ASH Clinical News August 2017 v3 | Page 29

CLINICAL NEWS
The overall ICB incidence rate was 0.8
per 100 person-years (95% CI 0.07-0.08),
and incidence rates for each bleeding type
were:
• 0.04 for ICH (95% CI 0.03-0.04)
• 0.03 for SDH (95% CI 0.02-0.03)
• 0.02 for SAH (95% CI 0.01-0.02)
When the investigators restricted their
cohort to the 58,551 patients with con-
tinuous low-dose aspirin use throughout
follow-up, the ICB incidence rate ap-
peared to be higher (0.13 per 100 person-
years; 95% CI 0.11-0.14), but p values
were not reported.
In the entire cohort, 21 percent of
all ICB events were fatal (n=185/881),
meaning a patient died within 30 days
of recorded ICB diagnosis. The median
age at the time of ICB-related death was
74 years, and ICB-related mortality rates
according to ICB location were:
• 27.3% (n=111/407) for ICH
• 9.9% (n=28/283) for SDH
• 24.1% (n=46/191) for SAH
The rates were lower than reported in pre-
vious population-based studies, in which
ICB-related fatality rates ranged from 28.7
to 42.0 percent.
“The net clinical
benefit is clearly
in favor of low-
dose aspirin.”
—LUCÍA CEA SORIANO
Trauma accounted for 28.4 percent
(n=250) of all ICB events, including 11.8
percent (n=48) of ICH, 59.7 percent
(n=169) of SDH, and 17.3 percent (n=33)
of SAH occurrences. The overall incidence
rates of non-trauma- and trauma-related
ICBs were 0.05 (95% CI 0.05-0.06) and
0.02 (95% CI 0.02-0.02) per 100 person-
years, respectively.
The overall incidence rate was similar
between men and women, but women
had higher rates of ICH and SAH events
(0.038 vs. 0.033 and 0.019 vs. 0.014 per
100 person-years, respectively; p values
not provided). The incidence rates of ICH
and SDH increased notably with age,
whereas SAH rates remained “broadly
similar, increasing only slightly with age,”
the authors wrote.
The ICB incidence was also higher
ASHClinicalNews.org
among those receiving low-dose aspirin
for secondary CVD prevention (0.09 per
100 person-years; 95% CI 0.08-0.01) than
among those receiving it for primary CVD
prevention (0.07 per 100 person-years; 95%
CI 0.06-0.07; p values not provided).
“The decision to prescribe low-dose
aspirin for CVD prevention is dependent
on several, largely age-dependent factors,
including whether the patient has previ-
ously experienced, or is at high risk of
experiencing, an ischemic CV event, and
the risk of major bleeding events,” the
authors concluded. “Even taking into ac-
count the risk of major bleeding associ-
ated with the long-term use of low-dose
aspirin, the net clinical benefit is clearly
in favor of low-dose aspirin use in the
secondary-prevention setting.”
The possibility that patients discon-
tinued low-dose aspirin during follow-up
was a potential limitation of the study,
as was its retrospective design and use
of population-level data. The study was
funded by Bayer AG, a manufacturer of
aspirin. ●
Contributing authors report research
funding from Bayer AG.
REFERENCE
Cea Soriano L, Gaist D, Soriano-Gabarró M, et al. Incidence of
intracranial bleeds in new users of low-dose aspirin: a cohort
study using The Health Improvement Network. J Thromb Haemost.
2017;15:1055-64.
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The Challenge of Cytomegalovirus
CMV seropositivity is common in the United States
Cytomegalovirus (CMV) is a highly transmissible and prevalent
herpesvirus that remains in the body after primary infection. 1 Data
from the National Health and Nutrition Examination Survey (NHANES) III
(1988–1994), a population-based survey meant to be representative of
the US population, established that 66.7% of the adult population aged
≥25 years were CMV seropositive. 1 CMV seroprevalence increases
with age, as a study representative of the US population (1999–2004)
revealed a CMV seroprevalence of 49.5% among 20- to 29-year-old
patients and 58.0% among 40- to 49-year-old patients. 2
Hematopoietic stem cell transplant (HSCT), solid organ transplant (SOT),
intensive care unit (ICU), and human immunodeficiency virus (HIV)-
infected patient populations are most frequently affected by CMV
infection. The risk of CMV infection and reactivation varies among these
patients, with a 50% to 90% incidence in HSCT patients, 30% to 75%
in SOT patients, 25.7% in HIV-infected patients with a diagnosis of
AIDS, and 15% to 20% in ICU patients. 3–6
The relationship between CMV and the immune response
A bidirectional relationship exists between CMV and the immune
system. Impaired immune defenses allow CMV replication and could
lead to CMV disease and associated complications. 6 On the other
hand, CMV infection can also alter immune defenses against infections
and could increase the likelihood of secondary infections, including
bacterial and fungal infections, as well as potentially enhance the
proinflammatory response. 6,7
Risk factors for CMV infection and reactivation
CMV serostatus is a significant risk factor for CMV infection and
reactivation and poor prognosis, especially in immunosuppressed
patients. In addition, there are multiple risk factors, such as high-dose
corticosteroids, acute and chronic GVHD, ICU admission, mechanical
