Category Archives: Virology

Ebola’s Chain of Infection

Chain of Infection A chain of infection is a method for organizing the basic information needed to respond to an epidemic.  I’ve gathered the best information I’ve been able to find. As the current epidemic is analyzed, there is no doubt some of the recommendations and basic knowledge will change.

The Ebola Virus (EBOV)

img8The Ebola virus is a Filovirus, an enveloped RNA virus containing only eight genes. Three of the five ebola virus species are highly pathogenic to humans: Zaire ebolavirus (Case fatality rate (CFR) 70-90%), Sudan ebolavirus (CFR ~50%) and Bundibugyo ebolavirus (CFR 25%). The 2014 epidemic is caused by the  Zaire ebolavirus.

Ebola attaches to the host cell via glycoproteins that trigger absorption of the virus. Once inside the cell it uncoats and begins replicating the eight negative sense RNA genes (seven structural genes and one non-structural gene). It initially targets immune cells that respond to the site of infection; monocytes/macrophages carry it to lymph nodes and then the liver and spleen. It then spreads throughout the body producing a cytotoxic effect in all infected cells. Death occurs an average of 6-16 days after the onset of symptoms from multi-organ failure and hypotensive shock.

Symptoms present 2-21 days after infection and the patient is contagious from the onset of symptoms.  Symptoms include a fever, fatigue, headache, nausea and vomiting, abdominal pain, diarrhea, coughing, focal hemorrhaging of the skin and mucus membranes, skin rashes and disseminated intravascular coagulation (DIC). In the 2014 epidemic, abnormal bleeding has only occurred in 18% of cases and late in the disease process.

The Reservoir

Fruit bats in Africa are believed to be the primary reservoir. Transmission between bats and other animals is poorly understood.

ebola_ecology_800px

Portal of Exit

Ebola leaves its reservoir by contact with body fluids of an infected animal, often by bushmeat hunters. The spill-over is usually very small with the vast majority of human cases being caused by human to human transmission.

Transmission 

Transmission between humans occurs by contact of skin or mucus membranes with the body fluids of an infected person. Viral particles are found in all body fluids: blood, tears, saliva, sputum, breast milk,  diarrhea, vomit, urine, sweat and oil glands of the skin, and semen. Ebola can be found in semen three months after recovery from an infection but transmission by this route is poorly understood. Viral particles are found in other body fluids for 15 days or less after the onset of symptoms. It lasts the longest in convalescent semen and breast milk. All fluids from dead bodies are highly infectious.

All materials touched by the infected person, body fluids, medical waste, and used PPE must be discarded and destroyed as infectious medical waste. Non-disposable items like rubber boots, furniture, and building structures must be professionally decontaminated.

Ebola virus is a Biosafety Level 4 pathogen and a category A bioterrorism agent along with other viral hemorrhagic fevers.

Portal of Entry

Ebola enters the human body through breaks in the skin, including micro-abrasions and splashes on mucus membranes. Personal protective equipment (PPE) includes full body coverage including hood, mask or face shield, a tight fitting respirator, boots or shoe coverings, and double gloving. A buddy system should be used for dressing and disrobing. Removing PPE is a point of frequent contamination and should be done with help from another robed person.

Vulnerable populations

The most vulnerable populations for ebola are defined by their occupation. Care givers in medical facilities are at the highest risk because the viral titers reach the highest levels in fatal cases shortly before death. Mortuary and burial workers are also at high risk. The infectiousness of the bodies means that the usual burial practices can not be done in any setting or country. Home caregivers and decontamination workers would also be at a higher risk.

Information is lacking on survival vulnerabilities such as age, gender, pregnancy, or pre-existing conditions. More information on these aspects should be available in the post-epidemic analysis of the current epidemic.

 

References and further reading:

Martines, R. B., Ng, D. L., Greer, P. W., Rollin, P. E., & Zaki, S. R. (2014). Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg Viruses. The Journal of Pathology, n/a–n/a. doi:10.1002/path.4456 [in press]

Chowell, G., & Nishiura, H. (2014). Transmission dynamics and control of Ebola virus disease (EVD): a review. BMC Medicine, 12(1), 196. doi:10.1186/s12916-014-0196-0

Toner, E., Adalja, A., & Inglesby, T. (2014). A Primer on Ebola for Clinicians. Disaster Medicine and Public Health Preparedness, 1–5. doi:10.1017/dmp.2014.115

Bausch, D. G., Towner, J. S., Dowell, S. F., Kaducu, F., Lukwiya, M., Sanchez, A., et al. (2007). Assessment of the Risk of Ebola Virus Transmission from Bodily Fluids and Fomites. Journal of Infectious Diseases, 196(s2), S142–S147. doi:10.1086/520545

