Cushing Syndrome Is Associated With Gut Microbial Dysbiosis and Cortisol-Degrading Bacteria.

CONTEXT: Cushing syndrome (CS) is a severe endocrine disease characterized by excessive secretion of cortisol with multiple metabolic disorders. While gut microbial dysbiosis plays a vital role in metabolic disorders, the role of gut microbiota in CS remains unclear. OBJECTIVE: The objective of this work is to examine the alteration of gut microbiota in patients with CS. METHODS: We performed shotgun metagenomic sequencing of fecal samples from 78 patients with CS and 78 healthy controls matched for age and body mass index. Furthermore, we verify the cortisol degradation capacity of Ruminococcus gnavus in vitro and identify the potential metabolite by LC-MC/MS. RESULTS: We observed significant differences in microbial composition between CS and controls in both sexes, with CS showing reduced Bacteroidetes (Bacteroides vulgatus) and elevated Firmicutes (Erysipelotrichaceae_bacterium_6_1_45) and Proteobacteria (Enterobacter cloacae). Despite distinct causes of hypercortisolism in ACTH-dependent and ACTH-independent CS, we found no significant differences in metabolic profiles or gut microbiota between the 2 subgroups. Furthermore, we identified a group of gut species, including R. gnavus, that were positively correlated with cortisol levels in CS. These bacteria were found to harbor cortisol-degrading desAB genes and were consistently enriched in CS. Moreover, we demonstrated the efficient capacity of R. gnavus to degrade cortisol to 11-oxygenated androgens in vitro. CONCLUSION: This study provides evidence of gut microbial dysbiosis in patients with CS and identifies a group of CS-enriched bacteria capable of degrading cortisol. These findings highlight the potential role of gut microbiota in regulating host steroid hormone levels, and consequently host health.

Pneumocystis pneumonia can complicate medical treatment of hypercortisolism even in outpatients with Cushing's disease.

Several cases of Pneumocystosis pneumonia (PCP) have been reported in patients with hypercortisolism, mainly in patients with severe ectopic ACTH syndrome (EAS). We report 2 cases of PCP that did not develop until after starting treatment with metyrapone, one of which occurred in an outpatient with Cushing's disease (CD) without pulmonary symptoms before medical treatment for CD. Patient 1 presented as an outpatient with CD and severe hypercortisolism but nonetheless in good general condition. Treatment with metyrapone was started before pituitary surgery. Patient 2 had EAS due to prostate cancer. Respiratory failure in the two patients occurred 4 days and 30 days, respectively, after the start of metyrapone treatment. In both cases, chest CT showed bilateral interstitial infiltrates, and Pneumocystis jirovecii was found on bronchoalveolar lavage (BAL). A literature review was performed to identify risk factors for PCP in patients with CD: we identified 20 other cases of PCP in patients treated for hypercortisolism, including 16 patients with EAS. Ninety percent of patients had free urinary cortisol greater than 6 times the upper limit of normal (ULN). In conclusion, onset of PCP after initiation of anticortisolic therapy is not limited to patients with EAS, and may occur in CD patients with elevated cortisol levels, even if the patient remains in good general condition and has no pulmonary symptoms before treatment. In such patients, routine prophylactic treatment with trimethoprim/sulfamethoxazole (TMP/SMX) should be considered.

Urinary tract infections in dogs with spontaneous hypercortisolism - frequency, symptoms and involved pathogens.