ventilation, and sepsis. These risk factors contribute to the overall state
of immunosuppression, which can lead to CMV infection
and reactivation. 6,8–12
CMV disease has serious clinical consequences
The development of CMV disease can have serious consequences,
including end-organ damage, increased risk of secondary infections,
and mortality. 6,7,13–16
The clinical impact of CMV can vary significantly by patient type. HSCT
patients most commonly manifest CMV disease as pneumonia or
gastrointestinal disease. 8 For SOT patients, the transplanted allograft is
typically involved if end-organ damage occurs. This has serious clinical
consequences as CMV disease has been associated with an increased
risk of acute allograft rejection and mortality. 17 In HIV-infected patients
with advanced immunosuppression (CD4+, <50 cells/μL), CMV retinitis
is the most common CMV end-organ disease, but since the advance of
HAART, CMV end-organ disease has declined by ≥95%. 14
In addition to end-organ damage, there is an increased risk of
secondary opportunistic infections, including bacterial and fungal
infections. 7 ICU patients with CMV infection, specifically, were observed
to have an increased risk for nosocomial infections. 6 Secondary
infections can also have serious clinical consequences, even
contributing toward mortality. 16
CMV viremia has also been identified as an independent risk factor
for mortality. This was established in a study of 14,153 subjects aged
≥25 years who were tested for CMV and eligible for mortality
follow-up on December 31, 2006, after being interviewed in NHANES
III (1988–1994). CMV seropositivity was associated with all-cause
mortality even after adjusting for age, gender, race/ethnicity, country of
origin, education level, BMI, smoking status, and diabetes status. 1
Challenges of monitoring CMV
CMV viral load threshold for CMV reactivation or viremia has been
difficult to establish due to variability in assay performance with respect
to quantitative measurement. 7,8 The typical testing methods of DNA
PCR, pp65 antigenemia assay, and pp67 mRNA assay perform well,
but assay variability is concerning in immunocompromised patients
where the viral load can increase rapidly. 8
The optimal strategy for CMV surveillance in posttransplant and
severely immunocompromised patients is not well defined. 18 This is
particularly important as the significance and role of monitoring varies
depending on preventative measures typically used across patient
populations. Different CMV monitoring practices are used depending
on the current standard of care or guideline recommendations for
various patient types. CMV in HSCT and some SOT patients may
rely heavily on monitoring for CMV viremia to determine whether
preventative measures should be initiated. Weekly monitoring is
recommended for HSCT and SOT recipients with either quantitative
PCR or detection of CMV RNA. Recommended monitoring is even
more rigorous and should continue beyond day 100 posttransplant
for HSCT patients who develop acute or chronic GVHD, had an
earlier CMV reactivation, or were mismatched or unrelated donor
transplants. 7,8,19,20 HIV-infected patients should maintain their CD4+
count in order to prevent CMV disease. 18 Finally, only ICU patients
considered at high risk, meaning those with impaired immune
systems, are monitored for CMV reactivation. 6
References: 1. Simanek AM et al. PLoS One. 2011;6(2):e16103. doi:10.1371/journal.pone.0016103. 2. Bate SL et al. Clin Infect Dis. 2010;50(11):1439–1447. 3. Peres RMB et al. BMC Infect Dis. 2010;10:147. doi:10.1186/
1471-2334-10-147. 4. van der Bij W, Speich R. Clin Infect Dis. 2001;33(suppl 1):S32–S37. 5. Wohl DA et al. J Acquir Immune Defic Syndr. 2005;38(5):538–544. 6. Papazian L et al. Intensive Care Med. 2016;42(1):28–37.
7. Kotton CN et al. Transplantation. 2013;96(4):333–360. 8. Boeckh M et al. Biol Blood Marrow Transplant. 2003;9(9):543–558. 9. Piñana JL et al. Bone Marrow Transplant. 2010;45(3):534–542. 10. Cohen L et al. Transpl Infect Dis.
2015;17(4):510–517. 11. Razonable RR, Humar A. Am J Transplant. 2013;13(suppl 4):93–106. 12. Schwarcz L et al. AIDS. 2013;27(4):597–605. 13. Ljungman P et al. Clin Infect Dis. 2017;64(1):87–91. 14. Panel on Opportunistic
Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National
Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. AIDSinfo website. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Revised November 10, 2016. Accessed February 16, 2017.
15. Jabs DA et al. Ophthalmology. 2005;112(5):771–779. 16. Nichols WG et al. J Infect Dis. 2002;185(3):273–282. 17. Beam E, Razonable RR. Curr Infect Dis Rep. 2012;14(6):633–641. 18. Bieniek R et al. Lab Med.
2011;42(6):339–343. 19. NCCN clinical practical guidelines on oncology (NCCN Guidelines ® ). https://www.nccn.org/professionals/physician_gls/PDF/infections.pdf. Accessed February 16, 2017. 20. Ljungman P et al. https://www.ebmt.org/
Contents/Resources/Library/ECIL/Documents/ECIL%204%20%20Update%202011%20CMV.pdf. Accessed February 16, 2017.
Learn more about CMV at www.aboutcmv.com.
Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.
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