Category Archives: evolution

An Unnatural History of Emerging Infections

Unnatural HistoryRon Barrett and George Armelagos. An Unnatural History of Emerging Infections. Oxford University Press, 2013 (e-book)

This is not a traditional review. In keeping with this blog’s function as my shared file cabinet, this post will be something like a précis /notes with a few of  my comments in italics.

Medical anthropologists Ron Barrett and George Aremelagos argue that there have been common factors in the disease ecology that has governed all three main epidemiological transitions in human health. They argue that there is nothing fundamentally new about the driving factors of the current ecology of emerging and re-emerging infectious diseases. In all three transitions, human factors have created the ecology for acute infectious disease to thrive.

Concept: “syndemics: interactions between multiple diseases that exacerbate the negative effects of one or more diseases” (p. 10). Examples: co-infections of HIV, and combinations of infection and chronic respiratory disease (asthma etc).

Metaphor: “seed and soil” where the microbe is the seed and the ecology is the soil. Historically used by physicians who accepted Germ theory but practiced environmental medicine (sanitarians) especially in the gap between the beginning of germ theory and the availability of antibiotics. I really like this metaphor; it still works today. 

Prehistoric baseline

  • Important as our evolutionary context, first 100,000 years of human history. (that’s about 90% of total human history). At its peak only 8 million people globally; small, nomadic groups  rarely in contact.
  • Temporary shelter and carried little with them to carry vectors (or fomites?). Hunter gatherers maintained near zero population growth. More diverse nutrition but could not support large groups. Little hierarchy within the group so few inequalities (at least not consistently detectable in the osteological record.)
  • Nutrition is closely tied to immunological competence.  Protein deficiencies reduces competence to the level of AIDS patients. Nomads can move to find better nutrition, avoiding ‘famine foods’. Diets higher in lean meats and  fiber, but low in carbohydrates.
  • Too small to support acute epidemics (ran out of hosts too soon) but at an increased risk for parasites. Heirloom parasites like pin worms and lice; souvenir parasites picked up while foraging like ticks and tapeworms. Mostly chronic infections that could remain with the nomads until they could be transmitted to new groups.  New zoonoses that can be passed human to human contracted from hunting would ‘flash out’ in a small group. Groups too small for diseases like measles, smallpox or influenza.

First epidemiological transition – Agricultural revolution

  • The first transition comes with people settle down and form villages.  Settlement and agriculture allow populations to grow large enough to support acute epidemic disease and animal domestication brings humans in prolonged contact with animals sparking some important zoonotic diseases.
  • They note that agriculture and settlement begin in multiple parts of the world independently but not at the same time. It took about 9000 years for 99.99 % of the population to shift to farming and domestic animals as their primary nutrition source. Once the shift to agriculture comes, there is no going back.  They debate which comes first, settlement or agriculture, but they note that in the end for heath it doesn’t matter. (The length of time here has important implications for the incomplete nature of the second transition.)
  • Decrease in overall health seen in all societies that shifted to agriculture. Correlations between more/better grave goods and better health; ie. social inequity was bad for health as early as the neolithic. Very high childhood mortalities bring the overall lifespan down considerably. Settlement increased densities of humans and newly domestic animals making conditions ripe for the first acute epidemics and zoonotic transfers. Most zoonotic transfers in this period come from domestic animals.
  •  Nutrition suffers with settlement. Reliance on a monoculture makes them vulnerable to bad years and nutritional deficiencies of essential nutrients not found in the monoculture.  There is a general reduction in stature, increase in signs of anemia, and increase in osteological signs of infection. Examples: Nubia and Dickson Mounds, IL, USA. Correlation of age with skeletal pathologies shows that is health declines are not due to the ‘osteological paradox’ (more pathologies in stronger people because they survive what would have killed others).

