M. Carmen Fariñas

Risk Factors, Clinical Features, and Outcomes of Listeriosis in Solid-Organ Transplant Recipients: A Matched Case-Control Study

BACKGROUND Solid-organ transplant (SOT) recipients are classically considered to be at increased risk for listeriosis. However, risk factors for this infection have not been assessed. METHODS We carried out a multicenter, matched case-control study (1:2 ratio) from January 1995 through December 2007. Control subjects were matched for center, transplant type, and timing. Conditional logistic regression was performed to identify independent risk factors. Clinical features and outcomes for all case patients were reviewed. RESULTS Thirty patients (0.12%) with cases of listeriosis were identified among 25,997 SOT recipients at 15 Spanish transplant centers. In a comparison of case patients with 60 matched control subjects, the following independent risk factors for listeriosis were identified: diabetes mellitus (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.6-19.6; ), P = .007 history of cytomegalovirus infection or disease within the preceding 6 months (OR, 35.9; 95% CI, 2.1-620; P = .014), receipt of high-dose prednisone within the preceding 6 months (OR, 6.2; 95% CI, 1.8-21.1; P = .003), and trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis (OR, 0.07; 95% CI, 0.006-0.76; P = .029). Twenty-six patients (86.7%) had bacteremia, and 7 had shock at presentation. Other manifestations included meningoencephalitis (10 cases), spontaneous peritonitis (2), pleural empyema (1), brain abscesses (1), and liver abscesses (1). The 30-day mortality rate was 26.7% (8 of 30 patients died). CONCLUSIONS Listeriosis in SOT recipients is uncommon but causes high mortality. Diabetes mellitus, cytomegalovirus infection or disease, and receipt of high-dose steroids are independent risk factors for this infection, whereas TMP-SMZ prophylaxis is a protective factor.

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

Clinical course and predictors of death in prosthetic valve endocarditis over a 20-year period

OBJECTIVE To compare early and late outcome of patients with prosthetic valve endocarditis treated medically versus surgically and to determine predictors of in-hospital death. We retrospectively reviewed patients clinical records, including laboratory findings, surgery, and pathologic files, in an acute-care, 1200-bed teaching hospital. METHODS One hundred thirty-three episodes of definite prosthetic valve endocarditis as defined by the Duke University diagnostic criteria occurred in 122 patients from January 1986 to December 2005. Logistic regression model was used to identify prognostic factors of in-hospital mortality. Long-term follow-up was made to assess late prognosis. RESULTS Bioprostheses were involved in 52% of cases and mechanical valves in 48%. The aortic valve was affected in 45% of patients. Staphylococcus epidermidis was isolated in 23% of cases, Streptococcus spp in 21%, S aureus in 13%, and Enterococcus in 8%. Cultures were negative in 18% of cases. Twenty-six patients were treated medically and 107 with combined antibiotics and valve replacement. The operative mortality was 6.5% and the in-hospital mortality, 29%. Presence of an abscess at echocardiography, urgent surgical treatment, heart failure, thrombocytopenia, and renal failure were significant predictors of in-hospital death. Kaplan-Meier survival at 12 months was 42% in patients treated medically and 71% in those treated surgically (P = .0007). Freedom from endocarditis was 91% at the end of follow-up. CONCLUSIONS Prosthetic valve endocarditis is a serious condition with high mortality. Patients with perivalvular abscess had a worse prognosis, and combined surgical and medical treatment could be the preferred approach to improve outcome.

Timing of Oseltamivir Administration and Outcomes in Hospitalized Adults With Pandemic 2009 Influenza A(H1N1) Virus Infection

BACKGROUND Data on the clinical effectiveness of oseltamivir in patients with pandemic 2009 influenza A(H1N1) (A[H1N1]) virus infection are scarce. We aimed to determine the effect of timing of oseltamivir administration on outcomes in hospitalized adults with A(H1N1). METHODS Observational analysis of a prospective cohort of adults hospitalized with laboratory-confirmed A(H1N1) was performed at 13 Spanish hospitals. Time from onset of symptoms to oseltamivir administration was the independent variable. Outcomes were duration of fever, hospital length of stay (LOS), need for mechanical ventilation, and mortality during hospitalization. Multivariate logistic regression was used to describe the association between the independent variable and the outcomes. RESULTS Five hundred thirty-eight hospitalized patients with A(H1N1) were studied. The median time from onset of symptoms to oseltamivir administration was 3 days (interquartile range [IQR], 2-5 days). With regard to outcomes, the median duration of fever was 2 days (IQR, 1-3 days), the median LOS was 5 days (IQR, 3-8 days), 49 patients (9.1%) underwent mechanical ventilation, and 11 patients (2%) died during hospitalization. In univariate analysis, prolonged duration of fever (above the median), prolonged LOS (above the median), need for mechanical ventilation, and mortality all increased with time to oseltamivir administration (χ(2) test for trend P = .001, P ≤ .001, P = .008, and P = .001, respectively). After adjustment for confounding factors, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with a prolonged duration of fever (OR, 1.10; 95% CI, 1.02-1.19), prolonged LOS (OR, 1.07; 95% CI, 1.00-1.15), and higher mortality (OR, 1.20; 95% CI, 1.06-1.35). CONCLUSIONS Timely oseltamivir administration has a beneficial effect on outcomes in hospitalized adults with A(H1N1), even in those who are admitted beyond 48 h after onset of symptoms.

