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Emerging Infections Thomas M. File, M.D., M.Sc. Chair, Infectious Disease Division Summa Health System; Professor of Internal Medicine, Chair Infectious Disease Section Northeast Ohio Medical University It is time to “close the book on infectious diseases.” Congressional testimony by the Surgeon General of Congressional testimony by the the United States, 1969 Surgeon General of the United States, 1969 EMERGING INFECTIONS New, Re-emerging, or Drug-resistant infections whose incidence in humans has increased within the past 2 decades or whose incidence threatens to increase in the near future. Institute of Medicine Report 1992 From: Woolhouse M Microbe 2006 1: 511 RECENT VIRAL OUTBREAKS Requirement for Pandemic Requirements for Pandemic SARS Avian Flu H1N1 2009 Flu Novel Virus + (Coronavirus) + (H5N1) + (Hsw1N1) Disease in Humans + + + - +** Degree of spread +* Human to human *Transmissible only during symptomatic disease **Transmissible prior to symptoms and many ‘subclinical ‘ cases NEJM Feb 1, 2012; 366: 454-61 NEJM Feb 1, 2012; 366: 454-61 Ebola Virus Prototype Viral Hemorrhagic Fever Pathogen Filovirus: enveloped, non-segmented, negativestranded RNA virus Severe disease with high case fatality >20 previous Ebola and Marburg virus outbreaks 2014 West Africa Ebola outbreak (Guinea, Sierra Leone, Liberia) Largest outbreak in history Absence of specific treatment or vaccine 11 Ebola Virus Transmission •The virus is spread through • direct contact (through broken skin or mucous membranes) with a sick person's blood or body fluids (urine, saliva, feces, vomit, and semen) • objects (such as needles) that have been contaminated with infected body fluids • infected animals •Healthcare workers, burial workers, and the family and friends in close contact with Ebola patients are at the highest risk of getting sick because they may come in contact with infected blood or body fluids. Pathophysiology of EBOLA Virus UpToDate 2014 EVD: Expected diagnostic test results over time Critical information: Date of onset of fever/symptoms IgM IgG viremia 0 3 10 days post onset of symptoms Fever RT-PCR ELISA IgM ELISA IgG IgM: up to 3 – 6 months IgG: 3 – 5 years or more (life-long persistance?) 15 EVD Clinical Manifestations •Acute onset: typically 8-10 days after exposure (range 2-21 d) •Stage I • Fever, chills, HA, myalgias, malaise,weakness • Diffuse erythematous Maculo papular rash (some) • GI symptoms common: N/V, diarrhea, Abd pain •Stage II (high mortality) • Hemorrhage • Hypotension; electrolyte Abn; Shock • Lab: Cytopenia; Abn LFTs; Coag Abn; Renal Abn Clinical Management of EVD: Supportive, but Aggressive Hypovolemia and sepsis physiology Aggressive intravenous fluid resuscitation Hemodynamic support and critical care management if necessary Electrolyte and acid-base abnormalities Aggressive electrolyte repletion Correction of acid-base derangements Symptomatic management of fever and gastrointestinal symptoms Avoid NSAIDS Multisystem organ failure can develop and may require Oxygenation and mechanical ventilation Correction of severe coagulopathy Renal replacement therapy • Reference: Fowler RA et al. Am J Respir Crit Care Med. 2014 17 Investigational Therapies for EVD Patients No approved Ebola-specific prophylaxis or treatment Ribavirin has no in-vitro or in-vivo effect on Ebola virus Therapeutics in development with limited human clinical trial data • Convalescent serum • Therapeutic medications o Zmapp – chimeric human-mouse monoclonal antibodies o Tekmira – lipid nanoparticle small interfering RNA o Brincidofovir – oral nucleotide analogue with antiviral activity o GS-5734—Filovirus