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To evaluate whether mediastinitis/deep sternal wound infection (Med/DSWI) is more common in ventricular assist device (VAD) with delayed sternal closure (DSC) compared to VAD with primary sternal closure (PSC).A literature search was done over the last four decades for studies that addressed this comparison.Two studies met our inclusion criteria, and their results are contradictory. The first study compared 184 VAD recipients with PSC to 180 VAD recipients with DSC. There was no difference in VAD-related infections between DSC and PSC (15% vs. 16%, respectively; odds ratio = 0.965, 95% confidence interval [CI] = 0.525-1.635). The second study compared 464 VAD recipients with PSC to 94 VAD recipients with DSC. The rate of surgical site infection was higher in the DSC patients (12.5% vs. 1.4%, respectively; odds ratio = 10.1; 95% CI = 3.8-27.0). DSC was identified as an independent risk factor for postoperative mortality, but no detailed infection information was given.There is no clear evidence of the association between DSC, compared to PSC, and Med/DSWI. Therefore, DSC is not an absolute indication for extended systemic antibiotic prophylaxis. The decision to extend the duration of systemic antibiotic prophylaxis should be made on a case-by-case basis, in collaboration with an infectious disease specialist.

Post-transplantation lymphoproliferative disorder (PTLD) is a complication of solid organ and hematopoietic stem cell transplantation. Cases with isolated central nervous system (CNS) disease are rare. Epstein-Barr virus (EBV) plays a causative role. We present a patient with EBV cerebellitis documented 5 months prior to development of primary CNS PTLD (PCNS-PTLD). This case report demonstrates progression from EBV CNS infection to lymphoproliferative disorder, highlighting the importance of serial clinical and imaging monitoring in transplant patients post-EBV CNS infection. PCNS-PTLD should always be considered in the differential diagnosis for transplant patients presenting with CNS symptoms, even in cases with no evidence of EBV viremia. Earlier diagnosis and appropriate treatment could result in improved outcomes.

Tick-borne relapsing fever (TBRF) is a bacterial infection transmitted by tick bites that occurs in several different parts of the world, including the western United States. We describe 6 cases of TBRF acquired in the White Mountains of Arizona, USA, and diagnosed during 2013-2018. All but 1 case-patient had recurrent fever, and some had marked laboratory abnormalities, including leukopenia, thrombocytopenia, hyperbilirubinemia, and elevated aminotransaminases. One patient had uveitis. Diagnosis was delayed in 5 of the cases; all case-patients responded to therapy with doxycycline. Two patients had Jarisch-Herxheimer reactions. The White Mountains of Arizona have not been previously considered a region of high incidence for TBRF. These 6 cases likely represent a larger number of cases that might have been undiagnosed. Clinicians should be aware of TBRF in patients who reside, recreate, or travel to this area and especially for those who sleep overnight in cabins there.

Donor-derived coccidioidomycosis has caused unexpected morbidity and mortality in transplant recipients. All proven or probable reports of donor-derived coccidioidomycosis to the Disease Transmission Advisory Committee between 2005 and August 2012 were reviewed. Six reports of proven or probable coccidioidomycosis were discovered. In four of six, the infection was first detected at autopsy in the recipient. In two cases it was first identified in the donor. Twenty-one recipients received organs from these six donors. Transmission occurred in 43% at a median of 30 days posttransplant with a mortality rate of 28.5%. Eleven recipients received preemptive antifungals, seven did not receive treatment, and treatment information was not reported for three recipients. Five of seven who did not receive prophylaxis/treatment died and all 11 who received early therapy survived. Six deaths occurred 14 to 55 days after transplant, with a median of 21 days. For exposed recipients, donor-derived coccidioidomycosis is a significant cause of morbidity and mortality. Evidence of infection in one recipient should prompt immediate evaluation for treatment of all other recipients from the same donor as preemptive treatment was effective. Further studies are needed to decide whether all donors from endemic areas should have routine serologic screening.

There are currently no guidelines for the management of infection and its prevention in mechanical circulatory support (MCS) device recipients. The International Society of Heart and Lung Transplantation (ISHLT) has initiated a multidisciplinary collaboration for the creation of a consensus document to guide clinicians in infection prevention and management in MCS patients. Most medical centers use local protocols that are based on expert opinion. MCS recipients are debilitated and have some immunological dysfunction. Over the years there have been technical advancements with smaller devices and drivelines with improved durability. The pulsatile devices have been replaced with newer-generation continuous-flow devices. Patient are living longer with MCSs for bridge to transplant (BTT) and destination therapy (DT). MCS centers have improved patient management by introducing standardized driveline protocols, leading to reduced infection rates among MCS recipients.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Background Tenosynovitis is an uncommon manifestation of disseminated infection with Coccidioides fungal species. Most experts treat this infection with combined surgical debridement and antifungal medication. The aim of our study was to examine the outcomes of patients with coccidioidal tenosynovitis of the hand and wrist. Methods We retrospectively searched for the records of patients with coccidioidal tenosynovitis of the hand and wrist at our institution. between 1987 and 2013. We also conducted a review of the literature from 1950 to 2014 to identify additional cases. Results We identified 9 cases of coccidioidal tenosynovitis of the hand and wrist at our institution, along with 5 other cases found in a review of the literature. The relapse rate was high overall (50%) and was higher after discontinuation of antifungal therapy (71%) in both immunocompromised and immunocompetent patients. Results of serologic testing were not predictive of relapse. Conclusions A treatment strategy for coccidioidal tenosynovitis should focus on long-term administration of antifungal agents.

