Pulmonary cryptococcosis after immunomodulator treatment in patients with Crohn’s disease:Three case reports

BACKGROUND Corticosteroids and anti-tumor necrosis factorαmAbs are widely used to treat Crohn's disease(CD).However,one disadvantage of this treatment is impairment of normal immune function,leading to an increased risk of infection.Cryptococcus infection is an opportunistic infection that occurs mainly in immunocompromised patients and poses a significant diagnostic challenge in patients with CD.CASE SUMMARY Here,we report three cases of pulmonary cryptococcosis in patients with CD after receiving immunomodulatory treatment.The patients presented with no or mild respiratory symptoms.Chest computed tomography scans revealed pulmonary nodules in the unilateral or bilateral lobes.Diagnoses were made using pathological examination and metagenomic sequencing.The patients were treated with fluconazole 400 mg once daily for 1 to 6 mo,and symptoms were resolved.Literature searches were conducted in PubMed,Web of Science,and Embase to retrieve previously reported cases and summarize patient characteristics.CONCLUSION The incidence of cryptococcus infection has increased along with immunomodulator use.Clinical vigilance is required for early identification and standardized treatment.

Cryptococcosis in kidney transplant recipients:Current understanding and practices

Cryptococcosis is the third most commonly occurring invasive fungal disease in solid organ transplant recipients(SOT).It is caused by encapsulated yeast,Cryptococcus species,predominantly Cryptococcus neoformans and Cryptococcus gattii.Though kidney transplant recipients are at the lowest risk of cryptococcosis when compared to other solid organ transplant recipients such as lung,liver or heart,still this opportunistic infection causes significant morbidity and mortality in this subset of patients.Mortality rates with cryptococcosis range from 10%-25%,while it can be as high as 50%in SOT recipients with central nervous system involvement.The main aim of diagnosis is to find out if there is any involvement of the central nervous system in disseminated disease or whether there is only localized pulmonary involvement as it has implications for both prognostication and treatment.Detection of cryptococcal antigen(CrAg)in cerebrospinal fluid or plasma is a highly recommended test as it is more sensitive and specific than India ink and fungal cultures.The CrAg lateral flow assay is the single point of care test that can rapidly detect cryptococcal polysaccharide capsule.Treatment of cryptococcosis is challenging in kidney transplant recipients.Apart from the reduction or optimization of immunosuppression,lipid formulations of amphotericin B are preferred as induction antifungal agents.Consolidation and maintenance are done with fluconazole;carefully monitoring its interactions with calcineurin inhibitors.This review further discusses in depth the evolving developments in the epidemiology,pathogenesis,diagnostic assays,and management approach of cryptococcosis in kidney transplant recipients.

Cutaneous Cryptococcosis Arising in a Patient with Idiopathic Lung Disease: Related Illnesses or “Ticks and Fleas”

Cryptococcus is a yeast typically found in bird feces such as pigeon droppings. Infection may occur through inhalation of spores or via direct inoculation into the skin. Typically there is a history of immunosuppression, but cases are also reported in immunocompetent hosts. Cryptococcus may manifest as pulmonary disease or primary cutaneous infection, but dissemination to a systemic illness is the most life-threatening concern. We present the case of a 71-year-old man with a four-year history of idiopathic lung disease, treated with oral prednisone and mycophenolate, presents with a new onset skin rash on the right wrist. He has a history of cleaning and clearing barns and sheds after a recent storm devastated the area. Birds and bats were present in these structures while he was working. Initial therapy failed, and subsequent biopsy showed the presence of Cryptococcus yeast. Further investigation yielded a positive, low titer Cryptococcus antigen screen but negative blood cultures. This case illustrates three valuable facets of patient care. Ideally, one diagnosis will explain all of the clinical presentation, but when that is not the case then multiple etiologies must be explored. Sometimes first-line therapy is ineffective, and the clinician should not be afraid to recognize that and change course. Importantly with skin lesions, failure to respond to treatment or worsening of the lesion in the face of topical and/or oral steroids should lead one to consider the possibility of infection, particularly in an immunosuppressed patient, and prompt biopsy is prudent.

