Infections from seven clinical trials of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriasis.

BACKGROUND: Infections are associated with biological therapies in psoriasis. OBJECTIVES: To summarize the incidence of infections in patients with moderate-to-severe psoriasis treated with ixekizumab, an anti-interleukin-17A monoclonal antibody. METHODS: Infections are summarized from an integrated database of seven controlled and uncontrolled ixekizumab psoriasis trials. Data are presented from placebo-controlled induction (weeks 0-12; UNCOVER-1, UNCOVER-2 and UNCOVER-3) and maintenance periods (weeks 12-60; UNCOVER-1 and UNCOVER-2), and all patients exposed to ixekizumab pooled from all seven trials. Comparisons with etanercept were made during the induction period of two trials (UNCOVER-2 and UNCOVER-3). Incidence and exposure-adjusted incidence rates (IRs) per 100 patient-years (PYs) are reported. RESULTS: Overall, 4209 patients were treated with ixekizumab (6480 PY). During induction (weeks 0-12), overall infection rates were higher in patients treated with ixekizumab (27%) vs. placebo (23%, P < 0·05); however, specific infection rates were comparable overall across treatment groups. IRs of infections did not increase with longer-term exposure. For all patients treated with ixekizumab (all seven trials), the incidence of serious infections was low (2%, IR 1·3). Candida infections, including eight cases of oesophageal candidiasis, were adequately managed with antifungal therapy, were noninvasive and did not lead to discontinuation. CONCLUSIONS: Overall, infections occurred in a higher percentage of patients treated with ixekizumab vs. placebo during the first 12 weeks of treatment; however, specific infection rates were comparable overall across treatment groups. Incidences of serious infections were low and similar across treatment groups.

Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study.

AIMS: Previously, a retrospective cohort study found no increased risk of acute pancreatitis with current or recent use of exenatide twice daily compared with use of other anti-diabetic drugs. This follow-up study investigated incident acute pancreatitis, with the use of a different data source and analytic method, in patients exposed to exenatide twice daily compared with patients exposed to other anti-diabetic medications. METHODS: A large US health insurance claims database was used. Eligible patients had ≥ 9 months continuous enrollment without a claim for pancreatitis and a claim for a new anti-diabetic medication on or after 1 June 2005 to 31 March 2009. Cases of acute pancreatitis were defined as hospitalized patients with an Internation Classification of Disease 9 code of 577.0 in the primary position. A discrete time survival model was used to evaluate the relationship between exenatide twice daily and acute pancreatitis. RESULTS: Of 482,034 eligible patients, 24,237 initiated exenatide twice daily and 457,797 initiated another anti-diabetic medication. Initiators of exenatide twice daily had more severe diabetes compared with initiators of other anti-diabetic medications. After adjustments for propensity score, insulin and use of medication potentially associated with acute pancreatitis, the odds ratio with exenatide twice daily exposure was 0.95 (95% CI 0.65-1.38). A secondary analysis that examined current, recent and past medication exposure found no increased risk of acute pancreatitis with exenatide twice daily, regardless of exposure category. CONCLUSION: This study indicates that exposure to exenatide twice daily was not associated with an increased risk of acute pancreatitis compared with exposure to other anti-diabetic medications. These results should be interpreted in light of potential residual confounding and unknown biases.

A cohort study of acute pancreatitis in relation to exenatide use.

AIM: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs. METHODS: This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (≥32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records. RESULTS: Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0). CONCLUSIONS: Exenatide use was not associated with an increased risk of acute pancreatitis.

Rapid detection of human infections with fluorine-18 fluorodeoxyglucose and positron emission tomography: preliminary results.

The purpose of this study was to evaluate the feasibility of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) and positron emission tomography (PET) for rapid detection of human infections. Eleven patients who were known or suspected to be harboring various infections were studied with FDG-PET. Dynamic scans over the putative infection sites were performed immediately after FDG (370 MBq) injection through 60 min, and static images including multiple projection images were then obtained. FDG uptake was assessed visually into four grades (0, normal; 1, probably normal; 2, probably abnormal; 3, definitely abnormal). For the semiquantitative index of FDG uptake in infections, the standardized uptake value of FDG normalized to the predicted lean body mass (SUV-lean, SUL) was determined from the images obtained at 50-60 min after FDG injection. PET results were compared with final clinical diagnoses. Eleven lesions in eight patients, which were interpreted as grade 2 or 3 by FDG-PET, were all concordant with active infectious foci. The SUL values of infections ranged from 0.97 to 6.69. In two patients, FDG-PET correctly showed no active infection. In one patient, it was difficult to detect infectious foci by FDG-PET due to substantial normal background uptake of FDG. In total, FDG-PET correctly diagnosed the presence or absence of active infection in 10 of 11 patients. Fusion images of PET with computed tomography showed the most intense FDG uptake to be within an abscess wall. In conclusion, FDG-PET appears to be a promising modality for rapid imaging of active human infections. More extensive clinical evaluation is warranted to determine the accuracy of this method.