Breast fungal infections are rare in nonlactating women. The present report is the first to describe a necrotizing cutaneous breast fungal infection. A 50-year-old woman with a remote history of breast cancer and autologous tissue reconstruction presented with a progressive cutaneous necrotic infection one year after implant augmentation of the reconstruction. Multiple eschars developed on the left breast, and pathological examination of debrided tissue revealed numerous fungal hyphae invading the epidermis, dermis and adipose tissue of the breast. Fungal cultures yielded Bipolaris species. She was treated with voriconazole. Five months later, the patient presented with an eschar on her back, indicative of disseminated disease. Bipolaris species are dematiaceous fungi; cutaneous or disseminated infections with Bipolaris species have rarely been reported in immunocompetent patients. Unresectable or recurrent lesions should be treated with antifun-gals. Cutaneous necrotizing breast fungal infections should be considered in patients who do not respond to antibacterial therapy.

In summer 2015, three unrelated solid organ transplant recipients in Phoenix, Arizona, had meningoencephalitis suggestive of West Nile virus (WNV) infection. Testing was inconclusive but was later confirmed as St. Louis encephalitis (SLE). We retrospectively reviewed clinical manifestations, treatment, and outcomes of these transplant recipients. Common symptoms were fever, rigors, diarrhea, headache, and confusion. One patient died 3 days after hospitalization. Therapy for the other two patients was initiated with interferon α-2b (IFN) and intravenous IgG (IVIG; IFN plus IVIG in combination). Both patients tested positive for WNV by serologic assay, but SLE virus (SLEV) infection was later confirmed by plaque reduction neutralization test at a reference laboratory. Clinical improvement was observed within 72 h after initiation of IFN plus IVIG. SLEV has been an uncommon cause of neuroinvasive disease in the United States. Accurate, timely diagnosis is hindered because of clinical presentation similar to neuroinvasive WNV and SLE, serologic cross-reactivity, and lack of a commercially available serologic assay for SLEV. There is currently no approved therapy for flaviviral neuroinvasive disease. Anecdotal reports indicate varying success with IFN, IVIG, or IFN plus IVIG in WNV neuroinvasive disease. The same regimen might be of value for immunocompromised persons with neuroinvasive SLEV infection.

BackgroundThorn injuries are common in the desert Southwest; however, the frequency and microbiology of thorn-associated infections have not been systematically described. Most information comes from case reports describing infections from atypical or environmental microorganisms. Our aim was to summarize the spectrum of thorn-associated infections.MethodsWe conducted a retrospective review of electronic health records for patients presenting to our institution from January 1, 2005 to December 31, 2014 for treatment of thorn-associated injuries and then focused on the patients with cultures.ResultsOf 2758 records reviewed, 1327 patients had thorn-associated injuries; however, only 58 (4.4%) had cultures. Of these patients, 37 (64%) had positive findings; 5 had polymicrobial infection. The most commonly identified organisms were Staphylococcus aureus (n = 22, 59.0%) and coagulase-negative Staphylococcus species (n = 8, 21.6%). Other pathogens included Nocardia species (n = 3, 8.1%), Streptococcus species (n = 2, 5.4%), Gram-negative bacteria (n = 2, 5.4%), Aspergillus species (n = 2, 5.4%), Paecilomyces lilacinus (n = 1, 2.7%), and Candida species (n = 1, 2.7%). There were no infections caused by Pantoea agglomerans, Sporothrix schenckii, or Coccidioides spp.ConclusionsIn contrast to most published case reports, we found that typical cutaneous microorganisms, such as Staphylococcus species, caused the majority of culture-positive, thorn-related infections.

Summary 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.

Convalescence is prolonged, regardless of whether the patient receives treatment., In Arizona, USA, primary pulmonary coccidioidomycosis accounts for 15%–29% of community-acquired pneumonia. To determine the evolution of symptoms and changes in laboratory values for patients with mild to moderate coccidioidomycosis during 2010–2012, we conducted a prospective 24-week study of patients with primary pulmonary coccidioidomycosis. Of the 36 patients, 16 (44%) were men and 33 (92%) were White. Median age was 53 years, and 20 (56%) had received antifungal treatment at baseline. Symptom scores were higher for patients who received treatment than for those who did not. Median times from symptom onset to 50% reduction and to complete resolution for patients in treatment and nontreatment groups were 9.9 and 9.1 weeks, and 18.7 and 17.8 weeks, respectively. Median times to full return to work were 8.4 and 5.7 weeks, respectively. One patient who received treatment experienced disseminated infection. For otherwise healthy adults with acute coccidioidomycosis, convalescence was prolonged, regardless of whether they received antifungal treatment.

Discrete nodules developed on the leg of a 27-year-old immunosuppressed woman after an allogeneic stem cell transplant. Biopsy and culture grew Legionella pneumophila serogroup 8. On day 7 of azithromycin treatment, respiratory distress and abnormal liver transaminases developed, and the patient died on day 14. Review of the medical literature identified 19 reports of Legionella species-associated skin or soft tissue infections (total of 20 patients, 13 with confirmed infection). Manifestations of the 13 confirmed cases included erythematous macular rash (n = 7), erythema after thoracentesis (n = 1), abscess formation (n = 4), respiratory symptoms (n = 6), and abnormal chest radiographs (n = 8). Six required surgical exploration and débridement, and 7 were immunocompromised. Rash and respiratory infection improved with antibiotics in 10, but 3 died. Immunosuppression may predispose transplant recipients to Legionella infections. Diagnostic biopsies may facilitate appropriate treatment.