Second epidemiological transition – Industrial revolution

  • Transition marked by decreasing deaths due to infectious disease and an increase in chronic diseases. Increasing life expectancy due in large part to decreasing childhood mortality. Total human population soars.
  • Germ theory vs. Sanitation reform: Germ theory is associated with quarantine tied to power of the church and state. (??) Sanitary reform has greater success in controlling diseases like cholera and food-bourne diseases. Sanitary reformers focused on building infrastructure, improving living conditions and personal hygiene. “Germ theorists had begun a revolution in medical thinking, but in the realm of medical practice, they could do little more than agree with existing recommendations of the miasmists.” “with the exception of a few vaccines and surgical asepsis, Germ Theory offered little…until well into the 20th century”. Not surprising that germ theory didn’t make much difference until antibiotics came along. 
  • McKeown Thesis: “identifies nutrition as the primary determinant in the decline of infection-related mortality” Improved nutrition best explains increasing population growth in different countries in a short time period; improved agricultural methods and transport of food. Urban growth with industrialization increased crowding and decreasing sanitation leaving nutrition as the cause for decreasing infectious disease. Correlation between increasing height and decreasing infant mortality, increasing maternal height (indicating good nutrition) increased indicators of infant health so that improving nutrition improved health from generation to generation.
  • McKeown’s critics: error rates in bills of mortality obscure particularly respiratory infections in the elderly. They also believe that he underestimates the significance of smallpox vaccination in decreasing death rates. Greatest criticism is that McKeown places too much emphasis on nutrition over non-medicinal factors.
  • “Comparing the Agricultural Revolution with the Industrial Revolution, we find the same human determinants of infectious disease: a) subsistence, via its affects on nutritional status and immunity; b) settlement, via its effects on population densisty, living conditions, and sanitation; and c) social organization, via distributions of these resources and their differences within and between groups…. As such, the First and Second Transition could be seen as two sides of the same epidemiological coin with human actions as the basic currency.” (p. 61)
  • Second transition is incomplete in many countries. Only seven nations began the transition before 1850 and 17 more by 1900 with most transitioning after World War II. “The ‘low mortality club’ consisted of richer nations whose life expectancies converged at around 75 years old at the turn of the millennium. The ‘high mortality club’ consisted of poorer nations whose life expectancies converged at the same time around 50 years of age.” (p. 66)  The poorer nations have relied more heavily on vaccines and drugs as a buffer against living conditions to achieve the transition. Drug resistant pathogens removes this buffer for poorer nations. High childhood moralities continued in the poorer countries for the same reasons as in the first transition.
  • Chronic diseases make people susceptible to different infections. example: diabetes + TB, infectious diseases causing cancer: HPV, H. pylori, EBV (lymphoma).
  • Developed world vulnerable to “reimportation epidemics” from poorer nations with agents like smallpox (prior to eradication). Increased speed of air travel allows people to travel between high and low disease areas during the incubation period through entry ports without detection.

Third epidemiological transition (current)

  • Convergence of chronic and infectious diseases in a global human disease ecology marks the Third epidemiological transition.
  • Human health determinants remain subsistence, settlement and social organization.
  • 335 novel pathogens discovered 1940-2004, mostly after 1980, 60% of which are zoonoses and 70% of those come from wild animals. With long exposure to zoonoses from domestic animals it makes sense for most new pathogens today to come from wild animals; also due to encroachment and habitat destruction.
  • Challenges of new zoonotic pathogens: establishing animal to human  transmission, then human to human transmission, and finally human population to population. Chatter is a pathogen trying to establishing the animal to human transmission but not yet getting the human to human. Chatter is often viral but can be other microbes as well. Viral chatter is a transitional moment in evolution; purely biological for the pathogen but primarily cultural for humans (human practices that help the pathogen make the transition by our behavior).
  • Attenuation hypothesis: evolutionary interests favor microbes not killing their hosts too soon. Works for the first transition when population groups were widely scattered.
  • Virulence hypothesis: Ewald’s concluded that evolution favors virulence for pathogens with multiple hosts. (ex. plague). We can’t take either hypothesis too far as both have contradicting examples.
  • We need to shift from just looking for drugs to combat pathogens and spend more time on factors of human ecology.
  • An interesting chapter on antibiotics and evolution.

Concluding focus: To dispel three myths

  1. Emerging infections are a new phenomenon. They are not. This is why the emerging infections page on this blog begins with emergences in Antiquity / Prehistoric. 
  2. Emerging and re-emerging infections are a natural or spontaneous phenomena. We have a part to play in microbial co-evolution. Epidemiological transitions are intended to balance microbiology in understanding these infections.
  3. Determinants of disease are different today than in the past. They are not.

