Histoplasma Capsulatum Research Articles

Antimicrobial Activity and Toxicity of Analogs of Wasp Venom EMP Peptides. Potential Influence of Oxidized Methionine.

The antibiotic and toxic properties for four synthetic analogs of eumenine mastoparan peptides (EMP) have been tested. These properties were compared to two natural peptides found in the venom of solitary wasps Anterhynchium flavomarginatum micado (natural peptide EMP-AF) and Eumenes rubrofemoratus (natural peptide EMP-ER), respectively. Only EMP-AF-OR showed concentration-dependent growth inhibition against all bacterial species tested. Gram positive species had MIC values of 10 μg/mL for B. subtilis and 25 μg/mL for S. aureus. Gram negative species had MIC values of 25 μg/mL for E. coli and 200 μg/mL for P. aeruginosa. Of the other tested peptides, EMP-ER-D2K2 also showed activity and inhibited growth of Bacillus subtilis in a concentration-dependent manner at 200 μg/mL. Peptide EMP-ER-OR reduced the final density of Escherichia coli and B. subtilis cultures but did not impact their growth kinetics. Peptides EMP-AF-OR, EMP-ER-OR, and EMP-ER-D2K2 showed limited antifungal activity against Candida albicans or Histoplasma capsulatum. The hemolytic activity of the analogs were moderated though reports of the natural peptides, especially EMP-AF-OR, already showed low toxicity against erythrocytes. These results are discussed in the context of the potential influence of oxidized methionine on EMP activity.

CENTRAL APNEA SECONDARY TO DISSEMINATED HISTOPLASMOSIS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Occupational exposures can be an important cause of pathology, especially in the respiratory system. Histoplasmosis is an endemic, yet oft-missed multisystem pathogen, which involves the central nervous system in up to 10% of cases (1). CASE PRESENTATION: A previously healthy man was found unresponsive in the driver's seat of his car in the parking lot at work; he did not arouse to narcan and was intubated. A new lung nodule with a "halo sign" prompted fungal work up, positive for urine and serum antigens consistent with disseminated histoplasmosis. Bronchoalveolar lavage and lumbar puncture fungal studies were negative. MRI had right cerebellar lesion and EEG showed left temporal focal delta waves. When ventilated he was well-appearing and followed commands, but failed initial extubation due to apnea and marked acidosis. He was initiated on amphotericin B and re-extubated, transitioned to 1 year azole. Urine drug screen was positive for methadone, a potential confounder, however the lack of response to narcan and his level of alertness while the ventilator was controlling his acid-base status makes opiates less likely. Later he admitted extensive exposure to bird feces over the month prior to admission; his work as a Heating, Ventilation, and Air Conditioning technician inside an old office building in the Midwestern United States involved "cleaning up dead birds." DISCUSSION: Mr. H's case is an atypical presentation in an atypical patient. While he did have a stereotypical lung nodule, his primary problem was neurologic, respiratory drive rather than the lung parenchyma. He was HIV-negative, not immunosuppressed, with excellent functional status. 5-10% of disseminated histoplasmosis will have CNS infection and up to half of those cases occurred in immunocompetent individuals (1). CNS histoplasmosis has varied symptoms; current review of literature does not yield any mentioning central apnea, however, one case series centered on the well-known outbreak in Indianapolis discussed 18 cases with CNS involvement, of which 4 had the presenting symptom of "coma" (1). Review of other cases (compilation of 104 case reports) showed that with CNS involvement of histoplasmosis, "altered level of consciousness" was present in 50% (1). CONCLUSIONS: Histoplasma capsulatum is an endemic mycose which can impact immunocompetent patients and involve the CNS. It is often taught in medical school that "histo hides" because it is notoriously difficult to detect; it is even harder to find if one is not looking for it, so careful review of imaging and thorough occupational history are critical to including fungal pathogens on the differential. REFERENCE #1: Riddell J 4th, Wheat LJ. Central Nervous System Infection with Histoplasma capsulatum. J Fungi (Basel). 2019 Jul 24;5(3):70. doi: 10.3390/jof5030070. PMID: 31344869; PMCID: PMC6787664. DISCLOSURES: No relevant relationships by Daniel O'Connor, source=Web Response