In endemic regions, coccidioidomycosis causes substantial morbidity and mortality for patients receiving solid organ transplants. We aimed to demonstrate the effect of antifungal coccidioidal prophylaxis in heart transplant (HT) recipients. We retrospectively reviewed the electronic health records of all patients who received HTs between October 19, 2005, and December 13, 2014. We collected information regarding antifungal regimens and determined whether patients subsequently developed infections. Our 174-person cohort all received antifungal prophylaxis for at least 6 months (mean follow-up, 53.8 months). One proven and one probable coccidioidal infection (each, 0.6%) occurred during the study period. The incidence of coccidioidomycosis was 0.6% at 1 year and 2.3% at 5 years. No cases of proven coccidioidomycosis occurred within 2 years after transplantation. No patients developed disseminated disease, and no sentinel events were attributed to coccidioidomycosis. Both fluconazole and voriconazole were well tolerated. In the absence of intolerance or contraindication, we suggest continuing a universal antifungal prophylactic regimen with fluconazole for at least 6-12 months in HT recipients residing in a coccidioidomycosis-endemic area. This article is protected by copyright. All rights reserved.

To describe the demographics, clinical manifestations, treatment and outcomes of patients with human adenovirus (HAdV) hepatitis. A case of fulminant HAdV hepatitis in a patient with chronic lymphocytic leukemia receiving rituximab and fludarabine is described. We conducted a comprehensive review of the English-language literature through May, 2012 in search of definite cases of HAdV hepatitis. Eighty-nine cases were reviewed. Forty-three (48 %) were liver transplant recipients, 19 (21 %) were bone marrow transplant recipients, 11 (12 %) had received chemotherapy, five (6 %) had severe combined immunodeficiency, four (4 %) were HIV infected, two had heart transplantation, and two were kidney transplant recipients. Ninety percent (46/51) of patients presented within 6 months following transplantation. Fever was the most common initial symptom. Abdominal CT scan revealed hypodense lesions in eight of nine patients. Diagnosis was made by liver biopsy in 43 (48 %), and on autopsy in 46 (52 %). The HAdV was isolated at other sites in 54 cases. Only 24 of 89 patients (27 %) survived: 16 whose immunosuppression was reduced, six with liver re-transplantation, and two who received cidofovir and intravenous immunoglobulin. HAdV hepatitis can manifest as a fulminant illness in immunocompromised hosts. Definitive diagnosis requires liver biopsy. Early consideration of a viral etiology, reduction in immunosuppression, and liver transplantation can be potentially life-saving.

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.

Summary Objective Primary pulmonary coccidioidomycosis can often be associated with hypersensitivity symptoms treatable with a short course of palliative corticosteroids. Long-term use of corticosteroids is a known risk factor for severe or disseminated infection but the effects of short-term use are not known. Methods A retrospective review was conducted of immunocompetent patients with acute pulmonary coccidioidomycosis who received systemic corticosteroids for relief of coccidioidal-related symptoms. Age- and sex-matched controls were also reviewed. Predetermined end-points were assessed. Results Seventy-four patients met inclusion criteria for the corticosteroid-treated group, and 74 controls were identified. Cumulative corticosteroid (prednisone-equivalent) doses were 10 mg→3,600 mg (mean = 206 mg; median = 120 mg). Corticosteroids were prescribed most commonly for rash 43/74 [58%] or asthma/wheezing/cough 30/74 [41%]. Coccidioidal-related hospitalization occurred in 19 patients in the corticosteroid group vs. 22 in the control group ( P = .58). Coccidioidal-related symptoms resolved within a mean of 19 weeks (median = 8 weeks [range = 2–208 weeks]) vs. 32.3 weeks (median = 8 weeks [range = 1–1040 weeks]) in the corticosteroid and control groups ( P = .38). Relapse of symptoms occurred in 12% of both groups ( P > .99). Extrapulmonary dissemination occurred in 3% vs. 4.0% ( P > .99) in the corticosteroid and control groups, respectively. Conclusion This study found no adverse effects of short-term corticosteroid therapy for early symptomatic treatment in acute pulmonary coccidioidomycosis.

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Coccidioidomycosis is a common infection in the desert southwestern USA; approximately 3 % of healthy persons in Arizona alone become infected annually. Coccidioidomycosis may be severe in immunocompromised persons, but experience among patients with solid organ cancer has not been fully described. Therefore, we aimed to describe the clinical courses of patients whose cancers were complicated by coccidioidomycosis at our institution, which is located in an area with endemic Coccidioides. To do so, we conducted a retrospective review from January 1, 2000, through December 31, 2014, of all patients with breast, colorectal, or ovarian cancer whose cancer courses were complicated by coccidioidomycosis. We identified 17,576 cancer patients; 14 (0.08 %) of these patients met criteria for proven or probable coccidioidomycosis diagnosed within the first 2 years after the cancer diagnosis. All of these patients had primary pulmonary coccidioidomycosis, none had relapsed prior infection, and 1 had possible extrapulmonary dissemination. Five had active coccidioidal infection during chemotherapy, 1 of whom was hospitalized for coccidioidal pneumonia. All were treated with fluconazole, and all improved clinically. Eleven did not require prolonged courses of fluconazole. There were no clearly demonstrated episodes of relapsed infection. In conclusion, coccidioidomycosis was not a common complication of breast, colorectal, or ovarian cancers in patients treated at our institution, and it was not commonly complicated by severe or disseminated infection.

