Serial Bronchoalveolar Lavage Fluid Aspergillus Galactomannan and Treatment Response in Invasive Pulmonary Aspergillosis.

We studied patients diagnosed with aspergillosis based on positive bronchoalveolar lavage (BAL) Aspergillus galactomannan (GM) who had follow-up BAL sampling within 180 days. GM trend and clinical outcome were concordant in only 60% (30/50). While useful for the initial diagnosis, BAL GM trending does not always correlate with treatment response.

Telangiectatic osteosarcoma in four dogs: Cytologic, histopathologic, cytochemical, and immunohistochemical findings.

Telangiectatic osteosarcoma is a rare variant of osteosarcoma histologically and clinically similar to hemangiosarcoma (HSA). This case series describes the imaging and cytologic features of four histologically confirmed telangiectatic osteosarcomas, including the use of cytochemical stains. Alkaline phosphatase (ALP) was applied to Wright-Giemsa-stained cytology slides, and Factor VIII immunohistochemistry was evaluated. Cytologic characteristics included atypical mesenchymal cells with evidence of acute and chronic hemorrhage. Telangiectatic osteosarcoma cases had positive ALP cytochemical staining, while control HSA cases were negative. Factor VIII immunohistochemistry was negative in telangiectatic osteosarcoma and positive in HSA. Cytologic diagnosis of telangiectatic osteosarcoma with positive ALP cytochemical staining can help differentiate this neoplasm from HSA.

Hyphae, pseudohyphae, yeasts, spherules, spores, and more: A review on the morphology and pathology of fungal and oomycete infections in the skin of domestic animals.

Fungi are among the most common infectious agents affecting the skin of animals. The skin can serve as a port of entry for fungal infections, which can eventually become disseminated. In some regions of the world, oomycetes, such as Pythium and Lagenidium, are also responsible for a significant number of severe cutaneous infections. Histologic evaluation of fungal morphology, including size, shape, septation, branching, and budding characteristics, combined with the distribution of inflammatory infiltrates within different skin layers can potentially identify etiologic agents, guiding selection of antifungals and additional diagnostics. Fungal infections of the skin surface are typically caused by Malassezia and rarely Candida, with opportunistic fungi also capable of colonizing the skin surface, especially when the barrier is broken. Folliculocentric infections, caused by dermatophytes, result in mild to severe inflammation and can occasionally penetrate deep into the skin. A wide range of fungi, including agents of hyalohyphomycosis, phaeohyphomycosis, and dimorphic fungal infections, as well as oomycetes, result in nodular cutaneous and subcutaneous lesions. With the occasional exception of dimorphic fungi, fungal speciation often requires cultures performed on fresh tissues. However, molecular techniques such as pan-fungal polymerase chain reaction on paraffin blocks is becoming an increasingly useful tool to distinguish between cutaneous fungal pathogens. This review focuses on describing the clinical and histologic features of the most common fungal and oomycete infections affecting the skin of animals, divided according to distribution patterns of lesions and fungal or oomycete morphology.

Subarachnoid hemorrhage and axonal degeneration after C1-C2 cervical centesis in 2 horses.

Ultrasound-guided cervical centesis has gained popularity as a method for collecting cerebrospinal fluid (CSF) from standing horses. There are anecdotal reports of neck stiffness, regional swelling, sensitivity to palpation, and fever after the procedure. We report 2 horses with complications that occurred within days of C1-C2 centesis and ultimately resulted in euthanasia. Both C1-C2 centesis were performed routinely, with CSF cytologic analysis providing no evidence of blood contamination. Post-mortem examination revealed equine degenerative myeloencephalopathy as the primary disorder causing Horse 1's initial neurologic deficits, whereas Horse 2 did not have a distinct lesion explaining the horse's deficits. Both horses had evidence of subarachnoid hemorrhage at or near the centesis site with Wallerian axonal degeneration in the cranial cervical spinal cord. Although hemorrhage with associated axonal degeneration at the cervical centesis site appears to be rare, this complication of C1-C2 centesis should be considered as this technique gains popularity.