CDC: Ebola Virus Disease portal

The Spotty History of Chicken Pox

For its extreme antiquity the virus that causes chicken pox, it has a surprising sparse documented history.  The earliest clear reference to the virus is actually to an emergence of its latent form as shingles, also called zoster. The ancient Greeks called it zoster after word for girdle, while shingles comes from the latin word cingulus (belt) both referring to the most common site of emergence along peripheral nerves of the back that wrap around the abdomen. There are many theories, but as far as I know, no one has successfully explained how it got the name chicken pox. It was not until histological and immunological investigations in the early twentieth century that the relationship between the primary phase infection, chicken pox (varicella), and the emergence of the latent virus as shingles (zoster) was confirmed.

Into the 18th century, chicken pox and smallpox were commonly confused as a severe and mild form of the same disease. There are subtle differences between the rashes than can distinguish them. Chicken pox produces watery pustules that concentrate on the head and trunk of the body, while smallpox lesions become hard and dimpled and are concentrated on the appendages.  Chicken pox lesions are sparse or absent from the palms of the hands and soles of the feet, while these areas are often heavily covered by smallpox lesions. But, both diseases can cause lesions anywhere in the body including internal cavities and both can leave deep scars.

Chicken Pox 1

They are also, of course, distinguished by their mortality rates. Smallpox has a mortality rate of around 30%, while chicken pox  has a mortality rate of less than 1%. However, pregnant women and immune compromised patients are at high risk for life threatening complications from chicken pox. The blisters can also develop secondary bacterial infections that can become life threatening. Unlike chicken pox, smallpox requires a constant supply of non-immune hosts to persist in a community.

 

Viral Lifecycle

The lifecycle of the varicella virus is ideal to persist in small communities over many generations without outside introduction. It is primarily transmitted as a respiratory virus, but it can also be transmitted by contact with fluid from the blisters. Both routes are critical. Respiratory transmission allows it to spread rapidly while contact with blisters transmission allows it to persist in the community (more on this below).

As the virus enters the body it replicates for 10 to 21 days before the chicken pox rash of virus filled blisters appears. Meanwhile, some of the virons are infecting the peripheral nerves where the virus becomes dormant (latent). A couple days before the rash appears people feel unwell with fatigue, headache and potentially a fever, and they become contagious by coughing or sneezing. By spreading the virus before the rash appears, they spread the virus far and wide before the disease is recognized and isolated. The blisters usually appear first on the scalp and on the trunk of the body with the number of blisters increasing with increasing age of the person. Young children can have as few as a dozen or less, while adults can have thousands of blisters. Over one to two weeks,  the immune system gains the upper hand and the pustules scab over. Once the rash is scabbed over, the person is no longer contagious. The length of time it takes for the rash to stop depends completely on the strength of the immune system.

The virus can remain dormant in the peripheral nerves for 50 years or more emerging when either the peripheral nerves become inflamed (often by injury) or immune suppression develops. It reemerges as shingles (zoster), a highly painful, high density group of blisters that break out along the line of the peripheral nerve they come from, usually spinal peripheral nerves. It will looks something like a whip mark of blisters wrapping around the body from the back to the front. Fluid from these blisters can cause chicken pox in non-immune people. This is a generational persistence strategy. In small communities, the virus persists by being transmitted from an elder’s shingles to children born after the last epidemic.

life long immunity usually follows recovery from chicken pox.  Young children who only have a few lesions in their first infection can contract chicken pox a second time. It is also possible for vaccinated people to develop a usually mild case of chicken pox. In the United States vaccine acceptance is high enough that many people under age 25 have never seen a case of chicken pox. There is little doubt that if vaccination coverage wains, chicken pox will quickly become endemic again.

Origins and Evolution

The ancestral  Varicella-Zoster Virus (VZV), that causes chicken pox and shingles, co-evolved with apes, hominids and humans. Along with VZV, its closest alphaherpesvirus relatives herpes simplex 1 (HSV1, ‘cold sores’) and herpes simplex 2 (HSV2, genital herpes) have a common ancestor that is approximately 120 million years old. If the age estimates for the herpes phylogenetic tree are accurate, the evolution of the alphaherpesviruses  (VZV, HSV1, HSV2) coincides with the split of Africa from the supercontinent Godwanaland.

VZV has the ideal lifecycle to persist in small, isolated groups of humans, allowing to easily survive through all three human epidemiological transitions. Latency and re-emergence in elders allowed the virus to survive in small hunter-gatherer groups, and continues to remain an advantage today. This process was observed in action on the small mid-Atlantic island of Tristan de Cunha where the population of about 200 people only experienced chicken pox outbreaks after an elder first exhibited shingles (Grose, 2012).