A SOLITARY ENDOBRONCHIAL BRONCHOLITH AS AN UNCOMMON PRESENTATION OF HISTOPLASMOSIS

TOPIC: Lung Pathology TYPE: Medical Student/Resident Case Reports INTRODUCTION: Broncholithiasis refers to calcified material within the airway lumen, often resulting from granulomatous reaction to endemic pathogens such as M. tuberculosis or Histoplasma, or aspiration of foreign material. Histoplasma broncholiths are thought to originate from adjacent lymph nodes that erode into the airway lumen. Here we present a case of a large isolated endobronchial broncholith secondary to Histoplasma without associated lymphadenopathy or parenchymal lung lesions. CASE PRESENTATION: A 69 year-old female with GERD presented with one month of dyspnea, cough, and wheezing thought to occur after a popcorn kernel aspiration. She was treated twice for bronchitis without improvement and was diagnosed with COPD based on obstruction on spirometry. The patient denied smoking or other inhalational exposures. Vital signs and oxygenation were normal on our evaluation. A CT pulmonary angiogram showed a 1.3 cm calcified foreign body (FB) consistent with an aspirated tooth in the left mainstem bronchus without significant lymphadenopathy. Bronchoscopy showed a white-yellow multilobulated FB partially embedded in and nearly occluding the left mainstem bronchus. Removal of the FB revealed a deep but not transmural ulceration of the mucosa. Though it grossly resembled a popcorn kernel, histologic examination of the broncholith showed well-formed granulomas and yeast forms consistent with Histoplasma capsulatum. The patient felt immediate relief of dyspnea post-removal and on follow up denied any symptoms. She was discharged and scheduled for repeat testing to ensure no further evidence of fungal disease. DISCUSSION: Although broncholithiasis from Histoplasma granulomata is common, to our knowledge this is the first report of the disease presenting as a solitary endobronchial broncholith. Given that no adjacent lymphadenopathy and/or calcifications were noted on CT, this case was likely secondary to calcification of a primary endobronchial inoculum. Patients with symptomatic or obstructing broncholithiasis should undergo attempted removal either with bronchoscopy or surgical intervention. Bronchoscopic removal should be undertaken with great caution since the extraluminal origin of many broncholiths can result in airway perforation or major hemorrhage with manipulation. Large broncholiths such as this sometimes require laser lithotripsy to facilitate extraction. CONCLUSIONS: Broncholithiasis is a condition often associated with pulmonary and mediastinal histoplasmosis and can present with transmural bronchial invasion. Isolated endobronchial lesions are uncommon. Prompt imaging and endoscopic evaluation is key to accurate diagnosis. Careful consideration of transmural extension and involvement of extrabronchial structures is crucial. REFERENCE #1: Alshabani K, Ghosh S, Arrossi AV, Mehta AC. Broncholithiasis: A Review. Chest. 2019 Sep;156(3):445-455. REFERENCE #2: Krishnan S, Kniese CM, Mankins M, Heitkamp DE, Sheski FD, Kesler KA. Management of broncholithiasis. J Thorac Dis. 2018;10(Suppl 28):S3419-S3427. REFERENCE #3: Olson EJ, Utz JP, Prakash UB. Therapeutic bronchoscopy in broncholithiasis. Am J Respir Crit Care Med. 1999 Sep;160(3):766-70. DISCLOSURES: No relevant relationships by Gregory Eisinger, source=Web Response No relevant relationships by Molly Howsare, source=Web Response No relevant relationships by Meghana Moodabagil, source=Web Response No relevant relationships by Alberto Revelo, source=Web Response No relevant relationships by Konstantin Shilo, source=Web Response