inhibitor (highly effective in monkeys; IDWeek 2015) Vaccines – in clinical use • Chimpanzee-derived adenovirus with an Ebola virus gene inserted; Attenuated vesicular stomatitis virus with an Ebola virus gene inserted • References: 1Huggins, JW et al. Rev Infect Dis 1989; 2Ignatyev, G et al. J Biotechnol 2000; 3Jarhling, P et al. JID 2007 S400; 4Mupapa, K et al. JID 199 S18; 5Olinger, GG et al. PNAS 2012; 6Dye, JM et al. PNAS 2012; 7Qiu, X et al. Sci Transl Med 2013; 8Qiu, X et al. Nature 2014; 9Geisbert, TW et al. JID 2007; 10Geisbert, TW et al. Lancet 2010; 11Kobinger, GP et al. Virology 2006; 12Wang, D JV 2006; 13Geisbert, . TW et al. JID 2011; and 14Gunther et al. JID 2011 18 EVD Management Patient Recovery Case-fatality rate 71% in the 2014 Ebola outbreak Fatality rate is lower with access to intensive care Patients who survive often have signs of clinical improvement by the second week of illness Associated with the development of virus-specific AB Antibody against Ebola persists greater than 12 years Prolonged convalescence Includes arthralgia, myalgia, abdominal pain, extreme fatigue, and anorexia; some symptoms may persist for >21 months Skin sloughing and hair loss has also been reported • References: 1WHO Ebola Response Team. NEJM 2014; 2Feldman H & Geisbert TW. Lancet 2011; 3Ksiazek TG et 20 al. JID 1999; 4Sanchez A et al. J Virol 2004; 5Sobarzo A et al. NEJM 2013; and 6Rowe AK et al. JID 1999. POST EBOLA SYNDROME •Manifestations • Arthralgias/Arthritis • Paresthesias • Short term memory loss • Headache • Vision changes •Santuary sites • Eye • Joints • Testes • CSF •3 patients • US physician with severe vitritis • 2 UK nurses with encephalitis • 27 patients; median age 36;70% male • Treatment: ICU care; 85% received investigational agents • Mortality 18.5% NEJM 2016; 374: 636-46 • 8638 patients administered vaccine • Well tolerated27 patients; median age 36;70% male • Treatment: ICU care; 85% received investigational agents NEJM 2016; 374: 636-46 • Mortality 18.5% EBOLA concern in Akron, Ohio OHIO: Monitored 164 contacts of EBOLA concern in Akron, Ohio • VISIT BY CDC; • DAILY CONFERENCES WITH COUNTY HEALTH; • FREQUENT TELCONF WITH OHIO DEPART HEALTH EBOLA concern in Akron, OH Novel betacoronavirus (HCoV) • MERS (Middle East Resp Syndrome • Sept 2012: 2 patients with severe pneumonia (Saudi Arabia; Qatar) in otherwise healthy • Sept 2016: 1800 cases (Middle East; Travel from Middle East--UK, France, Italy, US, Korea, 27 countries); • 30-40% mortality • Similar to SARS virus • Source: bats, camels • Human to human (low) NEJM Oct 17,2012 29 WHO SHOULD BE EVALUATED FOR MERS PATIENTS WHO MEET THE FOLLOWING: FEVER AND PNEUMONIA OR ACUTE RESPIRATORY DISTRESS SYNDROME AND EITHER: HISTORY OF TRAVEL FROM COUNTRIES IN OR NEAR THE ARABIAN PENINSULA1 WITHIN 14 DAYS OF SYMPTOMS OR CLOSE CONTACT2 WITH A SYMPTOMATIC TRAVELER WHO DEVELOPED FEVER AND ACUTE RESPIRATORY ILLNESS (NOT NECESSARILY PNEUMONIA) WITHIN 14 DAYS AFTER TRAVELING FROM RISK COUNTRIES OR IS A MEMBER OF A CLUSTER OF PATIENTS WITH SEVERE ACUTE RESPIRATORY ILLNESS (E.G., FEVER AND PNEUMONIA REQUIRING HOSPITALIZATION) OF UNKNOWN ETIOLOGY IN WHICH MERS-COV IS BEING EVALUATED OR: CLOSE CONTACT2 OF A CASE OF MERS Whirlpool Folliculitis From File and Stevens. Handbook of Skin Infections. 