Histology, prevalence, and environmental sources for pulmonary silicates depositions in domestic and wild animals.

The source and significance of pulmonary silicate crystals in animals and people are poorly understood. To estimate the prevalence and characterize the pulmonary crystalline material in animals from St. Kitts, tissue samples from dogs, horses, cattle, sheep, goats, pigs, chickens, mongooses, and monkeys were examined by light microscopy, scanning electron microscopy with energy-dispersive x-ray analysis (SEM/EDXA), and x-ray diffraction. Crystalline material was seen in 201 of 259 (77.6%) lung samples as perivascular and interstitial accumulations of heterogeneous crystalline particulate material, free or within macrophages (silicate-laden macrophages [SLMs]), mostly lacking evidence of chronic inflammation or fibrosis. The crystalline material was birefringent, basophilic on acid-fast, and composed of silicas on SEM/EDXA. Mongooses (100%) and monkeys (98%) had the highest prevalence of SLM, followed by cattle and chickens. Lesions were graded on a 3-point scale based on the histologic location and extent of silicates and SLM and were significantly more severe in mongooses (median = 3) than in monkeys (median = 2), dogs (median = 2), and chickens (median = 1). On EDXA, the crystalline material from lungs, air, and topsoil was composed of silicon, oxygen, aluminum, and iron, with a particulate matter size between 2.5 and 10 µm. We hypothesize Saharan dust, volcanic ash, topsoil, and rock quarry dust are potential sources of siliceous dust inhalation and SLM accumulations lacking chronic inflammation (silicosis); dust generation may be potentiated by road vehicle or wind suspension. Future investigations are warranted on the role of silicate inhalation and respiratory comorbidities in people, with monkeys, mongooses, or chickens serving as possible sentinels for exposure.

Clinicopathologic Characteristics, Treatment, and Outcomes of Post-transplant Lymphoproliferative Disorders: A Single-institution Experience Using 2017 WHO Diagnostic Criteria.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients' outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9-35) and 82 months (95% CI: 39-115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91-20) versus SMR 1.72 (95% CI: 1.26-2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma-related causes in those achieving EFS 24.

Prosthetic Joint Infections Due to Histoplasma capsulatum: A Report of 3 Cases.

Histoplasma capsulatum causes pneumonia and multisystemic disease in humans. Musculoskeletal involvement in histoplasmosis is most often tenosynovitis and rarely septic arthritis. Even more uncommon is the involvement of prosthetic joints. Here, we report a series of 3 cases of prosthetic joint failures caused by infection due to H capsulatum. Together with a review of 4 previously reported cases, we summarize host characteristics, clinical presentation, surgical approaches, antifungal management, and outcomes of this rare orthopedic joint infection.

Mucormycosis in Hematopoietic Cell Transplant Recipients and in Patients With Hematological Malignancies in the Era of New Antifungal Agents.

BACKGROUND: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. METHODS: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. RESULTS: Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136). CONCLUSIONS: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

D-index as a marker of bloodstream infections in patients with allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Neutropenia is a risk factor for development of infections; however, the direct effect of neutropenia on development of bloodstream infection (BSI) is not known. D-index, which is area between the neutrophil time curve and a neutrophil count of 0.5 × 109 /L, incorporates the combined effect of severity and duration of neutropenia. We aimed to evaluate whether D-index can be used as a marker for BSI in patients with allogeneic stem cell transplantation. METHOD: We conducted a retrospective cohort study of patients undergoing allogeneic stem cell transplantation between January 1, 2005, and September 30, 2015. The primary outcome measure was the development of BSI within 30 days of transplantation. RESULTS: A total of 714 patients were included in the study of whom 101 developed BSI. Patients with BSI had a significantly higher median D-index value compared with patients who did not have BSI (4990 vs. 3570, P < .001). As a marker, the performance of the D-index was similar to that of the duration of profound neutropenia (P = .18) and significantly better than the total duration of neutropenia (P = .001). CONCLUSION: The D-index performed better than the total duration of neutropenia as a marker for BSI in patients with allogeneic stem cell transplantation. There was no difference between D-index and, a more easily calculable indicator, duration of profound neutropenia.

