Category Archives: mortality

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.


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 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

Setting Affairs in Order During the Plague, Newcastle-Upon-Tyne 1636

9780300174472-1Keith Wrightson, Ralph Tailor’s Summer: A Scrivener, his City, and the Plague. New Haven and London: Yale University Press, 2011.

Newcastle-upon-Tyne is one of those cities that is rarely the focus of a plague study – an industrial town whose prosperity and continued existence was based on its economic impact. Coal was king in seventeenth century England and Newcastle had an abundant local supply that not only supplied southern England but was exported throughout the North Sea. The port brought the plague to Newcastle possibly from the Netherlands in October 1635, at least six months before it arrived in London. Initially the plague was light but it was percolating through the rats of Newcastle, and a note in May 1636 marks the the realization that the plague was intensifying.  Still, the port never closed entirely throughout the epidemic. Cities in southern England were willing to risk the plague to keep the coal flowing. Rather than isolate the city and close it port, they opted to board up the infected, their families and caretakers in their homes and quarantine ships. Wrightson hypothesizes that this forced quarantine/isolation was responsible for the high mortality rate within families. Some ships were even willing to visit the port and wait out quarantine more than once during the plague to keep the coal flowing. 

Railph Tailor Scr.

Wrightson was first drawn to Ralph Tailor by his fancy autograph. He explains that this nearly illegible signature was an anti-forgery device. Scriveners made their living writing documents in the proper style for a court or business contract. Ralph Tailor was a young scrivener still trying to get established when the plague arrived in Newcastle in 1636. With due diligence and some personal risk, Ralph Tailor established his footing in Newcastle by writing wills for the stricken sometimes through boarded up doors and windows, and later estate inventories for their probate.

Plague response in Newcastle depended upon a spontaneous community assistance to be workable. Keeping families boarded up in their homes for weeks requires external support primarily from friends and neighbors. Someone had to bring them food and be their contact with the outside world including summoning Ralph Tailor to write their wills and other documents. It says something about the straights of poor women that they were willing to take jobs as ‘keepers’ (nurses) who were shut up in houses with plague infected families for a small wage. Social safety nets as we know them today did not exist, but neighborly safety nets did. People wove their own safety nets through relationships with neighbors, fraternities and guilds, and kin. While craftsmen and service providers like scriveners were in competition, they also worked together for the good of their craft to support each other and their industries.

Very little narrative information survives of Ralph Tailor or his customers. Yet, a few bare records of deaths and marriages along with the wills and related documents provides a remarkable amount of information about their lives. By comparing witnesses, beneficiaries and debtors in wills the web of community connections can be partially reconstructed. It is possible in some cases to track the plague’s path through these networks as people refer to each other as beneficiaries or recently deceased so that not only was plague hitting some families much harder than others, it hit their support networks as well.  Wrightson was able to divide the city into parishes, very uneven in size and economic status, as another view at how these neighborhood networks were faring on a larger scale. This is the type of painstaking historical research that needs to be done to understand pre-modern plague epidemiology. Very few cities have adequate, perfectly preserved data for modern epidemiological analysis. It takes a skilled historical epidemiologist to make sense out of these incomplete records and to resurrect data from the scattered historical remains in archives.

Ralph Tailor did survive the plague and went on to be a man of means in Newcastle. Fourteen of the wills written by Ralph Tailor during the plague survive linking him personally with 92 people who served as witnesses, clients, co-appraisers of inventories, etc. He married during the plague and furnished his first home with items bought from estate sales of some of the plague victims. (Buyers and prices are recorded for estate sales because they are part of the probate record.) He later became a notary public and diversified his business interests in Newcastle. Writing documents for people must given him the opportunity to learn of good deals. When the hearth tax was taken in 1665, the notary public Ralph Tailor owned a six hearth home “in Corner Tower Ward, a relatively wealthy ward located below Allhallow’s church” in addition to other homes in the poorer wards that must have been rental property (p. 149). Only 6% of the homes in Newcastle that year had six or more hearths.   He managed to remain a prominent townsman and contracted civil servant without becoming personally entangled in the political and religious wars of the seventeenth century within Newcastle and beyond. Eventually twice married, he left no children and his heirs were relatives of his second wife when he died in 1669. He was buried under a now lost memorial stone in Allhallow’s church yard with his first wife.