Cryptococcosis in patients with liver cirrhosis:Death risk factors and predictive value of prognostic models

Background:Liver cirrhosis is associated with immune deficiency,which causes these patients to be susceptible to various infections,including cryptococcus infection.Mortality in cirrhotic patients with cryptococcosis has increased.The present study was to explore the risk factors of mortality and the predictive ability of different prognostic models.Methods:Forty-seven cirrhotic patients with cryptococcosis at a tertiary care hospital were included in this retrospective study.Data on demographics,clinical parameters,laboratory exams,diagnostic methods,medication during hospitalization,severity scores and prognosis were collected and analyzed.Student’s t test and Mann-Whitney test were used to compare characteristics of survivors and non-survivors at a 90-day follow-up and cerebrospinal fluid(CSF)manifestations of cryptococcal meningitis.Multivariate Cox regression analysis was used to identify the independent risk factors for mortality.Kaplan-Meier curves were used to analyze patient survival.Receiver operating characteristic(ROC)curves were used to evaluate the different prognostic factors.Results:The 30-and 90-day survival rates were 93.6%and 80.9%,respectively,in cirrhotic patients with cryptococcosis.Cryptogenic liver diseases[hazard ratio(HR)=7.567,95%confidence interval(CI):1.616-35.428,P=0.010],activated partial thromboplastin time(APTT)(HR=1.117,95%CI:1.016-1.229,P=0.022)and Child-Pugh score(HR=2.146,95%CI:1.314-3.504,P=0.002)were risk factors for 90-day mortality in cirrhotic patients with cryptococcosis.Platelet count(HR=0.965,95%CI:0.940-0.991,P=0.008)was a protective factor.APTT(HR=1.120,95%CI:1.044-1.202,P=0.002)and Child-Pugh score(HR=1.637,95%CI:1.086-2.469,P=0.019)were risk factors for 90-day mortality in cirrhotic patients with cryptococcal meningitis.There was significant difference in the percentage of lymphocytes in CSF between survivors and non-survivors[60.0(35.0-75.0)vs.95.0(83.8-97.2),P<0.001].The model of end-stage liver disease-sodium(MELD-Na)score was more accurate for predicting 30-day mortality both in patients with cryptococcosis[area under curve(AUC):0.826,95%CI:0.618-1.000]and those with cryptococcal meningitis(AUC:0.742,95%CI:0.560-0.924);Child-Pugh score was more useful for predicting 90-day mortality in patients with cryptococcosis(AUC:0.823,95%CI:0.646-1.000)and those with cryptococcal meningitis(AUC:0.815,95%CI:0.670-0.960).Conclusions:These results showed that cryptogenic liver diseases,APTT and Child-Pugh score were associated with mortality in cirrhotic patients with cryptococcosis and cryptococcal meningitis.MELD-Na score was important for predicting 30-day mortality,and Child-Pugh score was critical for predicting 90-day mortality.

Clinical characteristics of pulmonary cryptococcosis coexisting with lung adenocarcinoma:Three case reports

BACKGROUND Pulmonary cryptococcosis (PC) is an invasive fungal disease caused mainly byCryptococcus (C.) neoformans or C. gattii. It may be present in immunocompetent orimmunocompromised patients. The radiographic features of PC vary, and themost common computed tomography manifestation is the presence of solitary ormultiple pulmonary nodules or masses distributed in the outer zone of the lungfield. The appearance of nodular or mass-like PC on computed tomography scansresembles that of primary or metastatic lung cancers, and differential diagnosis issometimes difficult. The coexistence of PC and malignant tumors is rarelyobserved.CASE SUMMARY This paper reports three cases of PC combined with lung adenocarcinomadiagnosed by video-assisted thoracic surgery lung biopsy, which weresuccessfully managed by early diagnosis and treatment.CONCLUSION The present case report might serve as a reminder not to neglect PC coexistingwith adenocarcinoma. Early diagnosis and treatment lead to a better prognosis.