Human herpesvirus 6.

Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation.

Beyond vancomycin: new therapies to meet the challenge of glycopeptide resistance.

The incidence of infections caused by resistant Gram-positive pathogens is increasing, while emergence of vancomycin resistance is reducing the number of therapeutic options. New agents are being rapidly evaluated as candidates to replace vancomycin; some of the most promising include semisynthetic glycopeptides, quinupristin-dalfopristin, oxazolidinones and everninomycins. Alternative strategies, including immunization and therapeutic vaccines, may also have a role.

Meningococcal endocarditis presenting as cellulitis.

We report the case of a patient with mixed connective tissue disease who presented with two very unusual manifestations of meningococcal disease, cellulitis and endocarditis, concurrently. We also review the literature concerning Neisseria meningitidis as a causative agent of cellulitis or endocarditis. While meningococcal endocarditis or cellulitis is very rare, autoimmune disease predisposes patients to meningococcal infection. Therefore, unusual infections with this organism should be considered in the differential diagnosis of fever and rash in patients with connective tissue diseases.

Epstein-Barr virus coinfection and recombination in non-human immunodeficiency virus-associated oral hairy leukoplakia.

Human immunodeficiency virus-associated oral hairy leukoplakia (HLP) is characterized by coinfection with multiple types and strains of Epstein-Barr virus (EBV) and recombination within the EBV genome. HIV-seronegative immunosuppressed and immunocompetent patients with HLP were examined to determine the pathogenic contribution of EBV coinfection and recombination to the development of HLP. Multiple coinfecting EBV strains were detected in both HLP specimens and peripheral blood lymphocytes (PBL) of HIV-seronegative persons with HLP. One specific EBV strain was detected in HLP specimens from 3 of 4 patients. Also, viral recombination during productive replication within HLP generated variants of the latent membrane protein-1 (LMP-1) and nuclear antigen-2 (EBNA-2) genes. Some variants were also detected within PBL. Thus, EBV coinfection and recombination are consistent findings in persons with HLP regardless of immune status. Virally mediated determinants may be important features of EBV pathogenesis.

Presence and expression of human herpesvirus 6 in peripheral blood mononuclear cells of S100-positive, T cell chronic lymphoproliferative disease.

S100-positive, T cell chronic lymphoproliferative disease (S100-CLPD) is a rare and aggressive hematologic disorder in which the cytoplasmic protein S100 is expressed at high levels in abnormal lymphocytes. Using a DNA probe specific for human herpesvirus 6 (HHV-6), 2 cases of S100-CLPD were examined by DNA and RNA hybridization analysis. The results indicated that HHV-6 DNA was present in uncultured peripheral blood mononuclear cells (PBMC) and that a 1.3-kb viral transcript was expressed in both cases. Analysis of flow-sorted PBMC from 1 case demonstrated that HHV-6 DNA was present exclusively in the S100-positive fraction. Studies using other HHV-6 DNA probes suggested infection with HHV-6 variant B in both cases. Hybridization studies using DNA from PBMC of 27 cases of T cell chronic lymphoproliferative disease of other types showed no evidence of HHV-6. These studies suggest a possible specific association of HHV-6 with the unusual disorder S100-CLPD.

Primary cutaneous Nocardia otitidiscaviarum infection: case report and review.

Organisms of the genus Nocardia cause a variety of illnesses in humans and other mammals. Nocardiae normally enter the body via the respiratory tract, but they may also be directly inoculated into the skin, causing primary cutaneous disease. Nocardia otitidiscaviarum is one of the less commonly isolated species of Nocardia, but it can produce localized or disseminated infection. We report a case of primary cutaneous N. otitidiscaviarum infection and review the clinical and microbiological features of other reported cases. Cutaneous N. otitidiscaviarum infection usually occurs in the setting of trauma, most often in otherwise healthy hosts. The manifestations of N. otitidiscaviarum skin infection range from cellulitis and abscess formation to the development of mycetomas. Cutaneous infection by N. otitidiscaviarum can mimic disease caused by more common pyogenic organisms, often leading to delay in diagnosis and treatment. Appropriate antibiotic therapy, usually with a sulfa drug-containing regimen, is generally successful.

Cryptococcal infection of a prosthetic dialysis fistula.

Fungal infections of prosthetic dialysis fistulae are rare. We report the first case of infection of a polytetrafluoroethylene dialysis access graft with the yeast Cryptococcus neoformans. Therapy with antifungal agents alone failed to cure the infection and significant improvement was observed only when all prosthetic material was surgically removed. This case emphasizes the potential for fungal infection of prosthetic dialysis fistulae and the importance of removal of intravascular foreign material in conjunction with antifungal therapy for treatment of fungal prosthetic graft infections.