Pneumonia complicating pandemic (H1N1) 2009: risk factors, clinical features, and outcomes.

We performed an observational analysis of a prospective cohort of adults hospitalized for pandemic (H1N1) 2009 at 13 Spanish hospitals, from June to November 2009, to determine the risk factors, clinical features, and outcomes of pneumonia. Of 585 patients requiring hospitalization, chest radiography was obtained in 542. A total of 234 (43.1%) patients had pneumonia, of whom 210 underwent bacterial microbiologic studies. Of these patients, 174 (82.8%) had primary viral pneumonia and 36 (17.2%) had concomitant/secondary bacterial pneumonia. Bilateral pneumonia occurred in 48.3% of patients. Streptococcus pneumoniae was the most frequent pathogen among patients with bacterial pneumonia (26 of 36 patients). None of them had received pneumococcal vaccine. Compared with patients without pneumonia, those with pneumonia more frequently had shock during hospitalization (9.8% vs. 1%; p < 0.001), required intensive care unit admission (22.6% vs. 5.8%; p < 0.001), underwent mechanical ventilation (17.9% vs. 3.2%; p < 0.001), and had longer length of hospital stay (median, 7 d vs. 5 d; p < 0.001). In-hospital mortality was higher in patients with pneumonia than in the others (5.2% vs. 0%; p < 0.001). Absence of comorbid conditions (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.32-3.24) was found to be an independent risk factor for pneumonia, whereas early (≤48 h) oseltamivir therapy (OR, 0.29; 95% CI, 0.19-0.46) was a protective factor. In conclusion, pneumonia is a frequent complication among adults hospitalized for pandemic (H1N1) 2009 and causes significant morbidity. Mortality in pandemic (H1N1) 2009 is low, but occurs mainly in patients with pneumonia. Early oseltamivir therapy is a protective factor for this complication.Abbreviations: BMI = body mass index, CAP = community-acquired pneumonia, CI = confidence interval, CURB-65 = confusion, urea, respiratory rate, blood pressure, and age ≥65 years, ICU = intensive care unit, OR = odds ratio, PSI = pneumonia severity index, ROC = receiver operating characteristic, RT-PCR = reverse-transcription polymerase chain reaction.

Contribution of monocytes to the decreased lymphoproliferative response to phytohemagglutinin in patients with lung cancer

Patients with lung cancer (LC) have a reduced T‐cell proliferative response to phytohemagglutinin (PHA) compared with that of healthy individuals. This decreased response is a result of an inhibitory effect exerted by the monocytes as evidenced by: (1) a restoration to normal levels of the response to PHA when the peripheral blood mononuclear cells were depleted of adherent cells (AD) and (2) a dose‐dependent inhibition of the response to PHA when the nonadherent cell population was co‐cultured with increasing numbers of autologous AD cells. The addition of indomethacin to the cultures resulted in only a partial restoration of the response to PHA. Monocyte production of interleukin‐1 from patients with LC in response to lipopolysaccharide was normal. These findings support the hypothesis that the AD cell population plays a major role in the low T‐cell proliferative response to PHA in patients with LC. This suppressor effect is partially mediated by the prostaglandins released by the monocytes.

