Human cytomegalovirus infection in post left middle cerebral
artery ischemic stroke patients A Research Proposal 5-23-2013
Resident: John Ma, MD & PhD, PGY-2 Mentors: Jay Hammock, MD
& Erika Erlandson, MD Department of Physical Medicine &
Rehabilitation University of Kentucky School of Medicine Lexington,
KY
Slide 2
Background: HCMV is a member of the viral family Herpesviridae.
It is also known as human herpesvirus-5 (HHV-5). It is a DNA virus,
infects humans in early in childhood transmitted by saliva, urine
in daycare settings. After viremia, some individuals clear the
viral infection; however, most of us experience latent infection
throughout life. Like HSV, HCMV re- emerges when the host becomes
immunocompromised.
Slide 3
infects lung, liver, spleen, kidney, glands, bladder, bone
marrow, CNS etc. Initial HCMV infection HCMV viremia
Immunocompetent Immunocompromised or decreasing immunity level such
as HIV infection, immunosuppression, pregnancy, newborn, leukemia
etc. Latent infection, (months, years, life long) CMV reactive
infection
Slide 4
CMV infection has been reported in the following patient
populations: 1.HIV/AIDS 2.Immunosuppressed organ transplant
recipients 3.Newborns/infants with immature immune system
4.Pregnant women (Ma Z. et al, Chin. J of Clin & Exp Virol.
1992) 5.TB patients ( Ma Z et al, Acta of Qingdao Med. Coll. 1991)
6.Stroke : CMV infection is a risk factor for ischemic stroke
7.Leukemia or blood diseased patients 8.Congenital
immunocompromised patients
Slide 5
S/S of CMV infection: In immunocompetent people: No symptoms or
flu like symptoms such as fatigue, malaise, runny nose, sore
throat, low grade fever, muscle ache, or adenopathy In
immunocompromised people: - Visual impairment and blindness -
Pneumonia - Diarrhea - Ulcers of the digestive tract, possibly
causing bleeding - Hepatitis - Inflammation of the brain
(encephalitis) - Behavioral changes - Seizures - Coma
Slide 6
IN THE UNITED STATES, CMV INFECTS ~50-80% OF THE POPULATION BY
40 YEARS OF AGE. THE INFECTION RATE IS HIGHER WITH AGING. (
WWW.CDC.GOV/CMV/CLINICAL/) HCMV infection is very common in the
adult population. More than 90% of the population in developing
countries is (+). Cannon et al, Rev med virol, 2012, 20,
202-213
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As a physiatrist, why do we care about HCMV infection???
Slide 9
In US, ~ 790,000 patients suffer strokes each year, making it
the 3 rd leading cause of death, after heart disease and cancer; 1
st leading cause of disability > 50% stroke patients have latent
HCMV infection. Stroke is a huge stress to the body, it leads to a
compromised immune state, thus increasing the probability of latent
HCMV re-activation HCMV infection is usually a missed diagnosis in
the acute care hospital setting - As it is often latent, HCMV takes
time to become re-active: * First, it inhibits host DNA and protein
synthesis systems * Then, host DNA and protein synthesis systems
are solely utilized for viral replication HCMV would most likely
become active in a rehab hospital setting because it takes about
7-10 days to become completely re-active
Slide 10
1. Chronic CMV infection is a risk factor of ischemic stroke, [
Kis et al, New Microbiolgica, 2007, 30, 213-220], [Huang et al, CNS
Neuroscice & Therapeutic, 2012, 18, 457-460] 2. CMV and HSV
infection are risk factors for future myocardial infarction and
stroke [ Ridker et al, Circulation, 1998, 98, 2796-2799] Related
Research 3. Significantly higher rate of cognitive decline with
high levels of anti-CMV [Aiello et al, J. Am Geriatr Soc, 2006, 54,
1046-1054] 5. Chronic CMV infection is associated with prevalent
frailty [Schmaltz et al, J. Am Geriatr Soc, 2005, 53, 747-754] 4.
