Weekly Articles: Week of 12/6/2020

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Ighovwerha Ofotokun, Lauren F Collins, Kehmia Titanji, Antonina Foster, Caitlin A Moran, Anandi N Sheth, Cecile D Lahiri, Jeffrey L Lennox, Laura Ward, Kirk A Easley, M Neale Weitzmann, Antiretroviral Therapy–Induced Bone Loss Is Durably Suppressed by a Single Dose of Zoledronic Acid in Treatment-Naive Persons with Human Immunodeficiency Virus Infection: A Phase IIB Trial, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages 1655–1663, https://doi.org/10.1093/cid/ciz1027

This small, phase IIb clinical trial compared the effect of a one dose zolendronic acid in patients who were ART naive on their bone density, based on plasma C-terminal telopeptide collagen, osteocalcin, and BMD. 34 patients were randomized to ZOL while 29 were randomized to placebo. Both groups were fairly well matched, though most ZOL patients either were non-smokers and were less likely to use alcohol. Patients were started usually on TDF/FTC + ATZ/r and were followed out to 144 weeks. Most patients in the ZOL arm had lower C-terminal telopeptide of collagen (marker of bone turnover) than in the placebo arm all the way through 144 weeks:

The difference between groups by week 120 was not statistically significant. Similarly, osteocalcin (marker of bone formation) was increased in the placebo arm in the first 24 weeks, but this was not statistically significant by week 72. 

Most importantly, BMD of the lumbar spine was significantly higher in the ZOL arm compared to the placebo. There was a small decrease in BMD at the hip and femoral head in the ZOL arm, however. Furthermore, No patients in the ZOL arm developed either osteopenia or osteoporosis, compared to 8 and 1, respectively, in the placebo arm.

TDF has been known to be associated with bone demineralization, leading to a higher incidence of fractures and osteoporosis in people living with HIV. It is believed that most of the demineralization occurs within the first 2 years following ART. While TAF has been associated with less demineralization, it still occurs at a significant rate. This is a pretty neat proof-of-concept trial, though I’d be interested in whether another dose, one-year apart, would extend the benefits. Alternatively, is this something we should all do for all HIV patients whenever they get their diagnosis, as part of their “treatment package?” Would elderly females or other people at higher risk of fractures would benefit from a yearly dose? Stay tuned.

Alexia Y Zhang, Sarah Shrum, Sabrina Williams, Sarah Petnic, Joelle Nadle, Helen Johnston, Devra Barter, Brittany Vonbank, Lindsay Bonner, Rosemary Hollick, Kaytlynn Marceaux, Lee Harrison, William Schaffner, Brenda L Tesini, Monica M Farley, Rebecca A Pierce, Erin Phipps, Rajal K Mody, Tom M Chiller, Brendan R Jackson, Snigdha Vallabhaneni, The Changing Epidemiology of Candidemia in the United States: Injection Drug Use as an Increasingly Common Risk Factor—Active Surveillance in Selected Sites, United States, 2014–2017, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages 1732–1737, https://doi.org/10.1093/cid/ciz1061

Not a surprising study (spoiler alert, more IVDU = more candidemia). This population based cohort studie of 9 states evaluated the incidence of candidemia and whether IVDU is affecting the epidemiology 1191 cases of candidemia were evaluated, of which 128 were associated with IVDU. Shouldn’t be surprising, but those with IVDU were much younger (35 vs 63), more likely to have hepatitis C (54.7% vs 6.4%), more likely to be a smoker (68.8% vs 18.5%), though non-IVDU patients were more likely to have pulmonary diseases and CKD. Notably, overall mortality was higher for non-IVDU patients (29.4% vs 10.2%) and IVDU were more likely to have polymicrobial bacteremia (31.3% vs 16.0%). Again, not really surprising, but if you have an IVDU who has both MRSA and candida, then you’ll know why. This likely is more of a public health issue and it has more significance from a policy perspective with respect to the opiate crisis, but I do not do much public health. 

Jennie Johnstone, Emily Shing, Arezou Saedi, Kwaku Adomako, Ye Li, Kevin A Brown, Gary Garber, Discontinuing Contact Precautions for Vancomycin-Resistant Enterococcus (VRE) Is Associated With Rising VRE Bloodstream Infection Rates in Ontario Hospitals, 2009–2018: A Quasi-experimental Study, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages 1756–1759, https://doi.org/10.1093/cid/ciaa009

Stopping VRE contact precautions does lead to higher incidence of invasive VRE. This was a study evaluating incidence of VRE bacteremia in hospitals that were stratified into 2 cohorts: one that stopped screening for VRE after 2012 and another who did not stop screening. Study period included data from Jan 2009 to Dec 2018. 100 hospitals out of 211 reported >1 VRE bacteremia, 23/100 in the ceased screening cohort and 77/100 in the screening cohort. Using a interrupted time series POisson regression analysis to determine the slope change before vs after intervention, the annual IRR in the stopped screening cohort was 1.31 (95% CI 1.06-.1.63). The slope change was not seen in the VRE screening cohort. 

This suggests that contact precautions in VRE should be kept. Though this may say more about our general hygiene more than anything (not cleaning our stethoscopes, not washing our hands properly, etc). 

