Cryptococcal Antigen Research Articles

The performance of serum cryptococcal capsular polysaccharide antigen test, histopathology and culture of the lung tissue for diagnosis of pulmonary cryptococcosis in patients without HIV infection.

BackgroundClinicians may fail to make an early diagnosis of pulmonary cryptococcosis (PC) without HIV infection. Serum cryptococcal capsular polysaccharide antigen (CrAg) test, histopathology and culture of lung tissue play different roles in diagnosis of PC.ObjectiveTo investigate the performance of serum CrAg test, histopathology and culture of the lung tissue in diagnosis of PC without HIV infection.Patients/methodsFrom January 2011 to September 2017, patients with proven PC were recruited from a teaching hospital in southern China. Those patients with HIV infection, PC confirmed by surgery or PC with probable or possible diagnosis were excluded from the study. Latex agglutination test and CrAg lateral flow assay were used for detection of serum CrAg. Lung biopsy and needle aspiration were performed under computed tomography guidance.ResultsEighty-nine patients with proven PC including 41 male (46.1%) and 48 female (53.9%) were enrolled. Fifty-one (57.3%) patients had underlying disease. Positive CrAg test was found in 83 (93.3%) cases. Among six cases with negative CrAg test, PC was confirmed by histology in two cases and positive culture in four cases. The histopathological results of 77 (86.5%) cases revealed cryptococcal granuloma and 12 cases showed chronic inflammation, which was confirmed by positive culture. Among 65 cases, the diseased tissue of 46 (70.8%) cases presented Cryptococcus neoformans in the culture and one case was diagnosed with lung cancer coexisting with PC.ConclusionOur findings showed that serum CrAg test is rapid and sensitive in diagnosing PC, histology is important for confirming PC and culture plays a complementary role. Biopsied lung tissue should be submitted for cultures whenever feasible.

EQUAL Cryptococcus Score 2018: A European Confederation of Medical Mycology Score Derived From Current Guidelines to Measure QUALity of Clinical Cryptococcosis Management.

Cryptococcocis is an opportunistic fungal infection with high morbidity and mortality. Guidelines to aid clinicians regarding diagnosis, management, and treatment can be extensive and challenging to comply with. There is no tool to measure guideline adherence. To create such a tool, we reviewed current guidelines from the Infectious Diseases Society of America, the World Health Organization, the American Society of Transplantation, and recent significant publications to select the strongest recommendations as vital components of our scoring tool. Items included diagnostic tests (blood, tissue, and cerebrospinal fluid cultures, Cryptococcus antigen, India ink, histopathology with special fungal stains, central nervous system imaging), pharmacological (amphotericin B, flucytosine, azoles) and nonpharmacological treatments (intracranial pressure management, immunomodulation, infectious disease consultation), and follow-up of central nervous system complications. The EQUAL Cryptococcus Score 2018 weighs and aggregates the recommendations for the optimal management of cryptococcosis. Providing a tool that could measure guideline adherence or facilitate clinical decision-making.

Pulmonary cryptococcosis: A review of pathobiology and clinical aspects

Pulmonary cryptococcosis is an important opportunistic invasive mycosis in immunocompromised patients, but it is also increasingly seen in immunocompetent patients. The main human pathogens are Cryptococcus neoformans and C. gattii, which have a worldwide distribution. In contrast to cryptococcal meningitis, pulmonary cryptococcosis is still underdiagnosed because of limitations in diagnostic tools. It can mimic lung cancer, pulmonary tuberculosis, bacterial pneumonia, and other pulmonary mycoses both clinically and radiologically. Pulmonary nodules are the most common radiological feature, but these are not specific to pulmonary cryptococcosis. The sensitivity of culture of respiratory samples for Cryptococcus is poor and a positive result may also reflect colonisation. Cryptococcal antigen (CrAg) with lateral flow device is a fast and sensitive test and widely used on serum and cerebrospinal fluid, but sera from patients with pulmonary cryptococcosis are rarely positive in the absence of disseminated disease. Detection of CrAg from respiratory specimens might assist the diagnosis of pulmonary cryptococcosis but there are very few data. Molecular detection techniques such as multiplex reverse transcription polymerase chain reaction (RT-PCR) could also provide better sensitivity but these still require validation for respiratory specimens. The first line of treatment for pulmonary cryptococcosis is fluconazole, or amphotericin B and flucytosine for those with central nervous system involvement. Pulmonary cryptococcosis worsens the prognosis of cryptococcal meningitis. In this review, we summarize the biological aspects of Cryptococcus and provide an update on the diagnosis and management of pulmonary cryptococcosis.

Serum cryptococcal antigen titre as a diagnostic tool and a predictor of mortality in HIV-infected patients with cryptococcal meningitis.

