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.

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.

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.

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.

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.

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.

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.

Mycobacterium arupense flexor tenosynovitis: case report and review of antimicrobial susceptibility profiles for 40 clinical isolates.

We describe a case of chronic tenosynovitis in the hand of a 58-year-old cattle farmer. Surgical biopsy specimens grew Mycobacterium arupense. The patient responded to surgery and antimicrobial therapy based on in vitro susceptibility testing. The antimicrobial susceptibility profiles of the isolate from this patient and 39 additional clinical isolates are presented.

Mucormycosis in patients with inflammatory bowel disease: case series and review of the literature.

Mucormycosis is a rare and often fatal invasive fungal infection mostly seen in immune-compromised individuals. A high index of clinical suspicion is necessary, so that effective preemptive therapy can be started, as timely intervention is crucial. In this series we present three cases of invasive mucormycosis in patients with underlying inflammatory bowel disease that had received therapy with immunomodulators prior to the infection. All three had varied clinical manifestations. We also review the literature of invasive mucormycosis in patients with inflammatory bowel disease.

Campylobacter prosthetic joint infection.

A 75-year-old man was diagnosed with probable Campylobacter jejuni prosthetic knee infection after a diarrheal illness. Joint aspirate and operative cultures were negative, but PCR of prosthesis sonicate fluid was positive, as was stool culture. Nineteen additional cases of Campylobacter prosthetic joint infection reported in the literature are reviewed.

Cardiovascular implantable electronic device infections in left ventricular assist device recipients.

BACKGROUND: Most patients with left ventricular assist devices (LVADs) have concomitant cardiovascular implantable electronic devices (CIEDs). However, clinical presentation and outcome of CIED infection in the setting of LVAD has not been previously described. METHODS: We retrospectively reviewed 247 patients who underwent LVAD implantation at Mayo Clinic campuses in Minnesota, Arizona, and Florida, from January 2005 to December 2011. Demographic and clinical data of patients who met criteria for CIED infection were extracted. RESULTS: Of 247 patients with LVADs, 215 (87%) had CIED at the time of LVAD implantation and six (2.8%) subsequently developed CIED infections. Three patients developed CIED lead-related endocarditis and the other three had pocket infection. All three instances of CIED pocket infection were preceded by device generator exchange, whereas all three patients with CIED lead-related endocarditis had prior LVAD-related infections. Causative pathogens included Pseudomonas aeruginos (1), coagulase-negative staphylococci (2), methicillin-resistant Staphylococcus aureus (1), a gram-positive bacillus (1), and culture negative (2). All patients underwent complete CIED removal along with antimicrobial therapy. The three patients with CIED lead-related endocarditis and prior LVAD infections received chronic suppressive antibiotic therapy, and one patient had LVAD exchange. All but one remained alive at the last follow-up with a median duration of 15 months (7-46 months) from the time of CIED infection. CONCLUSION: Patients who are receiving LVAD therapy and develop CIED infection should be managed with complete CIED removal. Chronic suppressive antibiotic therapy is warranted in cases that have concomitant LVAD infection.

Clinical manifestations and management of left ventricular assist device-associated infections.

BACKGROUND: Infection is a serious complication of left ventricular assist device (LVAD) therapy. Published data regarding LVAD-associated infections (LVADIs) are limited by single-center experiences and use of nonstandardized definitions. METHODS: We retrospectively reviewed 247 patients who underwent continuous-flow LVAD implantation from January 2005 to December 2011 at Mayo Clinic campuses in Minnesota, Arizona, and Florida. LVADIs were defined using the International Society for Heart and Lung Transplantation criteria. RESULTS: We identified 101 episodes of LVADI in 78 patients (32%) from this cohort. Mean age (± standard deviation [SD]) was 57±15 years. The majority (94%) underwent Heartmate II implantation, with 62% LVADs placed as destination therapy. The most common type of LVADIs were driveline infections (47%), followed by bloodstream infections (24% VAD related, and 22% non-VAD related). The most common causative pathogens included gram-positive cocci (45%), predominantly staphylococci, and nosocomial gram-negative bacilli (27%). Almost half (42%) of the patients were managed by chronic suppressive antimicrobial therapy. While 14% of the patients had intraoperative debridement, only 3 underwent complete LVAD removal. The average duration (±SD) of LVAD support was 1.5±1.0 years. At year 2 of follow-up, the cumulative incidence of all-cause mortality was estimated to be 43%. CONCLUSION: Clinical manifestations of LVADI vary on the basis of the type of infection and the causative pathogen. Mortality remained high despite combined medical and surgical intervention and chronic suppressive antimicrobial therapy. Based on clinical experiences, a management algorithm for LVADI is proposed to assist in the decision-making process.

