Endemic Histoplasmosis Research Articles

Improving Lung Cancer Diagnosis with CT Radiomics and Serum Histoplasmosis Testing.

Indeterminate pulmonary nodules (IPN) are a diagnostic challenge in regions where pulmonary fungal disease and smoking prevalence are high. We aimed to determine the impact of a combined fungal and imaging biomarker approach compared with a validated prediction model (Mayo) to rule out benign disease and diagnose lung cancer. Adults ages 40 to 90 years with 6-30 mm IPNs were included from four sites. Serum samples were tested for histoplasmosis IgG and IgM antibodies by enzyme immunoassay and a CT-based risk score was estimated from a validated radiomic model. Multivariable logistic regression models including Mayo score, radiomics score, and IgG and IgM histoplasmosis antibody levels were estimated. The areas under the ROC curves (AUC) of the models were compared among themselves and to Mayo. Bias-corrected clinical net reclassification index (cNRI) was estimated to assess clinical reclassification using a combined biomarker model. We included 327 patients; 157 from histoplasmosis-endemic regions. The combined biomarker model including radiomics, histoplasmosis serology, and Mayo score demonstrated improved diagnostic accuracy when endemic histoplasmosis was accounted for [AUC, 0.84; 95% confidence interval (CI), 0.79-0.88; P < 0.0001 compared with 0.73; 95% CI, 0.67-0.78 for Mayo]. The combined model demonstrated improved reclassification with cNRI of 0.18 among malignant nodules. Fungal and imaging biomarkers may improve diagnostic accuracy and meaningfully reclassify IPNs. The endemic prevalence of histoplasmosis and cancer impact model performance when using disease related biomarkers. Integrating a combined biomarker approach into the diagnostic algorithm of IPNs could decrease time to diagnosis.

A Structured Program Maximizes Benefit of Lung Cancer Screening in an Area of Endemic Histoplasmosis

BackgroundLung cancer screening with low-dose computed tomography has demonstrated at least a 20% decrease in lung cancer–specific mortality, but it has the potential harm of unnecessary invasive procedures performed because of false-positive results. This study reports the outcomes of a structured multidisciplinary lung cancer screening program in an area of endemic histoplasmosis. MethodsA retrospective review of patients undergoing lung cancer screening from December 2012 to March 2019 was conducted. Findings suggestive of lung cancer were presented to a multidisciplinary thoracic tumor board. Patients were assigned to interval imaging follow-up, additional diagnostic imaging, or referral for an invasive procedure. Invasive procedures were then compared between benign and malignant diseases. ResultsA total of 4087 scans were performed on 2129 patients; 372 (9.1%) were suspicious and were presented to a multidisciplinary thoracic tumor board. Ultimately, 108 procedures were performed: 55 bronchoscopies, 7 percutaneous biopsies, and 46 operations. A total of 25 patients (1.2%) underwent bronchoscopy resulting in benign pathologic findings, significantly associated with an indication of an endobronchial lesion (P = .01). All percutaneous biopsy specimens revealed malignancy. Five patients (0.2%) who underwent resection had benign disease. Lung cancer was diagnosed in 67 patients (3.1% of the entire cohort), 46 of whom had stage I or II disease. ConclusionsLung cancer screening in a structured, multidisciplinary program successfully identifies patients with early-stage lung cancer with limited unnecessary surgical interventions. Patients with isolated endobronchial lesions should undergo short interval imaging follow-up to avoid bronchoscopy for benign disease. Future studies to minimize unnecessary procedures could incorporate biomarkers and advanced imaging analysis into risk assessment models.

Validation of Histoplasmosis Enzyme Immunoassay to Evaluate Suspicious Lung Nodules

Granulomas caused by infectious lung diseases can present as indeterminate pulmonary nodules (IPN). This study aims to validate an enzyme immunoassay (EIA) for Histoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) for diagnosing benign IPN in areas with endemic histoplasmosis. Prospectively collected serum samples from patients at Vanderbilt University Medical Center (VUMC [n= 204]), University of Pittsburgh Medical Center (n= 71), and University of Cincinnati (n= 51) with IPN measuring 6 to 30 mm were analyzed for Histoplasma IgG and IgM with EIA. Diagnostic test characteristics were compared with results from the VUMC pilot cohort (n= 127). A multivariable logistic regression model was developed to predict granuloma in IPN. Cancer prevalence varied by cohort: VUMC pilot 60%, VUMC validation 65%, University of Pittsburgh Medical Center 35%, and University of Cincinnati 75%. Across all cohorts, 19% of patients had positive IgG titers, 5% had positive IgM, and 3% had positive both IgG and IgM. Of patients with benign disease, 33% were positive for at least one antibody. All patients positive for both IgG and IgM antibodies at acute infection levels had benign disease (n= 13), with a positive predictive value of 100%. The prediction model for granuloma in IPN demonstrated an area under the receiver-operating characteristics curve of 0.84 and Brier score of 0.10. This study confirmed that Histoplasma EIA testing can be useful for diagnosing benign IPN in areas with endemic histoplasmosis in a population at high risk for lung cancer. Integrating Histoplasma EIA testing into the current diagnostic algorithm where histoplasmosis is endemic could improve management of IPN and potentially decrease unnecessary invasive biopsies.