DISSEMINATED HISTOPLASMOSIS IN A PATIENT WITH NEWLY DIAGNOSED AIDS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Disseminated Histoplasmosis (DH) is an AIDS-defining illness caused by the dimorphic fungus Histoplasma capsulatum. Outbreaks have been associated with exposure to bird or bat droppings and amongst construction workers. It remains unclear whether DH represents an acute infection or a reactivation of latent infection. We present a case of DH in a newly diagnosed AIDS patient. CASE PRESENTATION: A 50 year old male Hispanic construction worker presented with a month history of persisting fever, chills, diaphoresis, progressive shortness of breath on exertion, non-bloody diarrhea and 15lbs weight loss. HIV screen was positive (new diagnosis) and his CD4+ cell count was 3 per cubic millimeter with a viral load of over 1 million copies/ml. CXR showed diffuse interstitial infiltrates in both lung fields and CT chest showed numerous punctate miliary pattern pulmonary nodules in the lungs with necrotic appearing lymph nodes in the proximal jejunal mesentery. SARS-CoV2 PCR was negative. BAL culture grew Histoplasma capsulatum, Lung biopsy pathology showed broad based budding yeast and urine histoplasma antigen was positive at greater than 23 ng/ml. He was treated with highly active antiretroviral therapy (HAART), IV liposomal amphotericin, and steroid. Empiric anti-TB therapy was stopped with negative quantiferon TB gold, BAL AFB smear and BAL MTB complex PCR. Silver stain for PCP, serum cryptococcal antigen, serum galactomammanan and fungitell assays were all negative. Hospital course was complicated by pneumothorax, septic shock, line related bloodstream infections that resolved with line removal and antimicrobials. Despite appropriate antifungal therapy for 40 days with decrease in his urine histoplasma antigen to 11 ng/ml, and HIV viral load decreasing to 330 copies/ml after 3 weeks of HAART, he remained ventilator dependent, on chest tubes and could not be weaned off sedation. His family made him comfort care only on hospital day 43 and he died peacefully after. DISCUSSION: Histoplasmosis has been recognized as an opportunistic infection in patients with AIDS and typically presents as disseminated disease. DH in conjunction with HIV infection is particularly common among Hispanic persons in the United states. In AIDS patients, DH is associated with a nonspecific clinical presentation—usually unexplained fever and weight loss. Histoplasmosis causes significant morbidity and mortality. Fungal infections deaths in AIDS were estimated at more than 700, 000 deaths (47%) annually. The frequent occurence of histoplasmosis with other opportunistic infections especially tuberculosis requires that tuberculosis be ruled out even if histoplasmosis is diagnosed. CONCLUSIONS: This case highlights the fact that although miliary pattern on CT Chest typically signifies tuberculosis, it can also be seen in histoplasmosis. Also associated morbidity and mortality of DH remains high in AIDS patients not on HAART. REFERENCE #1: Rana A. Hajjeh. Disseminated Histoplasmosis in Persons Infected with Human Immunodeficiency Virus. Clinical Infectious Diseases 1995; 21(Suppl 1):S108 -10. REFERENCE #2: Stuart M. Levitz, and Eugene J. Mark. Case 38-1998 — A 19-Year-Old Man with the Acquired Immunodeficiency Syndrome and Persistent Fever. N Engl J Med 1998; 339:1835-1843. REFERENCE #3: David W. Denning. Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500 000 by 2020 to be realized. Philos Trans R Soc Lond B Biol Sci. 2016 Dec 5;371(1709). DISCLOSURES: No relevant relationships by Oluwadamilola Adeyemi, source=Web Response No relevant relationships by Ingrid Gils, source=Web Response No relevant relationships by Drew Ludwig, source=Web Response No relevant relationships by Biana Modilevsky, source=Web Response

S2409 Histoplasmosis Presenting as New-Onset Ascites in a Crohn’s Disease Patient on Adalimumab

Introduction: Histoplasma capsulatum is the most frequently diagnosed endemic mycosis in the United States. The majority of cases are self-limiting but infections in immunocompromised patients may result in severe pulmonary or disseminated disease. We report a rare case of disseminated histoplasmosis presenting as new- onset ascites due to granulomatous hepatitis in a patient with perianal Crohn’s Disease on Adalimumab. Case description/methods: A 39-year-old white female with perianal but no intraluminal Crohn’s Disease currently on adalimumab and azathioprine presented with cyclical fevers and rapid onset ascites. In the preceding weeks she was noted to have uptrending alkaline phosphatase (600s) with isoenzymes consistent with liver etiology, GGT 162, mildly elevated AST (53) with normal ALT and total bilirubin. Further workup included positive anti-smooth muscle (1:160) and F-actin antibodies. Anti-nuclear and anti-mitochondrial antibodies both returned negative. MRCP demonstrated a circumferential 1.9 x 1.3cm peribiliary mass with segmental biliary duct dilation. Paracentesis with peritoneal fluid analysis demonstrated a low serum-ascites albumin gradient, lymphocytic predominance, and negative cytology, acid-fast stain, tuberculosis PCR, and adenosine deaminase. Transjugular liver biopsy revealed multiple non-necrotizing granulomas surrounded by chronic inflammation, consisting predominantly of lymphocytes and eosinophils. Grocott’s methenamine sliver stain was positive for narrow-based budding yeast, with morphology suggestive of Histoplasma species. Additionally, a quantitative serum Histoplasmosis antigen returned positive at 2.53 ng/ml. Following these findings, a course of IV Amphotericin B was started with eventual transition to PO Itraconazole for 1 year. Discussion: Histoplasmosis capsulatum is a dimorphic fungus that is endemic to the United States, specifically the Ohio and Mississippi River valleys. The majority of infections are subclinical, but when diagnosed are primarily in immunocompromised patients. A high degree of clinical suspicion is required to facilitate early treatment and prevent poor outcomes. Pulmonary histoplasmosis is by far the most common clinical presentation. Progressive disseminated disease is rare, but may involve the liver, skin, adrenals, gastrointestinal tract, central nervous system, and bone marrow. With the use of immunomodulating therapies on the rise, it is important to consider opportunistic infections in patients with atypical presentations.Figure 1.: A: H&E staining at 200x magnification of liver biopsy demonstrating non-caseating granulomas. B: Liver biopsy shows narrow-based budding yeast with positive silver stain suggestive of Histoplasma.

