James Riddell

HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs

HIV causes a chronic infection characterized by depletion of CD4+ T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34+ cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34+ multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

Treatment of Endogenous Fungal Endophthalmitis: Focus on New Antifungal Agents

Endogenous fungal endophthalmitis, involving only the chorioretinal structures or extending to involve the vitreous (vitritis), is a sight-threatening infection requiring early appropriate therapy. Endophthalmitis is a relatively frequent complication of candidemia and less commonly occurs in patients who have invasive aspergillosis. Because the eye is a protected compartment, penetration of systemically administered antifungal agents is highly variable. In the posterior segment of the eye, amphotericin B (AmB) achieves very poor concentrations, but fluconazole concentrations are high. Among newer antifungal agents, voriconazole shows the most promise, because therapeutic concentrations for most Candida and Aspergillus species are achieved in the vitreous, and its antifungal activity is broad. In contrast, neither posaconazole nor the 3 echinocandins achieve adequate therapeutic concentrations in the vitreous. For sight-threatening macular involvement and vitritis, intravitreal injection of either AmB or voriconazole is helpful to achieve high local antifungal activity as quickly as possible. We review the available evidence regarding the most appropriate use of antifungal agents for endogenous fungal endophthalmitis, with the emphasis on treatment of infections due to Candida species.

HIV-1 utilizes the CXCR4 chemokine receptor to infect multipotent hematopoietic stem and progenitor cells

HIV infection is characterized by gradual immune system collapse and hematopoietic dysfunction. We recently showed that HIV enters multipotent hematopoietic progenitor cells and establishes both active cytotoxic and latent infections that can be reactivated by myeloid differentiation. However, whether these multipotent progenitors include long-lived hematopoietic stem cells (HSCs) that could establish viral reservoirs for the life of the infected person remains unknown. Here we provide direct evidence that HIV targets long-lived HSCs and show that infected HSCs yield stable, multilineage engraftment in a xenograft model. Furthermore, we establish that the capacity to use the chemokine receptor CXCR4 for entry determines whether a virus will enter multipotent versus differentiated progenitor cells. Because HSCs live for the life span of the infected person and are crucial for hematopoietic health, these data may explain the poor prognosis associated with CXCR4-tropic HIV infection and suggest HSCs as long-lived cellular reservoirs of latent HIV.

Bartonella henselae infections in solid organ transplant recipients: report of 5 cases and review of the literature.

Bartonella henselae is the causative agent of cat scratch disease and bacillary angiomatosis-peliosis. The spectrum of disease, diagnosis, and management of B. henselae infection in solid organ transplant recipients has not been well characterized. We identified 29 cases of solid organ transplant recipients who had Bartonella infection, 24 by a review of the English-language literature and 5 from our institution. Localized cat scratch disease was found in 8 patients (28%), and disseminated infection was found in 21 patients (72%). The mean time after transplantation to development of Bartonella infection among those with cat scratch disease was 5.6 ± 5.3 years, and among those with disseminated infection was 2.7 ± 2.4 years. Prominent clinical features included cat exposure in 26 patients (90%), fever in 27 patients (93%), lymphadenopathy in 12 patients (41%), and skin lesions in 7 patients (24%). Methods used in establishing the diagnosis of Bartonella infection included culture, polymerase chain reaction (PCR) assay, serologic assays, and histopathologic examination. Culture was positive in 2 of only 4 patients in whom this was performed, and PCR was positive in 12 of 14 patients (86%) in whom this test was performed. Serologic assays were positive in all 23 patients who were tested. Histopathologic examination of tissues in all 8 patients who had cat scratch disease revealed granulomatous inflammation in 4 (50%) and bacillary angiomatosis-peliosis in 2 (25%). Among the 15 patients who had disseminated infection and who had tissue examined, 8 (53%) had only granulomatous inflammation, 4 had only bacillary angiomatosis-peliosis (27%), and 2 had both granulomas and bacillary angiomatosis-peliosis (13%). A positive Warthin-Starry or Steiner stain was noted in 12 of 19 patients (63%) who had 1 of these stains performed. All 8 patients with cat scratch disease and 19 of 21 patients with disseminated bartonellosis were cured with antimicrobial therapy. Two patients, both of whom had endocarditis, died. Among solid organ transplant recipients, infection with B. henselae is uncommon and has diverse disease manifestations including disseminated disease. Persistent fevers or lymphadenopathy in a transplant recipient who has been exposed to cats should prompt clinicians to maintain a high index of suspicion for B. henselae infection. Identifying B. henselae as the causative organism often requires multiple diagnostic studies. Once the diagnosis is established, most solid organ transplant recipients respond appropriately to antimicrobial treatment. AbbreviationsAIDS = acquired immunodeficiency syndromeALT = alanine aminotransferaseAST = aspartate aminotransferaseCMV = cytomegalovirusCT = computed tomographyEBV = Epstein-Barr virusERCP = endoscopic retrograde pancreaticocholangiogramFDG = 18F-fluorodeoxyglucoseHHV-6 = human herpesvirus-6HIV = human immunodeficiency virusHSV = herpes simplex virusIFA = immunofluorescence assayIgG = immunoglobulin GIgM = immunoglobulin MMRI = magnetic resonance imagingPCR = polymerase chain reactionPET = positron emission tomographyWBC = white blood cell count

