Multiple Small Feedings of the Mind - Internal Medicine | ACP...• Van Nood et al. comparing duodenal FMT to vancomycin therapy was stopped early due clear efficacy benefit (94% vs

Multiple Small Feedings of the Mind

Brandon Webb, MDDivision of Infectious Diseases

Intermountain Healthcare

Objectives

1. Crash course in epidemiology2. Brief review of Zika virus3. Discussion of the microbiome4. Update on Fecal Microbiota Transplant

Emerging Infections

Crash Course in Epidemiology• Enzootic – environmental cycle between animal reservoir and

(usually) insect vector

• Epizootic – Temporary, sporadic shift in the cycle to include new vectors and/or hosts

• Endemic – Predictable constant or seasonal transmission in a geographic area

• Hyperendemic – exaggerated transmission in an endemic area

• Autochthonous – Establishment of endemic transmission in a previously disease-free area

• Epidemic – an increase, often sudden, in the number of cases of a disease above what is normally expected in that population in that area.

Crash Course in Global Epidemiology

Enzootic

Endemic Epidemic

AutochthonousEpizootic

J Clin Invest. 2004;113(8):1102-1107

https://youtu.be/3eAY7n0xu18

http://www.jci.org/113/8https://youtu.be/3eAY7n0xu18

The Proximity Issue

Factors Influencing Proximity

• Urbanization– 2% of the world’s population transition from rural

to urban developments each year– This is less a movement of people, but more

related to spread of urban developments into rural areas

– Over 200,000 km2 of tropical land is deforested or developed each year


• Globalization– Global commerce has expanded exponentially in

the last 3 decades– Global travel is prolific – more than 3 Billion airline

passengers traveled in 2014!– 37 million flights per year means more than

100,000 flights embark each day– Nearly 400 flights, carrying roughly 160,000

travelers, orginate from West Africa each week


• Vector Migration– There are 3500 species of mosquitoes on earth– Estimated 75 Quadrillion mosquitoes at any given

time– That’s roughly 25kg of insects per person – 25 million

mosquitoes for every human– Mosquito Tourism: Asian Tiger Mosquito – Aedes

albopictus• An aggressive daytime biting mosquito• Prefers human blood for egg laying, prefers artificial water• Introduced into the Americas, Europe and Africa via tire

shipments from Asia in 1985• Vector for Chikungunya, Dengue


• Climate Change– Affects ecosystems, bringing new vertebrate hosts

into contact with vectors– Changes environmental features

• El Nino shifts cause warming of Indian Ocean->heavier rainfall in East Africa->many more water sources->mosquito breading is amplified->herds and grazing attracted to new watering holes->dramatic uptick in infection of equids->large viremic reservoir->Rift Valley Fever Epidemic

– Shifting wind/storm patterns carry mosquitoes to new geographic areas


• Mutational Changes– Most emerging viruses are RNA viruses, more

prone to rapid mutation than DNA viruses– Results of genetic adaptation:

• transmission to new vectors (WNV and birds)• Adaptation to higher environmental temperatures• Increased virulence in humans• Increased virulence in reservoir hosts (increased

viremia)• Famously:

– https://youtu.be/SkWeMvrNiOM

https://youtu.be/SkWeMvrNiOM

Zika virus• Zika virus is an RNA flavivirus, in the same family as

Dengue, Yellow Fever and Hepatitis C.• Zika virus was first discovered in the Zika forest in

Uganda in 1947, and small outbreaks have documented sporadically track west from Southeast Asia to the Pacific Islands

• Most recently, 1400 cases were detected in an outbreak in French Polynesia in 2013

• Due to migration of mosquito species, the potential for Zika virus to cause more widespread outbreak has been known for some time.

• Since May 2015, autochthonous transmission has been reported throughout South America.

Current Outbreak• Since May 2015 South America: Brazil, Bolivia, Columbia,

Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Honduras, Mexico, Panama, Paraguay, and Venezuela.

• Caribbean: Barbados, Dominican Republic, Haiti, Martinique, Puerto Rico, Saint Martin and the Virgin Islands.

• Cape Verde, off the coast of Africa, and in Samoa.• Estimates place incidence near 1 million cases in S. America• Autochthonous transmission (transmission originating

within a country) has not yet been reported for the U.S. • 104 cases of Zika have been identified in ill travelers

returning to the U.S. • There is potential for local spread of Zika in the U.S.

Transmission

• Zika virus is primarily a vector-borne illness, spread from human to human by mosquitoes that carry the disease. Zika is transmitted by the Aedes aegyptimosquito, which also carry and transmit other viral diseases including Dengue and Chikungunya.

• A second related type of mosquito, Aedes albopictus,could also carry Zika virus as well.

• Aedes mosquitoes are found widely throughout Central and South America, the Caribbean, Mexico and are present in temperate areas in the southern United States.