INTRODUCTION: Dogs with hypercortisolism are predisposed to developing bacteriuria associated either with clinical signs of cystitis or without clinical signs (subclinical bacteriuria). Based on current guidelines, dogs with subclinical bacteriuria should not be treated with antibiotics because there is no evidence that treatment improves outcome and because unnecessary treatments should be avoided. Before these guidelines were published in 2019, dogs with hypercortisolism and bacteriuria were commonly treated with antibiotics irrespective of clinical signs. Comprehensive data on the frequency of bacterial cystitis, subclinical bacteriuria and the outcome of antimicrobial treatment in dogs with hypercortisolism is sparse. The aims of this study were to investigate dogs with hypercortisolism for the presence of bacterial cystitis and subclinical bacteriuria, to address the pathogens involved, and to assess the outcome of antibiotic treatment. Dogs newly diagnosed with hypercortisolism between 2005 and 2015 from which a urine bacterial culture was available were included. Statistical analysis was performed with non-parametric tests. Of the 161 client-owned dogs included, 29 (18%) showed bacteriuria, which was subclinical in 24 (83%) cases. Escherichia coli was the most commonly isolated pathogen (58%). Bacteriuria was not associated with sex or neutering status. In 14 dogs, follow-up data was available, of which 13 (93%) were treated with antimicrobials for 14 to 28 days. Follow-up bacterial culture (1 to 118 days after cessation of therapy) was negative in 10 (77%) treated dogs; a negative follow-up culture was not associated with gender, age or duration of treatment. Bacteriuria persisted in three treated dogs and the one untreated dog. The prevalence of positive bacterial urinary culture in dogs with hypercortisolism was lower than previously reported. In the majority of dogs, bacteriuria was subclinical. Most dogs had a negative bacterial culture result after antimicrobial treatment; however, more resistant bacteria were detected in persistently positive urine.

INTRODUCTION: Les chiens atteints d'hypercortisolisme ont tendance à développer une bactériurie associée avec ou sans signes cliniques de cystite. Selon les recommandations de traitement actuelles, les chiens atteints de bactériurie subclinique ne doivent pas être traités avec des antibiotiques, car il n'y a aucune preuve d'une amélioration du succès du traitement et des traitements inutiles doivent être évités. Avant la publication de ces lignes directrices en 2019, les chiens atteints de hypercortisolisme et de bactériurie étaient traités de façon standard avec des antibiotiques, quels que soient les symptômes cliniques. Les données sur la fréquence de la cystite bactérienne, de la bactériurie subclinique et du résultat du traitement antimicrobien chez les chiens atteints d'hypercortisolisme sont rares. Le but de cette étude était d'examiner des chiens souffrant d'hypercortisolisme quant à la présence d'une cystite bactérienne et d'une bactériurie subclinique, d'identifier les agents pathogènes impliqués et d'évaluer le succès thérapeutique du traitement antibiotique. Cent soixante et un chiens, diagnostiqués avec hypercortisolisme entre 2005 et 2015 et chez qui une culture bactérienne urinaire était disponible, ont été utilisés. L'analyse statistique a été réalisée avec des tests non paramétriques. Une bactériurie a été diagnostiquée chez 29 (18%) des chiens avec hypercortisolisme, de façon subclinique dans 24 (83%) cas. Escherichia coli était le pathogène le plus fréquemment isolé (58%). Il n'y avait aucune association entre la bactériurie et le sexe ou le statut de castration. Des données de suivi étaient disponibles chez 14 chiens, dont 13 (93%) ont été traités avec des antibiotiques pendant 14 à 28 jours. La culture bactérienne (1 à 118 jours après la fin du traitement) a été négative chez 10 chiens (77%) traités. Il n'y avait aucune différence entre le sexe, l'âge ou la durée du traitement. Une bactériurie persistante a été observée chez trois chiens traités et un chien non traité. La prévalence de la culture bactérienne d'urine positive chez les chiens atteints d'hypercortisolisme était moins fréquente que celle publiée précédemment. Chez la majorité des chiens, la bactériurie était subclinique. La plupart des chiens avaient une culture bactérienne négative après un traitement antimicrobien; cependant, les cultures d'urine positives persistantes ont démontré des germes plus résistants aux antibiotiques.

Case report: nocardia infection associated with ectopic cushings.