Histoplasmosis in Inflammatory Bowel Disease with Tumor Necrosis Factor-Alpha Inhibitors: Safe to Continue Biologics?

BACKGROUND: The advent of tumor necrosis factor-α (TNF-α) inhibitor therapy has transformed inflammatory bowel disease management; however, these medications carry a boxed warning for risk of serious infections, including invasive fungal infections. AIMS: We aimed to study the clinical features, severity, and outcomes of histoplasmosis in patients on TNF-α inhibitors for IBD. METHODS: We performed a retrospective review of IBD patients receiving TNF-α inhibitors who developed histoplasmosis from January 1, 2001, to May 31, 2018. Patients with drug indications other than ulcerative colitis or Crohn's disease were excluded. IBD was diagnosed histologically, radiographically, or endoscopically. RESULTS: We identified 49 patients (median age 44 years; range 19-76) with histoplasmosis on TNF-α inhibitors. Patients with disseminated disease had a median urine antigen of 10.76 ng/mL compared with pulmonary disease alone 0.375 ng/mL (p < 0.001). Charlson Comorbidity Index and urine antigen levels showed a trend toward predicting disease severity (p > 0.05). Median length of stay was 9.5 days. Itraconazole was used for maintenance in all patients. Median follow-up was 4.7 years. Total treatment duration ranged from 3 to 15 months. TNF-α inhibitor therapy was continued in nine and resumed in ten patients after completing antifungals. Three deaths occurred (6%). CONCLUSIONS: Histoplasmosis outcomes were mostly favorable. Many patients were young with few comorbidities; however, those with more comorbidities experienced more severe histoplasmosis. Compared to prior studies, many of these patients resumed or continued biologic therapy. There were no histoplasmosis recurrences after resuming TNF-α inhibitor therapy. Vigilance for disseminated fungal infections in this patient population is essential.

The D-index is not correlated with invasive fungal infection during the early-post engraftment phase among allogeneic hematopoietic stem cell transplant recipients.

The D-index assesses neutropenia dynamics. Prolonged neutropenia is a major risk for invasive fungal infection (IFI); we hypothesized that D-index is predictive of IFI risk. We retrospectively reviewed 789 adults who underwent allogeneic hematopoietic transplant (HSCT) from 1/1/2005 to 9/30/2015. Medical records were reviewed from transplant (D0) through Day 100. The D-index was calculated as area over the neutrophil curve until engraftment. 714 patients were included for analysis. Sixteen (2%) developed probable (11) or proven (5) IFI. Median time to IFI was 40 days (range 8-98) after HSCT. Groups with and without IFI did not differ significantly in duration of mild or profound neutropenia. Median D-index of those with IFI was 4293 days neutrophil/µl compared to 3590 days neutrophil/µl for those without IFI (P = 0.17). Patients who were neutropenic on D0 showed higher rates of IFI than those who were not (10/123 [8%] vs 6/591 [1%]; P < 0.001). Only 2% developed IFI, likely due to mold-active antifungal prophylaxis. The D-index was not significantly higher in those with IFI. Duration of profound neutropenia and neutropenia at D0 may be better markers for IFI among HSCT recipients during the first 30 and 100 days after transplant.

Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection Reduces Recurrent Urinary Tract Infection Frequency.

Broad-spectrum antibiotics for recurrent multidrug-resistant urinary tract infections (UTIs) disrupt the gut microbiome and promote antibiotic resistance. Fecal microbiota transplantation led to resolution of recurrent Clostridium difficile, significantly decreased recurrent UTI frequency, and improved antibiotic susceptibility profile of UTI-causing organisms.

Clinical and Microbiological Characteristics of Bacteroides Prosthetic Joint Infections.