Tuberculosis Prophylaxis With Levofloxacin in Liver Transplant Patients Is Associated With a High Incidence of Tenosynovitis: Safety Analysis of a Multicenter Randomized Trial

BACKGROUND It is necessary to develop a safe alternative to isoniazid for tuberculosis prophylaxis in liver transplant recipients. This study was designed to investigate the efficacy and safety of levofloxacin. METHODS An open-label, prospective, multicenter, randomized study was conducted to compare the efficacy and safety of levofloxacin (500 mg q24h for 9 months) initiated in patients awaiting liver transplantation and isoniazid (300 mg q24h for 9 months) initiated post-transplant when liver function was stabilized. Efficacy was measured by tuberculosis incidence at 18 months after transplantation. All adverse events related to the medication were recorded. RESULTS CONSORT guidelines were followed in order to present the results. The safety committee suspended the study through a safety analysis when 64 patients had been included (31 in the isoniazid arm and 33 in the levofloxacin arm). The reason for suspension was an unexpected incidence of severe tenosynovitis in the levofloxacin arm (18.2%). Although the clinical course was favorable in all cases, tenosynovitis persisted for 7 weeks in some patients. No patients treated with isoniazid, developed tenosynovitis. Only 32.2% of patients randomized to isoniazid (10/31) and 54.5% of patients randomized to levofloxacin (18/33, P = .094) completed prophylaxis. No patient developed tuberculosis during the study follow-up (median 270 days). CONCLUSIONS Levofloxacin prophylaxis of tuberculosis in liver transplant candidates is associated with a high incidence of tenosynovitis that limits its potential utility.

The IL-17 G-152A single nucleotide polymorphism is associated with pulmonary tuberculosis in northern Spain

BACKGROUND Interleukin 17 (IL-17) is induced during the early stages of tuberculosis infection, playing an important role in the defense against mycobacterial infection. To date, only one study performed in Chinese Han population has found an association between IL-17F sequence variants and susceptibility to tuberculosis, but no relationship has been found with another single nucleotide polymorphism (SNP) in IL-17A gene (rs2275913). METHODS To assess if rs2275913 (G-152A) SNP, could be associated with susceptibility to pulmonary tuberculosis (PTB) in a genetically homogeneous Caucasian population, we analyzed if its allele and genotype frequencies were statistically significant in a case-control study. One hundred and ninety-two patients with active PTB and 266 blood healthy donors were enrolled in this study. RESULTS The frequency of the GG versus GA+AA genotype was significantly more frequent in patients with PTB than in control subjects assuming a dominant model (50.52% versus 39.10% respectively, OR=1.59, 95%CI=1.09-2.31, p=0.015). Despite patients with PTB had higher serum IL-17 levels, we did not find an association of this SNP with IL-17 ex vivo production after stimulation with Mycobacterium tuberculosis (Mtb) antigens or phytohemagglutinin (PHA). CONCLUSION Our results would suggest an association between IL-17A rs2275913 - 152G allele and GG genotype with susceptibility to PTB for the first time.