Ilan S Schwartz, Daniel Z P Friedman, Lori Zapernick, Tanis C Dingle, Nelson Lee, Wendy Sligl, Nathan Zelyas, Stephanie W Smith, High Rates of Influenza-Associated Invasive Pulmonary Aspergillosis May Not Be Universal: A Retrospective Cohort Study from Alberta, Canada, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages 1760–1763, https://doi.org/10.1093/cid/ciaa007

EDITORIAL: Bart J A Rijnders, Alexander F A D Schauwvlieghe, Joost Wauters, Influenza-Associated Pulmonary Aspergillosis: A Local or Global Lethal Combination?, Clinical Infectious Diseases, Volume 71, Issue 7, 1 October 2020, Pages 1764–1767, https://doi.org/10.1093/cid/ciaa010

Its the flu season!! Double-whamy! Read here for more details, but to catch you up to speed, influenza is also a risk factor for invasive pulmonary aspergillosis (IPA), at least severe influenza requiring ICU admission. This cohort study from Canada evaluated ICU flu patients from November 2014 through April 2019, and used the AspICU criteria to evaluate the incidence of IPA in this population. 133 patients were admitted to the ICU, and 8 patients had IPA based on BAL cultulres, with 4 of these having positive BAL galactomannan. Notably, mortality was significantly worse in the IPA group, 50% vs 27.2% (p-value 0.22, not statistically significant due to small numbers). A nice editorial follows this article. As mentioned in the introduction of this article, incidence of IPA in European cohort studies ranged from 12-28%, and while this is lower than those, a 7% incidence is nothing to sneeze at. 

Smith BJ, Price DJ, Johnson D, Garbutt B, Thompson M, Irving LB, Putland M, Tong SYC. Influenza With and Without Fever: Clinical Predictors and Impact on Outcomes in Patients Requiring Hospitalization. Open Forum Infect Dis. 2020 Jul 3;7(7):ofaa268. doi: 10.1093/ofid/ofaa268. PMID: 33123614; PMCID: PMC7580166.

This study evaluated 578 patients who presented to a single center in Australia with influenza, and investigated factors and outcomes in these patients who presented with and without fever. Case definition for fever was a temperature >37.8C while in the ED. Patients without fever tended to be older, have higher rates of cardiorespiratory disease, and present later in the course of disease. More importantly, though, those who presented without fever took longer to have a diagnosis made, stayed in longer, and were less likely to get Tamiflu. They also had higher in-hospital mortality:

Multivariate analysis found that age >65, female sex, respiratory disease, and symptom duration >3d were associated with a lower likelihood of fever:

This is important, as it has been known that older and immunosuppressed patients may not mount an inflammatory response that will lead to fever, thus delaying diagnosis. Indeed, patients without fever were less likely to be diagnosed in the ED, less likely to receive oseltamivir, and have higher in-hospital mortality. 

Thus, if patients are older and are afebrile, it may be reasonable to proceed with flu testing if its flu season as this may impact hard outcomes. 

Some TB up in here!

Sosa-Moreno A, Narita M, Spitters C, Swetky M, Podczervinski S, Lind ML, Holmberg L, Liu C, Edelstein R, Pergam SA. A Targeted Screening Program for Latent Tuberculosis Infection Among Hematopoietic Cell Transplant Recipients. Open Forum Infect Dis. 2020 Jun 10;7(7):ofaa224. doi: 10.1093/ofid/ofaa224. PMID: 32671130; PMCID: PMC7348235.

This study evaluated the incorporation of a screening questionnaire in a population of patients undergoing HSCT. Prior screening involved universal TST. This time around, a screening questionnaire was performed and if any question was positive, the patient was then screened with a quant GOLD (an IGRA, as the cool kids call it) and then a TST. Patients who were positive or indeterminate and around half of those with negative results underwent additional chart review. 1290 patients were included, and 457/1290 (35%) had a positive screen. Incidence in this population of LTBI was 3.5% (16/457), with 14/457 having positive IGRA, 52 having indeterminate, and 391 having negative IGRA results. Of 52 indeterminate IGRA, none were TST positive, 33 were TST negative. Of those who where IGRA negative, only 2 were TST positive:

Risk factors included being born in a high incidence area and travel to a TB area. Within this type of patient population, a reduction in TST/IGRA testing was decreased by 65%. So if there there are no risk factors, TB screening may not be warranted. 

Stadelman AM, Ellis J, Samuels THA, Mutengesa E, Dobbin J, Ssebambulidde K, Rutakingirwa MK, Tugume L, Boulware DR, Grint D, Cresswell FV. Treatment Outcomes in Adult Tuberculous Meningitis: A Systematic Review and Meta-analysis. Open Forum Infect Dis. 2020 Jun 30;7(8):ofaa257. doi: 10.1093/ofid/ofaa257. PMID: 32818138; PMCID: PMC7423296.

This was a meta-analysis that evaluated outcomes in patients treated for TB meningitis in terms of mortality and CNS sequelae. 39 studies were included, mostly cohort or case series, with 8 being RCTs. 19 studies involved steroids, and median duration of therapy was 9 months. Mortality endpoints within studies ranged from 1 month to 5 year. As such, mortality was split into early (<3mo), 6 months (3-6mo), and 12mo (any >6mo). Pooled mortality was 24%, though notably, there was a lot of heterogeneity:

This seems to have been driven mostly by the HIV positive population:

In looking at neurological sequelae, the Modified Rankin Scale and the Barthel Index were used. Using the Rankin scale, the pooled proportion with some level of disability was 26% (95% CI 18-35), while using the Barthel index, the proportion of people with disability was 32% (95% CI 22-43). A few things to point out. Most of the mortality came within the first 3 months, however it should be noted the high degree of heterogeneity reported in this analysis. Studies after 2004 (following the Thwaites RCT) consistently used steroids, but regimens were not standardized. Lastly, mortality for this remains high, especially for those with concurrent HIV infection.

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