Gamma/delta T-cell posttransplantation lymphoproliferative disorder primarily in the spleen.

A 31-year-old renal transplant recipient developed an unusual T-cell lymphoproliferative disorder 3 years after transplantation. The neoplasm involved the spleen, without concomitant hepatomegaly, lymphadenopathy, or obvious bone marrow involvement. Peripheral blood involvement developed after splenectomy. Immunophenotypically, the neoplastic cells expressed CD2, CD3, CD7, CD16, CD45, CD56, and the gamma/delta T-cell receptor on the surface membrane. The neoplastic cells were negative for surface membrane CD4, CD5, and CD8. Serologic and/or DNA analyses for viruses, including Epstein-Barr virus, human T-cell lymphotropic virus-1, human immunodeficiency virus, and human herpesvirus-6, were negative. Cytogenetic findings included a translocation breakpoint at chromosome 7p15, consistent with involvement of the T-cell receptor gamma-chain locus. Although gamma/delta T-cell lymphomas have been reported to have a predilection for hepatosplenic localization, this is the first well-documented case to be described in the setting of posttransplantation immunosuppression.

Bilateral renal parenchymal malacoplakia presenting as fever of unknown origin: case report and review.

Malacoplakia is a rare inflammatory disorder seen most often in the urinary tract, where it is highly associated with coliform infection. Although first recognized by pathologists in 1902, it has received little attention from the infectious disease community. While there remains much uncertainty regarding the specific cause of malacoplakia, it appears to be associated with a defect in intracellular killing of ingested microorganisms by macrophages. We report a case of bilateral renal parenchymal malacoplakia that presented as fever of unknown origin, and we review 33 previously identified cases. Renal malacoplakia has traditionally been associated with high morbidity and mortality. More recently, treatment with antimicrobial agents such as trimethoprim or ciprofloxacin has yielded a better outcome than had been documented with other therapy. Malacoplakia should be considered in the evaluation of fever of unknown origin or of relapsing or refractory urinary tract infection. Therapy with antimicrobial agents capable of intracellular penetration is recommended.

Chronic rubella vaccine-associated arthropathy.

Rubella immunization or infection is an uncommonly recognized cause of acute, recurrent, or persistent musculoskeletal manifestations. After routine rubella immunization, two women presented with the onset of polyarthralgia, arthritis, maculopapular rash, fever, paresthesia, and malaise with persistent or recurrent manifestations lasting longer than 24 months after vaccination. The patients expressed rubella virus RNA in peripheral-blood leukocytes 10 and 8 months after vaccination, respectively, in contrast to repeated negative results in asymptomatic rubella-immunized controls. One patient developed significantly depressed antibody responses to rubella virus after vaccination and experienced a prolonged clinical improvement after a 3-month course of intravenous immune globulin. The second patient had normal antibody responses to rubella virus and underwent no clinical improvement during or after intravenous immune globulin therapy. Rubella immunization or infection should be considered as additional causative factors in evaluation of acute and continuing musculoskeletal syndromes.

Rhodotorula fungaemia: a life-threatening complication of indwelling central venous catheters.

A 30-year-old woman receiving total parenteral nutrition via an indwelling central venous catheter for an intestinal motility disorder developed fever, tachycardia, tachypnea, and hypotension. Multiple blood cultures drawn through the catheter prior to these events, as well as a peripheral blood culture obtained earlier, grew the red yeast Rhodotorula rubra. The patient was critically ill for over one month but eventually recovered with therapy including the systemic antifungal agents amphotericin B and flucytosine and removal of the catheter. Although Rhodotorula has generally been regarded as having low pathogenicity, this case emphasizes the serious nature of Rhodotorula sepsis and suggests the need for both systemic antifungal therapy and removal of a colonized indwelling catheter.

S100-positive, T-cell chronic lymphoproliferative disease: an aggressive disorder of an uncommon T-cell subset.