The aim was to determine the effectiveness of the serum cryptococcal antigen (CrAg) test in the diagnosis of concurrent cryptococcal meningitis (CM) and as a predictor of mortality in HIV-infected patients. In this retrospective study, all HIV-infected patients admitted to Shanghai Public Health Clinical Center from 1 January 2014 to 31 August 2016 were screened for serum CrAg using the latex agglutination test. Serum CrAg-positive patients underwent lumbar puncture to confirm CM prior to the initiation of appropriate antifungal therapy and were followed up for at least 6months. One hundred and four (7.1%) of the total of 1474 HIV-infected patients screened were serum CrAg-positive. CM was diagnosed in the majority of serum CrAg-positive patients (71.3%; 67 of 94) and was confirmed in all (46 of 46) of the patients with headache or coma and in 43.8% (21 of 48) of patients without neurological symptoms. CrAg titres ≥1:1024 showed a sensitivity of 82.5% and a specificity of 86.7% for the diagnosis of concurrent CM (P<0.001). The positive predictive value for CM in this population was 94.3%. A total of 13 serum CrAg-positive patients [13.8%; 95% confidence interval (CI) 7.5-22.4%] died (11 as a result of CM and two others as a result of bacterial pneumonia) despite early antifungal treatment initiation. Serum CrAg titres ≥1:1024 predicted all-cause mortality (hazard ratio3.69; P=0.03). Serum CrAg titres ≥1:1024 not only were associated with concurrent CM but also predicted mortality. HIV-infected patients with a positive serum CrAg test during screening should receive lumbar punctures regardless of symptoms to rule out CM and patients with serum CrAg titres ≥1:1024 should be offered immediate care.

District and sub-district analysis of cryptococcal antigenaemia prevalence and specimen positivity in KwaZulu-Natal, South Africa.

BackgroundCryptococcal meningitis (CM) is a leading cause of mortality among HIV-positive South Africans. Reflex cryptococcal antigen (CrAg) testing of remnant plasma was offered as a pilot prior to implementation in October 2016 in KwaZulu-Natal province. The national reflex CrAg positivity was 5.4% compared to 7.3% for KwaZulu-Natal.ObjectivesThe aim of this study was to interrogate CrAg positivity by health levels to identify hotspots.MethodData for the period October 2016 to June 2017 were analysed. Health district CrAg positivity and prevalence were calculated, with the latter using de-duplicated patient data. The district CrAg positivity and the number of CrAg-positive specimens per health facility were mapped using ArcGIS. For districts with the highest CrAg positivity, a sub-district CrAg positivity analysis was conducted.ResultsThe provincial CrAg positivity was 7.6%. District CrAg positivity ranged from 5.7% (Ugu) to 9.6% (Umkhanyakude) with prevalence ranging from 5.5% (Ugu) to 9.7% (Umkhanyakude). The highest CrAg positivity was reported for the Umkhanyakude (9.6%) and King Cetswayo (9.5%) districts. In these two districts, CrAg positivity of 10% was noted in the Umhlabuyalingana (10.0%), Jozini (10.2%), uMhlathuze (10.5%) and Nkandla (10.8%) subdistricts. In these subdistricts, 135 CrAg-positive samples were reported for the Ngwelezane hospital followed by 41 and 43 at the Hlabisa and Manguzi hospitals respectively.ConclusionCryptococcal antigen positivity was not uniformly distributed at either the district or sub-district levels, with identified facility hotspots in the Umkhanyakude and King Cetswayo districts. This study demonstrates the value of laboratory data to identify hotspots for planning programmatic interventions.

Cryptococcal antigenemia and associated risk factors among ART‐naïve and ART‐experienced HIV‐infected peoples at selected health institutions of Mekelle, Northern Ethiopia

Cryptococcal infection is a major cause of opportunistic infection in HIV/AID‐infected peoples. We determined cryptococcal antigenemia and cryptococcal meningitis among antiretroviral therapy (ART) initiated and ART‐naive HIV‐infected peoples. A cross‐sectional study was conducted at selected health facilities in Mekelle, Ethiopia. Blood was collected to determine CD4 and plasma cryptococcal antigen (CrAg). CSF CrAg and CSF culture and urease tests were also done. Socio‐demographic and clinical data were collected using a structured questionnaire and clinical chart review. From the enrolled study participants, 267 study participants had complete data, of which, 137 (51%) were females. From the study participants, 140 (52%) and 127 (48%) were ART experienced and ART naïve, respectively. The prevalence of cryptococcal antigenemia was 9 (3.4%). All the study participants, except one (CD4 = 120 cells/mm3), had CD4 count less than 100 cells/mm3. From CrAg‐positive peoples, 6 (4.7%) were ART naïve. Five CrAg‐positive peoples had cryptococcal meningitis. Being male, rural residence, and being hospitalized were associated with cryptococcal antigenemia. Cryptococcal infection poses a substantial risk of HIV‐positive peoples. This study provides relevant data for CrAg screening interventions in patients with low CD4 cell counts.

