 demonstrated that cryptococcus could demonstrate morphological flexibility in that under certain environmental conditions the yeasts produce hyphae and spores without a mating reaction; in other words, some cryptococcal strains were found to have the ability to haploid fruit, and thus a new part of the life cycle of cryptococcus was identified. Another study introduced the rigorous methodology of comparative, randomized trials into antifungal therapy and particularly cryptococcosis. This study validated the efficacy of combination antifungal therapy for cryptococcosis, and represented a major starting point not just for cryptococcosis but also for other invasive fungal infections. This study initially provided much of the infrastructure for understanding the management of cryptococcal meningitis. The first large outbreak of cryptococcosis was associated with cows and mastitis in the 1950s, probably related to direct inoculation with contaminated fomites. The history of cryptococcosis has been dynamic and continues to evolve. From its humble beginnings as single case reports to its model system status in molecular studies for fungal pathogenesis, it has become a sophisticated complex organism for study and management.
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Emerging environmental pathogenic fungal infections, including cryptococcosis, continue to pose a significant threat to humans with compromised immunity and, to some extent, healthy ones. Cryptococcus neoformans was originally identified as the main etiological agent of human cryptococcosis, but recent studies have also identified the occurrence of opportunistic infections caused by Cryptococcus gattii . These two saprophytic facultative yeasts present a paradox as they can infect humans without requiring a host for replication or survival, a phenomenon termed readymade virulence. Many cryptococcal virulence traits appear to have dual effects that provide survival advantages in both animal hosts and the environment. Several molecular techniques have been developed to provide in-depth knowledge of these species complexes. This review will focus on the description of the Cryptococcus neoformans and Cryptococcus gattii ( CnCg ) species complexes and associated cryptococcal pathogenesis, ecological niches, and virulence factors employed by the pathogens to cause disease.
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Cryptococcus neoformans and Cryptococcus gattii are the main pathogenic species of invasive cryptococcosis among the Cryptococcus species. Taxonomic studies have shown that these two taxa have different genotypes or molecular types with biological and ecoepidemiological peculiarities. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has been proposed as an alternative method for labor-intensive methods for C. neoformans and C. gattii genotype differentiation. However, Vitek MS, one of the commercial MALDI-TOF MS instruments, has not been yet been evaluated for this purpose. Thus, we constructed an in-house database with reference strains belonging to the different C. neoformans (VNI, VNII, VNIII, and VNIV) and C. gattii (VGI, VGII, VGIII, and VGIV) major molecular types by using the software Saramis Premium (bioMérieux, Marcy-l'Etoile, France). Then, this new database was evaluated for discrimination of the different genotypes. Our in-house database provided correct identification for all C. neoformans and C. gattii genotypes; however, due to the intergenotypic mass spectral similarities, a careful postanalytic evaluation is necessary to provide correct genotype identification.
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Cryptococcus neoformans and Cryptococcus gattii are the two etiologic agents of cryptococcosis.They belong to the phylum Basidiomycota and can be readily distinguished from other pathogenic yeasts such as Candida by the presence of a polysaccharide capsule, formation of melanin, and urease activity, which all function as virulence determinants.Infection proceeds via inhalation and subsequent dissemination to the central nervous system to cause meningoencephalitis.The most common risk for cryptococcosis caused by C. neoformans is AIDS, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than in the immunocompromised.There have been many chapters, reviews, and books written on C. neoformans.The topics we focus on in this article include species description, pathogenesis, life cycle, capsule, and stress response, which serve to highlight the specializations in virulence that have occurred in this unique encapsulated melanin-forming yeast that causes global deaths estimated at more than 600,000 annually. HISTORY OF THE ETIOLOGIC AGENTS AND CRYPTOCOCCOSISC ryptococcus neoformans was first isolated from peach juice by Sanfelice in 1894 in Italy and was named Saccharomyces neoformans (Sanfelice 1894).In the same year, Busse provided the first description of a case of cryptococcosis (Busse 1894) and isolated a yeast culture from a sarcoma-like lesion in the infected young woman's tibia.Busse called the fungus Saccharomyces, while naming the disease Sac-
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ABSTRACT We have developed a two-step method based on high-resolution melting (HRM) that reliably identifies species from the Cryptococcus species complex ( Cryptococcus neoformans var. grubii , Cryptococcus neoformans var. neoformans , and Cryptococcus gattii ). Our results indicate that HRM can provide a fast protocol to identify and distinguish among the main Cryptococcus species.
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Background: Cryptococcosis is an infectious disease with worldwide distribution caused by Cryptococcus species. Cryptococcus neoformans and Cryptococcus gattii are the common species in human cryptococcal infection. Cryptococcus neoformans is a major cause of illness in people diagnosed with Human Immunodeficiency Virus (HIV), with an estimated 220,000 cases of cryptococcal meningitis occurring worldwide each year. This is a retrospective study on the frequency of cryptococcosis in different age groups and gender; as well as to identify the types of Cryptococcus species isolated in this population in University Malaya Medical Center from year 2013 to September 2019. Methods and materials: Data on cryptococcosis diagnosed in University Malaya Medical Center from year 2013 to September 2019 was extracted from the laboratory information system at the center. 59 newly diagnosed cryptococcosis cases were included in this study. Cryptococcus species were isolated from blood, cerebrospinal fluid, pus, body fluid, tissue and skin. Methods of identification of Cryptococcus species were via API 20C AUX, Vitek 2 and MALDI-TOF. Results: In this population of study, the frequency of cryptococcosis is 83.06% and 16.94% in males and females respectively. The frequency of Cryptococcus neoformans is 81.36%, with 83.33% comprising males (age 10–87) and 16.67% comprising females (age 33–81). The frequency of Cryptococcus neoformans var. grubii is 3.39% (2 males aged 33 and 53), Cryptococcus albidus is 3.39% (2 females aged 65 and 70), Cryptococcus uniguttulatus is 3.39% (two males aged 35 and 87) and Cryptococcus sp. is 3.39% (2 males aged 25 and 36). Cryptococcus gattii (34 year old male), Cryptococcus laurentii (71 year old male) and Cryptococcus humicola (59 years old male) are 1.70% in frequency each. Conclusion: In conclusion, the frequency of cryptococosis in this period of study is high in the male population with Cryptococcus neoformans as the commonest isolated species. Early diagnosis followed by treatment of cryptococcosis offers good to excellent prognosis for the patients. However, the prognosis varies in the immunocompromised. Targeted screening programmes should be carried out to detect early cryptococcal disease, especially in HIV-infected persons to reduce morbidity and mortality, and improve the overall quality of life.
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