S100-positive T lymphocytes account for less than 3% of peripheral blood T cells. Rare cases of S100-positive T-cell lymphoma have been previously described. We report four such cases of S100-positive T-cell chronic lymphoproliferative disease. In all cases, hepatosplenomegaly was observed, without prominent lymphadenopathy. Central nervous system (CNS) involvement by the leukemic cells was suggested in three cases by physical symptoms and confirmed in two cases by cerebrospinal fluid studies. Despite treatment, three patients died at 3, 6, and 8 months after diagnosis. Although there was a leukemic presentation, only minimal bone marrow infiltration was evident. Splenectomy showed red pulp infiltration. Liver and lymph node biopsies showed sinusoidal leukemic involvement. In all cases, the leukemic cells expressed mature T-cell- and natural killer cell-associated antigens. Cytoplasmic S100 was detected in the leukemic cells in the blood, spleen, liver, and lymph node. Southern blot studies in two cases showed T-beta, T-gamma, and T-delta gene rearrangements. RNA Northern blots showed T-alpha and T-beta chain transcripts with no T-gamma or T-delta RNA identified. Southern blot analysis showed no hybridization to probes specific for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus-1, or human T-cell lymphotropic virus type-1. These findings show that S100-positive T-cell chronic lymphoproliferative disorder is an aggressive, extramedullary-based disease frequently associated with CNS involvement and characterized by short survivals.

Characterization of herpes simplex virus 1 alpha proteins 0, 4, and 27 with monoclonal antibodies.

Analyses of the reactivity and patterns of synthesis of infected cell polypeptides (ICPs) specified by herpes simplex virus (HSV) 1 and 2 and by HSV-1 X HSV-2 recombinants indicated that monoclonal antibody H1183 reacted with HSV-1 alpha ICP0, whereas monoclonal antibody H1113 reacted with both HSV-1 and HSV-2 alpha ICP27. H1083 and H1113 and a monoclonal antibody to ICP4 (H640) similar to one previously described (D. K. Braun et al., J. Virol. 46:103-112.) were then used to study the properties of these alpha proteins. The results were as follows: alpha ICP0, ICP4, and ICP27 accumulated primarily in the nuclei of infected cells. ICP4 and ICP27 were poorly soluble in nondenaturing buffer solutions. ICP0 was considerably more soluble than ICP4 and ICP27. ICP0, ICP4, and ICP27 were readily partially purified by immunoaffinity chromatography from lysates of infected cells solubilized with denaturing agents such as sodium dodecyl sulfate. ICP0 and ICP27 were phosphorylated in cells overlaid with medium containing 32P early (1 to 3 h) or late (18 to 20 h) postinfection. A fraction, but not all, 32P that was incorporated early was chased in the presence of unlabeled phosphate. ICP0, ICP4, and ICP27 labeled with either 32P or [35S]methionine yielded multiple spots upon two-dimensional separations. However, ICP4 quantitatively precipitated at the origin when the migration in the first dimension was from acid to base, and both ICP4 and ICP27 partially precipitated at the origin when the direction of migration was reversed.

Identification and genetic mapping of a herpes simplex virus capsid protein that binds DNA.

Herpes simplex virus virion protein 19C (VP19C) is a constituent of both unenveloped (nuclear) and enveloped (cytoplasmic) capsids. In this paper we report that 32P-labeled DNA, either supercoiled or linear double stranded, efficiently bound to VP19C electrically transferred from denaturing polyacrylamide gels containing electrophoretically separated proteins from purified capsids. Analyses of the polypeptides specified by herpes simplex virus type 1 X herpes simplex type 2 recombinants with respect to electrophoretic mobility and binding of 32P-labeled DNA indicate that VP19C maps at the same location as infected cell polypeptide 32 and is derived from it.

Characterization of post-translational products of herpes simplex virus gene 35 proteins binding to the surfaces of full capsids but not empty capsids.

We report on the properties of a genetically and immunologically related family of structural (gamma) polypeptides of herpes simplex virus 1 designated as infected cell polypeptides (ICP) 35. The members of this family were identified and studied with the aid of a panel of monoclonal antibodies exemplified by H745. This monoclonal antibody reacted with six bands (ICP35a to 35f) formed by ICPs contained in either HEp-2 or Vero cell lysates electrophoretically separated in denaturing gels and transferred to nitrocellulose sheets. The six bands had apparent molecular weights in the range 39,000 to 50,000. Traces of ICP35 with apparent molecular weights of 37,000 were also observed in some preparations. On two-dimensional separation ICP35 family members formed at least 20 spots reactive with H745. These differed in both isoelectric properties and electrophoretic mobility in denaturing gels. Pulse-chase experiments, together with results published earlier, indicate that ICP35a to 35d are cytoplasmic precursors to nuclear products. One of these corresponds to virion protein 22a, a component of capsids containing DNA accumulating in the nuclei of infected cells. ICP35 was labeled by 32Pi added to the medium, but the extent of phosphorylation varied and may be a determinant of isoelectric properties. Iodination studies indicate that ICP35e and 35f are the predominant forms of ICP35 present on the surface of full, nuclear capsids containing DNA. None of the members of the ICP35 family were detected in empty capsids. Surface iodination labeled the major capsid protein (ICP5) of empty capsids, but not of full capsids, indicating that ICP35e and 35f coat the surface of the viral capsid and block access to sites for iodination of ICP5, the major capsid protein.