“The purpose of this Unnatural History is to reveal the macroscopic determinants of human infection just as the germ theorists once revealed their microscopic determinants…. our approach has been one of both seed and soil, acknowledging the importance of pathogens while stressing their evolution in response to human activities: the ways we feed ourselves, the ways we populate and live together, and the ways we relate to each other for better or worse.” (p. 111)

 

I’m not an anthropologist so I’m not really going to look at this like an anthropologist.  Demographics shifts are what they are, facts. The underlying factors / variables  - subsistence (nutrition), settlement (living conditions/infrastructure), and social inequalities –are the same under all three transitions. As these conditions vary, so do the demographics. This is very useful; a reminder of the importance of human disease ecology. The Unnatural History of the title is reference to human manipulation of the environment creating the conditions for emerging infections. Epidemics are not ‘acts of god’, or simply a natural process that we are helpless to stop. We play our part. Often drugs are the easy way out of the problem, far easier and cheaper than building infrastructure or improving living conditions. 

The paradigm of epidemiological transitions is an anthropological tool. I don’t really have a practical use for labeling ‘transitions’.  As both the second and third transitions are incomplete, they are not of much use to me as concepts. The shortness of these transitions makes me wonder if we are not really looking at just one transition since ca. 1800 that is yet incomplete. It is more important to me to look at these underlying variables and their outcomes at specific times and places. From my point of view, taking generalizations about epidemiological transitions as more than a guide for research or a teaching paradigm can be problematic.

This is a short book and yet I probably highlighted more than any other e-book that I’ve read. The focus here is more theory than details. Some of their plague information is a little out of date but it doesn’t really detract from their main points. It’s a valuable resource for thinking about microbe-human co-evolution. 

Microbial Forensics of a Natural Pneumonic Plague Outbreak

For bioterrorism agents like Yersinia pestis it is necessary to identify the strain and its source specifically enough for forensic use. Categorizing an epidemic isolate and tracing its source is always important for public health measures, but the level of precision is far higher for legal uses. Developing forensic techniques to characterize and parse very similar strains of a species and trace it to a specific location robs terrorists (and states) of the ability to deny responsibility for an attack (Koblentz & Tucker, 2010). The ability to launch a secret and deniable attack on an enemy has been viewed as one of attractive advantages of biological warfare.

A Chinese group led by Ruifu Yang and Yujun Cui recognized that only whole genome sequencing could adequately parse the strains of the monomorphic species Yersinia pestis but that the computing power necessary to compare entire genomic sequences as the database enlarges is impractical (Yan et al, 2014). Unlike most pathogens, typing only specific regions of the genome are just not enough to get a unique genetic fingerprint for low genetic variability pathogens like Yersinia pestis. This is yet another indication of the genomic similarity of all Yersinia pestis strains.

The Chinese group developed a two stage method of classification detailed enough for forensic work.  They took a twelve person outbreak of pneumonic plague contracted from a dog in 2009 in the Qinghai area of Tibet / western China, specifically at Xinghai as their test case (Wang et al, 2010). In the first step they took six cases including the two dogs who died in the outbreak and compared them to 24 strains representing the 23 phylogroups of the phylogenetic tree. This comparison selected which branch of the phylogenetic tree the outbreak belonged. There were no SNP (single nucleotide polymorphisms) different between the seven isolates confirming a common source, one of the dogs based on outbreak narratives. The seven isolates were all the same strain belonging to branch 1.IN2 of the tree. The second step was to then compare the isolates to all known strains of 1.IN2 shown below. Since these strains all come from the Qinghai-Tibetan plateau, they were able to add other strains historically isolated from this region.

Distribution of 1.IN in Qinghai  (site source)
Distribution of 1.IN2 in Qinghai (Yan et al, 2014, click to enlarge)

The results localized the new isolates (r) as being from the same focus as strains g, r, s, t. u plus, interestingly, the 0.PE7 strain (green b) that is over 300 SNPs different from the 1.IN2 strains. All of these other strains from this branch are scattered around the Qinghai region near Lake Qinghai. The polysomy (branch point) that produced all of the 1.IN2 in Xinghai (g,r,s,t,u) is located closer to the eastern end of Lake Qinghai, where the Chinese team hypothesizes this these strains began. The new outbreak isolates did not match any previous isolates from Xinghai which is testimony to the degree of movement of these strains around the region. Without the case narrative, they would not have been able to identify the specific foci at Xinghai, but would have got it to the region of east Qinghai lake. This illustrates how important sampling all of these foci are because a biological attack is likely to be far from its site of environmental isolation. Characterization of all laboratory strains, obviously, needs to happen as well for forensic tracing.