Cryptococcal antigen testing of lung tissue homogenate improves pulmonary cryptococcosis diagnosis:Two case reports

BACKGROUND Pulmonary cryptococcosis(PC)is an opportunistic infectious disease of the respiratory system.Lung tissue biopsies,culture of respiratory samples(e.g.,sputum,lung tissue,pleural fluid,and bronchoalveolar lavage fluid),and cryptococcal antigen(CrAg)testing are helpful for a definitive diagnosis.However,these tests are sometimes falsely negative.PC is often misdiagnosed or underdiagnosed owing to the absence of obvert symptoms,poor imaging specificity,and false-negative laboratory tests.CASE SUMMARY We report two female patients who underwent computed tomography-guided percutaneous needle pulmonary biopsy of a lung nodule for a confirmed diagnosis.In both patients,the CrAg test on the lung biopsy tissue homogenate was positive,while the serum CrAg test was negative.Combined with the lung tissue pathology,we made the diagnosis of PC.Antifungal therapy was effective in both patients.CONCLUSION Given the findings of our cases and the literature review,lung tissue homogenate CrAg testing can be helpful in improving the diagnosis of PC.

Transmission of cryptococcosis by liver transplantation:A case report and review of literature

BACKGROUND Cryptococcosis is a fungal infection caused by the yeast-like encapsulated basidiomycetous fungus of the Cryptococcus neoformans(C.neoformans)species complex.These fungi are ubiquitous in soil and bird droppings,and infection by them is an important global health concern,particularly in immunosuppressed patients,such as organ transplant recipients and those infected by the human immunodeficiency virus.The fungus usually enters the body through the respiratory tract,but extremely rare cases of infection acquired by transplantation of solid organs have been reported.CASE SUMMARY We report a case of disseminated cryptococcosis in a liver transplant recipient,diagnosed 2 wk after the procedure.The patient initially presented with fever,hyponatremia and elevated transaminase levels,manifesting intense headache after a few days.Blood cultures were positive for C.neoformans.Liver biopsy showed numerous fungal elements surrounded by gelatinous matrix and sparse granulomatous formations.Magnetic resonance imaging of the brain showed multiple small lesions with low signal in T2,peripheric enhancement and edematous halo,diffuse through the parenchyma but more concentrated in the subcortical regions.Treatment with amphotericin B for 3 wk,followed by maintenance therapy with fluconazole,led to complete resolution of the symptoms.The recipients of both kidneys from the same donor also developed disseminated cryptococcosis,confirming the transplant as the source of infection.The organ donor lived in a rural area,surrounded by tropical rainforest,and had negative blood cultures prior to organ procurement.CONCLUSION This case highlights the risk of transmission of fungal diseases,specifically of C.neoformans,through liver graft during liver transplantation.

Associated Factors for In-Hospital Mortality in Patients with Meningeal Cryptococcosis and HIV Infection at a Local Hospital in Lima, Peru

Objective: To determine the associated factors for in-hospital mortality in patients with meningeal cryptococcosis and HIV infection at a local hospital in Lima, Perú. Materials and methods: We carried out a case-control study by reviewing the medical histories available at a local hospital in Lima, Peru. We determined the factors associated with mortality using a logistic regression model. Results: The information of 90 patients was analyzed, 37 dead and 53 alive. In the multivariate analysis we found two variables associated with mortality: Glasgow at admission (OR = 4.55 (1.61 – 12.20), p = 0.01) and serum antigen titer greater than 1024 (OR = 20.48 (1.6 – 261.04, p = 0.02). The protective factor found was a longer hospitalization stay (OR = 0.80 (0.69 – 0.93, p = 0.005).Conclusions: A low Glasgow score and serum antigen titer greater than 1024 are associated factors with mortality, whereas hospitalization length is a protective factor.