Invasive Cryptococcosis and Adalimumab Treatment

To the Editor: Tumor necrosis factor-α (TNF-α) antagonists are immunosuppressants that have shown efficacy in treating inflammatory disorders. However, a recent meta-analysis of controlled trials has shown evidence of increased risk for serious infections in patients with rheumatoid arthritis treated with TNF-α antagonists (1). Adalimumab is a human monoclonal antibody to TNF-α approved by the US Food and Drug Administration (FDA) for treatment of rheumatoid arthritis. The Spanish registry of adverse events of biologic therapies in rheumatic diseases reported that 1,080 patients were treated with adalimumab from 2003 through 2006 and no cases of cryptococcosis were recorded (2). No cases of cryptococcosis have been detected in 10,050 treated patients in the US postmarketing database for adalimumab (3). We report invasive cryptococcosis in a patient receiving adalimumab. This case underscores the relationship between TNF antagonists and emergence of severe and difficult-to-treat opportunistic infections. A 69-year-old woman with rheumatoid arthritis diagnosed in 2002 was referred to our hospital for severe acute inflammation of the second finger of the left hand. She had been treated with oral corticosteroids (prednisone, 7.5 mg/day) and several disease-modifying antirheumatic drugs, including chloroquine, methotrexate, and sulfasalazin, without improvement. One year before the current episode, therapy with adalimumab, 40 mg subcutaneously every 2 weeks for 52 weeks, was started and she showed an acceptable clinical response. She had no recent trauma. Examination showed severe tenosynovitis of the digital flexor tendon with intense edema and compartmental signs (Appendix Figure). She had an axillary temperature of 36.7°C and an admission leukocyte count of 5,900 cells/µL. Results of a neurologic examination and a chest radiograph were normal. Early surgical decompression was performed. Intraoperative findings indicated extensive subcutaneous celullitis with infiltration of vasculonervous bundles and flexor tendon synovitis. Culture of extracted material from 4 samples, including a biopsy specimen of subcutaneous tissue, identified Cryptococcus neoformans susceptible to amphotericin B, azoles, and flucytosine. Results of cerebrospinal fluid analysis were normal. A cranial computed tomographic scan showed no focal lesions. Results of a serum cryptococcal latex test and HIV serologic analysis were negative. Magnetic resonance imaging of the finger showed inflammation of soft tissues, including the flexor tendon, but no signs of arthritis or osteomyelitis. Treatment with adalimumab was discontinued. Intravenous liposomal amphotericin B, 300 mg once a day, and intravenous flucytosine, 2.5 g 3× a day, were administered for 7 days. Treatment with intravenous fluconazole, 400 mg twice a day for 21 days, was then started. Inflammatory signs decreased. Because residual soft tissue necrosis was extensive, reconstructive surgery was not performed, and her second finger was amputated during the third week after admission. A pathologic examination showed chronic necrotizing granulomatous inflammation with typical encapsulated fungal forms of Cryptococcus spp. inside multinucleated giant cells. These forms were observed by staining specimens with hematoxylin and eosin and Mayer mucicarmine (Figure). After an uneventful postoperative period, the patient was discharged and received oral fluconazole, 200 mg once a day for 6 months. Two years later, the patient remains asymptomatic and receives therapy with methotrexate, salazopyrin, and prednisone. Figure Histiocytic granuloma with lymphocytes and multinucleated giant cells and an encapsulated intracytoplasmic mucicarmine-positive structure identified as a Cryptococcus sp. (arrow) (hematoxylin and eosin– and Mayer mucicarmine–stained, magnification ... The rate of serious infections in the US clinical trial safety database of adalimumab as of April 2005 was 5.1/100 patient-years. This rate is similar to that reported in the general population with rheumatoid arthritis. However, as in our case, some infections associated with adalimumab are severe and difficult to treat (3). Cryptococcosis has not been previously associated with use of adalimumab. Cryptococcal infections have been described in 19 patients receiving TNF-α antagonists other than adalimumab (infliximab or etanercept) in the FDA Adverse Event Reporting System from 1998 to 2002 (4). Three cases of cryptococcosis in patients receiving TNF-α antagonists have been reported (5–7). The association between cryptococcosis and use of TFN-α antagonists can be explained by the immune response to C. neoformans, which relies on effective T-cell host defenses and in which TNF-α has an essential role. TFN-α is involved in maintaining a T-helper cell type 1 immune response because it induces production of interleukin-12 (IL-12) and IL-18, with subsequent production of fungicidal interferon-γ (8). In animal models, TNF-α blockers are associated with reduced recruitment of inflammatory cells to the area of infection and an increased risk for cryptococcal dissemination (9). Moreover, C. neoformans impairs production of TNF-α, IL-1β, and IL-6 and increases levels of IL-10, which induce a T-helper cell type 2 immune response (10). Cryptococcal virulence factors impart greater dependence upon TNF-α for a sufficient host response (9). Adalimumab may increase immunosuppression, which is required for a cryptococcal infection. Our patient received a low dose of prednisone. Although corticosteroids are a risk factor for cutaneous cryptococcosis, cases with serious outcomes rarely occur. However, the risk for fungal infection related to low doses of steroids is minimal. Active surveillance, as well as analysis of associated risk factors, is required to detect concurrence of severe opportunistic infections in patients treated with TNF antagonists and to identify patients who could benefit from these therapies with fewer risks.

Reduced incidence of pneumonia in influenza-vaccinated solid organ transplant recipients with influenza disease

Abstract Whether influenza vaccination influences the severity of illness in cases of clinical failure in solid organ transplant (SOT) recipients receiving influenza vaccine has not been extensively studied. Our goal was to evaluate the frequency of influenza vaccination among SOT recipients with influenza disease and its impact on the illness severity during the 2010–2011 season. Adult SOT recipients with confirmed influenza infection were included from December 2010 to April 2011. Follow-up data were recorded and antibody titres were determined using a microneutralization assay. Sixty-four SOT recipients were included in the study, ten (15.6%) with severe disease, requiring admission to intensive care units, of whom four (6.3%) died. In all, 34 (53.1%) received the 2010–2011 seasonal influenza vaccine and 32 (50.0%) received the 2009-H1N1 pandemic vaccine, and none had detectable antibodies against influenza at the time of diagnosis of influenza infection. Twenty-three (67.6%) of the patients that received the vaccine required hospital admission and presented less dyspnoea (10, 29.4% versus 14 (50.0%), p 0.09) and pneumonia (8, 23.8% versus 15, 50.0%, p 0.03, relative risk 0.3, 95% CI 0.1-0.9) than unvaccinated patients, with relative risk reductions of 60% and 70%, respectively. Although influenza vaccination confers protection on SOT recipients against developing influenza pneumonia, the rate of clinical failure is still high. New strategies to improve influenza immunization are needed for this group of patients.