CRYPTOCOCCAL PERICARDITIS IN THE HAART ERA

SESSION TITLE: Chest Infections 3 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Cryptococcus neoformans is an opportunistic fungal pathogen most frequently encountered in the Human immunodeficiency virus (HIV) infected host. However, due to advances in anti-retroviral therapy, HIV is no longer the most common predisposing factor for cryptococcal infections.1 Cryptococcus mainly affects the central nervous system, but cardiac manifestations like endocarditis, myocarditis, and rarely pericarditis, have been reported. CASE PRESENTATION: A 79 year old farmer presented with a non-productive cough, dyspnea and sore throat. His past medical history was significant for Crohn’s disease, hepatocellular carcinoma and cirrhosis secondary to untreated Hepatitis C and chronic kidney disease. He was initially treated with azithromycin for presumed bronchitis but subsequently admitted for progressive dyspnea. On examination, he had a pericardial rub and a holosystolic murmur over the left sternal border with basal crackles. In addition, pulsus paradoxus was appreciated with 20 mm Hg variation. EKG revealed atrial flutter with variable heart block. Laboratory workup showed pancytopenia and negative HIV antigen/antibody. The echocardiogram revealed large circumferential pericardial effusion, measuring 3.26 cm at its largest dimension with pre-tamponade physiology. Emergent pericardiocenthesis was performed with removal of one liter of fluid. Cryptococcal antigen was negative, but culture returned positive for Cryptococcus Neoformans. The patient was started on fluconazole 400 mg daily with good clinical response. A repeat echocardiogram in 2 weeks showed resolution of effusion and pre-tamponade physiology and normalization of ejection fraction. His pulmonary symptoms resolved, and he was discharged with close follow-up. DISCUSSION: Cryptococcal pericarditis in an uncommonly reported entity; prognosis and optimal treatment is therefore uncertain. Under-recognition of cryptococcal pericarditis may lead to significant morbidity and mortality, specially in those who are HIV negative. Comorbidities such as malignancy and end-stage liver disease (ESLD) should be considered important risk factors as well. In fact, Cryptococcal infections in patients with ESLD has been associated with higher mortality rates, even when compared to that of HIV-positive patients and HIV-negative patients without ESLD2. One rationale for this is liver’s role in clearing cytokines, bacteria, and endotoxins from the circulation.3 Furthermore, Cryptococcal antigen has been considered to be highly sensitive, but if negative and clinical suspicion is high, complementary cultures and histopathological examination should be pursued as well. CONCLUSIONS: Cryptococcosis is a globally distributed infection, affecting mainly immunocompromised hosts including those with ESLD, HIV and malignancy. In comparison to central nervous system, cardiovascular involvement including pericardial effusion and tamponade is rarely reported. Reference #1: Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33(5):690–9 Reference #2: Spec A, Raval K, Powderly WG. End-Stage Liver Disease Is a Strong Predictor of Early Mortality in Cryptococcosis. Open Forum Infect Dis. 2015 Dec 15;3(1):ofv197. Reference #3: Bonnel AR, Bunchorntavakul C, Reddy KR. Immune dysfunction and infections in patients with cirrhosis. Clin Gastroenterol Hepatol. 2011 Sep;9(9):727-38. DISCLOSURES: No relevant relationships by Kamran Manzoor, source=Web Response No relevant relationships by Amanda Noska, source=Web Response No relevant relationships by Paulette Pinargote Cornejo, source=Web Response No relevant relationships by Wilmer Salazar Morales, source=Web Response

