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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

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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.

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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

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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

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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

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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???

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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

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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

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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

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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

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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.