S1857 Gastrointestinal Histoplasmosis in an Immunocompetent Adult in a Non-Endemic Region

Introduction: Histoplasma capsulatum is an endemic fungus and infection is rarely seen in the United States outside of the Ohio and Mississippi River regions. Disseminated infection is typically seen in immunocompromised patients and primary gastrointestinal involvement is rare. We report the case of an immunocompetent adult who was diagnosed with disseminated histoplasmosis with primarily gastrointestinal symptoms. Case description/methods: A 34-year-old male with history of developmental delay and prior seizures presented with seven months of intermittent bloody diarrhea, abdominal pain, fever and chills. He had a similar presentation previously at another hospital and underwent colonoscopy with evidence of multiple ulcers throughout the colon. He was empirically treated with antibiotics but re-presented due to persistent symptoms. Patient was intermittently febrile on admission. Exam showed diffuse abdominal tenderness to palpation. Labs were notable for Hgb 9.1 g/dL and, WBC 12.3 × 10^9 cells/L Stool calprotectin 1570 mcg/g. CT abdomen showed diffuse colonic thickening. Colonoscopy showed discontinuous scattered non-bleeding deep ulcers throughout the entire colon (Figure 1) which were biopsied. Pathology showed histiocytes with intracellular fungal elements. Even duodenal biopsies showed intracellular fungal elements though the duodenal mucosa appeared normal aside from some lymphoid aggregates on upper endoscopy. Urine histoplasma galactomannan antigen was positive. He had no evidence of pulmonary disease. Further history revealed that the patient had never traveled outside of California but did have some close contact with relatives from Minnesota prior to the onset of symptoms. Other infectious work-up including Aspergillus, HIV, CMV, Coccidiomycosis, Cryptococcus were all normal. He was initially treated with oral itraconazole with no improvement of his symptoms, however symptom resolved after initiating IV amphotericin. Genetic testing is pending for underlying immunodeficiency. Discussion: This unique case illustrates disseminated histoplasmosis with mainly gastrointestinal symptoms in a seemingly immunocompetent adult in a non-endemic area. The patient had diffuse small bowel and colonic involvement led to symptoms mimicking inflammatory bowel disease and he even had a markedly elevated calprotectin. Prior case series of disseminated histoplasmosis have reported 100% mortality when untreated. Endoscopic biopsies were crucial to help make the diagnosis and appropriate therapy.Figure 1.: Deep, non-bleeding ulcerations found in transverse colon on colonoscopy.Table 1.: EGD and colonoscopy biopsy results.

S2858 An Unusual Case of Donor-related Disseminated Histoplasmosis with Systemic Complications Due to Patient Noncompliance

Introduction: Disseminated histoplasmosis is a mycosis that often occurs in immunosuppressed settings, such as following solid organ transplants. We present the case of a 61-year-old man with a history of liver transplantation resulting in donor-related disseminated histoplasmosis complicated by Cytomegalovirus viremia and C-difficile infection. This case was also complicated by the patient’s voluntary discontinuation of prophylactic therapy, precipitating disseminated histoplasmosis. Case Description/Methods: A 61-year-old man with a history of liver cirrhosis secondary to non-alcoholic steatohepatitis received a deceased-donor liver transplant. He was given induction immunosuppression with thymoglobulin and subsequently initiated on tacrolimus, prednisone, and mycophenolate. Following the transplant, pathologic evidence of histoplasmosis was identified on the donor spleen. The recipient was placed on prophylactic itraconazole with monthly Histoplasmosis Antigen (Histo Ag) checks. The patient voluntarily discontinued itraconazole after 3 months due to headaches, while still monitoring Histo Ag levels. Three months later, he presented with right lower quadrant abdominal pain, fever, and diarrhea. AST levels were elevated at 240 IU/L ( > 35 IU/L) and ALT levels at 261 IU/L ( > 78 IU/L). A liver biopsy showed granulomatous hepatitis suggestive of histoplasmosis. A CT guided biopsy of a subpleural lung nodule showed similar granulomas. Urine Histo Ag was positive at 13.9 ng/mL (negative: < 0.10 ng/mL). The patient was also found to have cytomegalovirus (CMV) viremia despite taking prophylactic ganciclovir. He concurrently developed C. difficile colitis which resolved with vancomycin. The patient was reinitiated on itraconazole with successful suppression of Histo Ag levels, along with CMV viral load and liver enzymes. He remained on itraconazole for the following 4 years with continued stability. Discussion: Immunodeficient hosts, such as those on post-transplant immunosuppressive therapy, are at an increased risk of developing disseminated histoplasmosis when infected with Histoplasma capsulatum, as with this case. Here, we recognize the value of frequent Histo Ag monitoring and the rapid histoplasmosis progression that can occur if prophylaxis is discontinued. While early monitoring and antifungal treatment can improve outcomes, it is also important to manage treatment noncompliance. This case emphasizes the need for early discussions with patients about prophylactic therapy compliance to avoid complications.