2010 56 y/o with recurrent cellulitis of leg Photo courtesy of T. File MD Photo courtesy of T. File MD Recurrent Cellulitis of lower extremity in patients with prior Heart Surgery •Almost always due to hemolytic Streptococcus • Usually NOT Grp A Strep • Responsive to most antimicrobials •Associated with disruption of venous and/or lymph drainage • Can occur after injury • Can be seen in upper extremeties (e.g., after breast surgery) •Look for associated tinea pedis or other chronic skin condition • Treat with antifungal • Use antibacterial soaps •Double blind study 28 hospitals England/Ireland • PCN 250 mg BD vs placebo over 3 years • 274 patients •Results--Recurrences: • PCN 22% (626 days to 1st recurrence) • Placebo 37% (532 days to 1st recurrence) • P=0.01 Thomas et al. 2013; 368: 1695 35 Case • 32 y/o preg woman from Connecticut presets in July at 26 weeks gestations with slight fever, arthralgia, HA and rash • How should she be managed? Lyme-stages • Early (days to weeks after tick bite; minority recall) • Erythema migrans (80%), fatigue, malaise , HA, myalgia, arthralgia, regional lymphadenopathy • Early disseminated: (weeks to months) • Musculoskelatal; neuro 15% (lymph meningitis, cranial neruropathy); carditis 1% • Late (months to years) • MS 60%; Neuro Lyme-Diagnosis •Early-clinical with rash; serology little value •Serology • 2 tiered: ELISA then Western Blot • VisE C6 ELISA • Measures AB to major protein sequence • More accurate, also good for European strains • Antibodies may persist for years after Lyme disease has been treated and cured •PCR Criteria for Western Blot for Lyme Type of Infection First few weeks After month Isotope Bands for Dx IgM Two of: 24,39,41 IgG Five of: 18,23,30,39,41,45,58,66, 93 Case Shapiro NEJM 2014; 370:1724 • Skin lesion consistent with erythema migrans. • 500 mg of amoxicillin three times a day for 14 days, doxycycline is contraindicated in pregnant women. • Outcomes are excellent and that congenital Lyme disease has never been documented. • Chemoprophylaxis would not have been indicated, because only doxycycline has been shown to be effective as chemoprophylaxis. How to Manage the following patients 23 y/o HIV infected man who lives with a person recently diagnosed with active TB. CD4# 130. Neg. CXR 44 y/o Respiratory therapist with “positive” Quantiferon test. Asymptomatic; CXR neg. 62 y/o female with rheumatoid arthritis scheduled to start anti-TNF agent; has ‘indeterminant’ Quantiferon 43 y/o male immigrant from Nepal with one month history of cough, fever, weight loss. CXR shows upper lobe infiltrates. TB Classification System Class 0 Stage of Disease No exposure, no infection 1 Exposure, no evidence of infection 2 TB infection, no disease 3 TB, clinically active 4 TB, not clinically active 5 TB suspect TB Exposure; No Infection Patients with immunocompromising conditions who are close contacts of active TB should be treated similar to LTBI regardlsess of results of skin test or interferon release assay (prevent infection). Repeat skin test or interferon release assay 8-10 weeks later; if negative can DC treatment Latent TB 45 Latent TB infection vs TB Disease Latent TBI TB Disease Positive Skin test or Interferon Gamma Release Assay (IGRA) Skin Test or IGRA usually + CXR normal CXR usually Abnormal No signs or symptoms Signs, symptoms present Culture neg. Smear, Culture + 50% 46 Latent TB (Quantiferon) • Less subjectively than Skin Test • No affect of BCG; but may have cross reactivity with M. kansaii, marinum or szulgari • Interpretation of Quantiferon test Quantiferon Result comment Mitogen – Nil Should be > 0.5 If < 0.5= “indeterminant” TB Ag – Nil Positve > 0.35; Neg. < 0.35 BUT most < 1.0 are unlikely LTBI!! 47 General Recommendations for Using IGRAs Preferred when testing persons Who might not return for TST reading Who have received BCG vaccination Immune suppressed Generally should not be used to test children <5 years of age, unless used in conjunction with TST STD-2016 GENERALIZATIONS Anyone is at Risk!!! –1/3 of Americans age 15-55 will have