DIAGNOSTIC ACCURACY OF FDG-PET/CT FOR PULMONARY NODULES IN THE SETTING OF ENDEMIC HISTOPLASMOSIS IN SOUTHWEST OHIO

SESSION TITLE: Wednesday Electronic Posters 1 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM PURPOSE: Lung cancer is the leading cause of cancer death in the United States, with a mortality higher than the next three cancers combined. Since the National Lung Screening Trial showed a mortality benefit with early screening, the increased number of pulmonary nodules detected have caused a concern for unnecessary biopsies for false positives findings. Suspicious pulmonary nodules with intermediate probability of lung cancer are commonly evaluated by positron emission tomography with 18-fluorodexoyglucose with CT (FDG-PET/CT) to help further delineate the likelihood of the nodule being malignant. A 2014 meta-analysis found the specificity of FDG-PET was lower in regions with endemic fungal infections while further studies from the upper Mississippi River Valley and the Ohio River Valley both found specificity of FDG-PET fell to 40% from 85% in non-endemic areas. METHODS: At our own academic institution in the heart of the Ohio River Valley, we retrospectively identified 175 patients who had undergone sampling of PET avid pulmonary nodules via bronchoscopy, transthoracic biopsy, or surgical biopsy. RESULTS: They had an average age of 64 years, with 52% being women, 64.6% Caucasian, 86.3% current and former smokers, and 40.6% having a prior history of cancer (18.3% previous lung cancer). The average size of these nodules were 30.5 mm with an average SUV of 6.72. Only 35.4% were solitary pulmonary nodules, with 45.7% having N0 disease per PET. Seventy-seven percent had a malignant diagnosis. Using a PET standardized update unit (SUV) of ≥2.5 as a cut off for predicting the possibility of a malignant lesion, the sensitivity was 89.63% (95% CI 83.21-94.21%), specificity 47.50% (95% CI 31.51%-63.87%), positive predictive value 85.21% (95% CI 81.01-88.61%), and a negative predictive value of 57.58% (95% CI 42.85%-71.07%). With a “non-diagnostic” prevalence of 18.9%, PET-CT as a tool for determining malignancy is only 80% (95% CI 73.30%-85.66%) accurate. Of the non-diagnostic lesions with an SUV ≥2.5, 23.8% had noncaseating granulomas, 19% reactive/inflammatory tissue, and 14.28% had an identifiable infection (ie Histoplasma, Aspergillus). These lesions had an average SUV of 5.1 and were around 19 mm on average. CONCLUSIONS: Our experience with false positive lung nodules at an academic center based in an area with endemic Histoplasmosis is consistent with other academic institutions along the Ohio River. CLINICAL IMPLICATIONS: It is our recommendation that lung cancer screening guidelines be modified in regions with endemic infections so as to prevent unnecessary procedures and reduce adverse events in those with false-positive lung nodules on PET-CT. DISCLOSURES: No relevant relationships by Yousef Ahmad, source=Web Response No relevant relationships by Arjan Flora, source=Web Response No relevant relationships by Miles Hagner, source=Web Response

Histoplasmosis and Tuberculosis Co-Occurrence in People with Advanced HIV.

Distinguishing between histoplasmosis, tuberculosis (TB), and co-occurrence of disease is a frequent dilemma for clinical staff treating people with advanced Human Immunodeficiency Virus (HIV) infection. This problem is most frequently observed in clinical settings in countries where both diseases are endemic. It is also a challenge outside these endemic countries in HIV clinics that take care of patients coming from countries with endemic histoplasmosis and TB. The gold standard for diagnosis of both of these diseases is based on conventional laboratory tests (culture, histopathology and special stains). These tests have several limitations, such as lack of laboratory infrastructure for handling isolates (biosafety level 3), shortage of laboratory staff who have appropriate training and experience, variable analytical performance of tests and long turn-around time. Recently, novel rapid assays for the diagnosis of histoplasmosis and TB became available. However, this technology is not yet widely used. Mortality in immunocompromised patients, such as people with advanced HIV, is directly linked with the ability to rapidly diagnose opportunistic diseases. The aim of this review is to synthesize the main aspects of epidemiology, clinical characteristics, diagnosis and treatment of histoplasmosis/TB co-occurrence in people with advanced HIV.