Liver transplant recipients have a high risk of infectious complications, compared with recipients of other solid organs, despite the improvement in surgical techniques, shortening of operative times, and the development of novel anti-infective agents in the last decade. A careful examination of risk factors, diligent surveillance for early signs of infection, and prompt intervention are necessary to minimize serious infectious complications, which often contribute to graft loss and death in this population. Future strategies to develop diagnostic assays that are rapid, cost-effective, standardized, and easily performed will improve our abilities to prevent donor-transmitted infections. Ability to assess the immune competence of the recipients and to optimally prescribe appropriate antimicrobial prophylaxis will allow us to prevent infection. Areas such as liver transplant in HIV coinfection and the prevention of recurrence of viral hepatitides after transplantation have made some progress but require further research before the establishment of accepted therapeutic strategies.

Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Consequently, infection prevention is an essential component of any organ transplant program. Given their frequent and often prolonged contact with the healthcare system, solid organ transplant recipients are at high risk for healthcare-associated infections, including those caused by antibiotic-resistant organisms. In this chapter we review several different healthcare-associated infections of importance to transplant recipients, including those caused by bacterial, viral, and fungal organisms. We also describe infection prevention and control strategies applicable to this patient population. These practices focus on clinical interventions and environmental controls designed to prevent the spread of potentially pathogenic organisms in the healthcare setting. We also describe post-exposure interventions applicable to solid organ transplant recipients exposed to potential pathogens in order to reduce their risk of subsequent infection.

Summary Objectives To describe the demographics, clinical manifestations, treatment, and outcomes of patients with pulmonary alveolar proteinosis (PAP) who developed an opportunistic infection with Nocardia spp., mycobacteria or fungal pathogens. Methods A case of PAP and Nocardia spp. brain abscess is described. A comprehensive review of the English-language literature was conducted to identify all reported cases of PAP and opportunistic infections between 1950 and July, 2010. Results Seventy five cases were reviewed. Thirty two patients (43%) had nocardial infection, 28 (37%) mycobacterial infection, and 15 (20%) fungal infection. Thirty nine patients (65%) were male. Seventeen patients (23%) were immunosuppressed. Twenty patients (27%) were active smokers. PAP was the initial diagnosis in 19 patients (33%), while infection presented first in 23 patients (40%); 16 patients (27%) had a concurrent diagnosis of PAP and infection. The average interval between PAP diagnosis and an opportunistic infection was 16 months. Lungs were the most common site of infection; extra-pulmonary infection was present in 27 patients (32%). Thirty nine patients (57%) survived through the follow-up period, while 31 died. Conclusions Opportunistic infections can either precede or follow a diagnosis of PAP. PAP should be considered in apparently immunocompetent patients who present with an opportunistic infection and diffuse alveolar infiltrates.

BK virus (BKV) and John Cunningham virus (JCV) are nonenveloped icosahedral DNA viruses, members of the family Polyomaviridae. Studies have estimated that the adult population worldwide is approximately 80% seropositive for BKV and approximately 50%–70% seropositive for JCV, with JCV seropositivity increasing with age [1–3]. Primary infection normally occurs during childhood, with the viruses then establishing latency/persistence in different organs, including the kidney [4, 5]. BKV and JCV undergo periodic reactivation and replication, and may cause disease in immunosuppressed hosts [6–10]. It is not known exactly which factors control the balance between latency and reactivation of BKV and JCV, but available data suggest that the cellular immune response exerts important control over these viruses [6, 11–14]. BKV is known to cause diseases of the genitourinary tract, such as hemorrhagic cystitis in bone marrow and hematopoietic stem cell transplant recipients and ureteric stenosis in renal transplant patients. However, the virus is most frequently implicated with the development of polyomavirus-associated nephropathy (PVAN) in kidney transplant patients [6, 9, 15, 16]. Reduced host immunity seems to play an important role, as studies indicate that lowering of the level of immunosuppression is associated with a decrease in BKV viral load and reduction of allograft inflammation in kidney transplant patients [6, 8, 15, 16]. Progressive multifocal leukoencephalopathy is a disease of the central nervous system, characterized by multiple foci of demyelination caused by lytic JCV infection of oligodendrocytes [7, 10, 17, 18]. Progressive multifocal leukoencephalopathy has been reported among heart, kidney, and liver transplant recipients, but its true incidence in these patient groups is not known [6, 19–21]. In addition, JCV has also been associated with some cases of PVAN in kidney transplant recipients [22–24]. Data suggest that JCV-associated PVAN may be characterized by sparse cytopathic changes but significant inflammation and fibrosis in kidney transplant patients [24]. However, the relationship between JCV reactivation and renal dysfunction is not clear, as systematic monitoring of JCV infection is not performed in kidney and nonkidney transplant patients. A high incidence of renal dysfunction has been reported in nonrenal transplant recipients [25, 26]. This renal disease has been attributed to the cumulative toxicity of calcineurin inhibitors, but many of these patients are not monitored for polyomavirus reactivation, so it is possible that polyomaviruses are more commonly associated with this clinical syndrome than currently appreciated. There is a need, therefore, for prospective studies to examine the role of BKV and JCV in renal dysfunction among nonrenal organ transplant patients. In addition, some questions remain concerning the clinical management of BKV and JCV following organ transplantation, such as the dynamics of reactivation of individual viruses in different organ transplant groups and the advisability of viral monitoring. In this prospective study, we examined BKV and JCV urinary shedding and their relationship with creatinine clearance (CrCl) in outpatient liver and kidney transplant recipients to determine whether the patterns of viral reactivation were similar in the 2 patient groups and if viral shedding was associated with renal dysfunction in liver transplant recipients.