BACKGROUND: Cushing's syndrome results from exposure to excess glucocorticoids. Ectopic Cushings is endogenous ACTH dependant form of Cushing's associated with markedly raised ACTH and cortisol levels. This leads to an impaired immune response, setting the stage for occurrence of opportunistic infections. Nocardiosis is a gram positive bacterial infection caused by aerobic actinomycetes in genus Nocardia. We report a series of patients diagnosed with ectopic Cushings, having pneumonia with Nocardia spp. In one of these cases, the manifestations of Cushing's disappeared with treatment for Nocardia. CASE PRESENTATION: Two middle aged men of Asian descent presented to the Endocrine clinic: the first with history of exertional shortness of breath, and weight loss for 1 year, the other with facial swelling, disturbed sleep and lethargy for a month. The third case was a young Asian male who presented with progressive weakness & weight loss for 2 months. All three patients had uncontrolled hypertension, high blood sugars & were hypokalemic (K: 2.52, 2.9, 1.5 mmol/l); 24 hour urine cortisol was elevated at 2000, 27216 and 9088 (32-243 ug/24 hours); ACTH 68.5, 159, 255 [0-48 pg/ml), respectively. Their MRI pituitary was normal, inferior petrosal sinus sampling revealed no central peripheral gradient. CT chest of these subjects demonstrated cavitatory lung lesions; microscopic analysis of respiratory samples was suggestive of infection with Nocardia spp. Histopathology of bronchoscopic-guided biopsy revealed no malignancy. Antihypertensives, insulin, potassium replacement, ketoconazole & trimethoprim-sulphamethoxazole (TS) were initiated. The patients' symptomatology improved & cavitatory lesions resolved with treatment. The primary source for the ectopic cushings remained unknown. The first case required bilateral adrenalectomy. The second case followed a progressively downhill course leading to death. In the third case, we were able to completely taper off ketoconazole, potassium, insulin & antihypertensives, after starting TS. CONCLUSION: Opportunistic infections are known to be associated with Cushing's syndrome, and higher levels of glucocorticoid secretion are found in patients with ectopically produced ACTH. Pulmonary nocardiosis is important differential to consider. This series includes the first case reported in which signs and symptoms of cushings subsided after treatment of Nocardia.

Dermatofitose por Tricophyton rubrum como infecção oportunista em pacientes com doença de Cushing / Dermatophytosis caused by Tricophyton rubrum as an opportunistic infection in patients with Cushing disease

O dermatófito Trichophyton rubrum é um agente comum nas micoses superficiais, podendo apresentar lesões extensas pauci-inflamatórias de evolução crônica, especialmente em imunocomprometidos. O hipercortisolismo, na síndrome de Cushing, aumenta o risco de infecções, resultado do efeito imunossupressor dos glicocorticóides. Os casos relatados apresentam duas formas distintas de dermatofitose, em pacientes com doença de Cushing, causadas por Tricophyton rubrum e posterior remissão após normalização da cortisolemia.

Trichophyton rubrum is a common agent found in superficial mycoses, which present ample nonin?ammatory lesions, with chronic evolution, especially in immunocompromised patients. The hypercortisolism in Cushing's syndrome increases the risk of infections as a result of the immunosuppressive effect of glucocorticoids. The reported cases here refer to two different types of dermatophytosis caused by Trichophyton rubrum in patients with Cushing's disease, resistant to antifungal treatment. The disease remitted after the levels of cortisol went back to normal.

Dermatophytosis caused by Tricophyton rubrum as an opportunistic infection in patients with Cushing disease.

Trichophyton rubrum is a common agent found in superficial mycoses, which present ample non-inflammatory lesions, with chronic evolution, especially in immunocompromised patients. The hypercortisolism in Cushing's syndrome increases the risk of infections as a result of the immunosuppressive effect of glucocorticoids. The reported cases here refer to two different types of dermatophytosis caused by Trichophyton rubrum in patients with Cushing's disease, resistant to antifungal treatment. The disease remitted after the levels of cortisol went back to normal.