WEAR A MASK NOT ONLY FOR COVID-19: TWO IMMUNOCOMPETENT COWORKERS WITH PULMONARY HISTOPLASMOSIS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acute Pulmonary Histoplasmosis (APH) can present in a broad variety of signs and symptoms in immunocompetent individuals but is generally a benign disease that may not require treatment. If symptoms are more severe or longer-lasting, treatment is indicated. CASE PRESENTATION: Two healthy 32- and 36-year-old males (Patient A and B respectively) presented with 1 week of high-grade fever, headache, shortness of breath, productive cough, pleuritic chest pain, and diarrhea. 2 weeks prior, they deep-cleaned a chimney filled with bat guano without wearing their respirators. Upon presentation, both patients had fever, tachycardia, tachypnea with normal resting pulse oximetry despite air hunger. Physical exam revealed diffuse crackle in both lung fields but was otherwise unremarkable. The initial lab only showed elevated procalcitonin and CRP. Viral panels were negative for COVID-19 and other viral infections. Chest CT for both cases showed extensive centrilobular and perilymphatic nodules with associated mediastinal and hilar adenopathy. Based on history and imaging, APH was suspected. Urine Histoplasma antigen was sent which later resulted in positive (3.9 and 7.3 ng/ml respectively). BAL sample was only obtained from patient B due to similarities in the two cases and a possible common pathogen. BAL fluid was grayish in color with 523 nucleated cells and monocytic predominance. Fungitell, aspergillus, fungal culture, and acid-fast stain were all negative. Meanwhile, due to the severity of our patients' presentation and extensive lung involvements, both patients were treated with daily infusion of Amphotericin B for a week and showed significant symptomatic improvement within 2 days. They were switched to oral itraconazole and were eventually discharged from the hospital. Intraconazole was continued for 12 weeks thereafter. DISCUSSION: Histoplasmosis is acquired by inhalation of Histoplasma capsulatum var. capsulatum. Clinical manifestations depend on the intensity of exposure and the patient's immunological status. It has 3 main forms which are acute pulmonary, chronic cavitary pulmonary, and disseminated histoplasmosis. it is generally a self-limited disease. Treatment may be indicated if patient becomes hypoxemic or symptoms persist over 1 month. Guidelines suggest itraconazole as treatment if symptoms persist for more than 1 month and liposomal amphotericin B followed by itraconazole in moderately severe to severe APH. However, in our two cases, patients had moderate symptoms but considering the high intensity of exposure, they were treated with a lower dose of liposomal amphotericin B followed by itraconazole and showed significant improvement. CONCLUSIONS: A detailed history of occupational exposures can help reach a prompt diagnosis and treatment of APH. Patients with moderate symptoms may be considered for treatment with lower doses of amphotericin B followed by itraconazole. REFERENCE #1: 1. Staffolani S, Buonfrate D, Angheben A, et al. Acute histoplasmosis in immunocompetent travelers: a systematic review of literature. BMC Infect Dis. 2018;18(1):673. Published 2018 Dec 18. doi:10.1186/s12879-018-3476-z REFERENCE #2: 2. Sobel JD. Practice guidelines for the treatment of fungal infections. For the Mycoses Study Group. Infectious Diseases Society of America. Clin Infect Dis. 2000 Apr;30(4):652. doi: 10.1086/313746. Epub 2000 Apr 20. PMID: 10770725. REFERENCE #3: 3. L. Joseph Wheat, Alison G. Freifeld, Martin B. Kleiman, John W. Baddley, David S. McKinsey, James E. Loyd, Carol A. Kauffman, Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 45, Issue 7, 1 October 2007, Pages 807–825. doi.org/10.1086/521259 DISCLOSURES: no disclosure on file for Ashlee Russo;No relevant relationships by Abolfazl Sodagar, source=Web Response No relevant relationships by Jeannie Ur, source=Web Response

Voriconazole is Less Effective than Other Triazoles for Treatment of Histoplasmosis

Background: Voriconazole is used to treat patients with histoplasmosis who are intolerant to itraconazole because of potential drug interactions. Hendrix reported higher mortality in patients treated with voriconazole than itraconazole raising the question if the Histoplasma isolates became less susceptible to voriconazole during treatment in those who failed treatment. Methods: Primary and failure isolates from a patient who failed treatment with fluconazole were incubated with increasing concentrations of voriconazole. Results: In vitro exposure of the patient’s primary isolate to voriconazole increased its MIC from 0.007 mcg/mL to 1.0 mcg/ mL (128-fold). Exposure of the failure isolate increased the MIC from 0.125 mcg/mL to 4 mcg/mL (32-fold). Exposure to voriconazole did not increase the MIC of the primary isolate to itracunazole but did increase the MIC of the failure isolate from 0.007 to 0.030 mcg/mL (4-fold). Conclusion: In vitro exposure Histoplasma capsulatum increased MICs to voriconazole 32 to 128-fold which could be a cause of treatment failure reported by Hendrix.