Phylogeny of VSV supports its origin in Africa before humans left the continent and subsequent spread through the world. Regionalism has likely occurred because VZV viruses undergo few replications per infection before they become latent so there is little chance for mutation or recombination between the clades (though it does occur).  Once many more sequences are available correlations between VZV evolution and human migration should become more clear.

The history of the chicken pox virus still has a long way to go. As a DNA virus, it is possible that it may be found in ancient DNA but as a virus with a low mortality rate, it will be extremely difficult to find specimens with a high enough viral copy number to detect. Those rare mummies found with pox scars should be tested for both the smallpox virus and varicella-zoster virus. Regardless we must be careful distinguishing smallpox and chicken pox in the historic record.

 

References:

Grose, C. (2012). Pangaea and the Out-of-Africa Model of Varicella-Zoster Virus Evolution and Phylogeography. Journal of Virology, 86(18), 9558–9565. doi:10.1128/JVI.00357-12

Schmidt-Chanasit, J., & Sauerbrei, A. (2011). Evolution and world-wide distribution of varicella–zoster virus clades. Infection, Genetics and Evolution, 11(1), 1–10. doi:10.1016/j.meegid.2010.08.014

Wood, M. J. (2000). History of Varicella Zoster Virus. Herpes : the Journal of the IHMF, 7(3), 60–65.

Centers for Disease Control and Prevention (CDC): Chicken Pox (Varicella) Information portal. Last updated February 26, 2014.

CDC, Varicella: People at High Risk for complications. Nov. 16, 2011.

Conger, Cristen.  “How Chicken Pox Works”  11 March 2008.  HowStuffWorks.com. <http://health.howstuffworks.com/skin-care/problems/medical/chicken-pox.htm&gt;  24 May 2014.

General Principles of Zoonotic Landscape Epidemiology

Zoonoses, pathogens with animal reservoirs, exist as part of a complex system of interactions between animal reservoirs, vectors, ecological factors and human interaction. Landscape epidemiology has existed as a field of study since Russian epidemiologist E.N. Pavlovsky coined the term and laid the groundwork in the 1960s. Landscape epidemiology is in essence the study of environmental foci of zoonotic disease, what Pavlovsky called a nidas. Many of the variables have been identified and studied in individual pathogen systems.

Each system seems so complex and unique that it can be easy to think that they each exist as separate entities with little to do with each other. It is necessary to develop some general principles to both see the bigger picture, and guide research and response to less studied and newly discovered pathogens. Lambin et al. set out to do just that by doing a meta-analysis of eight regional case studies of zoonotic diseases in Europe and East Africa: West Nile Virus in Senegal, Tick-borne Encephalitis in Latvia, Sandfly abundance (leishmaniasis vector) in the French Pyrenees, Rift Valley Fever in Senegal, West Nile Virus hosts in Camargue, Rodent-borne Puumala hantavirus in Belgium, human cases of Lyme borreliosis in Belgium, and risk of malaria re-emergence in Camargue. Obviously, as indicated, not all of these studies look at all factors involved in landscape epidemiology so validation is not solely based on the number of case studies that support each principle.

The ten proposed principles by Lambin et al are shown graphically below where they fit into the system of variables.

Graphical representation of the landscape determinants of disease transmission. The numbers refer to the ten propositions formulated in this paper. Lambin et al. International Journal of Health Geographics 2010 9:54   doi:10.1186/1476-072X-9-54
Graphical representation of the landscape determinants of disease transmission. The numbers refer to the ten propositions formulated in this paper.
Lambin et al. International Journal of Health Geographics 2010 9:54 doi:10.1186/1476-072X-9-54

Proposed general principles (Lambin et al, 2010):