Hypercortisolemia and infection.

Hypercortisolemia is a condition involving a prolonged excess of serum levels of cortisol that can develop as a result of disregulatory abnormalities in the hypothalamic-pituitary-adrenal axis or from exogenous-source steroids. Hypercortisolemia induces a state of immunocompromise that predisposes the patient to various bacterial, viral, fungal, and parasitic infections. To ensure optimal management of hypercortisolemia, the primary clinician must be cognizant of its different causes and aware of the different infections associated with cortisol excess. In the hypercortisolemic patient, it is necessary to restore normal cortisol levels to reduce the risk of infection or to improve the control and cure of established infection.

Espondilodiscitis micótica / Mycotic spondylodiscitis

Presentamos el caso de una paciente de 43 años con antecedentes de síndrome de Cushing, candidemia previa y terapia de suplencia con esteroides que ingresó con dolor lumbar, con demostración radiográfica de deformidad vertebral y compromiso discal. Tenía evidencia microbiológica de C. albicans. Se discute la epidemiología, microbiología, cuadro clínico y tratamiento de las discitis por especies de Candida

Disseminated cryptococcosis in a patient with pituitary Cushing's disease.

Disseminated cryptococcosis mainly occurs in patients with cell-mediated immunity disorders. A case of disseminated cryptococcosis, in a patient with pituitary Cushing's disease, is reported. Cultures of blood, cerebrospinal fluid (CSF) and aspirates of a skin lesion all grew Cryptococcus neoformans. Despite antifungal treatment, with amphotericin-B, the patient died within 3 weeks.

Candida onychomycosis--an evaluation of the role of Candida species in nail disease.

Nail infections caused by Candida species are normally associated with chronic paronychia or chronic mucocutaneous candidiasis (CMCC). However, the role of Candida in the pathogenesis of other primary nail dystrophies has been questioned in view of their response to antifungal therapy alone. In the present study of 86 patients with primary nail dystrophies from which Candida was isolated, three patterns of nail involvement were found. Nineteen patients, of whom 17 had CMCC, had total dystrophic onychomycosis of at least two nails. The second group consisted of 27 patients with paronychia and lateral onycholysis. In a further 40 patients, who did not have paronychia, Candida was isolated from nails showing primary distal and lateral onycholysis. These changes were mainly seen in patients with peripheral vascular disease, particularly Raynaud's disease, or Cushing's syndrome. Nail biopsies from patients in the latter two groups confirmed the presence of yeasts and mycelium in the nail plate and 17 (46%) of those receiving antifungal therapy with ketoconazole or itraconazole showed complete clearance of the nail dystrophy. Good responses to therapy were seen more frequently in patients with peripheral vascular disease or Cushing's syndrome of whom 15 (72%) recovered; distal erosion of the nail plate, mycelium in the nail plate on biopsy or direct microscopy together with the isolation of C. albicans were all associated with good responses to antifungals. In addition to patients with CMCC or paronychia, therefore, Candida appears to be a significant pathogen in some patients with primary onycholysis of the finger nails, particularly where there is underlying peripheral vascular disease or Cushing's syndrome.

[Pathomorphology of experimental infections caused by a virus isolated from a case of encephalomyelopathy]. / Patomorfologiia éksperimental'noi infektsii, vyzvannoi virusom, vydelennym ot bol'noi éntsefalomielopatiei

Experimental infection was produced in white mice, rats, hamsters and rabbits inoculated with a virus isolated from the blood of a patient suffering from encephalopathy. Investigation of the pathomorphology of the experimental infection in white mice with with manifest clinical picture revealed acute meningoencephalomyelitis characterized by marked disorders in the central nervous system. In white rats and rabbits showing no symptoms of disease chronic affection of the CNS was established characterized by signs of encephalomyelopathy pathomorphologically similar to lesions observed in human cases of encephalopathy.