A UNIQUE PRESENTATION OF EOSINOPHILIC GRANULOMA IN THE LUNG

SESSION TITLE: Diffuse Lung Disease 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Langerhans Cell Histiocytosis is characterized by granuloma formation in various organs. Pulmonary Langerhans Cell Histiocytosis (PLCH) is a more localized, rare disease. We present a case of a rapidly progressive interstitial lung disease. CASE PRESENTATION: A 58-year-old female, active smoker, with a history of chronic obstructive pulmonary disease (COPD) was referred to the pulmonology clinic for an incidental finding of lung nodules on chest imaging. She presented with upper respiratory tract symptoms to an urgent care center where a chest X-ray was done and showed pulmonary nodules. A CT of the chest then revealed multiple bilateral pulmonary nodules in the upper and middle lung zones, with the largest nodule measuring 12 x 10 mm without associated lymphadenopathy. Of note, these nodules were absent on CT imaging three months prior. She denied dyspnea, cough, fever, night sweats, weight loss, recent travel, exposure to tuberculosis, birds or chemicals. Vital signs and physical exam were unremarkable. Antinuclear antibodies, Cryptococcal antigen and Fungitell assay were negative. Position Emission Tomography was done and showed mild tracer uptake in the largest nodule (left lower lobe). An Interventional Radiology guided biopsy was done and histopathology showed bronchoalveolar tissue infiltrated with Langerhans cells and eosinophils. These Langerhans cells were highlighted by immunohistochemical stains of CD1a and S100, consistent with histiocytosis. She was advised to stop smoking with close follow up. DISCUSSION: Pulmonary Langerhans Cell Histiocytosis (PLCH) is rare and at least 90% of PLCH patients are active smokers [1].PLCH may present with pulmonary symptoms such as dyspnea or non-productive cough; extra-pulmonary manifestations such as bone pain, rash, diabetes insipidus, lymphadenopathy, and weight loss; or patients can be asymptomatic as seen in this case [3]. Diagnosis is by findings on high-resolution CT imaging, and biopsy proven histology with positive immunohistochemical staining for CD1a and S100.PLCH typically affects upper and middle lung zones with sparing of the costophrenic angles and the progression is insidious. However, it was interesting that this patient’s nodules involved bilateral lower lobes and progressed rapidly in size and number over a short interval of three-months.Treatment is individualized as little is known about the pathophysiology of the disease. Data on other treatment modalities is controversial; however smoking cessation has been shown to improve outcomes [2]. CONCLUSIONS: PLCH in elderly smokers may be mistaken for metastatic lung disease. Definitive diagnosis is by histopathology. Therefore, it is important to keep PLCH in the differential diagnosis in patients with diffuse pulmonary nodules, especially because it can be reversed with smoking cessation. Also, missing the diagnosis and delays in treatment can lead to lung fibrosis. Reference #1: Elia D, Torre O, Cassandro R, Caminati A, Harari S. Pulmonary Langerhans Cell Histiocytosis: A comprehensive analysis of 40 patients and literature review. Eur J Intern Med. 2015;26(5):351-356. Reference #2: Wolters PJ, Elicker BM. Subacute onset of Pulmonary Langerhans Cell Histiocytosis with resolution after smoking cessation. Am J Respir Crit Care Med. 2014;190(11):e64. Reference #3: Juvet SC, Hwang D, Downey GP. Rare lung diseases III: Pulmonary Langerhans Cell Histiocytosis. Can Respir J. 2010;17(3):e55-62. DISCLOSURES: No relevant relationships by Gunjan Gupta, source=Web Response no disclosure on file for Lirim Krveshi; No relevant relationships by QUOC NGUYEN, source=Web Response No relevant relationships by Rahila Ogunnaike, source=Web Response No relevant relationships by Aashutosh Ramakar, source=Web Response no disclosure on file for Sakshi Sethi