  1. Landscape attributes may influence the level of transmission of an infection” This proposal is found in all case species. Features of the landscape influence vector and host distribution across the region of study. Distribution and type of water (fresh, brackish, or salt water) is a common landscape feature that influences density of insect vectors.
  2. Spatial variations in disease risk depend not only on the presence and area of critical habitats but also on their spatial configuration“.   The sheer size of the critical area is not the only or necessarily the most important characteristic to determine risk in an area. Some vectors like ticks thrive along border zones between ecosystems, like edges between woodland and grasslands.
  3. Disease risk depends on the connectivity of habitats for vectors and hosts” Creating contact zones or contiguous zones that create linked areas are also important. The spatial configuration can create corridors for disease persistence in harsh landscapes. Type and connectivity of  vegetation is as important as terrain for vector habitats. Connectivity between suitable habitat for rodents and insects allows the disease to spread from one patch to the next amplifying the pathogen to a level that increases risks of human transmission. Connections between patches of critical habitats allows for recolonization after local extinction.
  4. The landscape is a proxy for specific associations of reservoir hosts and vectors linked with the emergence of multi-host disease.” Their principle could be better fleshed out; their primary evidence coming from West Nile Virus (WNV). Like other multi-host pathogens, WNV has some hosts that are much more important than others for transmission across wide regions. In WNV migratory birds are a key to understanding its spread and epidemic dynamics. WNV is also an example of a disease with different proxies and amplification hosts in different regions of the world.
  5. To understand ecological factors influencing spatial variations of disease risk, one needs to take into account the pathways of pathogen transmission between vectors, hosts, and the physical environment.” Vector-borne diseases require direct contact between humans and the vector. For other zoonoses like hantavirus contact between humans and animal hosts can be via aerosols of material with rodent feces or dust containing rodent remains. For example, people have contracted hantavirus by vacuuming up rodent remains in homes. When estimating risk of transmission to humans, abiotic (non-living) environmental conditions that can preserve or transmit to humans have to be considered. Climate and moisture content of the soil are common abiotic factors to be concerned about. Additional support for this principle comes from the role of the rodent burrow system on plague (Yersinia pestis) hosts and vectors.
  6. The emergence and distribution of infection through time and space is controlled by different factors acting at multiple scales” In their discussion of this principle, they focus on human interaction with the environment and particularly urbanization altering disease risk. They note that climate change and natural environmental change do not account for all emerging and re-emerging disease but the activities of humans including urbanization and ecological change like deforestation. Ben-Ari et al‘s study on plague and climate change also looks at the many factors at all levels from micro to macro scales effect the abundance and likelihood of transmission of the plague.

    Plague cycle including hosts and vectors with abiotic influences
    Plague cycle including hosts and vectors with abiotic influences (Ben-Ari et al, 2011).
  7. Landscape and meteorological factors control not just the emergence but also the spatial concentration and spatial diffusion of infection risk” This principle just adjusts the previous principles to take account of primarily rainfall by looking at temporary ponds or wetlands. This particularly affects mosquito abundance, but as the graphic above demonstrates also effects soil moisture.
  8. Spatial variation in disease risk depends not only on land cover but also on land use, via the probability of contact between, on one hand, human hosts and, on the other hand, infectious vectors, animal hosts or their infected habitats” Land use has been long known to affect mosquito abundance and disease transmission. Clearing land for settlements or agriculture always increases standing water in ditches, tire ruts, railroad ditches, animal troughs, incomplete building projects, and due to loss of water absorbing vegetation. A century of malaria research and management has focused on land use and the elimination of standing water.  Mature water management programs for cultivation or flood control can also alter vector abundance and human contact rates. For example flooding fields to grow rice not only provides habitat for mosquito production but also brings people into the fields to cultivate increasing contact rates. Irrigation canals would have a similar effect.
  9. The relationship between land use and the probability of contact between vectors and animal hosts and human hosts is influenced by land ownership” In Lambin et al, they looked at the contact rates between public (state) land and private ownership. In these studies state ownership increased access to forestland over private ownership.By the same token, state ownership could also prevent deforestation and urbanization by preserving the wilderness or reserving the land for other uses. Forest age and maturity also varies significantly between state forests and private land.
  10. Human behaviour is a crucial controlling factor of vector-human contacts, and of infection.”  Humans bring themselves into contact with vectors by risky behavior and can control exposure vectors and infections. Obviously, vaccination is one of the controlling factors of infection, although many zoonotic infections have either no or poor vaccines. Occupational and recreational exposure to vectors often explains gender difference in infection rates.

In conclusion these principles begin to mark out the three sides of a zoonotic triangle: biology of pathogen, vector and host; ecological system where they exist; and human behavior and ecological interaction. Human behavior including land use and constructed environments is as important as the other two sides of the triangle. Humans are not passive victims or collateral damage.

Reference:

Lambin, E. F., Tran, A., Vanwambeke, S. O., Linard, C., & Soti, V. (2010). Pathogenic landscapes: Interactions between land, people, disease vectors, and their animal hosts. International Journal of Health Geographics, 9(1), 54. doi:10.1186/1476-072X-9-54 [open access]

Ben-Ari T, Neerinckx S, Gage KL, Kreppel K, Laudisoit A, et al. (2011) Plague and Climate: Scales Matter. PLoS Pathog 7(9): e1002160. doi:10.1371/journal.ppat.1002160