IDSA News - May 2012
The Emerging Infections Network (EIN) is a forum for infectious diseases consultants and public health officials to report information on clinical phenomena and epidemiological issues with public health significance. Any diagnostic or therapeutic recommendations and all opinions presented are those of the individual contributor. They do not necessarily represent the views of EIN, IDSA (EIN’s sponsor), or the Centers for Disease Control and Prevention (CDC), which funds EIN. The reader assumes all risks in using this information.
The second case was a patient with lymphoma who had undergone chemotherapy (with resultant neutropenia) and developed pneumonitis. According to the pathology report, no granulomas were present. Findings from a chest CT involved both lungs. Bronchoalveolar lavage specimens grew Cryptococcus neoformans. “Again, there was no involvement of the CNS proven by culture, and cryptococcal antigen was negative as well,” the member noted.
The patients were seen in different hospitals, and assays were performed by different labs. “According to the literature and guidelines, the Cryptococcus antigen assay is supposed to be very sensitive and specific,” the member wrote, asking for comments.
“Was the prozone phenomenon ruled out?” a respondent in Michigan asked. “The titers may have been very high. Though rare, the other possibility is a non-capsular Cryptococcus isolate causing this patient’s disease.”
Another member suggested the “postzone phenomenon—an antigen version of the prozone phenomenon has been described with latex agglutination CrAg.” The member cited a letter to the editor in the Aug. 13, 1982, issue of the Journal of the American Medical Association. “Try diluting the serum and then repeat the test.”
An EIN member in Florida, referencing a December 2003 Chest article, noted that “primary cryptococcoma of the lung usually has a negative serum cryptococcal antigen (CA). In a study of cryptococcal meningitis, the sensitivity of serum CA was 91.4 percent, and the specificity 83.3 percent (J Med Assoc Thai. 1999;82:65-71). So it is possible to have negative serum CA with fungemia and disseminated infections. Also, a capsule deficient strain of Cryptococcus will be serum CA negative,” the member wrote, citing a letter to the editor in the April 1985 issue of Lancet.
A respondent in Oregon offered another possibility: “Are you sure it’s neoformans and not gattii? In Oregon we’ve found serum crypto Ag to be relatively insensitive for C. gattii lung infection.”
“Small colony variants have been described as a potential cause of this uncommon occurrence,” an EIN member in California wrote, citing a 2006 article from the Scandinavian Journal of Infectious Diseases. “We have had few such cases: One occurring in a 74-year-old non-immunocompromised patient with positive CSF and blood cultures for Cryptococcus neoformans (not gattii) with negative enzyme-linked immuno assay (EIA) and latex agglutination antigen, and another in a 64-year-old female with adrenocortical carcinoma, positive serum cryptococcal antigen (1:375 EIA), negative CSF cryptococcal antigen (EIA), and positive CSF culture for Cryptococcus neoformans (not gattii).”
A recent letter published in Emerging Infectious Diseases summarizes the results of a related EIN survey of ID physicians. The survey focused on the clinical approach to diagnosing cryptococcal infections, the relative regional frequency of C. gattii, and the capacity of clinical laboratories to differentiate cryptococcal species.
Additional resources related to cryptococcal disease and diagnosis include:
E-mail the Emerging Infections Network.
The Emerging Infections Network (EIN) is a provider-based sentinel network designed to help the public health community detect trends in emerging infectious diseases.
A joint project of IDSA and the Pediatric Infectious Diseases Society (PIDS) with funding from the Centers for Disease Control and Prevention (CDC), EIN tracks emerging infectious diseases and keeps the public health community up to date with new disease trends, difficult cases, and other issues affecting members’ clinical practices. The Network provides a great opportunity for members to share knowledge quickly across large geographical distances. Both IDSA and PIDS members are eligible to join. Click here for more information or to join EIN.
This month, studies investigating: valacyclovir and the suppression of herpes simplex virus type 2 meningitis recurrences; single-pill antiretroviral regimens and effects on adherence and hospitalizations; oral fluoroquinolones and the risk of retinal detachment; and performance of a rapid oral HIV test in high HIV prevalence settings.
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.
Herpes simplex virus type 2 (HSV-2) is one of the most common causes of aseptic meningitis and can lead to significant neurologic morbidity, including recurrent meningitis. Suppressive antiviral therapy with valacyclovir is effective at diminishing the frequency of genital HSV-2 recurrences but has not been tested for the suppression of meningitis recurrences.
In the May 1 issue of Clinical Infectious Diseases, researchers report the results of a prospective, randomized, double-blind, multicenter trial in Sweden comparing 0.5 gm of valacyclovir twice daily (N=50) versus placebo (N=51) for one year for the prevention of recurrent HSV-2 meningitis. Subjects were followed for two years. Surprisingly, recurrence of HSV-2 meningitis was more frequent in the valacyclovir group than in the placebo group during the treatment phase of the study, though the increase was not significant. After treatment was discontinued, recurrence of HSV-2 meningitis was significantly higher among patients previously exposed to valacyclovir (HR, 3.29 [95 percent CI, 10.06-10.21]. This difference remained significant when non-compliant subjects were excluded from the analysis. Of note, a cluster of cases of recurrent meningitis was observed shortly after valacyclovir was stopped.
The authors conclude that antiviral suppression with 0.5 gm of valacyclovir twice daily does not prevent the recurrence of HSV-2 meningitis. They speculate that the dose might not have been adequate to achieve sufficient penetration of the central nervous system. The authors also note that there appeared to be a rebound effect of cessation of active drug, which indicates that the drug may have had some activity during the treatment phase. The suggestion is that antiviral therapy with higher doses of valacyclovir may yet be beneficial for patients with frequent recurrences.