Disseminated Histoplasmosis in a Retropositive Young Male: A Case Report

Disseminated histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. This fungal infection is commonly seen in immunocompromised patients, especially in AIDS patients, children and elderly population. Here we present a case report of a 24-year-old male who was admitted with generalised fatigue and generalised lymphadenopathy. He was found to be retropositive on evaluation and FNAC of the node surprisingly revealed Histoplasmosis. Presence of these organisms were also seen on the peripheral smear which could be picked up only on reviewing the smear again. With this case report we wish to emphasize the need for careful and diligent search of these organisms in the peripheral smear.

Validation and Concordance Analysis of a New Lateral Flow Assay for Detection of Histoplasma Antigen in Urine.

Histoplasmosis is a major cause of mortality in people living with HIV (PLHIV). Rapid methods to diagnose Histoplasma capsulatum disease could dramatically decrease the time to initiate treatment, resulting in reduced mortality. The aim of this study was to validate a MiraVista® Diagnostics (MVD) Histoplasma urine antigen lateral flow assay (MVD LFA) for the detection of H. capsulatum antigen (Ag) in urine and compare this LFA against the MVista® Histoplasma Ag quantitative enzyme immunoassays (MVD EIA). We assessed the MVD LFA using a standardized reference panel of urine specimens from Colombia. We tested 100 urine specimens, 26 from PLHIV diagnosed with histoplasmosis, 42 from PLHIV with other infectious diseases, and 32 from non-HIV infected persons without histoplasmosis. Sensitivity and specificity of the MVD LFA was 96%, compared with 96% sensitivity and 77% specificity of the MVD EIA. Concordance analysis between MVD LFA and the MVD EIA displayed an 84% agreement, and a Kappa of 0.656. The MVD LFA evaluated in this study has several advantages, including a turnaround time for results of approximately 40 min, no need for complex laboratory infrastructure or highly trained laboratory personnel, use of urine specimens, and ease of performing.

Hepatic Histoplasmosis: An Update.

Histoplasma capsulatum is the most common cause of endemic mycosis in developing countries. It is a self-limited and asymptomatic disease in immunocompetent individuals but remains a frequent cause of opportunistic infection in patients with compromised immune status. Liver involvement as a part of disseminated histoplasmosis is well known. However, liver infection as a primary manifestation of histoplasmosis without evidence of primary lung involvement is rare. In conclusion, clinicians should be aware of isolated histoplasmosis affecting the hepatobiliary system, and careful evaluation is warranted to confirm the diagnosis. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in non endemic as well as endemic areas.

Mediastinal Mass with Unusual Etiology.

Mediastinal Mass with Unusual Etiology.

Tenosynovitis in a renal transplant recipient: Making the diagnosis firsthand

A 63-year-old man presented with 2 months of right upper extremity (RUE) redness and swelling 17 months after deceased donor renal transplant. He underwent hemodialysis for hypertension-induced renal failure for 3 years pretransplant via a left upper extremity radiocephalic arteriovenous fistula. Although not sensitized pretransplant, he received thymoglobulin induction for anticipated delayed graft function. Allograft function did not recover. He remained on dialysis and relisted for transplantation, while maintained on tacrolimus, mycophenolic acid, and prednisone. Two months before presentation, he noted gradual swelling involving his right hand second and fourth digits. This progressed to involve the right palm, wrist, and elbow with associated pain and erythema. He denied RUE trauma, fever, or systemic symptoms. He denied exposures to animals, gardening, caves, freshwater bodies, or construction sites. He lived in North Carolina with no travel outside the region. Examination revealed erythematous, tender, and fluctuant nodules involving the right wrist and palm, second and fourth digit dactylitis (Figure 1), and right olecranon bursitis. RUE joint range of motion was intact. His examination was otherwise unremarkable. Laboratory data: white blood cell count 1300 cells/mm3 (neutrophils 1058 cells/mm3, lymphocytes 138 cells/mm3), hemoglobin 7.6 g/dl, platelets 176 000/µl, and normal liver functions. RUE magnetic resonance imaging (MRI) demonstrated full-thickness soft tissue edema with large nodular areas of heterogeneous signal abnormality correlating with his examination, without abscess or osteomyelitis. Hypothenar eminence skin biopsy demonstrated extensive dermal and subcutaneous tissue necrosis (Figure 2). Periodic-acid Schiff stain and cultures from the olecranon bursa fluid aspirate and skin biopsy showed Histoplasma capsulatum. 1How do most transplant recipients acquire histoplasmosis?aEnvironmental fresh water exposurebInhalation of airborne sporescPerson to person transmissiondTransmission through an animal biteeTransmission via the donor allograft2Which study is most likely to reveal an additional site of infection in this case?aBone marrow biopsybEchocardiographycChest computed tomography (CT)dMRI braineMRI spine3Which clinical feature supports tenosynovitis with concomitant deeper soft tissue infection of the wrist and hand?aConcomitant olecranon bursitisbDactylitis with intact joint range of motioncLack of discrete abscess formation on imagingdSubacute progression of clinical findingseSubcutaneous tissue necrosis on skin biopsy4Despite discontinuing immunosuppression and administering liposomal amphotericin B (AMB) for 3 weeks, the patient’s right-hand abnormalities failed to demonstrate significant clinical improvement. What is the best next step in the management of this patient’s infection?aContinue with liposomal AMB to allow more time for a clinical responsebAdd an azole antifungal agent to the treatment regimencAdd empiric antibacterial coverage for possible superinfectiondAdminister high dose steroids to treat immune reconstitution syndromeePerform surgical exploration and debridement