Neuropsychic Disorders Unmasking the Coexistence of Fahr Syndrome and Neuromeningeal Cryptococcosis

Background: Fahr syndrome associates a set of neuropsychiatric manifestations with bilateral calcifications in the basal ganglia and phosphocalcic disorders. Neuromeningeal cryptococcosis can be present in its manifestations, neuropsychic disorders with or without meningeal signs. The objective was to describe a rare association between Fahr syndrome and neuromeningeal cryptococcosis which can be expressed by the same clinical symptomatology in the context of co-infection with the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV). Presentation: A 37-year-old patient without pathological history, who presented behavioral disorders that led to a fight with those around her and a psychiatric consultation. Then, she was hospitalized in the infectious diseases Department upon discovery of her HIV status and viral hepatitis B. She was logorrheic with behavioral disturbances and subsequently presented with tonic-clonic convulsions. Laboratory tests and imaging have concomitantly discovered Fahr syndrome due to pseudohypoparathyroidism and neuromeningeal cryptococcosis. The correct management of these two pathologies enabled stabilization of the patient’s clinical condition with regular monitoring for HIV-HBV coinfection. Conclusion: Farh syndrome and neuromeningeal cryptococcosis are two different entities but sometimes similar symptoms and risk factors. Treatment of metabolic disorders combined with anticryptococcal therapy improved the prognosis.

Cryptococcus and Cryptococcosis in Human and Animal Model:An Overview

Background: Yeasts from the genus Cryptococcus (species C. neoformans and C. gattii) are opportunistic pathogens that afflict humans with low immunity caused by diseases such as AIDS or by the usage of immunosuppressive drugs. It is a fatal disease that has been studied around the whole world and its most fatal form is the brain cryptococcosis. Purpose: The present review describes the disease from pathogen isolation, the various clinical presentations of the disease, the most important virulence factors of yeast in human and animal model and their clinical issues. Methods: On this review, several published studies about the disease are presented. Results: Numerous researches have been done worldwide in order to find a kind of therapy that is more effective against the disease. Amphotericin B, in all forms is still the drug of choice in the treatment of the cryptococcosis. Fluconazole, as well as voriconazole in combination with amphotericin B, is recommended in the cases of treatment failure. Conclusion: This study presented has elucidated a little more about the disease. Further studies should be conducted to find more diagnoses that are accurate as well as more effective treatments for eradicating the disease. In this study, the bibliographic survey makes reference to the world literature;with regard to ecology, taxonomy, mains factors related to virulence, the clinical manifestations, the action of antifungal drugs and histopathological analysis used in an animal model, were the objectives deleterious aspects of this study, thus informing, in a simple way, the importance of this microorganism for research and researchers working with this global disease, called Cryptococcosis.

Pulmonary cryptococcosis in an immunocompetent patient—A case report

Cryptococcosis is an infection caused by fungi that belong to the genus Cryptococcus. There are several species of Cryptococcus, but two species—Cryptococcus neoformans and Cryptococcus gattii—cause nearly all cryptococcal infections in humans. Cryptococcosis is one of the most common fungal infections in Brazil and becomes even more important after the onset of the AIDS epidemic. The lung is the main gateway, and also is the most common site, with diverse clinical manifestations ranging from an asymptomatic to severe pneumonia. When symptommatic, most patients present with fever and cough with expectoration or hemoptysis. The most common radiological findings in immunocompetent patients are located images of masses and nodules, while immunosuppression shows interstitial infiltrates and diffuses interstitial opacity. This is a case report of a patient in the third decade of life with breathing-dependent pain at the base of the left hemithorax, who has radiological examination of a mass in the left lung base in contact with the pleura mimicking malignant lung. Lobectomy was performed, as well as the pathological diagnosis of cryptococcosis.

Clinicopathologic and ultrastructural observation of primary pulmonary cryptococcosis:a study of 37 cases