Chronic CMV infection is associated with ADLs impairment [Aiello et
al, J. Gerontol. A Biol Sci Med Sci, 2008, 63(6), 610-618] At
present, there are no published data on HCMV prevalence in
post-stroke patients. In addition, there are no published studies
that have examined the relationship between active CMV infection
and rehab performance and/or hospital stay.
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CMV in Stroke Rehab: Rationale and hypothesis Lt MCA ischemic
Stroke Stress to immune system Latent HCMVs become active
Subclinical/clinical symptoms such as fatigue, low grade fever,
malaise, cognitive impairment, frailty and impairment on ADLs Poor
endurance, less motivated to anticipate in rehab programTaking more
time to reach maximal rehab goalProlonged rehab hospital stay and
increased Medicare/Medicaid expense
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Aim 1: Study the prevalence of HCMV in post Lt MCA stroke pts
CMV in Stroke Rehab: Specific Aims Aim 2: Study the active HCMV
infection in post-stroke pts Aim 3: Examine the relationship
between active CMV infection and rehab performance (FIM score,
PT/OT/SLP) Aim 4: Comparison of hospitalization stay of CMV (+)/(-)
patients
Slide 13
CMV in Stroke Rehab: Inclusion criteria 1. New onset 1st time
Left MCA ischemic infarct at age 60-70 2. Cognitively being able to
participate in rehab 3. Willing to participate in the research
study
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1.Known immunosuppression (e.g., organ transplants) 2.Known HIV
infection 3.Known active PNA or UTI 4.Known long term use of
steroid hormones 5.Recent major surgery peri-stroke or post-OP
stroke 6.End-stage renal, liver, and/or lung disease 7.Amputation
8.Recurrent and/or chronic stroke 9.Cancer patients with recent
chemotherapy and/or XRT 10.Very sick patients unable to participate
rehab program 11.Severe dementia/end stage of Alzheimers disease
CMV in Stroke Rehab: Exclusion Criteria
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CMV in Stroke Rehab: Methodology Age, gender, left MCA stroke
(closed size), similar co-morbidities such as DM, HTN, HLD, CKD,
CAD, COPD, social-economic status, BMI matched HCMV IgG in serum
(ELISA) HCMV IgG (-) HCMV IgG (+) qPCR (-) qPCR (+) Non CMV
infection Active CMV infection Latent CMV infection Comparison of
FIM, PT/OT/SLP and hospital stay ELISA: enzyme-linked immunosorbent
assasy qPCR: quantitative polymerase chain reaction
Slide 16
Group Initial & d/c FIM FIM PT/OT/SLP Rehab days HCMV IgG
(-) / fair/well HCMV IgG (+), qPCR (-) / fair/delay HCMV IgG (+),
qPCR (+) / longer. CMV in Stroke Rehab: Possible Outcomes FIM
scorePT.OT/SLP Viral copies by quantitative PCR Possible
relationship between FIM PT/OT/SLP performance and HCMV titer: 0 10
100 1,000 10,000 100,000
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1.If our hypothesis is true that active CMV delays pts
discharge, then we will further explore whether treatment of HCMV
will improve rehab performance and/or decrease their hospital stay.
2.If our hypothesis is confirmed to be true, then a similar study
design can be applied to TBI, SCI, and GRU patients. 3.Prevalence
and effects of other chronic infections such as HSV, EBV and H.
Pylori etc. can be evaluated in a rehab hospital setting. CMV in
Stroke Rehab: Future Directions
Slide 18
Acknowledgments Mentor: Dr. Jay Hammock Constant encouragement
and help from: Dr. Nickerson, Dr. Schleenbacker, Dr. Ortiz, Dr.
Stiles and Dr. Erlandson Enthusiastic comments on the proposal
from: Dr. Sawaki and Dr. Springer The GREATEST study partners &
friends : All the residents in this program, especially Dr. Thien
Ngo and Dr. Dwan Perry.