PULMONARY CRYPTOCOCCOSIS MASQUERADING AS LYMPHOMA

SESSION TITLE: Pulmonary SESSION TYPE: Global Case Reports PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM INTRODUCTION: Pulmonary cryptococcosis (PC) is an uncommonly diagnosed disorder. We describe a unique case of PC presenting as lymphadenopathy, diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) technique. CASE PRESENTATION: 58-year-old, never smoker, male with follicular lymphoma (status post completion of 6 cycles of R-CHOP (Rituximab, Cyclophosphamide, Vincristine, Doxorubicin)) was referred to for evaluation of new positron emission tomography/computed tomography (PET/CT) avid right hilar adenopathy, and left upper lobe nodular opacity. His review of systems was positive for mild shortness of breath on exertion; and an unremarkable physical exam. Laboratory studies were significant for lactate dehydrogenase level of 283, and no preceding neutropenia or lymphopenia. Significant interval history included hemophillus influenza pneumoni Patient underwent a EBUS-TBNA of the right hilar lymph node. Cytology was negative for malignant cells but showed intracellular yeast in histiocytes; the tissue culture was positive for Cryptococcus neoformans. Patient was started on fluconazole and CT of the chest done 2 months after treatment initiation, showed no evidence of hilar lymphadenopathy. DISCUSSION: PC is an uncommonly diagnosed disorder and seen in less than 4% of patients diagnosed with cryptococcosis. Common predisposing factors include AIDS, chronic corticosteroid use, and solid organ-transplants. Most common radiographic presentation is single or multiple, small, peripherally distributed, upper and middle lung zone predominant, pulmonary nodules and bilateral airspace consolidation. In studies by Li-Xuan et al and Chang et al, radiographic presentation of PC was compared amongst immunocompromised and immunocompetent host, pulmonary nodules were the most common finding and associated cavitation were more frequently seen in immunocompromised patients. In a study done by Lacomis et al, patients with HIV, solid organ transplant and non-HIV, non-solid organ transplants were looked at; lymph node enlargement was uncommon in all the groups but more commonly found in the HIV group and was always less than 1.5cm. SCrAg is positive in 71% of patients with disseminated disease; however only positive in 21% of patients with pulmonary disease alone. Cultures grown from biologic samples is the Gold standard test for diagnosis of cryptococosis9. In 2016, Schmalzle et al11, looked at 583 patients with malignancy with culture results positive for cryptococcus and found that 83% of patients had hematologic malignancy. Pulmonary disease was also more commonly seen in patients with hematologic malignancies and in these case cryptococcal antigen was negative in majority of the patients. CONCLUSIONS: Cryptococcal lymphadenitis should be considered in the differential diagnosis in an immunocompromised patient presenting with lymphadenopathy despite a negative serum cryptococcal antigen. Reference #1: Chang, Wei-Chou et al. “Pulmonary Cryptococcosis.” CHEST , Volume 129 , Issue 2 , 333 – 340. Reference #2: Chichra A, Lama KW, Koenig SJ. Respiratory failure with hilar mass: Role of endobronchial ultrasound-guided transbronchial needle aspiration in the medical intensive care unit. Lung India : Official Organ of Indian Chest Society. 2015;32(2):178-181. Reference #3: Li-Xuan, Xie. “Pulmonary Cryptococcosis: Comparison of Clinical and Radiographic Characteristics in Immunocompetent and Immunocompromised Patients.” Chest, Elsevier, 23 Dec. 2015. DISCLOSURES: No relevant relationships by Robert Lee, source=Web Response No relevant relationships by Priyanka Makkar, source=Web Response No relevant relationships by Carlie Sigel, source=Web Response No relevant relationships by Jonathan Vaucher, source=Web Response

Disseminated Adenovirus Infection in an Adult Orthotopic Liver Transplant Recipient

Adenovirus infections in liver transplant patients are important cause or morbidity and mortality. Our understanding of the adenovirus pathogenesis and management approach are limited. We present a rare case of self resolving disseminated adenovirus infection in a liver transplant recipient. A 60-year-old male with a history of orthotopic liver transplant 2010 for alcoholic cirrhosis and RNY hepaticojejunostomy 2011 for anastomotic stricture on cyclosporine 175 mg daily presented with fatigue, severe headache, bilateral eye pain with redness and light sensitivity for 3 weeks and fevers up to 104 F for one week. On examination left eye was swollen shut and painful to touch with minor dried blood on outside. Laboratory findings on admission were notable for ALP of 514, AST/ALT 206/237, total bilirubin 1.2, lipase 1674, amylase 201, APAP level < 2.0. Routine blood and urine cultures, serum CMV PCR, and serum cryptococcal antigen were negative. Nasopharyngeal respiratory virus panel was positive for adenovirus PCR but CXR did not show pneumonitis. Serum adenovirus PCR was strongly positive at 347014 copies/ml. Ophthalmology recommended supportive care for his acute hemorrhagic conjunctivitis likely from adenovirus. MRCP was performed and ruled out choledocholithiasis, biliary dilation, biloma or abscess of transplant liver. Since the patient did not have abdominal symptoms and his conjunctivitis improved, it was decided to manage the patient conservatively without using potentially toxic cidofovir. He was discharged 3 days later. Follow up serum adenovirus PCR showed decreasing viral load. Disseminated adenovirus infection is defined as documented disease in >= end organs and viremia is present in most but not all patients. Manifestations include hepatitis, pneumonia, pancreatitis, enterocolitis, hemorrhagic cystitis and nephritis. A high degree of clinical suspicion should be maintained for prompt diagnosis as standard diagnostic tests like blood and urine cultures do not yield adenovirus. Positive PCR (in serum or other body fluids or tissue) may suggest invasive disease in the appropriate context. Serial quantitative serum viral load is used for preemptive treatment in high risk allogeneic hematopoetic cell transplant recipients and also acts as a surrogate for clinical response to therapy. We believe that our patient probably had tissue invasive hepatitis, pancreatitis and conjunctivitis with an upper respiratory infection (without pneumonitis) along with significant adenoviremia. Interestingly, despite disseminated tissue invasive disease, the patient recovered without specific adenoviral therapy. There is no well-defined treatment for adenovirus infection. Management from limited clinical information for disseminated infections supports use of cidofovir. Unfortunately it is fraught with nephrotoxicity. A novel lipid formulation of cidofovir (brincidofovir) offers some hope as it seems to be kidney friendly. There are no good data on ribavirin and immunoglobulins, but adenovirus specific T cell therapy has occasionally been used successfully in recalcitrant disease. Our case illustrates that although disseminated adenovirus infection can be life threatening and has limited effective treatment options, it can occasionally resolve spontaneously.