Background Coccidioidomycosis is a fungal infection of the desert southwestern United States. It may be self-limited or may require antifungal therapy. Currently used triazoles (eg, fluconazole and itraconazole) have largely supplanted amphotericin B, which is fraught with adverse effects. Limited case reports and small open-label trials show that voriconazole and posaconazole benefit patients with coccidioidomycosis refractory to first-line agents. Methods We conducted a retrospective review of patients prescribed voriconazole or posaconazole for coccidioidomycosis at our institution between 1 January 2006 and 1 August 2010. Outcomes were assessed with both a retrospectively applied Mycosis Study Group score (ie, a composite score for symptoms, serology, and radiographic findings) and the documented impressions of treating medical practitioners. Results Twenty-one patients who received voriconazole and 16 who received posaconazole met study criteria. After a median duration of 6 months of voriconazole treatment, 14 of 21 patients (67%) were improved in overall status, 5 were unchanged, and 2 were unresponsive to voriconazole. After a median of 17 months of posaconazole treatment, 12 of 16 patients (75%) showed improvement, 1 was unchanged, and 3 were unresponsive due to medication intolerance or relapsed infection. Conclusions Voriconazole and posaconazole are reasonable but not infallible options for salvage treatment of refractory coccidioidomycosis. Prospective comparative trials are required to provide further insights into their efficacy and utility.

Background. The 2009 H1N1 influenza virus was first identified in April 2009 and rapidly evolved into a pandemic. There are limited reports of 2009 H 1N1 influenza in transplant recipients. We report on our experience with hospitalized transplant recipients with 2009 H1N1 influenza virus. Methods. Ongoing review of hospitalized 2009 H1N1 influenza cases identified six patients who had received transplants. Clinical characteristics and outcomes were abstracted from the medical record. Results. Between April 27 and November 30, 2009, 29 patients with influenza A virus were admitted to the Mayo Clinic Hospital. Six of the 29 patients were transplant recipients; 4 were confirmed to have 2009 H1N1 influenza virus. Most patients presented with an acute febrile respiratory illness. Duration of antiviral treatment was 5 to 7 days except for one patient who was treated for 11 days until withdrawal of care. Prolonged viral shedding was not noted, and the patients recovered promptly except for a patient with recalcitrant multiple myeloma who died because of the disease. Conclusion. 2009 H1N1 influenza disease in this cohort of hospitalized transplant recipients was relatively mild. The majority of the patients improved promptly, and prolonged viral shedding was not noted.

Coccidioidomycosis results from infection with Coccidioides species endemic to the southwestern United States. The mobile US population has resulted in incremental cases being found throughout the world. The fungal infection can result in pulmonary sequelae, including nodules, cavities, and complications requiring treatment by the thoracic surgeon.A retrospective chart review was conducted of 1,496 patients with coccidioidomycosis treated at our institution (January 1998 to December 2008) to identify those requiring surgery.Of the 1,496 patients, 86 (6%; mean age, 58 years [range, 18 to 81], 48 women) underwent operations. Radiographs revealed 59 nodules, 18 cavities, 2 infiltrates, and 7 complications of disease (e.g., effusion, pneumothorax, and empyema). Of the 86 patients, 40% underwent resection for persistent symptoms or disease progression despite adequate antifungal therapy. One third of the operations were performed by video-assisted thoracoscopic surgery. Morbidity, 21% (18 patients), and in-hospital mortality, 2% (2 patients), were greater after resection for cavitary lesions with resultant complications versus for nodular disease: 41% versus 12% (por = 0.002) and 8% versus 0% (p0.005). Prolonged air leaks or bronchopleural fistulas were the most common complications (13 patients). Postoperative antifungal therapy was administered to 42% of patients (89% of cavitary and complicated). There were no cases of recurrence at follow-up (mean, 24 months).Surgical intervention was indicated for only a few patients, most commonly for diagnostic dilemmas involving nodular disease, symptomatic nonresponsive cavitary disease, or complications. Prolonged air leaks were the main cause of morbidity. Resection should result in symptom resolution and long-term freedom from recurrence.

