Dannah Wray

Cryptococcus neoformans in Organ Transplant Recipients: Impact of Calcineurin-Inhibitor Agents on Mortality

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixty-one percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P=.048). The overall mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P=.023), renal failure at baseline (P=.028), fungemia (P=.006), and disseminated infection (P=.035) and was lower in those receiving a calcineurin-inhibitor agent (P=.003). In a multivariable analysis, the receipt of a calcineurin-inhibitor agent was independently associated with a lower mortality (adjusted HR, 0.21; P=.008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P=.037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients.

Pulmonary Cryptococcosis in Solid Organ Transplant Recipients: Clinical Relevance of Serum Cryptococcal Antigen

BACKGROUND The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. METHODS We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006. RESULTS Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008). CONCLUSIONS A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.

Calcineurin Inhibitor Agents Interact Synergistically with Antifungal Agents In Vitro against Cryptococcus neoformans Isolates: Correlation with Outcome in Solid Organ Transplant Recipients with Cryptococcosis

ABSTRACT Synergistic interactions were observed between CIs and antifungal agents against 53 (90%) of 59 Cryptococcus neoformans isolates from solid organ transplant recipients with cryptococcosis and may account for better outcomes in patients with cryptococcosis receiving these immunosuppressive agents.

In Vitro Resistance to Thrombin-Induced Platelet Microbicidal Protein in Isolates of Staphylococcus aureus from Endocarditis Patients Correlates with an Intravascular Device Source

Platelet microbicidal proteins (PMPs) are small antimicrobial peptides secreted by mammalian platelets. In vitro resistance of Staphylococcus aureus strains to PMPs correlates with more extensive disease in experimental infective endocarditis (IE). To determine whether this same relationship exists in human S. aureus IE, we evaluated the in vitro PMP susceptibility phenotype of isolates from 58 prospectively-identified patients with definite S. aureus IE. On multivariate analyses, patients with S. aureus IE complicating an infected intravascular device were significantly more likely to have IE caused by a PMP-resistant strain (P=.0193). No correlations were detected between in vitro PMP resistance among S. aureus strains and the severity of human IE. This work supports the concept that in vitro PMP resistance in clinical S. aureus strains is associated with important clinical characteristics of S. aureus endovascular infections in vivo.

Central Nervous System Cryptococcosis in Solid Organ Transplant Recipients : Clinical Relevance of Abnormal Neuroimaging Findings

Background. Prognostic implications of cryptococcal antigen and outcomes associated with central nervous system (CNS) cryptococcal lesions in solid organ transplant recipients have not been fully defined. Methods. Patients were derived form a cohort of 122 solid organ transplant recipients with cryptococcosis in a multicenter study from 1999 to 2006. Results. Central nervous system cryptococcosis was documented in 61 patients. Serum or cerebral spinal fluid antigen titers did not correlate with mortality at 90 days or cerebral spinal fluid sterilization at 2 weeks. Central nervous system lesions were identified in 16 patients and included leptomeningeal lesions in eight, parenchymal lesions in six, and hydrocephalus in two. Overall, 13/16 CNS lesions were present at the time of diagnosis. One parenchymal and two hydrocephalus lesions, however, developed after diagnosis and fulfilled the criteria for immune reconstitution syndrome. Cerebral spinal fluid antigen titers were higher with meningeal versus parenchymal lesions, and hydrocephalus (P=0.015). Mortality was 50% (3/6) for patients with parenchymal, 12.5% (1/8) for those with leptomeningeal, and 0/3 for patients with hydrocephalus. Mortality was 31% (4/13) for patients with CNS lesions at baseline and 0/3 in those with new onset lesions. Conclusions. Despite a higher antigen titer with meningeal lesions, outcomes tended to be worse with parenchymal compared with meningeal lesions or hydrocephalus. New onset CNS lesions may represent immune reconstitution syndrome and seemed to be associated with better outcome.

Unrecognized pretransplant and donor derived cryptococcal disease in organ transplant recipients.

BACKGROUND Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

Lipid formulations of Amphotericin B significantly improve outcome in solid organ transplant recipients with central nervous system Cryptococcosis

BACKGROUND Whether outcome of central nervous system (CNS) cryptococcosis in solid organ transplant recipients treated with lipid formulations of amphotericin B is different from the outcome of the condition treated with amphotericin B deoxycholate (AmBd) is not known. METHODS We performed a multicenter study involving a cohort comprising consecutive solid organ transplant recipients with CNS cryptococcosis. RESULTS Of 75 patients treated with polyenes as induction regimens, 55 (73.3%) received lipid formulations of amphotericin B and 20 (26.7%) received AmBd. Similar proportions of patients in both groups had renal failure at baseline (P = .94 ). Overall, mortality at 90 days was 10.9% in the group that received lipid formulations of amphotericin B and 40.0% in the group that received AmBd. In univariate analysis, nonreceipt of calcineurin inhibitors (P = .034), renal failure at baseline (P = .016), and fungemia (P = .003) were significantly associated with mortality. Compared with AmBd, lipid formulations of amphotericin B were associated with a lower mortality (P = .007). Mortality did not differ between patients receiving lipid formulations of amphotericin B with or without flucytosine (P = .349). In stepwise logistic regression analysis, renal failure at baseline (odds ratio [OR], 4.61; 95% confidence interval [CI], 1.02-20.80; P = .047) and fungemia (OR, 10.66; 95% CI, 2.08-54.55; P = .004 ) were associated with an increased mortality, whereas lipid formulations of amphotericin B were associated with a lower mortality (OR, 0.11; 95% CI, 0.02-0.57; P = .008). CONCLUSIONS Lipid formulations of amphotericin B were independently associated with better outcome and may be considered as the first-line treatment for CNS cryptococcosis in these patients.

Predictors of Immune Reconstitution Syndrome in Organ Transplant Recipients with Cryptococcosis: Implications for the Management of Immunosuppression

BACKGROUND Risk factors including how changes in immunosuppression influence the occurrence of immune reconstitution syndrome (IRS) in solid organ transplant (SOT) recipients with cryptococcosis have not been fully defined. METHODS SOT recipients with cryptococcosis were identified and followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS Of 89 SOT recipients, 13 (14%) developed IRS. Central nervous system (CNS) disease (adjusted odds ratio [AOR], 6.23; P = .03) and discontinuation of calcineurin inhibitor (AOR, 5.11; P = .02) were independently associated with IRS. Only 2.6% (1/13) of the patients without these risk factors developed IRS compared with 18.8% (6/32) with 1 risk factor, and 50% (6/12) with both risk factors (χ(2) for trend, P = .0001). Among patients with CNS disease, those with neuroimaging abnormalities (P = .03) were more likely to develop IRS, irrespective of serum or CSF cryptococcal antigen titers and fungemia. Graft rejection after cryptococcosis was observed in 15.4% (2/13) of the patients with IRS compared with 2.6% (2/76) of those without IRS (P = .07). CONCLUSIONS We determined variables that pose a risk for IRS and have shown that discontinuation of calcineurin inhibitors was independently associated with 5-fold increased risk of IRS in transplant recipients with cryptococcosis.

Cutaneous cryptococcosis in solid organ transplant recipients

Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis.

Phylogenetic Analysis of Viridans Group Streptococci Causing Endocarditis

ABSTRACT Identification of viridans group streptococci (VGS) to the species level is difficult because VGS exchange genetic material. We performed multilocus DNA target sequencing to assess phylogenetic concordance of VGS for a well-defined clinical syndrome. The hierarchy of sequence data was often discordant, underscoring the importance of establishing biological relevance for finer phylogenetic distinctions.