Epidemiology of infections requiring hospitalization during long-term follow-up of pancreas transplantation.

BACKGROUND.: Pancreas transplantation (PT) provides the best glycemic control option for diabetes mellitus but is associated with significant morbidities related to infectious disease. METHODS.: We performed a retrospective study of a cohort of consecutive PT recipients in whom PT was performed from 1998 to 2006 (n=216) and followed up them until July 2008. Data regarding infections, rejection, infection chemoprophylaxis, graft failure, absolute lymphocyte counts (ALCs), and mortalities were collected. RESULTS.: Simultaneous pancreas and kidney, pancreas transplantation alone, and pancreas after kidney (PAK) transplantations were performed in 42, 67, and 107 patients, with a mean (standard deviation) age at transplantation of 46.8 (8.03), 40.6 (10.1), and 43.7 (8.19) years. Of the simultaneous pancreas and kidney, pancreas transplantation alone, and PAK transplant recipients, 54.7%, 37.3%, and 58.8% were men. Overall, 63% developed a serious infection during the median follow-up of 6.4 years. Mean (range) number of infectious episodes was 2.3 (1-12), with mostly bacterial infections both within (68%) and after 1 year (78%). Incidence of bacterial and viral infections was greatest in the first 3 months after transplantation. Fungal infections were more constant. Bladder exocrine drainage was associated with higher risk of infection (hazard ratio=2.5, P<0.001). Infection within the first 3 months after transplantation was related to higher mortality after the first 3 months (hazard ratio=3.19). ALC was associated with the risk of first infections (P=0.005) and bacterial infections (P<0.001). CONCLUSIONS.: Incidence of infections after PT was 63% and mostly bacterial. Bladder drainage increases infection risk and low ALC partially predicts episodes. Limitations include retrospective design, unequal composition of PT groups, and lack of data between kidney and PT for PAK.

The impact of invasive fungal diseases on survival after lung transplantation.

BACKGROUND: Recipients of lung transplants are at high risk of infectious complications. We investigated the epidemiology of infections after lung transplantation and determined their impact on survival. METHODS: We retrospectively reviewed the medical records of patients who underwent lung transplantation at Mayo Clinic (Rochester) during 1990-2005. Survival analyses were performed using Kaplan-Meier estimation and Cox proportional hazard modeling. RESULTS: Sixty-nine lung transplants were performed during the 16-yr study period. The mean (+/-SD) patient age was 50.5 +/- 9.7 yr; 45% were male. During the mean (+/-SD) follow-up period of 1188 (+/-1288) d, the cumulative percentage of patients with infections were: bacteria (52%), cytomegalovirus (CMV) (49%), other viruses (32%), fungi (19%), mycobacteria (7%), and Pneumocystis jiroveci (1%). The median survival time after lung transplantation was 5.02 yr. Kaplan-Meier estimation of one-, three-, and five-yr survival was 80%, 61%, and 50%, respectively. Overall, 37 (54%) patients died due to graft rejection and failure (35%), invasive fungal diseases (16%), post-transplant lymphoproliferative disorder and other malignancies (14%), cardiovascular diseases (5%), CMV disease (3%), bacterial infection (3%), or other causes (24%). Survival analysis using Kaplan-Meier estimation showed that invasive fungal disease (Aspergillus sp., n = 9, Candida sp., n = 2, Alternaria sp., n = 1, Rhizopus sp., n = 1, and/or Mucor sp., n = 1) was significantly associated with mortality (p = 0.0104). After adjusting for age and graft rejection, invasive fungal disease remains a significant predictor of mortality (p = 0.0262). CONCLUSION: Invasive fungal disease is significantly associated with all-cause mortality after lung transplantation. An aggressive antifungal preventive strategy may lead to improved survival after lung transplantation.