Transmission

• Person-to-person transmission appears possible through close contact with infected blood or reproductive fluids

• Blood transfusion• 3 cases of possible sexual transmission• Viral kinetics and tissue tropism have not yet been well

worked out yet. • Viral shedding in urine has been reported up to 20 days

after symptom onset.• These potential modes of transmission haven not been

confirmed and are being investigated currently.

Vertical Transmission

• Intrauterine and intrapartum transmission of Zika virus have both been reported.

• Transplacental spread was recently confirmed (Ref)

• Zika virus has been detected in breast milk, but there are no reports to date of the infection being transmitted in this way.

Clinical Manifestations

• Incubation period estimated between 3 and 12 days.• High rate of asymptomatic infection (estimated 80%)• Common symptoms include: Fever, maculopapular

rash, arthralgia, conjunctivitis or headache.• Symptoms last between 3-7 days. Severe disease is

uncommon and the case fatality rate for Zika is very low.

• Neurological complications including temporary sensorineural hearing loss and Guillain-Barre syndrome have been reported.

Congenital Infection

• Strong epidemiological association with microcephaly

• An increased incidence has been reported in Brazil and 7 other countries during the current outbreak.

• Much remains unknown about Zika and possible birth defects, including how much other factors such as poor nutrition, other infections, and environmental factors, may contribute as well.

Diagnosis• Testing is recommended for persons with clinical syndrome

compatible with Zika virus and recent travel to affected areas .• No commercially available diagnostic tests for Zika virus disease.

Testing is performed by the CDC, and coordinated through Utah state health department.

• Assays: PCR of serum within 1 week of symptom onset or immunoglobulin M (IgM) antibody testing at least 4 days after symptoms onset.

• The antibody test is known to cross-react with other flaviviruses, including the yellow fever vaccine as well.

• PCR testing can be performed on amniotic fluid after 15 weeks gestation

• Because of the common mosquito vector, CDC recommends testing for Dengue and Chikungunya as well.

• Serology for Dengue fever and PCR and serologic testing for Chikungunya is available through ARUP.

Future Directions

• High priority need to determine duration of shedding in symptomatic and asymptomatic infection

• Need to determine the transmissibility of virus in various body fluids and tropism to recipient tissues

• Need to confirm link between congenital and neurological disease

• No treatment is available; mosquito control and disruption of vector-reservoir cycle is key

Human Microbiome Project

• A consortium of researchers at National Institute of Health

• 80 universities, 5 yrs of research• Mapping normal microbial make-up of

healthy individuals• 300 volunteers• 15 sites on men, 18 sites on women• Body contains trillions of microorganisms

– Outnumber human cells 10:1• Bacterial contribution critical for human

survival

Nature. The Human Microbiome Project Consortioum. June 14 2012. Vol 486

Microbiome Sites

• Skin• Oropharynx• Lung• GU tract• Gastrointestinal microbiome

• Includes bacteria as well as mycobiome, virome, protozoa etc.

Gastrointestinal Microbiome (GIMb)

• Complex ecosystem comprised of up to 15,000 different species of commensal bacteria.1

• Most species are not recoverable using conventional culture techniques; 16s rRNA gene DNA sequencing

• Identify species and quantify degree of diversity (Shannon or Simpson index)

• This symbiotic system plays an important role in homeostasis of many host physiologic systems

• Metabolism, immune function, polysaccharide metabolism, mucosal integrity

• Disruption of the normal balance of microdiversity of the GIMb (dysbiosis) is now implicated in a number of important inflammatory and infectious processes.2

GIMb• The GIMb is populated during and shortly

after birth,1

• Species are largely conserved among individuals.5

• Composition can differ significantly between individuals

• When considered collectively, there are more than 100 times more bacterial genes in the GIMb than in the human genome.6

• Members of the phyla Bacteroidetes and Firmicutes families comprise the vast majority of species, of which most are anaerobes.7

Normal Diversity of GIMb

M Arumugam. Nature, vol 473. May 12 2011.

GIMb

So if 1012 bacteria live in every ml, and if there are more immune cells in the GI tract than anywhere else in the body, how aren’t we constantly febrile?

Development and Tolerance• The GIMb and nascent immune system develop in parallel in

a co-dependent developmental waltz.• In a germ-free mouse model where this interaction is

absent, dysfunctional development of both the immune system and intestinal vasculature and histology occurs.8-10

• Germ free mice have less plasma cells, are deficient in IgA, have depleted Payer’s patches and fewer lymph nodes

• Intestinal surface area is also decreased• Need a higher caloric intake to maintain same body weight

as non germ-free animals• Resistant to diet induced obesity• Prone to vitamin deficiencies (K and B)

GIMb and Immune Function• During development, host innate and adaptive immune cells are co-educated

with bacterial flora resulting in a delicate balance of permissive colonization and immune tolerance.11

• Host Paneth cells maintain diversity of the GIMb and prevent dominant colonization by secreting antimicrobial peptides12

• Promote an anti-inflammatory milieu via Treg and Th17 cells11• Maintain integrity of the GI mucosal epithelia11

Clostridium difficile - The prototypical consequence of dysbiosis

• Exposure->Colonization->Alteration of normal intestinal diversity (antimicrobials, IBD, GI infections, immunosuppression)->Pathological expansion in GI tract, toxin production->mucosal injury

• Huge impact – annually >500,000 cases of CDI, 30,000 deaths• Up to 30% recurrence rate• Cost of treating CDI in the hospital is $3,427-&9,960 for initial

infection• Cost of treating recurrent CDI is $11,631 with a total cost of

$1.2 BILLION annual in United States alone

Fecal Microbiota Transplantation

• Fecal microbiota transplantation (FMT) is an emerging alternative treatment of refractory or recurrent CDI.

• Performed by direct instillation of homogenized liquid supernatant from stool provided by a healthy donor.

• The mechanism of FMT is to reestablish balance to the intestinal microbiome and suppress pathogenic colonization.2

• Performed via capsules, nasogastric/naso-jejunal tube, upper endoscopy, colonoscopy or retention enema – No data suggesting superiority of either route; highest success

rates are for lower instillation

FMT• Currently considered a biologic therapy by the FDA, but

granted exceptional IND status• Latest revision of FDA guidance has been in draft form since

2013; calls for donor to be known either to the patient or the treating physician

• Not reimbursed by most insurance companies• No standardized method for identifying appropriate donors• No standardized health and behavioral screening for donors• No standardized laboratory screening for donors• OpenBiome, a not-for-profit company in Boston has a stool

bank populated by post-docs and grad students. $375 plus $150 shipping

Alternative Uses of FMT

• Studied in ulcerative colitis, Crohn’s disease, Clostridium difficile recurrence*, pancreatitis, pouchitis, multidrug resistance reversal, obesity, irritable bowel syndrome, MRSA enterocolitis, NASH, diabetes, multiple sclerosis, and Parkinson’s disease

FMT – Efficacy Data

• A recent meta-analysis of 11 studies comprising 273 patients reported a clinical response rate of 89%.22

• Two RCTs have now been published.23,24

• Van Nood et al. comparing duodenal FMT to vancomycintherapy was stopped early due clear efficacy benefit (94% vs. 23%) in the FMT group compared to controls.23

• RCT using frozen inoculum from unrelated donors also reported an overall cure rate of 90% at 8 weeks.24

• Recent study compared frozen to fresh showed that both methods were efficacious (Lee et al JAMA Jan 2016)

FMT Safety Data• No serious adverse events were reported in the meta-analysis or

RCTs. • Colonoscopy or sedation-related adverse events are most serious

reported to date.• One long-term longitudinal study reported that mild, transient

gastrointestinal complaints are the most common AE.25

• Some concern about possible association with neurological or autoimmune complications

• Massive weight gain reported in one thin recipient whose donor was obese

• One case report of E. coli bacteremia after FMT; not clear whether due to FMT because patient had had multiple prior bacteremiasbefore FMT

LDS FMT Protocol• Donors known to patient or physician identified;• Screened using modified American Red Cross blood donor

questionnaire plus questions about travel, GI illnesses, antibiotic use, neuro, rheum, metabolic dz

• BMI

Donor Fecal Processing

LDS Hospital FMT Experience

• 11 FMT procedures since February 2015• Median recurrences: 3; 3 maintained on PO vanco because of

recurrences• Median follow up 5 months post FMT. 9 NJ, 2 colonoscopy, 8

fresh, 3 frozen.• 10/11 (91%) with no recurrence to date. One patient recurred

6 months later after taking cefdinir for a viral URI. Retransplanted.

• 2 patients had improvement in GvHD symptoms, 2 with concomitant Crohns with significant improvement in IBD symptoms

Questions?

[email protected]

Multiple Small Feedings of the MindObjectivesEmerging InfectionsCrash Course in EpidemiologyCrash Course in Global EpidemiologyThe Proximity IssueFactors Influencing ProximityFactors Influencing ProximityFactors Influencing ProximityFactors Influencing ProximityFactors Influencing ProximityZika virusCurrent OutbreakTransmissionTransmissionVertical TransmissionClinical Manifestations�Congenital InfectionDiagnosisFuture DirectionsHuman Microbiome ProjectMicrobiome SitesGastrointestinal Microbiome (GIMb)GIMbNormal Diversity of GIMbGIMbDevelopment and ToleranceGIMb and Immune FunctionClostridium difficile - The prototypical consequence of dysbiosisFecal Microbiota TransplantationFMTAlternative Uses of FMTFMT – Efficacy DataFMT Safety DataLDS FMT ProtocolDonor Fecal ProcessingDonor Fecal ProcessingDonor Fecal ProcessingLDS Hospital FMT ExperienceSlide Number 40

Documents

Multiple Small Feedings of the Mind - Internal Medicine | ACP...• Van Nood et al. comparing duodenal FMT to vancomycin therapy was stopped early due clear efficacy benefit (94% vs