Clinical and microbiological characteristics of patients with Bacteroides prosthetic joint infection (PJI) have not been well described in the literature. The aim of this retrospective cohort study was to assess the outcome of patients with Bacteroides PJI and to review risk factors associated with failure of therapy. Between 1/1969 and 12/2012, 20 episodes of Bacteroides PJI in 17 patients were identified at our institution. The mean age of the patients in this cohort at the time of diagnosis was 55.6 years; 59% (n=10) had knee involvement. Twenty four percent (n=4) had diabetes mellitus, and 24% had a history of either gastrointestinal (GI) or genitourinary (GU) pathology prior to the diagnosis of PJI. Thirty five percent (n=6) were immunosuppressed. The initial medical/surgical strategy was resection arthroplasty (n=9, 50%) or debridement and implant retention (n=5, 28%). Thirty seven percent (n=7) were treated with metronidazole. Eighty percent (n=4) of patients that failed therapy had undergone debridement and retention of their prosthesis, as compared to none of those treated with resection arthroplasty. Seventy percent (n=14) of patient episodes were infection free at their last date of follow up. In conclusion, a significant proportion of patients with Bacteroides PJI are immunosuppressed and have an underlying GI or GU tract pathology. Retention and debridement of the prosthesis is associated with a higher risk of treatment failure.

The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive candidiasis (IC) is a common cause of mortality in solid organ transplant recipients (OTRs), but knowledge of epidemiology in this population is limited. METHOD: The present analysis describes data from 15 US centers that prospectively identified IC from nearly 17 000 OTRs. Analyses were undertaken to determine predictors of infection and mortality. RESULTS: A total of 639 cases of IC were identified. The most common species was Candida albicans (46.3%), followed by Candida glabrata (24.4%) and Candida parapsilosis (8.1%). In 68 cases >1 species was identified. The most common infection site was bloodstream (44%), followed by intra-abdominal (14%). The most frequently affected allograft groups were liver (41.1%) and kidney (35.3%). All-cause mortality at 90 days was 26.5% for all species and was highest for Candida tropicalis (44%) and C. parapsilosis (35.2%). Non-white race and female gender were more commonly associated with non-albicans species. A high rate of breakthrough IC was seen in patients receiving antifungal prophylaxis (39%). Factors associated with mortality include organ dysfunction, lung transplant, and treatment with a polyene antifungal. The only modifiable factor identified was choice of antifungal drug class based upon infecting Candida species. CONCLUSION: These data highlight the common and distinct features of IC in OTRs.

Pseudomonas Prosthetic Joint Infections: A Review of 102 Episodes.

Background: The outcome of patients with Pseudomonas prosthetic joint infection (PS PJI) has not been well studied. The aim of this retrospective cohort study was to assess the outcome of patients with Pseudomonas PJI and to review risk factors associated with failure of therapy. Methods: Between 1/1969 and 12/2012, 102 episodes of PS PJI in 91 patients were identified. Results: The mean age at the time of diagnosis was 67.4 years; forty three percent had knee involvement. Over 40 percent had either diabetes mellitus or a history of gastrointestinal or genitourinary surgery. Nearly half (48 out of 102 episodes) received aminoglycoside monotherapy, while 25% received an anti-pseudomonal cephalosporin. The 2-year cumulative survival free from failure was 69% (95% CI, 56%-82%). Patients treated with resection arthroplasty, two-stage exchange, and debridement with implant retention had a 2-year cumulative survival free from failure of 80% (95% CI, 66%-95%), 83% (95% CI, 60%-100%), and 26% (95% CI, 23%-29%) respectively (P=0.0001). Conclusions: PS PJI's are associated with a high failure rate. Patients treated with debridement and implant retention had a worse outcome.

Gastrointestinal mucormycosis in immunocompromised hosts.