Performance of community-based lung cancer screening program in a region with a high rate of endemic histoplasmosis.

58 Background: Lung cancer screening (LCS) with Low dose computed-tomography (LDCT) has been recommended by USPSTF for high-risk population since 2013 largely based on 20% relative reduction in lung cancer mortality shown in National Lung Screening Trial (NLST). The success of NLST was related to its high adherence rate and thorough ascertainment of lung cancers and deaths. This study evaluated performance of lung cancer screening program in Histoplasmosis endemic community. Methods: Demographic and clinical information was collected through retrospective review on all patients in the lung cancer screening program of a Kentucky health system comprising 21 centers from 2016 and 2017. A positive LDCT screen is defined as Lung-RADS version 1.0 assessment categories 3 or 4. Results: A total of 4500 LDCT screens were performed in 2016 (39%) and 2017 (61%) with 49% adherence rate to repeat annual screen in 2017. Mean age of patients was 64 years, majority being females (54%) and current smokers (69%) with average 52-pack year smoking history. The rate of positive LDCT was 13.3% (600) varying based on initial (14.6%) vs annual (9.5%) screen. A total of 70 lung cancers were diagnosed among all positive LDCT screens (11.7%) with a false positive rate of 12%. Conclusions: Comparing to NLST results updated with Lung-RADS categories, baseline positive screens in our community are similar (14.6% vs 13.6%, p = 0.15) despite being a Histoplasmosis endemic region. Our higher rate of annual positive screens (9.5% vs 6%, p &lt; 0.001) and false positive rate (12% vs 8%, p &lt; 0.001) may be explained by poor adherence to annual screens and an inability to thoroughly ascertain lung cancer diagnosis in all patients due to lost to follow up. In community setting with &lt; 50% adherence to annual screens compared to 95% adherence in NLST, it is unclear if LCS mortality benefit still holds and needs intervention to increase adherence to LCS.

Pulmonary nodule tracking using chest computed tomography in a histoplasmosis endemic area

ObjectiveIn areas with endemic histoplasmosis, incidental pulmonary nodules are common. Rate of malignancy and applicability of current tracking guidelines in these regions remain unclear. MethodsA total of 148 cases of incidental pulmonary nodules tracked with chest computed tomography were reviewed for radiologic characteristics, diagnosis, number, and size. ResultsOf the nodules, 87.8% were benign and 12.2% malignant; 30% of nodules >20mm were malignant. Number of nodules (P=.14) and granulomatous disease (P=.71) were not related to malignant diagnosis. ConclusionMalignancy was lower than expected in nodules >20mm. Appropriate tracking guidelines for incidentally discovered nodules in histoplasmosis endemic regions must be determined.

Infectious Diseases Associated with Caves

In recent times, caving has become increasingly popular, with almost 2 million people visiting national park caves each year in the United States. Although the 2 million tourist visits are extremely low risk, smaller numbers of sport cavers are at risk for some high risk conditions, and expedition cavers are at risk for some obscure infections. Infectious diseases like histoplasmosis, rabies, leptospirosis, and tick-borne relapsing fever may be transmitted by the underground fauna. To reduce the risk of illness or injury while caving, knowledge of potential risks before engaging in this activity is important. Caving preparation needs to be carefully planned and executed, including vaccinations, prophylactic medications, and advice regarding safe conduct and behaviors.

Can lung cancer screening by computed tomography be effective in areas with endemic histoplasmosis?

Low-dose chest computed tomography (CT) is being evaluated in several national trials as a screening modality for the early detection of lung cancer. The goal of the present study was to determine whether lung cancer screening could be done while minimizing the number of benign biopsy specimens taken in an area endemic for histoplasmosis. The subjects were recruited by letters mailed to area physicians and local advertisement. The inclusion criteria were age older than 50 years and at least a 20 pack-year smoking history. The exclusion criteria were symptoms suggestive of lung cancer or a history of malignancy in the previous 5 years. The participants completed a questionnaire and underwent a chest CT scan at baseline and annually for 5 years. The management of positive screening results was determined using a defined algorithm: annual follow-up CT scan for nodules less than 5 mm; 6-month follow-up CT scan for nodules 5 to 7 mm; review by our multidisciplinary tumor board for nodules 8 to 12 mm; and biopsy for nodules greater than 12 mm. A total of 132 patients were recruited. Of the 132 patients, 61% had positive baseline CT findings and 22% had positive findings on the annual CT scans. Six cancers were detected. Of these 6 patients, 5 had stage I disease and underwent lobectomy, and 1 had stage IIIA disease and underwent induction chemotherapy and radiotherapy followed by lobectomy. All patients were alive and disease free at a mean follow-up of 41.7 ± 18.6 months. No biopsies were performed for benign lesions. Also, no cancers were missed when the protocol was followed. Screening with CT can be done effectively in an area endemic for histoplasmosis while minimizing benign biopsies.