What Is the Part of Tropical Diseases Among Infectious Complications in Renal Transplant Recipients in the Amazon? A 12-Year Multicenter Retrospective Analysis in French Guiana

Infectious complications in kidney transplant recipients (KTRs) are well studied in temperate countries but remain barely known in tropical ones. The main objective of this study was to describe infection-related hospitalizations in patients living in the Amazon, where it has never been described. All KTRs residing in French Guiana between 2007 and 2018 were included retrospectively. Infection-related hospitalizations were collected in the main medical centers of the territory. Eighty-two patients were included, and 42 were infected during the study period (51%). Eighty-seven infections were identified. The main sites of infection were urinary, in 29% of cases (25/87), and pulmonary, in 22% of cases (19/87). When documented (48/87), bacterial infections were predominant (35/48), followed by viral (8/48), fungal (4/48), and parasitic infections (1/48). Endemic so-called tropical infections accounted for 6% of infections (5/87). Histoplasma capsulatum was the most commonly isolated fungus (2/4). This study suggests that the spectrum of infections in KTRs in French Guiana differs little from that of temperate countries. Nevertheless, some tropical infections are described. More studies on fungal infections in KTRs should be undertaken to clarify the weight of histoplasmosis in these patients.

Histoplasmosis: diagnostic and therapeutic aspect

Histoplasmosis has been reported since 1932 in various regions in Indonesia. This disease is caused by thermally dimorphic fungus Histoplasma capsulatum var. capsulatum which is experiencing an increasing incidence worldwide. Human infection occurs when spores in soil contaminated with bird and bat droppings are inhaled and change to form yeast in the lungs. The majority of these forms of infection are mild and can heal on their own, but if large numbers of spores/ inoculum are inhaled, or the host is immunosuppressed, serious lung disease and even dissemination may occur with a high mortality rate. The diagnosis can be made by combining clinical symptoms with laboratory test results. Conventional laboratory methods such as direct examination or histopathology and culture are the gold standards for histoplasmosis diagnosis. The weakness of culture is the nature of H. capsulatum as a slow grower fungus that takes 4-6 weeks to grow. In addition, laboratory tests can be carried out with antibody detection or antigen detection. Antigen detection is more benefi cial for hosts with immunosuppression or acute form, while antibody detection is more important in the chronic form of the diseases. Molecular-based assays have high specifi city but are not yet available commercially and are more widely used for culture identifi cation to confi rm the species of H. capsulatum. Histoplasmosis therapy usually begins with the administration of amphotericin B for around two weeks, followed by maintenance with itraconazole for 6 - 9 months duration. A careful history of possible exposure and the appropriate laboratory diagnostic approach is essential to provide appropriate therapy.

Post-treatment bacterial endocarditis mimicking fungal organisms: a morphologic comparison and tips for avoiding this diagnostic pitfall

BackgroundHistopathologic differentiation of bacterial endocarditis from yeast-like fungal endocarditis is usually straightforward; however, an underappreciated phenomenon is the effect of antimicrobial therapy on bacterial size, shape and septa (cross-wall) formation resulting in bacterial forms that mimic yeast-like fungi. In this article we illustrate the alterations that occur in antibiotic-treated Staphylococcus aureus endocarditis and compare these changes to histopathologic findings in unaltered S. aureus and Histoplasma endocarditis, respectively. MethodsResected valves from three cases of endocarditis were compared based on the type ofinflammatory reaction, organism morphology and culture results. Case 1 was S. aureus endocarditis initially misclassified as Histoplasma due to its atypical morphologic and histopathologic features. The two cases included for comparison were an S. aureus endocarditis with more classic features and an Histoplasma capsulatum endocarditis. Hematoxylin and eosin (H&E), Gram, periodic acid Schiff (PAS), Gomori-Grocott methenamine silver stains (GMS), and culture results were compared in all cases. Molecular and immunohistochemistry tests were used for confirmation of first case. High power oil-immersion was used to visualize organisms’ characteristics in all three cases. ResultsCase 1 and Case 3 (Histoplasma-infected valves) had fibrinous exudates with scattered macrophages. The microorganisms observed in the first case of methicillin-sensitive S. aureus (MSSA) were ∼ 2-3 μm by GMS stain and had prominent septations. Histoplasma yeast were round to oval, ∼ 3-4 μm in size and demonstrated budding. S. aureus without alterations were round, ∼ 1 μm in size, and lacked prominent septations. Necrotizing purulent inflammation was present in the unaltered case of MSSA. The MSSA case with alterations from antibiotic treatment did not stain well with the Gram stain and organisms were best visualized with the PAS and GMS stains. ConclusionsAntibiotic therapy for bacterial endocarditis can alter the inflammatory reaction to infection, bacterial size, septa formation, and staining characteristics. Knowledge of these therapy-related effects and use of high-power magnification helps to avoid misclassification as yeast-like fungi.