Invasive mucormycosis is a rare fungal infection in immunocompromised hosts, but it carries a high mortality rate. Primary gastrointestinal disease is the least frequent form of presentation. Early diagnosis and treatment are critical in the management; however, symptoms are typically non-specific in gastrointestinal disease, leading to delayed therapy. To describe the clinical presentation, diagnosis, treatment and outcomes of gastrointestinal mucormycosis in immunocompromised hosts, we reviewed all cases of primary gastrointestinal mucormycosis in immunocompromised hosts reported in English literature as well as in our Institution from January 1st 1991 to December 31st 2013 for a total of 31 patients. About 52% of patients underwent solid organ transplant (SOT), while the rest had an underlying haematologic malignancy. Abdominal pain was the most common presenting symptom, followed by gastrointestinal bleeding and fever. Gastric disease was more common in SOT, whereas those with haematologic malignancy presented with intestinal disease (P = 0.002). Although gastrointestinal mucormycosis remains an uncommon condition in immunocompromised hosts, it carries significant morbidity and mortality, particularly in cases with intestinal involvement. A high index of suspicion is of utmost importance to institute early and appropriate therapy and improve outcomes.

Phaeohyphomycosis in transplant recipients: Results from the Transplant Associated Infection Surveillance Network (TRANSNET).

Transplant recipients are at a high risk for developing invasive fungal infections. The agents of phaeohyphomycosis are environmental molds found worldwide, and they cause a broad spectrum of disease including skin and subcutaneous lesions, pneumonia, central nervous system disease, fungemia, and disseminated disease. Using data from the Transplant Associated Infection Surveillance Network (TRANSNET), we evaluated patients with proven and probable phaeohyphomycosis. Centers collected data on demographics, co-morbid conditions, clinical features, treatment, and three-month mortality. Fifty-six patients with phaeohyphomycosis were identified from 15 centers, comprising 26 stem cell transplant (SCT) and 30 solid organ transplant (SOT) recipients. Median time to diagnosis post-transplant was 358 days (SCT 100 days; SOT 685 days; P = <.001). The most frequent pathogen was Alternaria species (32%). Disseminated disease was found in 55.4%. Cutaneous infection was more common in SOT (53.3% vs 23.1%; P = .021), while pulmonary disease was more common in SCT (57.7 vs. 26.7; P = .019). Voriconazole (44.6%) and amphotericin B preparations (37.5%) were the most common antifungal therapies. Overall mortality was 25% and was higher in SCT than in SOT (42% vs 10%; P = <.001). A wide variety of organisms encompass phaeohyphomycosis contributing to varying types of infection in transplant recipients. Site of infection, time to disease, and mortality varies significantly between SCT and SOT recipients. Lipid formulations of amphotericin B and voriconazole were the most common antifungals used to treat this disorder.

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

BACKGROUND: Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. METHODS: We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. RESULTS: The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. CONCLUSIONS: In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.

Stability in the cumulative incidence, severity and mortality of 101 cases of invasive mucormycosis in high-risk patients from 1995 to 2011: a comparison of eras immediately before and after the availability of voriconazole and echinocandin-amphotericin combination therapies.

As invasive mucormycosis (IM) numbers rise, clinicians suspect prior voriconazole worsens IM incidence and severity, and believe combination anti-fungal therapy improves IM survival. To compare the cumulative incidence (CI), severity and mortality of IM in eras immediately before and after the commercial availability of voriconazole all IM cases from 1995 to 2011 were analysed across four risk-groups (hematologic/oncologic malignancy (H/O), stem cell transplantation (SCT), solid organ transplantation (SOT) and other), and two eras, E1 (1995-2003) and E2, (2004-2011). Of 101 IM cases, (79 proven, 22 probable): 30 were in E1 (3.3/year) and 71 in E2 (8.9/year). Between eras, the proportion with H/O or SCT rose from 47% to 73%, while 'other' dropped from 33% to 11% (P = 0.036). Between eras, the CI of IM did not significantly increase in SCT (P = 0.27) or SOT (P = 0.30), and patterns of anatomic location (P = 0.122) and surgical debridement (P = 0.200) were similar. Significantly more patients received amphotericin-echinocandin combination therapy in E2 (31% vs. 5%, P = 0.01); however, 90-day survival did not improve (54% vs. 59%, P = 0.67). Since 2003, the rise of IM reflects increasing numbers at risk, not prior use of voriconazole. Frequent combination of anti-fungal therapy has not improved survival.