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration in a Geographical Region With Endemic Histoplasmosis Infection

In a geographical area with high prevalence of calcific granulomatous inflammation, calcified lymph nodes may affect the diagnostic adequacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to describe the diagnostic performance of EBUS-TBNA in a region endemic of histoplasmosis related granulomatous inflammation. A retrospective review was done for all patients referred for EBUS-TBNA over a 7-month period at 2 institutions. Computed tomographic (CT) chest studies were reviewed in a blinded manner by 2 radiologists. In parallel, CT images from 100 unselected sequential control patients were reviewed. Cytologic analysis of EBUS-TBNA aspirates was compared with a reference standard of definitive pathologic tissue diagnosis or a composite of ≥6-month clinical follow-up. The prevalence of calcified lymph nodes in the 100 control patients was 56%. All 61 patients undergoing EBUS-TBNA were included. In total, 97 lymph nodes (mean size=13.8 mm) and 7 masses were biopsied. Definitive lymph node sampling was achieved in 51 of 61 patients (83%). The sensitivity, specificity, and positive and negative predictive values of EBUS-TBNA for malignancy (primary lung cancer staging, restaging, and reevaluation after cancer therapy, small cell lung cancer, lymphoma, and metastatic cancer) were 81%, 100%, 100%, and 84% respectively. On pre-EBUS CT chest scan, 60.6% had nodal calcification. The prevalence of cancer was not different in those with and without nodal calcification (49%). There was no difference in frequency of definitive lymph node sampling in those patients with or without nodal calcification. In a geographical area with endemic histoplasmosis-related nodal calcification, there was no evidence of nodal calcification affecting the frequency of EBUS-TBNA definitive lymph node sampling.

Histoplasmosis in two aboriginal patients from Australia's tropical Northern Territory

Endemic histoplasmosis occurs uncommonly in Australia and has not previously been reported in the tropical Northern Territory, nor in Aboriginal Australian patients. We report one suspected and one confirmed case of severe disseminated histoplasmosis in Aboriginal Australians from the Northern Territory. Underlying illness included chronic cardiac disease and Type 1 diabetes mellitus, respectively, and neither patient was infected with HIV. The clinical presentations resembled malignancy. Diagnosis of histoplasmosis was made on the basis of bowel histology in Case 1, demonstrating characteristic yeasts, and lymph node histology and culture in Case 2. Histoplasmosis should be considered in relevant clinical situations, even in HIV-negative patients who have not left Australia.

A case of idiopathic sclerosing mediastinitis in a 7-year-old Japanese boy

Sclerosing mediastinitis is a very rare benign disorder characterised by the development of dense fibrous tissue within the mediastinum. Affected patients are typically young adults with infant cases being uncommon especially in areas without endemic histoplasmosis. We report a Japanese boy with markedly elevated serum inflammatory markers for more than 1 year in the absence of any clinical manifestations. 67Ga-scintigraphy demonstrated an accumulation in the mediastinal region and an open biopsy revealed a hard fibrous mass in the anteriosuperior mediastinum. Thus, a diagnosis of idiopathic sclerosing mediastinitis was made. To the best of our knowledge, this case is the youngest patient reported with this disorder. In patients with mediastinal mass lesions the diagnosis of sclerosing mediastinitis should be considered as well as infectious, autoimmune or neoplastic disease even in children.

Retrospective serological study of histoplasmosis in Mexico.

Mycotic immunodiagnosis was performed in 325 patients with clinical evidence of systemic mycoses, over a 5-year period, from different hospitals of Mexico City. Results showed 168 individuals that presented one positive serological test to Histoplasma capsulatum antigens. From these, only 27 patients were serologically positive to two or more tests, such as tube precipitin, immunodiffusion, complement fixation, and ELISA, and developed signs and symptoms of a histoplasmosis clinically classified as primary pulmonary. Four of them presented an underlying disease including one positive HIV patient. Twenty-two came from endemic histoplasmosis zones of the country and most of them acquired the disease in caves or uninhabited houses. The diagnosis of histoplasmosis should be based on reliable laboratory data which could raise more significant information of its incidence in Mexico.

