Shedding light on IRIS: from Pathophysiology to Treatment of Cryptococcal Meningitis and Immune Reconstitution Inflammatory Syndrome in HIV-Infected Individuals.

OBJECTIVES: The aim of this work was to review current treatment options and propose alternatives for immune reconstitution inflammatory syndrome (IRIS) in HIV-infected individuals with cryptococcal meningitis (CM) (termed 'HIV-CM IRIS'). As a consequence of the immunocompromised state of these individuals, the initial immune response to CM is predominantly type 2 T helper (Th2) /Th17 rather than Th1, leading to inefficient fungal clearance at the time of antiretroviral initiation, and a subsequent overexaggeration of the Th1 response and life-threatening IRIS development. METHODS: An article-based and clinical trial-based search was conducted to investigate HIV-CM IRIS pathophysiology and current treatment practices. RESULTS: Guidelines for CM treatment, based on the Cryptococcal Optimal Antiretroviral Timing (COAT) trial, recommend delayed antiretroviral therapy (ART) following antifungal treatment. The approach aims to decrease fungal burden and allow immune balance restoration prior to ART initiation. If the initial immune balance is not restored, the fungal burden is not sufficiently reduced and there is a risk of developing IRIS post-ART, highlighted by a Th1 immune overcompensation, leading to increased mortality. The mainstay treatment for Th1-biased IRIS is corticosteroids; however, this treatment has been shown to correlate with increased mortality and significant associated adverse events. We emphasize targeting a more specific Th1 mechanism via the tumour necrosis factor (TNF)-α cytokine antagonist thalidomide, as it is the only TNF-α antagonist currently approved for use in infectious disease settings and has been shown to decrease Th1 overreaction, restoring immune balance in HIV-CM IRIS. CONCLUSIONS: Although the side effects and limitations of thalidomide must be considered, it is currently being successfully used in infectious disease settings and warrants mainstream application as a therapeutic option for treatment of IRIS in HIV-infected patients with CM.

Rationale and development of a business case for antimicrobial stewardship programs in acute care hospital settings.

Background: Antimicrobial stewardship programs (ASPs) have been shown to reduce inappropriate antimicrobial use and its consequences. However, these programs lack legislative requirements in many places and it can be difficult to determine what human resources are required for these programs and how to create a business case to present to hospital administrators for program funding. The objectives of the current paper were to review legislative requirements and outline human resource requirements for ASPs, and to create a base business case for ASPs. Methods: A working group of antimicrobial stewardship experts from across Canada met to discuss the necessary components for creation of a business case for antimicrobial stewardship. A narrative review of the literature of the regulatory requirements and human resource recommendations for ASPs was conducted. Informed by the review and using a consensus decision-making process, the expert working group developed human resource recommendations based on a 1000 bed acute care health care facility in Canada. A spreadsheet based business case model for ASPs was also created. Results: Legislative and /or regulatory requirements for ASPs were found in 2 countries and one state jurisdiction. The literature review and consensus development process recommended the following minimum human resources complement: 1 physician, 3 pharmacists, 0.5 program administrative and coordination support, and 0.4 data analyst support as full time equivalents (FTEs) per 1000 acute care beds. Necessary components for the business case model, including the human resource requirements, were determined to create a spreadsheet based model. Conclusions: There is evidence to support the negative outcomes of inappropriate antimicrobial use as well as the benefits of ASPs. Legislative and /or regulatory requirements for ASPs are not common. The available evidence for human resource recommendations for ASPs using a narrative review process was examined and a base business case modelling scenario was created. As regulatory requirements for ASPs increase, it will be necessary to create accurate business cases for ASPs in order to obtain the necessary funding to render these programs successful.

Characteristics of hospital admissions for pneumonia in HIV-positive individuals in Winnipeg, Manitoba: a cross-sectional retrospective analysis.

Lung infection in human immunodeficiency virus (HIV)-positive individuals remains an important cause of morbidity and mortality, even in the current antiretroviral therapy era. Pneumonia is the most common cause of admission in HIV-positive individuals in our centre as reported in a previously published study. The objective of this retrospective observational study was to further characterize these admissions, with respect to index of disease severity at presentation, organisms identified, and investigations pursued including bronchoalveolar lavage (BAL). There were 123 unique patients accounting for a total of 209 admissions from 2005 to 2015. An organism was isolated in only 33% of all admissions (68/209). The most common organism was Pneumocystis jirovecii with a frequency of 29% of all admissions. Eighty-seven percent of presentations were mild, and 13% were moderate by CURB-65 criteria. A total of 39 BALs were performed, of which 27 yielded an organism (69%). Considering the burden of disease, low diagnostic yield of the current diagnostic strategy and increased morbidity and mortality caused by pneumonia in HIV-positive individuals, further methods are needed to more accurately target therapy. The preponderance of mild disease in this study suggests that better diagnostic tests may identify individuals that can be candidates for outpatient therapy.