A CASE OF LARGE MEDIASTINAL MASS SECONDARY TO HISTOPLASMOSIS

SESSION TITLE: Chest Infections 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: The differential diagnosis for anterior mediastinal masses classically includes lymphomas and neoplasms of thymus, thyroid, and germ cell origins. Mycotic etiologies such as Histoplasma capsulatum are rare in immunocompetent populations. The following is a pediatric case of a large anterior mediastinal mass secondary to histoplasmosis in an immunocompetent patient. CASE PRESENTATION: A 7-year-old boy with a past medical history of asthma was transferred to the pediatric hematology/oncology service from an outside hospital for evaluation of a paratracheal mass incidentally noted on chest radiograph after presenting with vague abdominal pain, weight loss, and a fever of 38°C.Chest CT revealed calcified pulmonary nodules in the right upper lobe and a 3.1 x 2.7 x 3.7 cm mass with areas of calcification at the confluence of the brachiocephalic veins. Initial workup was targeted towards lymphoma and germ cell neoplasm, but mycotic etiologies were also screened for with serum Cryptococcus antigen and Histoplasma antibody titers that were weakly positive at 1:20 and 1:32 respectively. An M band was present for Histoplasma. The patient had no recent travel to endemic areas, exposure to soil with bird or bat guano, or history of recurrent infections.The mass’s location was not amenable to minimally invasive biopsy. Consequently, pediatric surgery performed a thoracotomy with excisional biopsy of the mass and a right upper lobe wedge resection of the lung nodules. The mass was noted to have caseous drainage upon removal, and intraoperative frozen sections were not concerning for malignancy. Final pathology of the mass and pulmonary nodules revealed lymph node and lung tissue respectively with necrotizing granulomatous inflammation and fungal yeast forms. The fungal stains were compatible with H. capsulatum. Repeat serum Cryptococcus antigen and fungal cultures were negative. He was started on long-term oral itraconazole for 12 weeks. Other than intermittent low fevers, the remainder of hospital course was uneventful. DISCUSSION: H. capsulatum is endemic to the Mississippi, Missouri, and Ohio river valleys and is also commonly found in other temperate climates around the world. The dimorphic fungus preferably grows in soil containing bird or bat guano. Disruption of the soil can lead to inhalation of the mold form’s conidia. An overwhelming majority of pulmonary infections are entirely asymptomatic in immunocompetent patients although <1% of those affected can develop fever, malaise, headache, fatigue, and dry cough which are typically self-limiting. Rarely, as with this case, granulomatous mediastinitis can occur where mediastinal lymph nodes undergo massive enlargement and caseous necrosis. CONCLUSIONS: This process is insidious and the mass can be confused for more common etiologies such as lymphoma in pediatric patients, so it is important to consider mycotic etiologies even in non-endemic areas. Reference #1: Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007 Jan;20(1):115-32. Reference #2: Shersher DD, Hong E, Breard J, Warren WH, Liptay MJ. Anterior mediastinal mass secondary to histoplasmosis. Ann Thorac Surg. 2012 Jan;93(1):e9-10. DISCLOSURES: No relevant relationships by Narayana Gowda, source=Web Response no disclosure on file for Supriya Gupta; No relevant relationships by jayanth keshavamurthy, source=Web Response No relevant relationships by Daniel Kleven, source=Admin input No relevant relationships by Ivan Morales, source=Web Response no disclosure on file for Gilberto Sostre

Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis.

Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ≥5 white cells/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. NCT01802385.

Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings. We compared two cohorts before (2008-2010) and after (2012-2013) policy change on ART timing after TB and examined the effectiveness of early versus delayed ART on mortality in HIV-TB co-infected participants with CD4 cell count 100 cells/μl or less. We used inverse probability censoring-weighted Cox models on baseline characteristics to balance the study arms and generated hazard ratios for mortality. Of 356 participants with CD4 cell counts 100 cells/μl or less, 180 were in the delayed ART cohorts whereas 176 were in the early ART cohorts. Their median age (32.5 versus 32 years) and baseline CD4 cell counts (26.5 versus 26 cells/μl) respectively were similar. There was no difference in mortality rates of both cohorts. The risk of death increased in participants with a positive Cryptococcal antigen (CrAg) test in both the early ART cohort (aHR = 2.6, 95% CI 1.0-6.8; P = 0.045) and the delayed ART cohort (aHR = 4.2, 95% CI 1.9-9.0; P < 0.001 CONCLUSION:: Early ART in patients with HIV-TB co-infection was not associated with reduced risk of mortality in routine care. Asymptomatic Cryptococcal antigenaemia increased the risk of mortality in both cohorts.