Objective To investigate the pathologic diagnosis and ultrastructure features of primary pulmonary cryptococcosis (PC). MethodsRetrospective analysis was made on 37 cases of PC with histochemical stain and light microscopy observations. Transmission electron microscopy was performed on 19 cases. ResultsThree of 37 cases were confirmed by fine needle aspiration biopsy while the other 34 patients by open-chest exploratory operation.Pathologic findings: cryptococcosis neoformans (CN) were detected in all cases,2 with gelatinous lesions and 35 non-casating granuloma. The revealing rate of CN with the mucicarmine stain(MC),periodic acid-Schiff stain(PAS), alcian blue (AB) and Grocott methenamine-silver (GMS) was 85.2% (23/27), 97.3% (36/37), 64.9% (24/37) and 96.3% (26/27), respectively. All CNs detected by transmission electron microscopy had capsules and most of them possessed simple structure with undeveloped cellular organelles and cell cataplasia. Some CNs had cellular nucleus, nucleoli, mitochondria and vacuoles. The detective rate of CNs by transmission electron microscope was 89.5 % (17/19). ConclusionAbsent of specific clinical manifestations and radiographic features, fine needle aspiration biopsy and open biopsy remain the chief approaches in the diagnosis of PC. It could be further helpful by using light microscopy and transmission electron microscopy to make definitive diagnosis and differential diagnosis as well as MS, GMC and PAS histochemical staining.

Extent of Lung Involvement and Serum Cryptococcal Antigen Test in Non-Human Immunodeficiency Virus Adult Patients with Pulmonary Cryptococcosis

Background： Serum cryptococcal antigen （CrAg） test is the most used noninvasive method to detect cryptococcal infection. However, false-negative CrAg test is not uncommon in clinical practice. Then, the aim of this study was to investigate the factors associated with false-negative CrAg test among non-human immunodeficiency virus （HIV） adult patients with pulmonary cryptococcosis and its clinical features. Methods： One hundred and fourteen non-HIV adult patients with pulmonary cryptococcosis, proven by biopsy, were retrospectively reviewed. Finally, 85 patients were enrolled; 56 were CrAg positive （CrAg＋ group） and 29 were negative （CrAg- group）. It was a cross-sectional study. Then, baseline characteristics, underlying diseases, clinical symptoms, laboratory findings, and chest radiological findings were reviewed and analyzed. Chi-square test was used to analyze categorical variable. Odds ratio （OR） was used to measure correlation. Student＇s t-test was obtained to analyze continuous variable. Results： No difference in baseline characteristics, underlying diseases, clinical symptoms, and laboratory findings were found between two groups （P 〉 0.05 in all）. Nevertheless, diffuse extent lesion was 82.1% in CrAg＋ group and 10.3% in CrAg- group （χ2 = 40.34, P〈 0.001; OR = 39.87）. Conclusions： Among patients with limited pulmonary involvement, a negative serum CrAg does not preclude the diagnosis of pulmonary cryptococcosis. However, among patients with extensive pulmonary involvement, serum CrAg is a useful diagnostic tool for pulmonary cryptococcosis. Furthermore, we also noticed that the untypical and mild presentations with extensive pulmonary lesion might be the features of pulmonary cryptococcosis, which needs further investigation.

False positive detection of serum cryptococcal antigens due to insufficient sample dilution:A case series

At present,with the development of technology,the detection of cryptococcal antigen(CRAG)plays an increasingly important role in the diagnosis of cryptococcosis.However,the three major CRAG detection technologies,latex agglutination test(LA),lateral flow assay(LFA)and Enzyme-linked Immunosorbent Assay,have certain limitations.Although these techniques do not often lead to false-positive results,once this result occurs in a particular group of patients(such as human immunodeficiency virus patients),it might lead to severe consequences.

Cryptococcal pneumonia in a human immunodeficiency virusnegative patient: A case report

BACKGROUND Cases of cryptococcal pneumonia are frequently observed in patients with various innate or acquired immunodeficiencies,including organ transplant patients,cancer patients undergoing chemotherapy,patients with acquired immune deficiency syndrome,or patients on dialysis.Fluconazole is most often used to treat this condition when it is detected.CASE SUMMARY In the present report,we describe the case of a 42-year-old human immunodeficiency virus-negative man with normal immune function who had cryptococcal pneumonia that was diagnosed after undergoing computed tomography-guided percutaneous lung puncture.We successfully treated this patient via administration of 200 mg voriconazole twice per day for 9 mo.CONCLUSION This report provides evidence of the successful treatment of pulmonary cryptococcosis using voriconazole.