Surgical implications of endemic histoplasmosis in children

During a recent urban outbreak, histoplasmosis was diagnosed in 42 children, 27 of whom required surgical evaluation (1978 to 1981). There were 19 boys and 8 girls. Ages ranged from 18 months to 17 years. Clinical presentation included mediastinal mass in 15 cases (4 with recurrent lobar pneumonia or wheezing from bronchial compression); interstitial pneumonitis or pulmonary nodules in 5 immunocompromised patients with cancer (leukemia, 3; Ewings sarcoma, 1; osteogenic sarcoma, 1); cervical abscess due to adenitis (2); acute-bilateral parotitis (1); sclerosing mediastinitis with pulmonary-artery obstruction (1); superior vena caval obstruction (SVC) (1); and pericardial effusion with cardiac tamponade (2). Twenty-two children had systemic symptoms (fever, malaise, weight loss, and anorexia) while five were asymptomatic. Diagnosis was made by chest x-ray, histologic examination of tissue, complement fixation, gel immunodiffusion, or combinations of these tests in each case. Fifteen children underwent surgical procedures: excision of mediastinal disease for diagnostic biopsy (4), or relief of bronchial obstruction (1); open lung biopsy (3) or excision of lung nodules (2); debulking of mediastinal disease for SVC (1) and pulmonary artery obstruction (1); excision of abscessed cervical nodes (2); and a pericardial window (1). All the children survived. Immunocompromised children were treated with amphotericin-B, while the remaining patients improved without specific therapy. Histoplasmosis in children can often present with a confusing clinical picture simulating other serious conditions (eg, lymphoma and metastatic sarcoma); is a serious pathogen in the immunocompromised patient; and may rarely be a cause of bronchial compression, vena caval obstruction, and pericardial effusion. Operative intervention may be both diagnostic and therapeutic in selected cases. These data indicate a need for the pediatric surgeon to be familiar with the unusual clinical manifestations of histoplasmosis in childhood.

Relationship of starling-blackbird roosts and endemic histoplasmosis.

Histoplasmin skin tests of school children in two cities with large blackbird roosts from which H. capsulatum was recovered revealed a significantly higher percentage of reactors to histoplasmin than was observed in two nearby cities without bird roosts. The prevalence of cutaneous sensitivity to histoplasmin was highest among children residing or attending schools near the roosts. The prevalence among children who had lived on farms was greater than among those who had not, but it was the same among children living near a bird roost. The data suggest that urban blackbird roosts harboring H. capsulatum contribute significantly to the prevalence of sensitivity to histoplasmin of residents of the community in which such roosts are located.

Class session: histoplasmosis.

Those of us who have followed the reports of the United States Public Health Service teams working on histoplasmosis have been fascinated by their detective-like expose of this disease. From the original observation of Palmer that a sizeable percentage of calcification on chest roentgenograms is not associated with tuberculin skin sensitivity, through the various processes of narrowing their observations to the areas of endemic histoplasmosis, and finally the demonstration of previously unsuspected clinical states of this disease, it has been a dramatic demonstration of deductive ciinical and epidemiological research. This whole drama can effectively be recapitulated in an hour's class session. Using the Socratic method, whereby members of the class are encouraged to reason this thing,out as a group exercise, the problem is started by making Palmer's original observation1 that all pulmonary calcification may not be tuberculous. Films to demonstrate this are easily available today. As a matter of fact, we have used the chest roentgenograms of several class members as clinical material to initiate the discussion. The second step to consider is the large scale skin testing of student nurses in different cities throughout the United States2 which focused the attention on the endemic areas, especially the Mississippi Valley. Following this Furcolow and Mantz3 skin tested almost 17,000 school children in Kansas City, Missouri to demonstrate the early age at which histoplasmosis sensitivity is contracted. Their next step, the mass chest roentgenograms of 16,000 school children in Kansas City, Missouri, revealed 72 symptom-free cases with combined pulmonary infiltration and positive histoplasmin skin tests.4 Reproduction on slides of some of these cases, as illustrated in their reports, are valuable at this point. The class generally has little difficulty in suggesting the next procedure which was the confirmation by culture of the organism from 10 of these cases, whose clinical pictures run the gamut of symptom-free infiltrates to fatal systemic disease. Again slide reproductions of some of these cases reported by Bunnell and Furcolow5 create considerable interest. At some point in these slides, generally at the end, the roentgenogram of a patient with pulmonary tuberculosis is unexpectedly thrown in to emphasize the similarity of these two disease infiltrates. This, supposedly,