Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients
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Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients A R esearch P roposal 5-23-2013 PowerPoint PPT Presentation


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Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients A R esearch P roposal 5-23-2013 Resident: John Ma, MD & PhD, PGY-2 Mentors: Jay Hammock, MD & Erika Erlandson , MD Department of Physical Medicine & Rehabilitation

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Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients A R esearch P roposal 5-23-2013

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Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

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


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

Background:

HCMV is a member of the viral family Herpesviridae. Itis 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.


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

Initial HCMV infection

HCMV viremia

infects lung, liver, spleen, kidney, glands, bladder, bone marrow, CNS etc.

Immunocompetent

Latent infection, (months, years, life long)

Immunocompromised or decreasing immunity level

such as HIV infection, immunosuppression, pregnancy, newborn, leukemia etc.

CMV reactive infection


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

  • CMV infection has been reported in the following patient populations:

  • HIV/AIDS

  • Immunosuppressed organ transplant recipients

  • Newborns/infants with immature immune system

  • Pregnant women (Ma Z. et al, Chin. J of Clin & Exp Virol. 1992)

  • TB patients ( Ma Z et al, Acta of Qingdao Med. Coll. 1991)

  • Stroke : CMV infection is a risk factor for ischemic stroke

  • Leukemia or blood diseased patients

  • Congenital immunocompromised patients


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

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


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

  • HCMV infection is very common in the adult population.

  • More than 90% of the population in developing countries is (+).

  • in the United States, CMV infects ~50-80% of THE

  • POPULATIONby 40 years of age. The infection rate is

  • higher with Aging. (www.cdc.gov/cmv/clinical/)

Cannon et al, Rev med virol, 2012, 20, 202-213


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

Cannon et al, Rev med virol, 2012, 20, 202-213


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

As a physiatrist, why do we care about HCMV infection???


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

  • In US, ~ 790,000 patients suffer strokes each year, making it the

  • 3rd leading cause of death, after heart disease and cancer; 1st 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


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

Related Research

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]

3. Significantly higher rate of cognitive decline with high levels of anti-CMV[Aiello et al, J. Am Geriatr Soc, 2006, 54, 1046-1054]

4. Chronic CMV infection is associated with ADLs impairment [Aiello et al, J. Gerontol. A BiolSci Med Sci, 2008, 63(6), 610-618]

5. Chronic CMV infection is associated with prevalent frailty [Schmaltz et al, J. Am Geriatr Soc, 2005, 53, 747-754]

  • 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.


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

CMV in Stroke Rehab: Rationaleand 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 program

Taking more time to reach maximal rehab goal

Prolonged rehab hospital stay and increased Medicare/Medicaid expense


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

CMV in Stroke Rehab: Specific Aims

  • Aim 1: Study the prevalence of HCMV in post Lt MCA stroke pts

  • 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


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

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


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

CMV in Stroke Rehab: Exclusion Criteria

Known immunosuppression (e.g., organ transplants)

Known HIV infection

Known active PNA or UTI

Known long term use of steroid hormones

Recent major surgery peri-stroke or post-OP stroke

End-stage renal, liver, and/or lung disease

Amputation

Recurrent and/or chronic stroke

Cancer patients with recent chemotherapy and/or XRT

Very sick patients unable to participate rehab program

Severe dementia/end stage of Alzheimer’s disease


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

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

Latent CMV

infection

Active CMV

infection

Comparison of FIM, PT/OT/SLP and hospital stay

ELISA: enzyme-linked immunosorbentassasy

qPCR: quantitative polymerase chain reaction


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

CMV in Stroke Rehab: Possible Outcomes

Group Initial & d/c FIM ∆ FIM ∆ PT/OT/SLP Rehab days

HCMV IgG (-)  /☻ ☻☻fair/well

HCMV IgG (+), qPCR (-)  /☺ ☺☺ fair/delay

HCMV IgG (+), qPCR (+)  /  longer .

Possible relationship between FIM PT/OT/SLP performance and HCMV titer:

FIM score

PT.OT/SLP

0 10 100 1,000 10,000 100,000

Viral copies by quantitative PCR


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

CMV in Stroke Rehab: Future Directions

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.

If our hypothesis is confirmed to be true, then a similar study design can be applied to TBI, SCI, and GRU patients.

Prevalence and effects of other chronic infections such as HSV, EBV and H. Pylori etc. can be evaluated in a rehab hospital setting.


Human cytomegalovirus infection in post left middle cerebral artery ischemic stroke patients a r esearch p roposal 5 23 2013

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.


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