Wrightson’s microhistory provides a vivid look into life in Newcastle during the plague of 1635-6. This book will be of interest for those interested in plague in 17th century England, especially among craftsmen and port workers. Noble, elites and clergy are rarely mentioned in this book. Through the works of Ralph Tailor we see that extra-ordinary year through the life and work of an ordinary man.

Tracking a Live Yersinia pestis Infection with Bioluminescence

The day has finally arrived when an experimental infection can be tracked real-time over the entire course of the infection. Developing a natural history of a rapidly lethal infectious disease has been a challenge because individual variation clouds the progression and individuals can only be studied after death.

The traditional method to study these infections involves infecting many animals so that cohorts of animals can be sacrificed at set time points, have their organs harvested and bacterial load of the organ determined. Some of the flaws of this method are that the right organs may not be selected to survey and individual variation in infection progression means that wide variation may be found at the time points.

Tracking the progression of an infection with bioluminescence allows the infection to run its full course within each experimental animal, rather than taking cohorts at time points. Elizabeth Carniel’s lab at the Institut Pasteur in Paris created bioluminescent Yersinia pestis, and after doing all the controls to ensure a consistent signal under all growth conditions, demonstrated that a live bubonic plague case can be tracked real-time until  death .

In the first figure below the mouse was sacrificed before septicemia set in to correlate the external signals with specific organs. The bioluminescent Y. pestis was injected at the midline near the navel into the linea alba, a tendon-like covering of the abdominal muscles, to simulate a flea bite. Signals represent the injection site, lymph nodes, and the spleen and liver.

Identifying the bioluminescent signals by dissection. 1. axillary lymph nodes, 2. liver, 3. injection site, 4. inguinal lymph node, and 5. spleen. (Nham et al, 2012)

For 74% of the animals injected, the infection followed the same spread pattern. In all the animals the injection site was lit up from the first day. From there it spread to the inguinal lymph node and then surprisingly to the axillary lymph node. The signal then concentrated in the spleen and liver before it becomes completely systemic. Nham et al (2012) note that the signal completely covers the animal from the their ears to the tails. Confirmation of septicemia came from Y. pestis isolated from blood after the death of the animal. Death occurred on average by the sixth day, coming very quickly after septicemia.

Progression of a bubonic plague infection (Nham et al, 2012)

Some of the mice provided clues on how the bioluminescence jumped from the inguinal node to a axillary node. As the linear glow below suggests, they found a lymph vessel that connects the inguinal node to the axillary node. It is consistent with Y. pestis spreading to linked lymph nodes. Confirmation of the lymph vessel linking the inguinal and axillary nodes is shown by bioluminescence and by dye injected dissected mouse in the figure below.

Identification of the lymph vessel connecting inguinal and axillary lymph nodes. (Nham et al, 2012)

The signal next appears under the diaphragm in areas consistent with the liver and spleen (shown in the first figure). This would not necessarily be a direct line from the axillary lymph node to the spleen and liver but that the spleen and liver became infected at about the same time as the axillary node. Colonization of the liver and spleen are related to their blood clearing functions and are indications of a very early phase of septicemia too low to yield systemic bioluminescence.  Death occurred on average by the sixth day, coming very quickly after septicemia.  Nham et al (2012: 5) report that their “results revealed two important phenomena: (i) the variations in the kinetics of bacterial spread were essentially attributable to the length of time the signal remained limited to the injection site, and (ii) as soon as the signal reached lymph nodes, the disease progressed very rapidly, leading to the animal death within two days.” Time between the injection site and first lymph node varied from one to seven days.

The 26% of mice that did not follow this pattern died rapidly with symptoms of a direct septicemic infection (skipping lymph node signals entirely). This suggests that they either hit a blood vessel at the injection site or may have penetrated the abdominal cavity with the injection.

This study is an important first step in developing the method. From here there are many studies that could be done including the effect of changing individual genes on virulence and progression.


Nham, T., Filali, S., Danne, C., Derbise, A., & Carniel, E. (2012). Imaging of Bubonic Plague Dynamics by In Vivo Tracking of Bioluminescent Yersinia pestis PLoS ONE, 7 (4) DOI: 10.1371/journal.pone.0034714