Category Archives: epidemiology

Changing the Plague-Flea Transmission Paradigm

The old paradigm is dead! Long live the new paradigm!

X. cheopis, the rat flea
Xenopsylla cheopis, the rat flea

Rebecca Eisen, David Dennis, and Kenneth Gage just published an article gathering all the evidence that should put an end to the blocked flea model  as the only significant method of plague transmission.  They summarize the data proving that unblocked fleas can and do transmit Yersinia pestis at levels that readily cause infection in rodents and humans. They call all transmission by unblocked fleas early phase transmission (EPT), even in flea species that never block.

Important findings summarized:

  • The blocked flea model –  that only a biofilm blocked Xenopsylla cheopis which can not eat so it tries to aggressively feed and  regurgitates high numbers of Yersinia pestis into the bite site – is insufficient to account for either epizootics or large human outbreaks. Blocked fleas do transmit the plague but are simply insufficient to account for the speed and volume of epizootic and epidemic transmission.
  • Transmission can occur as quickly as the very next blood meal taken by the flea, at times within 1-2 hours. Y. pestis does not need to replicate in the flea for transmission to occur. This makes it much more likely that the flea will survive long enough to transmit the infection.
  • Early phase transmission has been experimentally observed to cause infections after exposure to a single Oropsylla montana flea. Therefore, exposure to large numbers of unblocked infected fleas is not required for transmission. Epidemiologic findings suggest that most US cases come from bites from a single or at most a few fleas, and this is consistent with findings around the world were fleas that do not block are primary vectors.
  • Many reservoirs of plague are maintained by fleas that never block. Prairie dog reservoirs in the western US and great gerbil reservoirs in central Asia are both maintained by fleas that are never blocked by a biofilm.
  • “In short, EPT was observed in all flea species evaluated at varying temperatures. Transmission occasionally occurred as early as 3 h post-infection but usually was observed over 1-4 dpi [days post infection]. Although all flea species tested were capable of EPT, efficiency in these studies varied among species, suggesting that some fleas are likely to be more important than others in the rapid spread of plague in nature, especially those that are both efficient transmitters and abundant on susceptible hosts.” (p. 3)

  • Strains of Y. pestis that can not form a biofilm transmit as effectively by EPT as biofilm competent strains. Virulence factors that are necessary for biofilm production are not necessary for EPT.
  • EPT – compared to a contaminated “dirty needle” – is a mechanical form of transmission that “requires no modification or multiplication of the pathogen in the vector for transmission to occur” (p. 4).
  • In the pre-antibiotic era, many human bubonic plague infections and all septicemic and pneumonic cases would have produced bacteremia levels sufficient to infect fleas for EPT. In the 71 fatal plague cases recorded by the CDC between 1956 and 2013, 86.8% were either primary or secondary septicemic cases.
  •  “Epidemic support in favor of interhuman flea borne transmission comes from records of limited bubonic plague outbreaks in isolated rural communities under exceptional circumstances of heavy human flea infestations, high familial attack rates, and a lack of evidence for concurrent rat-flea borne plague. … [studies in Africa, the Middle East and the Andes mentioned]… Based on epidemiologic pattern of person to person spread, especially the high attack rates among contacts of the sick, an absence of domestic rats, and an unusual abundance of P. irritans infesting villages and their homes, investigators concluded that the outbreak resulted from infective bites by P. irritans.” (p. 7-8)

  • They note that interhuman plague transmission by pulex irritans has been documented early in the 20th century and supported by laboratory experiments. As covered here a year ago, infected Pulex irritans were recovered from the homes of plague patients in Madagascar in 2013. They end with a call for more work on P. irritans to evaluate its role in modern and historical human epidemics.

It is worth noting here that throughout the article they cite many studies using many different fleas. EPT studies have also been demonstrated  for mouse fleas (Aetheca wagneri Baker)  and cat fleas (Ctenocephalides felis).  I’ve never really understood why studies of historic plagues often overlook mice as a source of fleas.

I also have to add that mechanical transmission by the flea makes a lot of evolutionary sense.  It gives evolution a place to start tinkering. ‘Good enough’ is the stuff of evolution! Optimization only occurs after a very long evolutionary process, and may never be achieved. The fact that X. choepis evolved a method (via bioflim blockage and regurgitation [LPT]) to keep transmission going longer does suggest that the rat flea has been historically important to Y. pestis evolution. Obviously mechanical transmission has also allowed Y. pestis to expand into areas and exploit new opportunities where a more complicated, required transmission system would have been an obstacle.

Experiments proving that EPT is possible have been scattered over the last 50 years! And, yet the old paradigm still reigned. Why? Obviously there has been a lack of communication within science and between science and the humanities. It would really be helpful for a historian of 20th century science to look into how this could have happened.

Reference:

Eisen, R. J., Dennis, D. T., & Gage, K. L. (2015). The Role of Early-Phase Transmission in the Spread of Yersinia pestis. Journal of Medical Entomology, tjv128–10. http://doi.org/10.1093/jme/tjv128. Advanced access, Aug. 19, 2015. (Open access)

Multi-strain Plague Blooms Over Landscapes

Two articles have come to my attention over the couple months that argue strongly for an environmental role in plague epidemics/epizootics over clonal expansion. Taken together these studies suggest that multiple strains of Yersinia pestis percolate out of multiple reservoirs at the same time.

Sites of Madagascar cases, 2007 (Riehm et al, 2015)
Sites of Madagascar cases, 2007 (Riehm et al, 2015)
Strains isolated in Madagascar, 2007 (Riehm et al, 2015)
Strains isolated in Madagascar, 2007 (Riehm et al, 2015)

The strongest support comes from Madagascar where ten MLVA defined strains from 93 human clinical specimens representing the two major groups of Yersinia pestis (based on, if I recall correctly, their introduction source) all emerged within one single year, 2007, scattered over a large range of the central island. These ten strains represent eight previously known strains and two discovered in this investigation. As the map shows, several locations had cases from more than one lineage.  This pattern does not suggest to me that one strain was more successful than another; there is no new mutation that allowed one strain to erupt on the scene or transmission advantage caused by chance or mutation. (Yes, chance does play a role sometimes.) That one strain is more widespread than another probably represents years of enzootic spread and so multiple emergences of a more common strain. With multiple strains emerging at the same time, there is relatively little clonal or territorial expansion, and no reason to expect a major selective advantage by any particular strain. They are emerging where ever the right environmental conditions exist. This study is not directly informative on the underlying epizootic. There may have been even more strain diversity in the epizootic.

There are at least two relevant findings for future surveillance. First, these strains were genotyped directed from DNA in clinical specimens without culturing the specimen. This means that specimens that previously were difficult to culture can still be genotyped and it also should be safer for lab staff to handle. It suggests again that they need a new case classification system since only culturable isolates are considered confirmed. As encouraging as this is, the bad news for reservoir surveillance is that they will have to monitor very large zones based on climate and other environmental factors instead of just trying to project the direction of an ongoing outbreak.

This is supported by another study published in May by Jennifer Lowell’s team on plague in the western US. They analyzed 34 isolates of Yersinia pestis collected from fleas, humans, cats, and a variety of other animals between 1980 and 2006 primarily in Colorado (21) and some scattered sites across the southwest. In Colorado isolates geographically close but temporally spaced showed an evolutionary relationship demonstrating that they had evolved in place over seven years. Mountain isolates were also distinctive between valleys and on the plains suggesting that they evolved in isolation.

During the initial introduction of Yersinia pestis to a region, there is a rapid spread of a single clone but following this, there the creation of local reservoirs with evolution occurring in place. Subsequent epizootics emerge from these new reservoirs and remain small. It follows that large epizootics are usually the emergence of several reservoirs stimulated by the right environmental conditions.

What I take from this is the idea that large scale spread of epizootics or epidemics over different ecological regions require human assistance. There is a anthropogenic factor to the largest epizootics/epidemics. Left to their own means, epizootics remain local spreading only as far as the contiguous environment allows. Some agent, usually humans, must carry them between permissive environments. It is possible that the permissive environment will be urban as it was in Madagascar in the 1990s (Vogler et al, 2013).

Now thinking historically, what we need is serial aDNA results from the same city over many centuries. London and Marseille would be good options, so would Constantinople and Alexandria. With enough aDNA samples it should be possible to estimate how many introductions of Yersinia pestis from the Asia occurred for each pandemic and to discern a role for European or Mediterranean local reservoirs. These modern studies are absolutely necessary to make sense out of the patterns that will eventually emerge when we have enough aDNA specimens.

References:

Riehm, J. M., Projahn, M., Vogler, A. J., Rajerison, M., Andersen, G., Hall, C. M., et al. (2015). Diverse Genotypes of Yersinia pestis Caused Plague in Madagascar in 2007. PLoS Neglected Tropical Diseases, 9(6), e0003844. doi:10.1371/journal.pntd.0003844.s002 (h/t to Matt Wilson for this one!)

Lowell, J. L., Antolin, M. F., Andersen, G. L., Hu, P., Stokowski, R. P., & Gage, K. L. (2015). Single-Nucleotide Polymorphisms Reveal Spatial Diversity Among Clones of Yersinia pestis During Plague Outbreaks in Colorado and the Western United States. Vector Borne and Zoonotic Diseases (Larchmont, N.Y.), 15(5), 291–302. doi:10.1089/vbz.2014.1714

Vogler, A., Chan, F., Nottingham, R., Andersen, G., Drees, K., Beckstrom-Sternberg, S., Wagner, D., Chanteau, S., & Keim, P. (2013). A Decade of Plague in Mahajanga, Madagascar: Insights into the Global Maritime Spread of Pandemic Plague mBio, 4 (1) DOI: 10.1128/mBio.00623-12

Spring Reading

spring1
It has been a busy spring. I haven’t had a chance to blog as much as I would have liked to, but I have done quite a bit of reading. Some of my reading has been on the complex world of the first plague pandemic. To say that it was transformative would be an understatement.  One of the social questions for the first plague pandemic is how does plague and other natural disasters effect a population that is the midst of conversion?  When the Black Death came it encountered a fully Christian and Muslim world, but not so during the first pandemic. Most of Europe was not yet Christian in 541. There were some Jews, Christians of several varieties, Roman pagans, Germanic pagans, Celtic pagans, Zoroastrians, North African and Middle Eastern pagans, etc. Yet at the end of the pandemic period, Islam is born (and fast growing) and Christianity is dominant in Europe (and united by Rome). The plague began in a polytheistic world and ended in a monotheistic one. What role did the plague play, if any? Yet to be determined. This really isn’t a peripheral issue. Every writer of the first pandemic was involved in this transformation (winners and losers) in some way and it effected how they wrote about the plague and other calamities. So I have a lot of reading to do; below is a start and a few other things that caught my attention.

Books:

Marilyn Dunn. (2010) The Christianization of the Anglo-Saxons, c. 497- c.700: Discourses of Life, Death and Afterlife.

Marilyn Dunn (2013) Belief and Religion in Barbarian Europe, c. 350-700. Bloomsbury.

Peter Brown (2015) The Ransom of the Soul: Afterlife and Wealth in Early Christianity. Harvard University Press.

Peter Heather (2013) The Restoration of Rome: Barbarian Popes and Imperial Pretenders. Oxford University Press.

Articles:

Balbir Singh and Cyrus Saneshvar (2013) Human Infections and Detection of Plasmodium knowlesi. Clinical Microbiology Reviews. 26 (2): 165-184.

Runfola, J. K., House, J., Miller, L., Coltron, L., Hite, D., Hawley, A., et al. (2015). Outbreak of Human Pneumonic Plague with Dog-to-Human and Possible Human-to-Human Transmission — Colorado, June–July 2014. MMWR. Morbidity and Mortality Weekly Report, 64(16), 429–434.

Smith-Guzmán, N. E. (2015). Cribra orbitalia in the ancient Nile Valley and its connection to malaria. International Journal of Paleopathology, 10, 1–12. doi:10.1016/j.ijpp.2015.03.001

Benovitz, N. (2014). The Justinianic plague: evidence from the dated Greek epitaphs of Byzantine Palestine and Arabia. Journal of Roman Archaeology. doi:10.1016/S1473-3099(13)70323-2)

Bernard Bachrach, (2007) Plague, Population, and Economy in Merovingian Gaul. Journal of the Australian Early Medieval Association. 3: 29-57.

Sarris, P. (2002). The Justinianic plague: origins and effects. Continuity and Change, 17(02), 169–182. doi:10.1017/S0268416002004137

Newfield, T. P. (2015). Human–Bovine Plagues in the Early Middle Ages. Journal of Interdisciplinary History, 46(1), 1–38. doi:10.1179/146141010X12640787648612

Inskip, S. A., Taylor, G. M., Zakrzewski, S. R., Mays, S. A., Pike, A. W. G., Llewellyn, G., et al. (2015). Osteological, Biomolecular and Geochemical Examination of an Early Anglo-Saxon Case of Lepromatous Leprosy. PLoS ONE, 10(5), e0124282. doi:10.1371/journal.pone.0124282.s001

Shanks, G. D., & White, N. J. (2013). The activation of vivax malaria hypnozoites by infectious diseases. The Lancet Infectious Diseases, 13(10), 900–906. doi:10.1016/S1473-3099(13)70095-1

Dick, H. C., Pringle, J. K., Sloane, B., Carver, J., Haffenden, A., Stephen Porter, H. A., et al. (2015). Detection and characterisation of Black Death burials by multi-proxy geophysical methods. Journal of Archaeological Science, 1–50. doi:10.1016/j.jas.2015.04.010

Lowell, J. L., Antolin, M. F., Andersen, G. L., Hu, P., Stokowski, R. P., & Gage, K. L. (2015). Single-Nucleotide Polymorphisms Reveal Spatial Diversity Among Clones of Yersinia pestis During Plague Outbreaks in Colorado and the Western United States. Vector Borne and Zoonotic Diseases (Larchmont, N.Y.), 15(5), 291–302. doi:10.1089/vbz.2014.1714

Neil, B. (2013). The Papacy in the Age of Gregory the Great. A Companion to Gregory the Great, 3–28.

Brogiolo, G. P. (2015). Flooding in Northern Italy during the Early Middle Ages: resilience and adaption. Post-Classical Archaeologies, 5, 47–68.

Kostick, C., & Ludlow, F. (2015). The dating of volcanic events and their impact upon European society, 400-800 CE. Post-Classical Archaeologies.  5, 7–30.

Riehm, J. M., Projahn, M., Vogler, A. J., Rajerison, M., Andersen, G., Hall, C. M., et al. (2015). Diverse Genotypes of Yersinia pestis Caused Plague in Madagascar in 2007. PLoS Neglected Tropical Diseases, 9(6), e0003844. doi:10.1371/journal.pntd.0003844.s002

Makundi, R. H., Massawe, A. W., Borremans, B., Laudisoit, A., & Katakweba, A. (2015). We are connected: flea–host association networks in the plague outbreak focus in the Rift Valley, northern Tanzania. Wildlife Research, 42(2), 196. doi:10.1071/WR14254