BACKGROUND Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. METHODS In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. RESULTS Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables. CONCLUSIONS The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

The number of cases of tuberculosis (TB) in the United States declined by 45% between 1993 and 2006. This decline occurred disproportionately among United States–born persons (66%) compared to foreign-born individuals, among whom the number of cases actually increased by 5%. In solid-organ transplant recipients, the incidence of Mycobacterium tuberculosis (MTB) infection worldwide ranges between 0.35% and 15%, depending on the level of endemicity. This rate can be 36to 74-fold greater than that in the general population. The majority of MTB cases after transplantation represent reactivation of latent tuberculosis infection (LTBI), although acquisition of primary TB infection posttransplant and transmission of MTB via the transplanted organ are infrequent possibilities. Active TB in the posttransplantation setting can pose a number of challenges: atypical presentation leading to a delay in diagnosis, therapy associated with drug interactions and toxicities, graft rejection, and formidable morbidity and mortality. This is of particular concern in both patients with end-stage liver disease awaiting liver transplantation and liver transplant recipients, given the hepatotoxicity of several anti-TB medications and their associated drug interactions with immunosuppressants. In this issue of Liver Transplantation, Holty et al. present a systematic review and meta-analysis of TB in liver transplant recipients. They included cases of active MTB infection following liver transplantation as well as transplant candidates or recipients who received 6 months of therapy for LTBI prior to transplantation. The prevalence of active TB in liver transplant recipients was 1.3%. Extrapulmonary infection was seen in 67%, multiorgan involvement was seen in 27%, and 31% died. Tuberculin skin test (TST) results were as follows: a) Among 38 cases of posttransplant active TB with known pretransplant TST status, 37% were TST-positive, 53% were negative, and 11% were anergic; among 17 of these patients who had a posttransplant TST, only 35% were positive. b) In 3 studies with 2972 patients who underwent liver transplantation, 31% of the patients had a pretransplant TST, and 13% of these were positive. None of the TST-positive patients who received isoniazid therapy for at least 6 months developed active TB, whereas 7 TST-positive patients developed active disease without such therapy (mean follow-up, 54 months). Short-term mortality in patients with active posttransplant TB was 31%, with 65% of deaths directly attributed to MTB infection. Because reactivation of LTBI represents the majority of posttransplant cases of active TB, it is prudent to screen and identify such patients before transplantation for consideration of appropriate therapy for LTBI. Until recently, TST was the only test available for LTBI diagnosis. As noted previously, TST was notoriously insensitive: 64% of patients with posttransplant active TB were either TST-negative or anergic prior to transplantation, and 65% of patients had a negative posttransplant TST in the setting of active TB. TST has

Background. Coccidioidomycosis is an endemic fungal infection of the southwestern United States that causes considerable morbidity and mortality in transplant recipients, often as the result of reactivated infection. Methods. A retrospective review of the medical records of 47 patients with prior coccidioidomycosis who underwent solid organ transplantation (18 liver, 24 kidney, 3 pancreas, and 2 combined organ) at our tertiary care academic medical center. Results. Of 47 transplant recipients with a history of coccidioidomycosis, 44 had quiescent infection at transplantation. Of the three with active coccidioidomycosis at transplantation, two were taking azole prophylaxis and had no further coccidioidal infection after transplantation. One of the three had positive serologic findings identified only on the day of transplantation, and prophylaxis was initiated a few hours after surgery along with immunosuppression; nevertheless, the treatment course was complicated by disseminated coccidioidomycosis. Seven patients did not initiate or self-discontinued prophylaxis; one patient who discontinued prophylaxis experienced recurrent pulmonary infection. Conclusions. For patients undergoing transplantation in an area endemic for coccidioidomycosis, we recommend routine evaluation for evidence of prior infection and initiation of azole prophylaxis. For our patients with quiescent infection, azoles suppressed any recrudescent coccidioidomycosis after transplantation. The selection of patients who would benefit from prophylaxis and the optimal dose and duration of such prophylaxis should be studied further.

Kluyvera species are opportunistic, gram-negative bacilli in the family Enterobacteriaceae. Ordinarily occurring as a commensal, Kluyvera have been reported to cause serious infections in immunosuppressed and immunocompetent hosts, causing diarrhea, urinary infections, peritonitis, and cholecystitis. We report Kluyvera infections in 2 solid organ transplant recipients. An 18-year-old female with alpha-1 antitrypsin deficiency underwent living donor liver transplantation and presented 6 months later with a liver abscess. The abscess aspirate grew mixed organisms including Kluyvera cryocrescens. A 22-year-old female with renal failure secondary to focal segmental glomerulosclerosis underwent a deceased donor kidney transplant and presented 3 months later with pyelonephritis; the urine culture grew Kluyvera ascorbata. Both patients improved only when their antibiotic coverage was broadened to include Kluyvera. The isolation of Kluyvera as a pathogen in transplant patients emphasizes that this commensal organism may be virulent in this patient population.

Zygomycetes are ubiquitous fungi that can cause invasive disease associated with high mortality. We report 10 solid organ transplant recipients with zygomycosis (incidence 2 per 1000) and reviewed 106 cases in the English-language literature. These included renal (n = 73), heart (n = 16), lung (n = 4), heart/lung (n = 2), liver (n = 19) and kidney/pancreas (n = 2) transplant recipients. All patients were receiving immunosuppression and the vast majority steroids. The clinical presentation included rhino-sino-orbital (n = 20), rhinocerebral (n = 16), pulmonary (n = 28), gastrointestinal (n = 13), cutaneous (n = 18), renal (n = 6) and disseminated disease (n = 15). Most frequently isolated genera were Rhizopus (73%) followed by Mucor (13%). The overall mortality was 49%. While rhino-sino-orbital disease had the best prognosis, rhinocerebral disease had high mortality (93%) comparable to disseminated disease. A favorable outcome was associated with limited, surgically accessible disease and early surgical intervention along with amphotericin B administration.

JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) are deoxyribonucleic acid (DNA) viruses, members of the family Polyomaviridae. These viruses establish persistent infections, and reactivate from latency in their host under immunosuppression. During the last few years there has been recognition of the morbidity related to polyomaviruses, particularly BKV in kidney transplant recipients. More importantly, recent studies indicate the potential implication of JCV, BKV, and SV40 in renal dysfunction among nonrenal organ transplant patients. Polyomaviruses are tumor-inducing viruses and animal models have provided evidence of the oncogenicity of these pathogens. Although data are not conclusive, molecular studies suggest an association of BKV and SV40 with malignancies among solid organ transplant patients. As new and potent immunosuppressive agents are introduced into clinical practice, it is believed that the incidence of polyomavirus-related diseases in organ transplantation might increase. This review evaluates the biologic and epidemiologic features of these 3 viruses, the data regarding their infections in nonkidney organ transplant patients and describes future directions in the management and research of these opportunistic pathogens. Liver Transpl 12:1457-1463, 2006. © 2006 AASLD.

The clinical utility of Platelia trade mark Aspergillus galactomannan antigen for the early diagnosis of invasive aspergillosis was prospectively assessed in 70 consecutive lung transplant recipients. Sera were collected twice weekly and tested for galactomannan. Invasive aspergillosis was documented in 17.1% (12/70) of the patients. Using the generalized estimating equation model, at the cutoff value of >or= 0.5, the sensitivity of the test was 30%, specificity 93% with positive and negative likelihood ratios of 4.2 and 0.75, respectively. Increasing the cutoff value to >or= 0.66 yielded a sensitivity of 30%, specificity of 95%, and positive and negative likelihood ratios of 5.5 and 0.74. A total of 14 patients had false-positive tests, including nine who had cystic fibrosis or chronic obstructive pulmonary disease. False-positive tests occurred within 3 days of transplantation in 43% (6/14) of the patients, and within 7 days in 64% (9/14). Thus, the test demonstrated excellent specificity, but a low sensitivity for the diagnosis of aspergillosis in this patient population. Patients with cystic fibrosis or chronic obstructive pulmonary disease may transiently have a positive test in the early post-transplant period.

Serious infection due to strains of Pseudomonas aeruginosa that exhibit resistance to all common antipseudomonal antimicrobials increasingly is a serious problem. Colistin was used as salvage therapy for 23 critically ill patients with multidrug-resistant P. aeruginosa infection. Twenty-two patients who had septic shock (n=14) and/or renal failure (n=21) received mechanical ventilatory support at baseline. The most common types of infection were pneumonia (n=18) and intra-abdominal infection (n=5). Colistin was administered for a median of 17 days (range, 7-36 days). Seven patients died during therapy, at a median of 17 days (range, 4-26 days) after initiation of treatment. A favorable clinical response was observed in 14 patients (61%); only 3 patients experienced relapse. Bacteremia was the only significant factor associated with treatment failure (P=.02). One patient manifested diffuse weakness that resolved after temporary cessation of colistin therapy. Colistin provides an important salvage therapeutic option for patients with otherwise untreatable serious P. aeruginosa infection.

Clostridium innocuum is a relatively antimicrobial resistant, frequently misidentified anaerobe that has only rarely been associated with bacteremia. A 38-year-old female with chronic hepatitis C underwent a second kidney transplant operation. Two weeks after surgery a computed tomography scan of the abdomen showed a heterogeneous hematoma with pockets of gas adjacent to the allograft, which extended into the pelvis and left abdominal wall, associated with low-grade fever. An anaerobic blood culture grew a Clostridium initially identified as C. subterminale and later re-identified as C. innocuum. At abdominal exploration liquefied blood was evacuated, and the patient completed a course of antibiotics and recovered. C. innocuum should be considered as a cause of gas-producing anaerobic infection in transplant patients. Because C. innocuum is frequently misidentified by the use of commercial anaerobic identification kits, its true incidence in serious infections is likely underestimated.

Survival and allograft function in lung transplant recipients are limited by the development of bronchiolitis obliterans. The precise pathogenesis of bronchiolitis obliterans remains unknown. However, studies indicate that epithelial injury in the lung allograft can be induced by a variety of factor

Invasive aspergillosis (IA) in liver transplant recipients is associated with poor response rates and a very high mortality rate, despite administration of therapy with conventional amphotericin B. We conducted a single-center, retrospective study to compare the outcome of liver transplant recipients with IA who received amphotericin B lipid complex (ABLC) or conventional amphotericin B. IA was present in 12 ABLC-treated patients (definite, 4; probable, 8) and 29 amphotericin B recipients (definite, 11; probable, 18) in the historical cohort. The 60-day mortality rate was lower in the ABLC cohort: 4 (33%) of 12 patients versus 24 (83%) of 29 patients (P=.006). Only 1 of 4 ABLC recipients with definite IA died, compared with all 11 in the amphotericin B group. Sixty-day survival probability curves was significantly lower in the amphotericin B cohort (P=.008). ABLC therapy was the only independent mortality-protective variable (odds ratio, 0.31; 95% confidence interval, 0.07-0.44; P=.02). First-line or early salvage therapy for IA with ABLC was associated with significantly improved survival relative to a comparable historical group treated with amphotericin B.