Antiretroviral treatment (ART) regimens consisting of a single pill per day have been shown to be associated with increased adherence, patient satisfaction, and better virologic outcome. In the February 2012 issue of PLoS ONE, researchers presented the results of a retrospective database review that aimed to assess the effect of ART as a single pill on adherence and hospitalization.
Data from approximately 7,000 commercially insured patients who received care from 1997 to 2008 were reviewed. Subjects were divided into three cohorts: those receiving a single-pill-per-day ART regimen (n = 2,365), those receiving two pills per day (n = 411), and those receiving three or more pills per day (n = 4,297). Though age, insurance status, and concomitant co-morbid conditions including mental health and substance abuse issues did not vary greatly between the three cohorts, there was a significantly greater number of treatment-naïve patients in the single-pill-per day cohort. All subjects completed at least 60 days of their ART regimen. Multivariate logistic regression was used to analyze the association between treatment regimens, adherence, and hospitalizations.
Adherence was significantly improved in the single-pill-per-day cohort. Forty-seven percent of these patients achieved ³95 percent adherence to their regimens compared to 41 percent in the two-pills-per-day cohort and 34 percent in the three or more pills per day cohort (p = 0.019 and <0.001). Additional factors associated with achieving ³95 percent adherence were receipt of two pills per day rather than three or more, being treatment naïve, and receiving treatment in 2008 versus 2006. Subjects who achieved ³95 percent adherence, regardless of the number of pills in their regimen, had significantly fewer hospitalizations. A separate analysis showed that the likelihood of hospitalization was significantly lower for those who received a single pill per day versus three or more.
The authors do note that they were unable to identify all potential confounding variables. Specifically, clinicians may have preferentially prescribed boosted protease inhibitor regimens (which contain three or more pills per day) to less adherent patients, as multiple trials have shown that such regimens are associated with improved virologic outcomes. Notwithstanding such minor limitations, this study found that single-pill-per-day regimens are associated with increased adherence and decreased hospitalizations. Single-pill-per-day regimens may therefore be linked to improved clinical outcome and economic benefit.
Fluoroquinolones are one of the most commonly prescribed antibiotics and, although generally well tolerated, they have been associated with a wide array of adverse events including arrhythmia, tendinopathy, neuropsychiatric events, and dysglycemia. Additionally, case reports have suggested ocular toxicity may uncommonly occur and these findings have been verified in animal models.
In a study in the April 4 issue of the Journal of the American Medical Association, investigators performed a pharmacoepidemiological nested case-control study to examine the association between oral fluoroquinolone use and the risk of retinal detachment. From a cohort of close to 1 million patients, the current use of fluoroquinolones was associated with a statistically significant risk of developing retinal detachment (3.3 percent of cases vs. 0.6 percent of controls). Recent use, defined as the receipt of an oral fluoroquinolone within 1-7 days of event, and past use did not predispose to retinal detachment—findings suggesting retinal detachment as an acute adverse event.
Fluoroquinolones interfere with collagen synthesis, and these fibers are known to play a pivotal role in the structure and integrity of the vitreous body. Breakdown of collagen from concurrent fluoroquinolone use may thus promote the development of posterior vitreous detachment—a mechanism with biologic plausibility from known side effects of this antimicrobial class.
The authors estimate 1,440 cases of retinal detachment in the United States may be attributed to fluoroquinolone use annually, with a number needed to harm of approximately 2,500 patients. The individual risk of this potential event is therefore low. However, patient counseling and attention to symptoms may be altered by the findings of this study.
In the United States, approximately 1 in 5 HIV-infected individuals do not know that they are infected. In addition, of those who receive traditional HIV testing, it is estimated that nearly a third of those who test positive do not return for their results. The increased utilization of rapid HIV testing represents an important strategy in expanding the coverage of HIV testing in the United States and worldwide. How these rapid oral and blood-based tests will be used will be heavily influenced by their test characteristics. In the May issue of Lancet Infectious Diseases, researchers performed a systematic review and meta-analysis to compare the diagnostic characteristics of a rapid HIV point-of-care test when used on oral or blood-based specimens (Oraquick advance rapid HIV-1/2).
Using the studies that directly compared oral versus blood-based testing, the authors found that sampling oral fluid alone led to a lower test sensitivity (98.03 percent vs. 99.68 percent). The studies were also categorized into those tested in high HIV prevalence (>1 percent) or low prevalence (≤1 percent) settings. In high-prevalence settings, the positive predictive value (PPV) was similar between oral and blood-based tests (98.65 percent vs. 98.50 percent), but in low-prevalence settings, the PPV was lower for oral versus blood-based testing (88.55 percent vs. 97.65 percent).
This study confirms the excellent diagnostic accuracy of the Oraquick rapid HIV test in high HIV prevalence settings, but makes the important point that there is an increased risk of both false positive and false negative results in low prevalence scenarios. However, the deficiencies of the rapid oral fluid-based test have to be weighed against its advantages, namely its convenience, ease of use, and non-invasive nature. With these advantages in mind, the U.S. Food and Drug Administration’s (FDA) Blood Products Advisory Committee, a panel of outside experts, recommended earlier this month that FDA approve the test for sale over-the-counter as a home-based test. FDA regulators are expected to announce their decision later this year.
For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases: