Update: a ReEmerging Infectious Disease

Global-to-Local Info for Health Care Professionals October 2014

Robert Ball, MD MPH FACP Adjunct Professor: MUSC Dep’t. Public Health Sciences Adjunct Professor: MUSC Dep’t. Medicine, Division of Infectious Diseases Adjunct Professor, Department of Public Health: CofC

many thanks to Eric Brenner, MD, et al for some slidesR. Ball, MD MPH FACP Global Perspective: Emerging Infectious Diseases (EIDs) “The microbe that felled one child in a distant continent yesterday can reach yours today and seed a global pandemic tomorrow.” HENCE, TRAVEL Hx IS IMPERATIVE !

-Dr. Joshua Lederberg (1925-2008), Nobel Laureate- Medicine: 1958

R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP ”Spanish Influenza” 1917-1919: type A, subtype H1N1

21st century concerns re: “bird flu” A-H5N1

R. Ball, MD, MPH Global Air Travel- 1 day, mid-2009

Thanks to Mike Schmidt, PhD- MUSC for this graph

R. Ball, MD MPH FACP EIDs: HIV-AIDS: A Retrospective slide courtesy of Charles Bryan, MD, MACP, FRCP (retired Chair, Dep’t. Medicine, USC; Editor, J.SCMA: President American Osler Society, etc…) HIV-AIDS is THE prototype of an Emerging Infectious Disease becoming a pandemic Influenza and Coronavirus Virions

Segmented ssRNA(- sense) genome, 13-14 kb ssRNA(+ sense) genome, 27-32 kb Nuclear + cytoplasmic Cytoplasmic replication. replication. 4+ mutations !!! Eg: SARS, MERS-CoV 2012… MERS: Middle East Respiratory Syndrome (Saudi Arabia  global)

Penttinen et al., Euro Surveill, online 9.26.2013 CDC. Emerging Infectious Diseases. June 2011

Eg, Nipah (75% CFR), Hendra (70-100% CFR, etc… R. Ball, MD, MPH Many mammals (eg, bats) may be long-term carriers of many viruses, whereas most primates seldom become long-term carriers.

R. Ball, MD, MPH R. Ball, MD, MPH Outbreak: 1995 Film from Warner Brothers 1995 1995 Film Film ‘Outbreak’ Outbrea k 1995 Film Outbreak “Today’s science fiction is tomorrow’s science fact.” - Isaac Asimov (1920-1992) At the CDC, Dr. Ally Hextall finds that the 2011 Film: Contagion virus is a mix of genetic material from Gwyneth Paltrow Succumbing to the Mysterypig and bat viruses. Investigations into Killer Virus cures via treatment protocols or vaccines initially stall as scientists can't find a cell culture in which to grow the newly identified Meningoencephalitis Virus One (MEV-1). UCSF professor Dr. Ian Sussman violates orders from Cheever (relayed through Hextall) to destroy his samples and identifies a usable line of bat cells. Hextall then uses this breakthrough to begin to investigate possible vaccines. The virus turns out to spread via fomites with a basic reproductive number of two; that is, each patient infects two more patients on average — increasing to four after the virus mutates, with one in twelve of the population catching the virus, and a 25-30% mortality rate for Virus ‘Hybrid + Virus = MEV-1 those infected. www.vershatutorials.org/virus-classification-and-structure/ Structure of the Ebola Virus NEJM 5.7.2014

The glycoprotein spikes attach to numerous mammalian dendritic cells & macrophages, enter our cells, & multiply by the millions within 1-3 days! Time Magazine Cover October 13, 2014

Ebola mutations are frequent ~ to HIV & HCV & other RNA exotic viruses. Simple virus: only 6 structural proteins: 18,959 codons. Very fragile too. RAPID multiplication!

- Richard Preston, author:

The Hot Zone Robert Ball, MD MPH FACP 8.20.2014

R. Ball, MD, MPH FACP EM photo of the Ebola virus showing typical filovirus morphology

Could this be a Current W. African Ebola strain filovirus is ~5-8% genetically mutated “treble clef” ?? from original Zaire (DRC) strain http://www.huffingtonpost.com/2014/08/17/ www.cdc.gov/vhf/ebola/resources/virus-ecology.html

1. Ebola Virus (EVO Disease= EVD)

2. Ebola Hemorrhagic Fever (EHF): complication

3.Other names…

Mathematical view of disease propagation:

The Reproductive Rate (R0)

• R0 = Average no. of new infections resulting from each case

• R0 < 1 outbreak will eventually die-out

• R0 = 1 continuing “endemic” spread

• R0 > 1 outbreak may progress to “epidemic” or even “pandemic” proportions0 Emerging Pathogen Transmission Scenarios

• Multiple introductions  risk of adaptation to R0>1 Chauchemez et al., Euro Surveillance 13 June 2013 Robert Ball, MD MPH FACP CDC. MMWR 10.3.14

Robert Ball, MD MPH FACP Ebola in West Africa: Spring – www.nytimes.com/interactive/2014 /07/31/world/africa/ebola-virus- Summer 2014 outbreak-qa.html Cases to date (through August 27, This showing to date: 2014) 1427 deaths & 2615 cases CFR = 1427 / 2615 = 55% CFR = 51% of lab+ cases. Many more cases exist!

R. Ball, MD, MPH FACP “The west African Ebola epidemic is spiraling out of control” In 10.2014, Frieden ordered Epi response teams to every US hospital with an Ebola case.

R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP 8.20.2014

R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP 8.20.2014

R. Ball, MD, MPH FACP 8.20.2014

R. Ball, MD, MPH FACP “As of 27 August 2014, the cumulative number of Ebola cases in the affected countries stands at more than 3000, with over 1400 deaths, making this the largest 28 August 2014 Ebola outbreak ever recorded, despite significant gaps in reporting Globally, as of 10.22.2014: in some intense transmission areas. > 10,000 known lab (+) cases An unprecedented number of health > prob. over 10-15 K suspected etc care workers have also been > 4800 known lab (+) dead (~50% CFR) infected and died due to this outbreak.”

BUT CFR (mortality) rate is prob. MUCH US cases as of 10.24.2014: 9 HIGHER (~70%) per recent reports ! 1 died, 4 released, 4 under Tx

Globally, as of 10.16.2014: # HCWs infected > 427 # HCWs died > 236

R. Ball, MD, MPH FACP Ebola Case Count - 1 (From CDC.GOV October 23, 2014)

CFR (Case Fatality Rate) ~ 46-83% Ebola Case Count -2 (From CDC.GOV October 23, 2014) R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP Estimated range:

R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP R. Ball, MD, MPH FACP 9.23.2014 Primary source of info: www.cdc.gov/ebola CDC infographics for citizens

Q: do people really read & understand these? OR…..

10.16.2014 CDC infographics for citizens

Q: do people really read & understand these? OR….. 1st US Case & cases as of 10.22.2014, now = 9

• 1 Liberian-American- front line HCW, exposed & infected in Liberia, flew to US (Dallas 9.20.2014) w/ fatigue, then developed Sx 9.24.14 (fever, etc)- Texas Hosp. ED missed Dx 9.25, sent home on Anbx! He returned critically ill Sun. 9.28.14. Developed EHF 9.29, ventilated & dialysis… He died on 10.8.2014 with a DNR order in place. • Texas Pres. Hospital HCWs took all precautions (eg, PPE, etc) as CDC had recommended to date. • Nonetheless, 2 direct-care nurses, under quasi- quarantine, temp-taking, etc contracted Ebola within 2-3 weeks, tested +, on Tx (IVF, Ab’s+), isolated, doing OK…

Robert Ball, MD MPH FACP Great news: 10.24.14 Nurse Nina Pham released from Tx/ quarantine, then met with Pres. Obama in Oval Office, & will soon be reunited with her dog Bentley (still in quarantine). Nurse Vinson soon to follow.

Use of the statistical properties of the “normal distribution” to think through important public health issues relating to the incubation period for Ebola Virus Disease Oops! In any case data Might this suggest that from this study suggest “contacts” to Ebola cases ought that a certain small to be quarantined and observed proportion (e.g. ~2-4%) of for > 21 days!? For example for Ebola cases may have perhaps as much as 25 days just incubation periods longer to be safe!? than 21 days !! 34% 34% How to decide? (Actually ~2.5% in And on what each “tail” of the basis? curve. 14% 14% 4.3 d 2.5% 4.3 d 4.3 d 4.3 d 2.5%

4.1 d 8.4 d 12.7 d 17.0 d 21.3 d Chronology of the ‘Liberian Dallas Ebola Case’ Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sept 14 15 16 17 18 19 20 Monrovia -> Brussels- > Washington DC- Arrival in Dallas >Dallas 21 22 23 24 (PECT) 25 (PECT) 26 (PECT) 27 (PECT) Initial hospital visit… Onset of symptoms sent home (!?) Oct 28 (PECT) 29 (1) 30 (2) 1 (3) 2 (4) 3 (5) 4 (6)

Hospitalized and Media frenzy re "contacts being traced" ======> Dx made 5 (7) 6 (8) 7 (9) 8 (10) 9 (11) 10 (12) 11 (13)

Patient dies

12 (14) 13 (15) 14 (16) 15 (17) 16 (18) 17 (19) 18 (20*)

PECT = “Possible Ebola (N) = no. of days (#) =quarantine policy ~21 days ! Community Transmission” since last PECT Est quarantine time > 21 days, but ranges from 0.1% - 12% beyond 21 days Amber Vinson

As of Thurs. 10.23.2014, none of Duncan’s community contacts have become ill, and all are now released from 21-day quarantine. Robert Ball, MD MPH FACP

Recommendations similar to BSL 3: PPE with gloves, masks, gowns, & footwear, + decon. upon exit.

Robert Ball, MD MPH FACP R. Ball, MD, MPH FACP 10.23.2014 (WHO): 2yoF from Guinea

WHO as of 10.22.2014

Robert Ball, MD MPH FACP WHO as of 10.22.2014 Robert Ball, MD MPH FACP Ebola cases globally> W. Africa 10.23.2014

Source: New York Times, Thurs. 10.23.2014pm Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Ebola Update: Clinical Considerations Much info via CDC webinar Mon. 10.20.2014 Representatives of Nebraska, Emory Hospitals + CDC www.cdc.gov Ebola  beaucoup hyperlinks

http://emergency.cdc.gov/coca/about.asp Days 1-3: acute onset flu-like nonspecific Sx (malaise, fatigue, anorexia, myalgias, headache, fever, etc). May be gradual or sudden. Days 4-7: abdominal pain, nausea & vomiting; profuse diarrhea; rash (usually maculopapular). Occas. conjunctivitis, glossitis. Hypovolemic ! Days 7-10: systemic organ dysfunction w/ thrombocytopaenia (leukocytosis or normal); hepatocellular dysfunction (^AST >ALT), LOW Na+, K+, Ca++, Mg++, others. petechiae; GI bleeding hemorrhage via mult. orifices; pulm. edema w/ dry cough; neurologic Sx (eg, confusion, paresthesias, delirium, tremor); nephritis (ATN) renal failure, acidosis; DIC; protein-wasting enteropathy; hypovolemic + DIC shock. (stool loss up to 10 liters/day). Death in > 50%, usu. ~ 70% unless max. aggressive care (dialysis, ventilator, etc), but Pts signed DNR orders. Robert Ball, MD MPH FACP Some forms of Tx for Ebola Virus Disease

Days 1-3: frequent monitoring of all metabolic parameters, ABGs, FIO2, ORT  IVF, TPN, etc. (Hypovolemia may be ~10% of adm. body weight.)

Days 4-7: GI Sx: anti-nausea & vomiting Rx ; profuse diarrhea- Imodium; acetaminophen for fever. Aggressive fluid balance/ monitoring.

Days 7-10: systemic multi-organ support (short of a code).

Convalescent plasma and/or Zmapp (if you can get it) Antivirals: none FDA-approved, but several on compassionate trial basis, IND, or company trials. Cidofovir derivatives, others being tried.

Death: autopsies difficult to obtain. Cremate or deeply bury bodies.

If Pt survives, 2 criteria for discharge: 1) If 2 sequential (-) RT-PCR tests > 3 days apart 2) If Pt feels strong enough to perform all ADL Robert Ball, MD MPH FACP http://www.cdc.gov/vhf/ebola/hcp/procedures-for-ppe.html Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP TRIAGE: 1. Thorough travel Hx, evaluate Sx, take temps, keep away from people 2. Isolate patient & staff. Minimize # specially-trained, PPE’d HCWs for Rx 3. Px exam & lab eval. (flu, Ebola RT-PCR, CBC, LFTs, etc)

Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP TRIAGE QUESTIONS !

Robert Ball, MD MPH FACP “Donning” and “Doffing”: HCW + “buddy” in anteroom + supervisor

www.hlntv.com/video/2014/10/14/?hpt=hp_bn12

Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP http://www.nytimes.com/interactive/2014/10/15/us/changes-to-ebola-protection-worn-by-us-hospital-workers.html Robert Ball, MD MPH FACP http://www.nytimes.com/interactive/2014/10/15/us/changes-to-ebola-protection-worn-by-us-hospital-workers.html

Robert Ball, MD MPH FACP http://www.nytimes.com/interactive/2014/10/15/us/changes-to-ebola-protection-worn-by-us-hospital-workers.html

Initial: gloves, >N95 mask, etc. Quickly don full PPE, even use PAPRs.

Robert Ball, MD MPH FACP Key elements of initial screening by medical providers in any setting 1.Triage Qs (preferably via sign on door to call staff- not enter- if they have any Ebola-like Sx + travel Hx) 2. If Px evaluate, have Pt enter via back door 3. If suspect case, immediately minimize # of HCWs who see Pt & don max. PPE 4. If suspect case, immediately call I.D. docs, IPs, Employee Health, Lab, Public Relations, Administration, Public Health Dep’t., etc 5. Arrange for surplus of supplies, even for community providers (citizen hysteria + “flu season”) 6. Diarrhea, vomitus, & body fluids can go into standard sanitary (city) sewers. 7. Arrange (contracts) for Mx of hazardous waste (usu. Incinerate) Robert Ball, MD MPH FACP As of 10.24.14, SC: MUSC, Richland-Palmetto, & GHS. Others to follow.

Robert Ball, MD MPH FACP Robert Ball, MD MPH FACP ZMapp as Ebola Treatment

ZMappTM Is composed of three “humanized” monoclonal antibodies manufactured In plants, specifically Nicotiana. It is an optimized cocktail combining the best components of MB-003 (Mapp) and ZMAb (Defyrus/ PHAC) in coordination with the public health services of the USA and Canada. Experimental in 2014, but FDA has Expanded Access Program, hence its use in an Ebola outbreak (either in US or abroad, under rigorous rules). http://en.wikipedia.org/wiki/ZMapp Scientists in US & Canada are working on an . On 8.31.2014, China announced successful development of an Ebola drug JK-05. - ProMed 9.1.2014 R. Ball, MD MPH FACP ZMapp as Ebola Treatment In 2014, Samaritan's Purse worked with FDA &Mapp Biopharmaceutical to make the drug available to 2 of its health workers, who were infected by Ebola during their work in Liberia, under the Expanded Access Program. At the time, there were only a few doses of ZMapp. Per news reports, received the 1st dose of ZMapp 9days after falling ill. According to Samaritan's Purse, Brantly received a blood transfusion from a 14-y.o. boy who survived an Ebola virus infection before being treated with the ZMapp serum. Nancy Writebol, working alongside Brantly, was also treated with ZMapp. The condition of both health workers improved, especially in Brantly's case, before being transported back to the US to Emory Univ. Hospital for specialized Ebola treatment. Writebol and Brantly were released from hospital on 8.21.14. A Catholic priest, 75-year- old Miguel Pajares, was flown back to Spain from Monrovia on 8.7.14 after being infected with Ebola. With the permission of Spain’s drug safety agency, he was given ZMapp but died on 8.12, 2 days after receiving the drug. The west African nation of Liberia has secured enough ZMapp to treat 3 Liberians with the disease. One of the 3 to receive the drug, Dr. Abraham Borbor, a Liberian doctor and deputy chief physician at Liberia's largest hospital, died 8.25.14. William Pooley, a British nurse who contracted Ebola while working in Sierra Leone, was also treated with ZMapp in August 2014. Mapp announced on 8.11.14 that its supplies of the drug had been exhausted.

http://en.wikipedia.org/wiki/ZMapp R. Ball, MD, MPH FACP 8.20.2014

R. Ball, MD, MPH FACP ZMapp protected 12 of 12 NHPs given up to 5 d. post-lethal dose of IM EBOV Nature 8.2014 Convalescent plasma from recovered Ebola patients has shown some benefit.

As of 10.22.2014, 4 candidate vaccines are being studied in multiple countries, some now into Phase 2, with hope for use in W. Africa by early 2015. Efficacy est. < 100%

Robert Ball, MD MPH FACP 10.9.2014

Robert Ball, MD MPH FACP ~Incident Command Structure Pres. Obama has ordered >10K troops to set up field hospitals in Liberia (not provide direct health care).

Robert Ball, MD MPH FACP US Airport Screening: ALL arrivees from the 4 affected countries Checklist: -Travel Hx - Contact w/ traveler(s) - Detailed Sx - Monitoring

Newest Ebola case in USA: NYC

Dr. Craig Spencer, 33, ED physician & Instructor: Columbia Univ., NYC direct-care physician w/ MSF in Guinea: departed 10.14.2014via mult. flights . Arrived NYC asymptomatic on Friday 10.17.2014. Fatigued Tues. 10.20.2014…

Stayed mostly at apartment in Harlem, took temp BID, remained generally aSx… Jogged, rode NYC subway system 1 night: 3-4 close contacts: mostly his fiancée. Onset Wed. 10.22.2014 of T0 100.3103F, Fri.10.24.14pm: immed.  Bellevue Hosp., Manhattan. Returnee HCW Now in BSL 4 isolation. Rapid RT-PCR(+), w/ fever CDC confirmatory PCR (+) Fri. 10.24.14 quarantined Robert Ball, MD MPH FACP Recent US Ebola cases, healthy contacts

Nina Pham released Amber Vinson released

Army unit quarantined Healthy NJ Nurse quarantined involuntarily And just when you thought it can’t get any crazier… Thurs. eve, dozens of New Yorkers showed up in EDs for Ebola testing !

Most US citizens on the street are now demanding mandatory quarantine for all returnees, and many politicians are now calling for a total US ban on all flights from any African country (1 even included India).Robert Ball, MD MPH FACP Barriers to Ebola Control & Prevention (most not viral-related) 1. Lack of PPE, isolation/ quarantine units, disinfectants, other equip… 2. Lack of political/ government supplies, personnel, control, etc… 3. Lack of community trust: refusal of care; insistence on continuation of local tribal customs (eg, kissing & touching the deceased body, no use of gloves in handling infected villagers, burial without sanitary practices, etc); increasing hostility towards “foreigners” there to help & provide medical care; several extremist groups killing foreign aid workers; riots in quarantined areas (eg, the West Point slum); sick persons fleeing standard medical care/ facilities (eg, 21-yo student who recently crossed the porous border between Guinea to Senegal); etc… 4. Lack of general community education, in spite of many efforts… 5. Institution of barriers to the above (eg, “border closings”, many flight cancellations, local governmental “leaders” onerous requirements, etc… 6. Many other factors… [how many more can you name?] R. Ball, MD MPH FACP Control and Prevention of Communicable Diseases ISOLATION, QUARANTINE: ie, cases, contacts etc.- still need

VACCINATION: of susceptible persons (eg, all susceptible people in W. Africa re: Ebola, flu vax. for >6mos.)

TREATMENT OF SPECIFIC SYNDROME OR ETIOLOGY: ie, Antibacterials for true bacterial infections, Antivirals for specific viruses (Tamiflu for influenza, HAART for HIV, etc)

POST-EXPOSURE PROPHYLAXIS for Contacts: ie, Tamiflu for influenza household, Hep.B vaccine- close contacts, Z-pack for pertussis contacts, HIV meds for HIV+ needlestick, etc. R. Ball, MD, MPH Mother Earth in Today’s World

R. Ball, MD, MPH FACP Thank you. Questions ?

“Those who carry on great public schemes must be proof against the most fatiguing delays, the most mortifying disappointments, the most shocking insults, and what is worst of all, the presumptuous judgments of the ignorant.”

- Edmund Burke (1729 - 1797)

R.R. Ball, Ball, MD MD, MPH MPH FACP FACP