STD • Sequelae: Infertility, Ectopic preg, Cong/Perinatal Infection, Cancer • If one STD increases likelihood of another!!! • Simple urine test for painless diagnosis and highly effective, single dose therapies for chlamydia and gonorrhea • Quinolones and Cefixime no longer recommended for empiric GC therapy • Mycoplasma genitalium • Promise of HPV Vaccines 29 y/o male presents with urethral discharge. What is your approach? A. Obtain culture and await results B. One dose of a fluoroquinolone C. Obtain nucleic acid test for GC & Chlamydia & await results D. Obtain nucleic acid test for GC and Chlamydia and treat with ceftriaxone and one dose of azithromycin E. Treat with a fluoroquinolone and one dose of azithromycin Testing GC and Chlamydia •Positive test influences compliance and partner notificaton •Noninvasive: • Nucleic acid amplification tests, NAAT (on urethral secretions or first void urine) •Minimally Disruptive • Patient obtained vaginal swabs •Reduces incidence of PID Neisseria gonorrhea Cervix, Urethra, Rectum Ceftriaxone (Rocephin) 250 mg IM* or , if not an option: Cefixime (Suprax) 400 mg po PLUS CHLAMYDIAL THERAPY *Acceptable for pharyngeal GC also •Beta-lactam ‘Allergy’ • Crossover for ceftriaxone probably < 1% • Spectinomycin • Azithromycin 2 mg PO? Non Specific Urethritis Chlamydia trachomatis: Treatment • AZITHROMYCIN 1 GM AS SINGLE ORAL DOSE* • DOXYCYCLINE 100 MG PO BID X 7 DAYS • OFLOXACIN 300 MG PO BID X 7 DAYS • LEVOFLOXACIN 500 MG PO X 7 DAYS • ERYTHROMYCIN 500 MG QID X 7 DAYS *MOST COST EFFECTIVE Azithro vs Doxycycline for Chlamydia • Randomized trial adolescents in correctional facilities1 • Azithro (1 gm X 1) 5/155 (3%) had treatment failure • Doxy (100 mg BD X 7 d) 0/155 had treatment failure • Unclear why difference: resistance unlikely; azithro levels may not be sufficient in some patients • Editorial: “not reasonable to recommend doxy over azithro as preferred….In populations in which adherence can be monitored and ensured, 7-da7 doxy might be preferred; if adherence ? Azithro still excellent option for the ease of use..”2 1. Geisler et al NEJM 2015; 373: 2512; 2. Quinn et al NEJM 2573 Mycoplasma genitalium (CDC STD Guidelines 2015) •Causes 20% of non gonococcal urethritis; Cases of cervicitis ? •Resistant to doxycycline •NO commercial test •AZITHROMYCIN 1 GM AS SINGLE ORAL DOSE • ? Resistance •If fails azithromycin---moxifloxacin 400 mg X 7-14 days Genital ulcer 1.Painless, indurated ulcer 2. Painful, mulitple ulcers a. Syphilis b. Chancroid (ceftriaxone 250 mg X1; azithro 1 gm) Primary syphilis - chancre Primary syphilis - chancre SYPHILIS •Diagnosis •Darkfield •Serology •RPR •FTA SYPHILIS; stages •Incubation (10-90 days) ave. 3 weeks •Primary (chancre) • Initial site infection; heals within few weeks •Secondary (rash, fever, HA, malaise, adenoapthy) • Weeks to months later; resolve •Latent (early ≤ 1 year; late > 1 year) •Tertiary (many years later) • CNS; Cardiovascular; Gumma •http://www.cdc.gov/std/treatment/2015/default.htm 32 y/o woman presents with rash of 3 days duration. Last sexual encounter 4 weeks earlier Lab: RPR 1:256; FTA +; HIV - 42 y/o with 2 week history of nonpruritic rash. Treated in ER with prednisone THERAPY: EARLY SYPHILIS •Primary, Secondary, Early Latent (<1 yr) •Therapy - Benzathine PCN 2.4 million units 1M x 1 •Alternative (data limited) - Doxycycline 100 mg po BID x 14 days - (Ceftriaxone 1 gm IM QD x 10-14 days) Guidelines for STD, USPH & CDCP The patient is treated and repeat serology is done 6 months afterwards. RPR + 1:32. Should this patient receive additional testing and/or management? SYPHILIS THERAPY Follow-Up • Repeat Serology 6, 12 Months (Also 3 if HIV and 