1. Lengthy Clinical Presentation Ellen Mattes Barbouche, MD Primary Care Conference 10 March 2004

2. No Funding for this Discussion

3. Case – Initial Presentation Day 4 of illness Provider #1 33 year old female with 3 days of headache, nausea, fatigue, facial pressure History of migraine with aura, mononucleosis as teenager Topical pimecrolimus for atopic dermatitis Penicillin allergy, no alcohol or tobacco Married researcher at UW Primate Center FH: mother hypothyroidism PE: Afebrile, injected posterior oropharynx, left- sided, anterior cervical adenopathy, otherwise unremarkable head, neck, chest exam

4. Initial presentation – cont’d Laboratory: Negative urine pregnancy Diagnosis: Probable recurrent sinusitis Treatment: Azithromycin 500 mg day 1, then 250 mg daily, days 2-5

5. Second clinic visit – Day 15 Provider #1 No improvement with azithromycin Continued daily (AM) headaches, some relief with ibuprofen PM “indigestion” Sore throat, post-nasal drainage, myalgias, fatigue PE: T 99.4, pale and fatigued, left tonsillar and anterior cervical adenopathy, otherwise normal head, neck, chest, and neurologic exams

6. Clinic visit 2, day 15 – cont’d Laboratory: Normal CBC with 40% lymphocytes and normal free T4 and TSH Impression: Possible viral illness Recommendation: Discontinue ibuprofen. Acetominophen if necessary, rest, and hydrate well. Call if symptoms continue.

7. Immediate Care/Emergency Department Visit – Day 23 Provider #3 3 days of left leg pain after days off work to recuperate from illness 3 cm linear erythema and pain to palpation left lower extremity Diagnosis: Superficial venous thrombophlebitis Treatment: Elevate for 48 hours with moist heat QID, ibuprofen 400 mg TID or aspirin 325 mg QID with ranitidine 150 mg BID Follow up with primary MD if symptoms persist over 2 days

8. Clinic Visit 3 – Day 29 Provider #5 Continued headache, facial pain, and low-grade fever Recurrent epigastric discomfort after ibuprofen for leg pain Immediate care visit discontinued ibuprofen, encouraged ranitidine, which helped PE: Afebrile. Posterior oropharyngeal erythema, no adenopathy, otherwise normal head and chest exam

9. Clinic visit 3, day 29 – cont’d Laboratory: Normal CBC, although 64% lymphocytes, normal sinus films, ESR 21, ALT 256, AST 145, CRP 2, Lyme EIA 0.02 Impression: Prolonged illness with NSAID-induced gastritis Follow up with primary MD

10. Clinic visit 4, Day 31 Provider #6, Primary MD Myalgias, fatigue, low-grade fevers persist Headaches decreased Post-prandial right upper quadrant abdominal discomfort for one week No jaundice, but “dark urine” No acetominophen PE: Afebrile, weight stable for 6 months, normal funduscopic exam, no icterus, small superior, anterior adenopathy, no hepatosplenomegaly, normal neuro, heart, lung, skin exams

11. Clinic visit #4, day 31 – cont’d Diagnostic test performed

13. Objectives: Review CMV in Immunocompetant Patient Epidemiology Pathology Laboratory features Clinical presentation and complications

14. CMV spectrum of disease Asymptomatic to mononucleosis syndrome in normal host Congenital CMV syndrome frequently fatal Potential for much more severe disease in immunocompromised BMT: CMV pneumonia most common life- threatening infection AIDS: most common viral infection Mandell, 5 th ed., 2000;1586-1596.

15. Epidemiology Common, but socioeconomically determined –Developing countries near 100% during childhood –US population Lower socioeconomics approach 90% CMV IgG by age 40 Upper socioeconomics near 50% by adulthood Transmitted by body fluid contact

16. CMV pathology Largest herpes virus to infect humans CMV glycoproteins complex with HLA-1 molecules –Prevents recognition and destruction by CD8 lymphocytes Nuclear inclusion cells (cytomegaly) Allows latent infection Most antivirals target CMV DNA polymerase Beersma. J Immunology. 1993;151:4455-4464.

17. Laboratory Diagnosis of CMV Detection of nuclear inclusion-cells in urine sediment,saliva, blood, biopsy specimens Immunocompetant: IgM CMV (SLC $30) –Specificity increased by removing IgG and rheumatoid factor prior to testing –Remains elevated < 4 months Immunocompromised: CMV DNA probe

18. CMV Mononucleosis Classic triad of infectious mononucleosis: FEVER, LYMPHADENOPATHY, LYMPHOCYTOSIS Hematologic hallmark of infectious mononucleosis: >50% lymphocytes, of these >10% atypical Of infectious mononucleosis cases, approximately 80- 90% EBV, 10-20% CMV –CMV usually heterophile agglutinin negative –CMV usually more systemic – fever, adenopathy –CMV more likely older young adults (20-35) –EBV more likely sore throat, exudative tonsils Klemola. J Infectious Disease. 1970;121: 608-614.

19. CMV Complications Hepatic –Frequent subclinical transaminitis –Rare granulomatous hepatitis Gastrointestinal –Inflammatory colitis –Gastritis –Esophagitis –Ileitis Stam. J Clinical Gastroenterology. 1996;22:322.

20. CMV Complications, cont’d Neurologic –Meningitis –Encephalitis –Guillain-Barre syndrome CMV and campylobacter most frequently identified Younger patients Increased sensory deficits, more frequent respiratory insufficiency and cranial nerve impairment Slower recovery

21. CMV Complications, cont’d Cardiovascular –Pericarditis –Myocarditis –Atherosclerosis Mechanism: infected vascular endothelium increased proliferation smooth muscle cells which increase oxygenated scavengers and decrease LDL uptake CAD risk correlates with CMV IgG titers High. Clinical Infectious Disease.1999:28(4)746-749. Sorlie. Archives Internal Medicine. 2000;160(13)2027-2032.

22. CMV Complications Pulmonary –Pneumonitis Ocular –Retinitis Hematologic –Anemia: hemolytic – cold agglutinins –Thrombocytopenia – if infected megakaryocytes Rheumatologic –Frequent arthralgias, RARE arthritis –25-35% develop positive rhematoid factor

23. CMV Prevention Good hygeine Child and health care workers Immunocompromised population –Prophylaxis soon after transplant

24. CMV during pregnancy Primary infection in 1-3% of U.S. pregnant women Most mothers asymptomatic, few mononucleosis 2/3 infants not infected, of the remaining third, only 10-15% symptomatic at birth Effected fetus may develop hepatosplenomegaly to death 80-90% of infected infants will develop complications within 2 years: hearing loss, visual impairment, mental retardation cdc.gov/ncidod/diseases/cmv.htm

25. Case follow up Gradual return to normal health and normal transaminases over 2.5 months Repeat CMV IgM fell

26. Conclusions CMV may cause atypical mononucleosis syndrome Diagnosis –Lymphocytosis with atypical lymphs –CMV IgM level