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.

Cryptococcal antigen screening cost effective in Uganda

Cryptococcal antigen screening cost effective in Uganda

Cryptococcal meningitis in an immunocompetent patient with obstructive hydrocephalus: A case report

BackgroundCryptococcal infections of the central nervous system are very rare in immunocompetent patients. They usually present as meningitis or as fungal cysts with or without hydrocephalus. Rapid diagnosis and treatment is crucial to the prognosis. Case reportWe report the case of an immunocompetent 40-year-old male patient with no medical or surgical history and no recent travel, who was hospitalized in our neurosurgery department because of a rapidly worsening headache. The neurological examination revealed no focal deficit but worrying signs of increased intracranial pressure. Magnetic resonance imaging (MRI) with contrast showed thick and large-scale cortico-pial cerebellar enhancements, associated with severe obstructive hydrocephalus. This required emergency endoscopic ventriculocisternostomy during which we observed cottony tissues along the ventricular walls. Biopsied tissues and cerebrospinal fluid samples (CSF) were not contributive. A CT scan of the chest and abdomen and blood markers of common primary tumors were all negative. No evidence of HIV infection or any cause of immunosuppression was identified. Symptoms and a second MRI slightly improved with intravenous corticosteroid therapy. The hypothesis of a lymphoma or granulomatous disease was made initially for which direct surgical biopsies were scheduled. The diagnosis of cryptococcal meningitis was obtained later on by simultaneous plasma and CSF Cryptococcus antigen detection. Cryptococcus neoformans (formerly C. neoformans var. grubii [serotype A]) was then identified by PCR. Clinical improvement was obtained with antifungal therapy. ConclusionCryptococcal meningitis is a well-known condition in immunocompromised patients, often causing hydrocephalus requiring neurosurgical management. The diagnosis is more difficult in patients with no history of HIV or organ transplant. Neurologists and neurosurgeons must consider this possibility in case of diffuse, thick leptomeningeal enhancement on MRI.

Correlation between serum cryptococcal antigen titre and meningitis in immunocompetent patients.

The aim of this paper was to determine the correlation between serum cryptococcal antigen and a diagnosis of cryptococcal meningitis in the immunocompetent cohort. A retrospective multicentre analysis of immunocompetent patients diagnosed and treated for cryptococcal meningitis between January 2000 and December 2017 was performed. Sixty-seven of the 143 cases of cryptococcosis occurred in immunocompetent patients. The serum cryptococcal antigen titre was significantly higher in the meningitis group [1 : 256 (IQR: 64-1024)] compared with that for non-meningitis patients [1 : 64 (IQR: 8-256)], P=0.012. The relative risk of meningitis with a serum cryptococcal antigen (CRAG) >1 : 64 was 1.8 (95 % CI: 1.15-2.82). This study demonstrates a clear correlation between serum cryptococcal antigen titre and meningitis. While the serum titre is not definitive for meningitis, in resource-limited settings or cases where lumbar puncture may be contraindicated, this evidence may aid diagnosis and subsequent therapeutic decisions.

Brief Report: Point of Care Cryptococcal Antigen Screening: Pipetting Finger-Prick Blood Improves Performance of Immunomycologics Lateral Flow Assay.

Cryptococcal antigen (CrAg) screening at the point of care could improve cryptococcal meningitis prevention where laboratory resources are limited. We evaluated the accuracy of Immunomycologics (IMMY, Norman, OK) CrAg lateral flow assay (LFA) using different techniques at point of care. Two tertiary-level hospitals in Johannesburg and a community health clinic in Soweto, South Africa. A case-control diagnostic validation study and a prospective clinic-based implementation study using the IMMY CrAg LFA on finger-prick blood. Accuracy, using direct application of LFA to sample, or pipette to transfer sample to diluent, and reading after 10 and 20 minutes, was compared with laboratory-based plasma testing. The validation study tested 64 CrAg-positive and 152 CrAg-negative patients with no symptoms or signs of meningitis, identified by routine laboratory screening, recruited by convenience sampling. Consecutively diagnosed HIV-infected adults (n = 654) were included in the implementation study. Sensitivity was 82% and 20% when the LFA was read 10 minutes after direct application to finger-prick blood in the validation and implementation studies, respectively. Using a pipette to transfer blood and reading after 20 minutes improved sensitivity to 100%, while retaining 100% specificity, in both studies. Although the IMMY CrAg LFA performs well when applied directly to finger-prick blood for diagnosing cryptococcal meningitis, this technique may not provide adequate volume to detect low concentrations of CrAg when screening asymptomatic patients. Using a pipette to transfer larger volumes of blood to diluent before CrAg LFA testing and reading results after 20 minutes is a more reliable point-of-care method.