24 if late syphilis) • Consider Failure if: - Titers Increase - Failure to Decline Fourfold - Signs or Symptoms Persist/Develop • Consider CSF Exam • Retreat - 7.2 Benzathine PCN if CSF Neg Guidelines for STD, USDH-CDCP THERAPY: LATER SYPHILIS • Late Latent (> 1 yr or Unknown Duration) - Benzathine PCN 2.4 Million U IM Qwk x 3 (7.2 total) - Pen Allergic (Non Preg; data limited): Doxycycline 100 mg BID x 4 wks - Pen Allergy and Pregnant: Desensitize • Tertiary (Gumma, Cardiovascular) - If Symptomatic, do CSF Exam - Benzathine PCN 2.4 Million U IM Q wk x 3 (7.2 total) NEUROSYPHILIS •Consider if: - Neurologic, Ophthalmic, (Auditory) Manifestations - Tertiary Disease - Treatment Failure - HIV • CSF: WBC, Protein, + VDRL (+FTA less specific) • Therapy: Aqueous PCN G 18-24 Million U/d x 10-14 days; Alternative - Procaine PCN 2.4 Million U/d + Probenecid 500 mg QID for 10-14 days (AllergyDesensitize); ? Ceftriaxone 2 gm IM QD x 10-14 d CASE •56 y.o male referred for + RPR (1:8) • History movement disorder and RPR ordered as part of Neurology evaluation • No known history of prior infection or test •LP: • Protein 78; glucose normal; WBC 5 (lymphs) • VDRL + •Treatment: • 14 days 18 million units Pen G/day Syphilis: New Testing •New testing method •Reversed sequence: Treponemal test followed by RPR •Cost effective in laboratory •Treponemal test remains + after first infection • Cannot distinguish past vs. re-infection •Need RPR for following infection (hope to go to neg. or low titer) 71 US Preventative Services Task Force: “Increase Screening for Syphilis” •Incidence in US increased 15% from 2013 to 2014 •Focus groups: • HIV • Men who have sex with men • Men ages 20-29 •Promote Safe Sex Practices-especially condom use JAMA June 2016 Herpes, female Therapy for Genital Herpes • Primary • Acyclovir 400mg tid X 7-10d • Valacyclovir 1000mg bid X 7-10d • Famciclovir 250 mg tid X -10d • Recurrent • Acyclovir 400 mg tid X5d (800 bid x 5d or 800 mg tid X 2 d); Valacyclovir 500 mg bid X 3d or 1 gm QD X 3d; Famciclor 125 mg bid X 5d (1 gm bid x 1 d) • Suppressive • Acyclovir 400 bid; Valacyclovir 500mg or 1 gm qd; Famvir 250 bid • Acyclovir-Resistant HIV • Foscarnet; Cidofovir; Trifluridine Vaginitis features Candidiasis Bacterial Vaginosis diagnosis Pruritis, ; Whitish discharge; dyspareunia pH < 4.5; Morphology of stain or wet mount; Culture Malodorous pH > 4.5, discharge “clue” cells on wet mount Trichomonas Copious foamy Ph > 4.5; wet mount treatment Topical, oral azoles Metronidazol e (po or vag); clinda vag cream Metronidazol e 2 gm X1 STD: multiple pathogen testing •STD: multiple pathogen testing •Nucleic acid amplification test (PCR) based • GC, HSV 1 and 2, • Trichomonas vaginalis (TVA), and Chlamydia • Mycoplasma, Ureaplasma, •Urethral/Vaginal/cervical Swab •Diatherix proprietary Quinter C et al. ICAAC 2013 77 STD-2016: Take Home • If one STD increases likelihood of another!!! –Check for HIV • Simple urine test for painless diagnosis and highly effective, single dose therapies for chlamydia and gonorrhea • Penicillin drug of choice for syphilis • Quinolones and Cefixime no longer recommended for empiric GC therapy • Promise of HPV Vaccines Painless chronic skin ulcer enlisted person coming home from Iraq Cutaneous Leishmaniasis Treatment: pentavalent antimonial compound, pentamidine, or amphotericin B Case: Patient presents to ER with fever, cough, chest pain The diagnosis is most likely by? a. Sputum culture b. Blood culture c. Sputum PCR d. IgM ELISA e. Urinary Antigen EMERGING INFECTIONS “Humanity has but three great enemies: fever, famine and war; of three by far the greatest, by far the most terrible, is fever.” Sir William Osler