Histoplasma capsulatum var. duboisii: A KwaZulu-Natal, South Africa public sector perspective.

Histoplasma capsulatum var. duboisii (H. duboisii) causes potentially fatal disease in the immunocompromised patient, and the literature on these cases is limited. The study was undertaken to describe the cases of H. duboisii seen in a resource-limited setting. A 5-year retrospective, laboratory-based histopathologic review of all H. duboisii cases. A total of 24 patients were diagnosed with cutaneous H. duboisii infection. The male-to-female ratio was 1.4. All the patients were human immunodeficiency virus (HIV) positive, and 70.83% (17 of 24 patients) were on antiretroviral therapy. The clinically identified lesions were as follows: plaques, nodular plaques, papules, papulo-pustules, and umbilicated papules. Histopathological appraisal revealed organisms typical of H. duboisii. The commonest epidermal alterations were interface change, parakeratosis, spongiosis, ulceration, acanthosis, hyperkeratosis, transepidermal elimination, and exocytosis in decreasing order. The dermal changes included histiocytic pattern (n=14), neutrophil-rich (n=13), non-necrotizing granulomatous inflammation (n=9), and karyorrhexis (n=6). Histoplasma was confirmed in 53% (8 of 15 samples) of the tissue samples submitted for routine fungal culture. This study showed the demographics, clinical and histopathology features of H. duboisii infection in a resource-limited setting. Further research on histopathological features of this rare infection is essential to expand on the knowledge base and support findings in this study.

A metabolic inhibitor arms macrophages to kill intracellular fungal pathogens by manipulating zinc homeostasis.

Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource-poor environment by marshaling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog 2-deoxy-D-glucose (2-DG) armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages, decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This effect promoted the antifungal machinery of macrophages and expanded the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.

Recovery and Its Dynamics of Filamentous Fungi from Clinical Specimen Cultures: An Extensive Study.

ABSTRACTThe culture method remains vital in diagnosing fungal infections, but extensive data-based evaluation of the method, especially for filamentous fungi (molds), is minimal. The purpose of this study was to characterize mold recoveries from fungal cultures and the impact of media and incubation duration. Clinical specimens for fungal cultures were submitted primarily from the eastern and central United States, and mold isolation data were prospectively collected and analyzed. A total of 1,821 molds in 59 genera were isolated from 1,687 positive specimens, accounting for approximately 5.6% of our cohort of 30,000 fungal cultures. Within 2 weeks, nearly 90% of molds and 97.3% of Aspergillus fumigatus complex were recovered (>95% confidence interval [CI]). All Mucorales fungi were recovered within 11 days of incubation. The recovery peak time was day 3 for Mucorales fungi, day 4 for hyaline molds, day 5 for dematiaceous molds, and day 7 for Onygenales fungi. The recovery of Histoplasma capsulatum and Trichophyton species in the fourth week of incubation reveals that a 3-week incubation time is insufficient. Inhibitory mold agar was the best medium for recovering all mold types among all tested specimen types, yielding nearly 78% of mold growth overall, indicating the necessity of selective medium for fungal cultures.IMPORTANCE Fungal culture is the gold standard method of diagnosing fungal infections, but important information, such as the impact of media and incubation times on fungal recovery, is not well documented. This study addressed these gaps using extensive data-based evaluation focused on molds. We identified the best medium types and incubation times for better fungal culture practice. We analyzed 1,821 molds from 1,687 positive specimens in our cohort of approximately 30,000 fungal cultures. Mold recovery peaked between 3 and 7 days of incubation, dependent upon the type of mold. Some well-defined fungal pathogens, such as Histoplasma capsulatum and Trichophyton species, were isolated in the fourth week of incubation. Inhibitory mold agar was identified as the best medium for recovering all mold types among all tested specimen sources. As we are aware, this is the largest study of fungal culture methods and supports 4 weeks of incubation for optimal mold recovery.