Negative latent tuberculosis at time of incarceration: identifying a very high-risk group for infection.

The main aim was to measure the incidence of latent tuberculosis infection (LTBI) and identify risk factors associated with infection. In addition, we determined the number needed to screen (NNS) to identify LTBI and active tuberculosis. We followed 129 prisoners for 2 years following a negative two-step tuberculin skin test (TST). The cumulative incidence of TST conversion over 2 years was 29·5% (38/129), among the new TST converters, nine developed active TB. Among persons with no evidence of LTBI, the NNS to identify a LTBI case was 3·4 and an active TB case was 14·3. The adjusted risk factors for LTBI conversion were incarceration in prison number 1, being formerly incarcerated, and overweight. In conclusion, prisoners have higher risk of LTBI acquisition compared with high-risk groups, such as HIV-infected individuals and children for whom LTBI testing should be performed according to World Health Organization guidance. The high conversion rate is associated with high incidence of active TB disease, and therefore we recommend mandatory LTBI screening at the time of prison entry. Individuals with a negative TST at the time of entry to prison are at high risk of acquiring infection, and should therefore be followed in order to detect convertors and offer LTBI treatment. This approach has a very low NNS for each identified case, and it can be utilized to decrease development of active TB disease and transmission.

HLA B51 is associated with faster AIDS progression among newly diagnosed HIV-infected individuals in Manitoba, Canada.

Human leucocyte antigen (HLA) alleles influence the rate of CD4 decline among HIV-infected individuals. We investigated the association between HLA B35 and HLA B51 and the rate of CD4 decline and/or opportunistic infections, among 294 HIV-positive individuals from Manitoba, Canada. All individuals presenting with a CD4 count >200 cells µL(-1) , who had at least two CD4 counts, and no evidence of co-infection were included. Individuals bearing HLA B35 or HLA B51 were compared to controls. A multivariate model demonstrated that HLA B35 allele was associated with a hazard ratio of 2.05 (95% CI 1.31-3.18) for reaching AIDS and HLA B51 allele with HR of 2.03 (95% CI 1.18-3.49) for reaching the same end-point. High prevalence of HLA B35 was seen in the patient population receiving care in Manitoba. Our observations confirm the association of HLA B35 with rapid disease progression. We report, for the first time, faster CD4 decline among individuals with HLA B51 allele.

Vitamin D binding protein polymorphism protects against development of blastomycosis.

Blastomycosis is an uncommon endemic fungal infection. It is presumed that in the endemic regions, the number of exposed individuals is significantly greater than those in whom clinical manifestations develop. We conducted a case-control study of individuals with clinical blastomycosis and controls with similar exposure but who did not develop disease. A genetic association was observed between the Gc-2 allele of vitamin D binding protein and reduced susceptibility to blastomycosis in a Canadian cohort. The Gc-2 allele can affect increased antimicrobial activity of macrophages. It may be possible to mimic this mechanism of protection by vitamin D supplementation.

High prevalence and risk factors associated with latent tuberculous infection in two Colombian prisons.

SETTING: Two prisons in Medellín and Itagüí, Colombia. OBJECTIVE: To determine the prevalence of tuberculin skin test (TST) positivity in prisoners and the annual risk of tuberculous infection (ARTI), to identify risk factors associated with a positive result, and to describe progression to active disease. DESIGN: Cross-sectional study. Inmates were included if time of incarceration was ⩾1 year and excluded if subjects had had previous or active tuberculosis (TB), or conditions that could hamper TST administration or interpretation. RESULTS: We screened 1014 inmates. The overall prevalence of TST positivity was 77.6%. The first TST administration resulted in 66% positivity, and the second TST an additional 11.6%. In Prison One, the ARTI was 5.09% in high TB incidence cell blocks and 2.72% in low TB incidence blocks. In Prison Two, the ARTI was 2.77%. Risk factors associated with TST positivity were history of previous incarceration and length of incarceration. Among all those included in the study, four individuals developed active pulmonary TB. CONCLUSION: Prevalence of TST positivity in prisoners and the ARTI were higher than in the general population, but differed between prisons; it is important to apply a second TST to avoid an overestimation of converters during follow-up.