Pleural effusion in an immunocompetent host with cryptococcal pneumonia:A case report

BACKGROUND Pulmonary cryptococcosis is an opportunistic infection that mainly occurs among immunocompromised patients although it can sometimes occur in immunocompetent individuals.However,the imaging findings of pulmonary cryptococcosis in immunocompetent hosts differ from those in immunosuppressed patients.In addition,the most common imaging findings of isolated pulmonary cryptococcosis are single or multiple nodules.Cavities and the halo sign are,however,prevalent in immunosuppressed patients.In immunocompetent patients,lung consolidation,pleural effusion or cavities are scarce.CASE SUMMARY A 29-year-old Asian male was admitted to our hospital with complaints of cough and fever that had persisted for a month.As a chest computed tomography scan showed consolidation in his left lower lobe,he was initially diagnosed with pneumonia and received antibiotic treatment.A second review of the chest computed tomography image revealed multiple cavities and pleural effusion.Flexible fiberoptic bronchoscopy was subsequently performed,bronchoalveolar lavage fluid and serum cryptococcal antigen tests were positive.Cryptococcus capsules were observed in bronchoalveolar lavage fluid ink stain.Histopathological examination of a percutaneous lung biopsy from the left lower lobe further revealed granulomatous inflammation,and periodic acid-Schiff staining showed red-colored yeast walls,signifying pulmonary cryptococcosis.The patient was then treated with a daily dose of fluconazole(0.4 g),but the cough and fever still persisted.We therefore changed treatment to voriconazole(0.2 g,twice a day),and the patient’s clinical outcome was satisfactory.CONCLUSION Although rare,clinicians should not disregard the possibility of cavities and pleural effusion occurring in immunocompetent hosts without underlying diseases.

Pleural involvement in cryptococcal infection

Pleural involvement of cryptococcal infection is uncommon and is more commonly observed in immunocompromised hosts than in immunocompetent ones.Pleural involvement in cryptococcal infections can manifest with or without pleural effusion.The presence of Cryptococcus spp.in the effusion or pleura is required for the diagnosis of cryptococcal pleural infection,which is commonly determined by pleural biopsy,fluid culture,and/or detection of cryptococcal antigen in the pleura or pleural fluid.

Ophthalmic manifestations of Cryptococcus gattii species complex:a case series and review of the literature

AIM:To report 4 cases of Cryptococcus gattii(C.gattii)species complex infection with diverse ophthalmic manifestations,and to review the literature to examine pathobiology of disease,classical ophthalmic presentations and outcomes,and treatment modalities for this emerging pathogen.METHODS:Cases of C.gattii meningoencephalitis with ophthalmic manifestations were identified via chart review at two institutions in Australia and one institution in the mid-west region of the United States and are reported as a case series.Additionally,a MEDLINE literature review was conducted to identify all reported cases of C.gattii with ophthalmic manifestations from 1990-2020.Cases were reviewed and tabulated,together with our series of patients,in this report.RESULTS:Four cases of C.gattii with ophthalmic manifestations are presented;three from Australia and one from the USA.A literature review identified a total of 331 cases of C.gattii with visual sequelae.The majority of cases occurred in immunocompetent individuals.Blurred vision and diplopia were the most common presenting symptoms,with papilloedema the most common sign,reported in 10%-50%of cases.Visual loss was reported in 10%-53%of cases,as compared to rates of visual loss of 1%-9%in C.neoformans infection.Elevated intracranial pressure,cerebrospinal fluid(CSF)fungal burden,and abnormal neurological exam at presentation correlated with poor visual outcomes.The mainstays of treatment are anti-fungal agents and aggressive management of intracranial hypertension with serial lumbar punctures.CSF diversion procedures should be considered for refractory cases.Acetazolamide and mannitol are associated with high complication rates,and adjuvant corticosteroids have demonstrated higher mortality rates;these treatments should be avoided.CONCLUSION:Permanent visual loss represents a devastating yet potentially preventable sequelae of C.gattii infection.Intracranial hypertension needs to be recognised early and aggressively managed.Referral to an ophthalmologist/neuro-ophthalmologist in all cases of cryptococcal infection independent of visual symptoms at time of diagnosis is recommended.