Screening for cryptococcal antigenemia and analyzsis of the related cryptococcal lesions in hospitalized human immunodeficiency virus infected patients

Objective To evaluate the prevalence of cryptococcal antigenemia and explore the related cryptococcal lesions in hospitalized human immunodeficiency virus (HIV)-infected patients. Methods Medical records of 517 HIV-infected patients, including patients' age, sex, clinical features, previous medical history, laboratory tests, chest CT, treatment and the response to treatment, in the Second Hospital of the Nanjing between January 2016 and February 2018 were retrospectively analyzed. The serum cryptococcal antigen (sCrAg) was detected by lateral flow immunoassay. The χ2 test or Fisher exact test was used to perform the statistical analysis. Results Among 517 HIV-infected cases, 51 were sCrAg positive, of whom 96.1% (49 cases) were men. The cases with CD4+ T lymphocyte count <100×106 cells/L accounted for 66.2% (342 cases), while 90.2% (46 cases) in sCrAg-positive patients showed CD4+ T lymphocyte count <100×106 cells/L with statistical significance (χ2=14.6, P<0.01). Multivariable analysis revealed that CD4+ T lymphocyte count <100 ×106 cells/L was independent risk factor for cryptococcal antigenemia (OR=4.7; 95%CI: 1.8-12.5, P<0.01). Clinical cryptococcal diseases were found in 76.4% (39/51) of patients with cryptococcal antigenemia, and cryptococcal meningitis (CM), pulmonary cyptococcosis (PC) and cryptococcal septicemia were found in 56% (28/50), 52.9% (27/51) and 44.4% (16/36) of the patients, respectively. Cryptoccal disease was not identified in 21.6% (11/51) of the patients with cryptococcal antigenemia (isolated cryptococcal antigenemia). The median (range) sCrAg titers of the patients with and without CM were 1∶1 280 (1∶10-1∶2 560) and 1: 15 (1∶2-1∶2 560), respectively (P<0.01). The proportion of CM in patients with sCrAg titers ≤1∶5, 1∶10-1∶320 and ≥1∶640 were 0 (0/10), 50% (10/20) and 90% (18/20), respectively. When cryptococcal infection was restricted to the lung, 87.5% (7/8) of the patients had sCrAg titers ≤1∶20. 30% (3/10) of the patients with sCrAg titers ≤1∶5 had PC. The median (range) sCrAg titers of the patients with cryptococcal septicemia and with isolated cryptococcal antigenemia were 1∶1 280 (1∶10-1∶2 560) and 1∶5 (1∶2-1∶320), respectively. Conclusions The prevalence of cryptococcal antigenmia is high in hospitalized HIV-infected patients. Most patients with cryptococcal antigenemia have developed cryptococcal diseases. The sCrAg titer in HIV patients may, in some extend, predicts the condition of cryptococcal infection. sCrAg titers ≥1∶640 are strongly suggestive of CM. Patients with sCrAg titers ≤1∶5 seems unlikely to have CM or cryptococcal septicemia, however, clinician should still be alarmed of possible PC. Key words: HIV; Meningitis, cryptococcal; Cryptococcal antigenemia; Pulmonary cryptococcosis; Cryptococcal septicemia

CLINICAL-EPIDEMIOLOGICAL CHARACTERISTIC OF AIDS-ASSOCIATED CRYPTOCOCCOSIS: DIAGNOSTICS AND THERAPEUTIC ASPECTS OF THE PROBLEM

Introduction Currently, cryptococcosis is among the three most life-threatening opportunistic infections in AIDS patients. Materials and methods. The analysis of cases of cryptococcosis in HIV-infected patients in the world, the Russian Federation and the Chelyabinsk region using the methods of descriptive and analytical epidemiology. Two clinical cases of verified cryptococcosis were analyzed in detail in patients in the phase of HIV infection progression in the absence of antiretroviral therapy. Results. The manifestation of the disease was observed in the phase of progression of HIV infection in the absence of antiretroviral therapy with low immune status of patients (CD4 + lymphocyte level less than 100 cells in 1 μl of blood). The diagnosis is verified on the basis of a complex of clinical, instrumental, biochemical, immunological and mycological methods. Successful courses of treatment with antifungal drugs: amphotericin B, itraconazole, fluconazole. Conclusions. The definition of cryptococcal antigen is not a method for evaluating the effectiveness of treatment due to its long-term persistence in CSF and serum, even with successful treatment. Prescribing antiretroviral therapy significantly increases the effectiveness of cryptococcosis treatment. In AIDS patients, antifungal therapy is stopped only after effective for 3-6 months ART (the number of CD4 + lymphocytes in the blood is more than 100-200 cells/μl).