Comparison between transthoracic and transesophageal echocardiography in screening for infective endocarditis in patients with Staphylococcus aureus bacteremia.

Echocardiography is an important diagnostic tool in evaluating a patient with Staphylococcus aureus bacteremia (SAB) for diagnosing infective endocarditis (IE). We sought to compare the utility of transthoracic echocardiography (TTE) with transesophageal echocardiography (TEE) in screening for IE in patients with SAB. We performed a retrospective chart review of 285 adult patients from two tertiary care hospitals with at least one positive blood culture for S. aureus between 2010 and 2012. Patients who underwent echocardiography were divided into two groups: TTE (screened with TTE only) and TEE (screened with both TTE and TEE). The demographic factors and clinical outcomes were compared between the groups. Of the 285 charts reviewed, 213 (74.7 %) patients were screened with echocardiography: 183 (85.9 %) were screened with TTE alone and 30 (14.1 %) were screened with both TTE and TEE. TEE disclosed more cases of definite IE than TTE (8 [26.7 %] vs. 22 [12.0 %], p = 0.046). The TEE group had higher mortality than the TTE group (15 [50.0 %] vs. 43 [23.5 %], p = 0.004). In patients with definite IE, mortality was higher in the TEE group than in the TTE group (6 [75.0 %] vs. 6 [27.3 %], p = 0.034). TEE discovered additional findings that were missed by TTE in 36.7 % of cases and refuted the findings of TTE in 13.3 % of cases. We do not support the routine use of TEE in patients with uncomplicated SAB. High-risk patients in which IE is a serious consideration should undergo investigation with TEE.

The role of polymorphisms in host immune genes in determining the severity of respiratory illness caused by pandemic H1N1 influenza.

Following the influenza epidemics, it has become clear that severity of illness is not uniform. Comorbidities and immunocompromise account for only a fraction of severe cases and do not explain the differential severity among the otherwise healthy during pandemics. During the 2009 H1N1 pandemic, a focus has been placed on better understanding of the determinants and pathogenesis of severe influenza infections. Much of the current literature has focused on viral genetics and its impact on host immunity as well as novel risk factors for severe infection (particularly within the H1N1 pandemic). The improved understanding of the cellular mechanisms and pathways involved in the pathogenesis of severe disease along with technological advances have allowed a more systematic approach to the exploration of the host genetic determinants of susceptibility and severe respiratory illness. By better defining the role of genetic variability in the immune responses to influenza, and identifying key polymorphisms that either protect against severe manifestation or those that impair the host immune response, it is possible to envision better methods to identify at-risk populations and new targets for therapeutic interventions and vaccines. This review will summarize the accumulated literature examining the immunogenetic factors associated with propensity for the development of severe pandemic H1N1 (pH1N1) manifestations. We will focus on novel and key insights gained through study of ethnic populations that appeared more vulnerable to severe disease during the 2009 H1N1 pandemic.

The microbiology of endophthalmitis: global trends and a local perspective.

Endophthalmitis is a rare but frequently devastating infection, caused by diverse organisms, including bacteria, viruses, fungi, and parasites. The causative agents of endophthalmitis vary according to the mechanism. The involvement of intraocular structures can result from exogenous spread from ocular trauma, infection of adjacent structures, or as a complication of intraocular surgery. Of the causes of exogenous endophthalmitis, post-operative endophthalmitis is the most frequently encountered; specifically, cataract surgery is the most frequent eye surgery and, thus, leads the list of surgery-associated endophthalmitis. Exogenous source is far more common than endogenous endophthalmitis, a disease that is caused by the hematogenous spread of organisms from a remote infectious site to the eye, leading to severe visual loss. Several large series estimate that endogenous endophthalmitis accounts for 2-15 % of all cases of endophthalmitis. Progressive vitritis is a hallmark for all forms of endophthalmitis, accompanied by intraocular inflammation, loss of vision, pain, and hypopyon. The common presentation consists of reduced vision, conjunctival injection, pain, and eyelid swelling. We reviewed the microbiology of endophthalmitis during a 9-year period in Winnipeg, Canada. Gram-positive bacteria with coagulase-negative staphylococci are the most common causative organisms, reflecting the association with surgical procedures.