Background. This study determines whether the spectrum, risk factors, and outcome of invasive candidiasis in liver transplant recipients have changed.

While studies in kidney recipients have found meningitis to be the most common clinical manifestation of cryptococcosis (Cry), it is unclear if the clinical presentation of Cry differs among various solid-organ transplant (SOT) recipients and whether the serum cryptococcal antigen (SCA) might predict the site of infection. We report the clinical manifestations and the correlation with a positive SCA among 55 consecutive SOT recipients diagnosed with Cry at the University of Pittsburgh Medical Center. These included: heart (n=13), lung (n=4), liver (n=28), kidney (n=9) and small bowel (n=1) recipients. While there were no significant differences in the manifestations of Cry in heart and lung recipients, kidney recipients had disseminated disease as the most common presentation (P=0.02). In contrast, pneumonia (P=0.003) and meningitis (P=0.02) were more frequent than disseminated disease in liver recipients. Positive SCA was higher in patients with disseminated disease and meningitis than in patients with isolated pneumonia (P=0.0001). Significant differences in the manifestations of Cry were observed among types of SOT populations. A positive SCA may be predictive of dissemination and meningitis, but it may not be sensitive for pulmonary disease.

A variety of viruses, such as the influenza viruses A and B, the human respiratory syncytial virus, the parainfluenza viruses, and the adenoviruses, cause seasonal respiratory tract infections in young children and adults. Also, studies indicate that these viruses are an important group of pathogens in pediatric and adult lung transplant recipients. More importantly, accumulating data on these infections among lung transplant patients suggest that these illnesses may have immediate and long-term implications for the function of the transplanted lung, including the development of bronchiolitis obliterans. This is important because patient survival and allograft function in lung transplantation remain limited by the development of bronchiolitis obliterans. Models of lung transplantation indicate that respiratory viral infections cause acute and chronic airway damage after transplantation. The mechanism leading to allograft damage by respiratory viruses may be related to the production of alloreactive cytokines such as interleukin (IL)-1, tumor necrosis factor, IL-6 and IL-8 during viral replication. Current clinical data are suggestive of a possible role for respiratory viruses in the development of bronchiolitis obliterans, but further control studies are required to evaluate the significance of respiratory virus infections as a causal factor in the development of bronchiolitis obliterans in lung transplantation.

Parainfluenza virus is a common cause of seasonal upper respiratory tract infections in children and adults. Studies indicate that parainfluenza virus may play an important role in the etiology of respiratory tract infections in lung transplant recipients with an estimated incidence of 5.3 per 100 patients. Parainfluenza virus type 3 is the most frequent serotype in lung transplant patients. The rate of lower respiratory tract infections with parainfluenza virus among lung transplant recipients is between 10 and 66% of cases. In addition, trans-bronchial biopsy at the time of parainfluenza infection shows signs of acute allograft rejection. Subsequently, 32% of patients have been found to have active bronchiolitis obliterans at a median time of 6 months (range 1-14) postviral infection. These findings indicate that parainfluenza virus infections may have long-term implications for lung transplant recipients. Further studies are required to identify the mechanisms of immunomodulation of parainfluenza virus among these patients. In addition, controlled studies are needed to evaluate the efficacy of aerosolized ribavarin in the treatment of parainfluenza virus infection and to determine whether vaccines may be effective in these high-risk patients.

To discern whether the characteristics and outcome of invasive aspergillosis in liver transplant recipients have evolved during the past decade, 26 patients who underwent transplantation during 1990-1995 (known as "the earlier cohort") were compared with 20 patients who underwent transplantation during 1998-2001 (known as "the later cohort"). Twenty-three percent of the Aspergillus infections in the earlier cohort occurredor =90 days after transplantation, compared with 55% of such infections in the later cohort (P=.026). The earlier cohort was significantly more likely to have disseminated infection (P=.034) and central nervous system (CNS) involvement (P=.0004) than was the later cohort. The mortality rate was significantly higher for the earlier cohort (92%) than for the later cohort (60%; P=.012). Only disseminated infection (not the year of transplantation) approached statistical significance as an independent predictor of outcome. In the current era, invasive aspergillosis occurs later in the posttransplantation period, is less likely to be associated with CNS infection, and is associated with a lower mortality rate, compared with invasive aspergillosis in the early 1990s.

Invasive fungal infections are an important cause of morbidity and mortality in organ transplant recipients. Because conventional diagnostic tools such as culture lack sensitivity and specificity, alternative diagnostic tests have been developed in recent years. Serologic tests and molecular assays such as polymerase chain reaction of blood or other body fluids have become increasingly important for the diagnosis of invasive fungal infections in organ transplant recipients. Among the most useful antigen detection systems are the detection of cryptococcal and histoplasma polysaccharide antigen for the diagnosis of cryptococcosis and histoplasmosis. A promising assay is the detection of circulating galactomannan, which is known to be a sensitive marker for invasive aspergillosis. However, advances in the management of invasive mycoses have been limited, perhaps as a result of difficulties in performing randomized clinical trials of fungal infections. This review summarizes current knowledge of the rapid diagnostic tests and treatment of invasive fungal infections in organ transplant recipients.