Mycobacterium avium complex immune reconstitution inflammatory syndrome: Long term outcomes

BackgroundTo describe long term outcomes of Mycobacterium avium complex (MAC) immune reconstitution inflammatory syndrome (IRIS).MethodsCases of MAC IRIS were retrospectively identified at four HIV clinics (Michigan, Maryland, Rhode Island, and Indiana) from 1996–2004. Patients were included if they were initially diagnosed with AIDS and found to have evidence of focal MAC infection documented by tissue culture or PCR after initiating HAART, and at least 6 months of follow up.ResultsAmong the 20 patients included, the mean age was 40 years, mean CD4 cell count was 24/mm3 at pretreatment baseline and 100/mm3 at time of MAC IRIS diagnosis. Sites of disease included lymph nodes (15 patients [8 peripheral, 8 abdominal and 1 peripheral and abdominal]), gastrointestinal tract (7) and liver (3). Sixteen patients (80%) responded to treatment and were disease free after a mean of 17.4 months of therapy for MAC IRIS; IRIS therapy was withdrawn in 6 without relapse. Four patients (non-responder group) had persistent or relapsing disease despite 27 months of ongoing MAC IRIS treatment. At the time of resolution or last follow-up, the mean CD4 cell count and viral load was 143/mm3 and 7,000 c/mL for responders, and 65/mm3 and 17,000 c/mL for non-responders, respectively. Most patients with peripheral adenopathy were responders (7/8; 88%); many with abdominal adenopathy (4/8; 50%) were nonresponders.ConclusionThe majority of patients with MAC IRIS eventually responded to treatment. Our sample size was not adequate to perform statistical analysis, but there was a tendency towards adequate CD4 response to HAART and peripheral rather than intraabdominal adenopathy among responders.

Epidemiology of Head and Neck Squamous Cell Cancer Among HIV-Infected Patients

Background:HIV-infected individuals have a higher incidence of head and neck cancer (HNC). Methods:Case series of 94 HIV-infected HNC patients (HIV-HNC) at 6 tertiary care referral centers in the US between 1991 and 2011. Clinical and risk factor data were abstracted from the medical record. Risk factors for survival were analyzed using Cox proportional hazard models. Human papillomavirus (HPV) and p16 testing was performed in 46 tumors. Findings were compared with Surveillance Epidemiology and End Results HNC (US-HNC) data. Results:This study represents the largest HIV-HNC series reported to date. HIV-HNC cases were more likely than US-HNC to be male (91% vs. 68%), younger (median age, 50 vs. 62 years), nonwhite (49% vs. 18%), and current smokers (61% vs. 18%). Median HIV-HNC survival was not appreciably lower than US-HNC survival (63 vs. 61 months). At diagnosis, most cases were currently on highly active antiretroviral therapy (77%) but had detectable HIV viremia (99%), and median CD4 was 300 cells per microliter (interquartile range = 167–500). HPV was detected in 30% of HIV-HNC and 64% of HIV-oropharyngeal cases. Median survival was significantly lower among those with CD4 counts ⩽200 than >200 cells per microliter at diagnosis (16.1 vs. 72.8 months, P < 0.001). In multivariate analysis, poorer survival was associated with CD4 <100 cells per microliter [adjusted hazard ratio (aHR) = 3.09, 95% confidence interval (CI): 1.15 to 8.30], larynx/hypopharynx site (aHR = 3.54, 95% CI: 1.34 to 9.35), and current tobacco use (aHR = 2.54, 95% CI: 0.96 to 6.76). Conclusions:Risk factors for the development of HNC in patients with HIV infection are similar to the general population, including both HPV-related and tobacco/alcohol-related HNC.