Reconstructing the historical epidemiology of this region will be an area of continuing research. The location of 0.PE7, the most genetically ancestral strain ever found — the closest the common ancestor of all Yersinia pestis, plus the likelihood that the ‘big bang’ epidemic (or epizootic), that produced the third pandemic, represented by node 12, was also in this region. (Each of the nodes represents a bang of evolutionary diversity, with all major branch points in the lineage probably representing large epidemics or epizootics.) The full diversity of strains in this region (unrelated to the outbreak isolates) are not shown in the figure above. This same group lead by Ruifu Yang  produced the primary phylogenetic tree of Yersinia pestis in China that noted that the molecular clock is not constant (Cui et al, 2012), here calculates that N12 is about 212 years old (95% confidence being 116 to 336 years ago) (Yan et al, 2014).  They note that in the history of Qinghai, there was a major human outbreak in the year 1754 CE linked to a Buddhist missionary working in Qinghai and Gansu provinces (Yan et al, 2014). Its is unclear if we can trust this narrative at all; scapegoats are common in plague narratives. Linking the 1.IN2 strains from Qinghai to four of the five o.IN2 isolates from Tibet suggest that the epidemic moved from Qinghai to Tibet in one ancient epidemic, though remaining isolate from Tibet looks like a more recent transmission from Qinghai. Regardless of the movements of 1.IN2, this area is believed to have been a site of long-term survival of Yersinia pestis, potentially over a thousand years, so that it has a lot to teach us about enduring foci.

Microbial forensics has already been used in criminal investigations, court cases and intelligence operations, such as the ‘Amerithrax’ (anthrax) attacks of 2001, anthrax spores sprayed over Japan by a cult, and suspicious plague cases in New York City (Yan et al, 2014). Phylogenetic microbial forensics was successfully used to show the intentional transmission of HIV from Dr Richard Schmidt to his girlfriend in his 1998 trial. This was the first successful use of microbial forensics in a court case (Koblentz & Tucker, 2010). In these cases, isolates are taken from the accused, the victim, other sexual partners, and the local population so show phylogenetic linkage between the accused and victim in the context of the local epidemiology.  The United States, United Kingdom, Sweden, the Netherlands, Japan, Canada, Germany, Australia, Singapore, and now China are involved in the development of microbial forensics (Koblentz & Tucker, 2010; Yan et al, 2014).

Reference

Koblentz, G. D., & Tucker, J. B. (2010). Tracing an Attack: The Promise and Pitfalls of Microbial Forensics. Survival, 52(1), 159–186. doi:10.1080/00396331003612521

Yan Y, Wang H, Li D, Yang X, Wang Z, et al. (2014) Two-Step Source Tracing Strategy of Yersinia pestis and Its Historical Epidemiology in a Specific Region. PLoS ONE 9(1): e85374. doi:10.1371/journal.pone.0085374

Wang, H., Cui, Y., Wang, Z., Wang, X., Guo, Z., Yan, Y., et al. (2010). A Dog-Associated Primary Pneumonic Plague in Qinghai Province, China. Clinical Infectious Diseases, 52(2), 185–190. doi:10.1093/cid/ciq107

Cui, Y., Yu, C., Yan, Y., Li, D., Li, Y., Jombart, T., et al. (2012). Historical variations in mutation rate in an epidemic pathogen, Yersinia pestis. Proceedings of the National Academy of Sciences, 110(2), 577–582. doi:10.1073/pnas.1205750110/-/DCSupplemental/sd01.xls

Antibiotic Resistance, Agriculture, and the Plague

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Antibiotics have ended the uncontrollable outbreaks of plague in humans that stalked our ancestors. Today, outbreaks are usually snuffed out after a couple of cases with antibiotic treatment of patients, prophylactic treatment of contacts and vector control. Our greatest risks from plague today are a pneumonic plague outbreak/attack and the emergence of antibiotic resistance.

Beginning in 1995 several antibiotic resistant strains of Yersinia pestis emerged in Madagascar. Two strains isolated from different districts of Madagascar in 1995 were resistant to multiple antibiotics (1). Genetic analysis shows that not only are the resistance plasmids of different derivation but the ribotypes of the Yersina pestis are also different. There is no discernible connection between the development of these two strains. Strain 17/95 is resistant to multiple drugs including all of the antibiotics used to treat plague and for prophylaxis (1). The second strain isolated that year, strain 16/95, is resistant to Streptomycin the primary drug of choice but vulnerable to other drugs commonly used to treat plague. From 1996 to 1998, several more Y. pestis strains each resistant to a single antibiotic were also isolated in Madagascar in humans, rats and fleas (1).