Medical ward admissions among HIV-positive patients in Winnipeg, Canada, 2003-10.

Canadian data regarding the characteristics of HIV-positive patients admitted to hospital as well as the causes and patterns of admissions remain limited. Chart reviews were performed to ascertain admission diagnosis, co-morbidities and CD4 counts among this sub-population, which had an over-representation of Aboriginal persons. Infectious diseases, particularly pneumonia, represent the most common admission diagnosis for HIV-positive persons in Winnipeg. Further, individuals presenting to hospital often have very low CD4 counts, representing significant immune suppression. Earlier HIV diagnosis and treatment in an effort to delay the onset of advanced disease and hospitalization is needed.

Clinical and phenotypic differences between classic and hypervirulent Klebsiella pneumonia: an emerging and under-recognized pathogenic variant.

The purpose of this study was to increase awareness, gain insight into acquisition, and assess the virulence of the hypervirulent (hypermucoviscous) clinical variant (hvKP) that is entrenched in the Pacific Rim but emerging in Western countries. A case of community-acquired liver abscess with metastatic spread to the spleen is described. Comparative in vitro and in vivo virulence studies on this isolate (hvKP1) and four randomly chosen blood isolates of "classic" K. pneumonia strains (cKP1-4) were performed. Cases of hvKP infection are occurring in Western countries and are under-recognized. A hypermucoviscous phenotype is a surrogate laboratory marker for this variant. The propensity of hvKP strains for metastatic spread in non-compromised hosts is both a defining and unusual trait. The mode of acquisition in the described case was unclear but potential means are discussed. hvKP1 was more resistant to complement and neutrophil-mediated bactericidal activity and was more virulent in a rat subcutaneous abscess model than cKP1-4. Recognition of the hypermucoviscous phenotype, defined by a positive "string-test", will alert the microbiologist or clinician that the infecting strain may be a hvKP, which is hypervirulent compared to cKP. This will improve our understanding of the epidemiology and clinical spectrum of infection, which may be more extensive than appreciated.

Cellular immune responses to recurring influenza strains have limited boosting ability and limited cross-reactivity to other strains.

Influenza vaccine provides protection against infection with matched strains, and this protection correlates with serum antibody titres. In addition to antibodies, influenza-specific CD8+ T-lymphocyte responses are important in decreasing disease severity and facilitating viral clearance. Because this response is directed at internal, relatively conserved antigens, it affords some cross-protection within a given subtype of influenza virus. With the possibility of a broader A(H1N1) Mexico outbreak in the fall of 2009, it appeared worthwhile studying the degree of cellular immune response-mediated cross-reactivity among influenza virus isolates. The composition of the 2006-2007 influenza vaccine included the A/New Caledonia/20/1999 strain (comprising a virus that has been circulating, and was included in vaccine preparations, for 6-7 years) and two strains not previously included (Wisconsin and Malaysia). This combination afforded us the opportunity to determine the degree of cross-reactive cellular immunity after exposure to new viral strains. We analysed the antibody responses and the phenotype and function of the T cell response to vaccine components. The results obtained show that antibody responses to A/New-Caledonia were already high and vaccination did not increase antibody or cytotoxic T lymphocyte responses. These data suggest that repeated exposure to the same influenza stain results in limited boosting of humoral and cellular immune responses.

Transient osteoporosis associated with hyperhomocystinemia: a possible role for hyperbaric oxygen therapy.

Transient osteoporosis of the hip is considered by some to be an early stage of avascular necrosis. Hyperbaric oxygen (HBO2) therapy, which may be of benefit in the treatment of avascular necrosis, might therefore be used in the treatment of transient osteoporosis of the hip. We present a case of transient osteoporosis associated with elevated levels of homocysteine in a 33-year-old white male, who was treated by HBO2. Treatment was administered at 2.5 ATA for 90 minutes once daily, five days per week. Regular follow-up examinations in the course of the HBO2 therapy revealed improvement in the patient's complaints and the findings of the physical examination. Repeated magnetic resonance imaging (MRI) performed after 40 and 90 sessions showed decreased edema and complete resolution of the edema, respectively. Evaluation 6 months after the completion of treatment revealed complete resolution of symptoms, with a normal physical examination.