Mycobacterium neoaurum Bloodstream Infection: Report of 4 Cases and Review of the Literature

We describe a cluster of 4 bloodstream infections with Mycobacterium neoaurum and 5 additional cases from the literature. Infections occurred mainly in immunocompromised hosts who had central venous catheters. Fever was universal at presentation, but local signs of inflammation were rare. Combination antimicrobial therapy and catheter removal resulted in clinical cure.

CD133+ Hematopoietic Progenitor Cells Harbor HIV Genomes in a Subset of Optimally Treated People With Long-Term Viral Suppression

BACKGROUND Hematopoietic progenitor cells (HPCs) in the bone marrow of human immunodeficiency virus (HIV)-infected individuals have been proposed as a persistent reservoir of virus. However, some studies have suggested that HIV genomes detected in HPCs arise from T-cell contamination. METHODS CD133-sorted HPCs and CD133-depleted bone marrow cells were purified from bone marrow specimens obtained from 11 antiretroviral-treated donors in whom the HIV load had been <48 copies/mL for at least 6 months. CD133 and CD3 expression on the cells was assessed by flow cytometry. HIV DNA was quantified by real-time polymerase chain reaction analysis. RESULTS HIV genomes were detected in CD133-sorted samples from 6 donors, including 2 in whom viral loads were undetectable for >8 years. CD3(+) T cells represented <1% of cells in all CD133-sorted samples. For 5 of 6 CD133-sorted samples with detectable HIV DNA, the HIV genomes could not be explained by contaminating CD3(+) T cells. Donors with detectable HIV DNA in HPCs received their diagnosis significantly more recently than the remaining donors but had had undetectable viral loads for similar periods. CONCLUSIONS HIV genomes can be detected in CD133-sorted cells from a subset of donors with long-term viral suppression and, in most cases, cannot be explained by contamination with CD3(+) T cells.

Blood culture contamination: a randomized trial evaluating the comparative effectiveness of 3 skin antiseptic interventions.

OBJECTIVE To determine relative rates of blood culture contamination for 3 skin antisepsis interventions-10% povidone iodine aqueous solution (PI), 2% iodine tincture (IT), and 2% chlorhexidine gluconate in 70% isopropyl alcohol (CHG)-when used by dedicated phlebotomy teams to obtain peripheral blood cultures. DESIGN Randomized crossover trial with hospital floor as the unit of randomization. SETTING Teaching hospital with 885 beds. PATIENTS All adult patients undergoing peripheral blood culture collection on 3 medical-surgical floors from May 2009 through September 2009. INTERVENTION Each antisepsis intervention was used for 5 months on each study floor, with random crossover after a 1-month washout period. Phlebotomy teams collected all peripheral blood cultures. Each positive blood culture was adjudicated by physicians blinded to the intervention and scored as a true positive or contaminated blood culture. The primary outcome was the rate of blood culture contamination for each antisepsis agent. RESULTS In total, 12,904 peripheral blood culture sets were evaluated, of which 735 (5.7%) were positive. There were 98 contaminated cultures, representing 13.3% of all positive cultures. The overall blood culture contamination rate for the study population was 0.76%. Intent-to-treat rates of contaminated blood cultures were not significantly different among the 3 antiseptics ([Formula: see text]), yielding 0.58% with PI (95% confidence interval [CI], 0.38%-0.86%), 0.76% with IT (95% CI, 0.52%-1.07%), and 0.93% with CHG (95% CI, 0.67%-1.27%). CONCLUSION Choice of antiseptic agent does not impact contamination rates when blood cultures are obtained by a phlebotomy team and should, therefore, be based on costs or preference. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01216761 .

Cardiovascular Implantable Electronic Device Associated Infections

Infectious complications of cardiovascular implantable electronic devices (CIED) have risen out of proportion to overall increases in use. Although CIED can provide potentially life-saving benefits, device-associated infections can be a devastating complication. This article examines the epidemiology and microbiology of CIED infection and reviews specific host and procedural risk factors. Recent advances in the diagnosis of CIED infections and the multifaceted approach required for successful management in this complex patient population are also considered.