Like the majority of microbes with antibiotic resistance, Y. pestis gained these plasmids by conjugation, a type of lateral gene transfer.  Experiments have shown that Y. pestis readily exchanges antibiotic resistance plasmids with E. coli and other species in the flea gut (1). This is believed to be the primary site where Y. pestis interacts with other plasmid bearing bacterial species. The plasmid isolated from Strain 17/95 (IP275) in 1995 has been identified as “nearly identical” to multi-drug resistant (MDR) plasmids isolated from Salmonella enterica (ser. Newport) and Yersinia ruckeri, a fish pathogen and with a similar core to MDR plasmids found in E. coli, Klebsiella species, and multiple serotypes of Salmonella isolated from agricultural products (2). These plasmids have a common plasmid backbone categorized as IncA/C.

Past interaction between Salmonella enterica and Yersinia pestis has been known for a long time. The Yersinia pestis plasmid pFra is 97% identical to the exclusively human pathogen Salmonella enterica ser. typhi’s cryptic pHMC2 plasmid (2). The pFra plasmid contains the F1 capsule protein and the murine toxin, important virulence factors. The location of transfer between Yersinia pestis and the human only Salmonella enterica ser. typhi has not been determined (2, 4).

Antibiotic resistant plasmids linked to IP275 have been found in many agricultural products — in livestock, grocery stores, and ill humans (2). It is not hard to imagine flea mediated transfer of an antibiotic resistant pathogen from livestock to rats and Yersinia pestis picking up the resistance plasmid where-ever co-infection is occurring.  Antibiotic resistance in livestock enteric pathogens must now be considered a risk for not only Y. pestis but also other similar zoonotic pathogens (2). Rats feeding on livestock feed containing antibiotics would set up a situation that favors the retention of the antibiotic resistance plasmids.

In an effort to see how wide-spread the problem is, an antibiotic resistance survey was conducted on 392 isolates Y. pestis from 17 countries (3). The survey was conducted for all eight antimicrobials commonly used for treatment or prophylaxis. The good news is that they found no resistance in human, animal or flea isolates (3). However, the survey was not as wide-spread as it sounds on the surface. The United States, Uganda and Madagascar contributed 84% of the 229 human cases, and the United States alone contributed 81.7% of animal cases and 92% of the flea isolates (3).  Known antibiotic resistant Y. pestis strains could not be included due to restricted access (3). Isolates from central Asia are meager: four each from China and India, three from Nepal, one from Iran, and eight from Kazakhstan; most collected in the 1960s or earlier (3).  Of the 229 human cases, 32 died and 10 of these had been treated with antibiotics that the strains were shown to be susceptible (3). This gives a 14% fatality rate overall with approximately a third of the deaths occurring despite antibiotic treatment. These survey results make it all the more important that we understand what happened in Madagascar in the 1990s.

Surveillance for antibiotic resistance should now be standard on all Y. pestis isolates.  Once we could begin with the belief that antibiotic resistant plague was an act of biological warfare but no longer. Active monitoring is, as always, the key, now with special attention to areas where livestock and plague foci overlap.

 

References

  1. Galimand, M. ,  Carniel, E.  and Courvalin, P. Resistance of Yersinia pestis to Antimicrobial Agents. Antimicrob. Agents Chemother. 2006, 50(10):3233. DOI:10.1128/AAC.00306-06 [Mini-review]
  2. Welch TJ, Fricke WF, McDermott PF, White DG, Rosso ML, Rasko DA, Mammel MK, Eppinger M, Rosovitz MJ, Wagner D, Rahalison L, Leclerc JE, Hinshaw JM, Lindler LE, Cebula TA, Carniel E, & Ravel J (2007). Multiple antimicrobial resistance in plague: an emerging public health risk. PloS one, 2 (3) PMID: 17375195
  3. Urich SK, Chalcraft L, Schriefer ME, Yockey BM, & Petersen JM (2012). Lack of antimicrobial resistance in Yersinia pestis isolates from 17 countries in the Americas, Africa, and Asia. Antimicrobial agents and chemotherapy, 56 (1), 555-8 PMID: 22024826
  4. Prentice MB, James KD, Parkhill J, Baker SG, Stevens K, Simmonds MN, Mungall KL, Churcher C, Oyston PC, Titball RW, Wren BW, Wain J, Pickard D, Hien TT, Farrar JJ, & Dougan G (2001). Yersinia pestis pFra shows biovar-specific differences and recent common ancestry with a Salmonella enterica serovar Typhi plasmid. Journal of bacteriology, 183 (8), 2586-94 PMID: 11274119