Category Archives: public health

Plasmodium knowlesi: A New Ancient Malaria Parasite

There are over a hundred different species of the malaria-causing Plasmodium parasites in reptiles, birds and mammals. Being so widespread among terrestrial vertebrates, zoonotic transfer of Plasmodium has come at humans from multiple different sources. Plasmodium knowlesi had been known for some time as a parasite of long-tailed macaques but was not considered a significant human parasite until 2004 when a large number of human infections were identified in Borneo. Molecular analysis implies that Plasmodium knowlesi is as old as Plasmodium vivax and Plasmodium falciparum.

Cover image the phases of Plasmodium knowlesi from the April 2013 issue of Clinical Microbiology Reviews.

Diagnosis is complicated by the histological similarity between Plasmodium knowlesi and Plasmodium malariae. They can’t be distinguished in blood smears like those shown here, so infections were most often misdiagnosed as P. malariae even though they cause a quotidian (daily) fever. The WHO recommends that microscopic detection in areas where P. knowlesi is found report positive results as “P. malariae/P. knowlesi”.  It can only be securely diagnosed by molecular methods  that can distinguish all five human malarial species. PCR based detection methods have shown promise but no one method has been clinically tested with a large enough number of cases to become the standard of care. Antibody-based Rapid Diagnostic Tests (RDT dipstick tests) for malaria do not reliably detect knowlesi malaria which was discovered in humans after the RDT tests were developed. For now in resource poor areas, microscopic analysis followed by molecular testing where available is the only way to detect knowlesi malaria. Clinical research continues for a RDT test that can be employed areas with poor laboratory resources.

Infections have now been confirmed in all of the countries of southeast Asia. Between 2000 and 2011, 881 cases of local P. knowlesi local transmission have been identified in Borneo, with only 8 cases of P. malariae.  It is now suspected that past diagnoses of P. malariae in the region were actually P. knowlesi. Unlike other forms of malaria, P. knowlesi infects more adults than children, although actual infection rates are still not known.

Long-tailed and pig-tailed macaques are the reservoirs for P. knowlesi. In some areas of Malaysia the macaques are around 90% seropositive for malaria, in one study 87% were P. knowlesi. The malaria vector for P. knowlesi and other malarial parasites is Anopheles leucosphyrus group which is also concentrated in southeastern Asia.  Anopheles balabacensis is the most efficient vector, capable of transmitting P. knowlesi from monkey-to-human, human-to-human and human-to-monkey. A. latens, on the other hand, has been most commonly indicated as the vector to humans in Borneo, where it feeds in the high elevation canopy.  As the map below shows, the macacque reservoir and the mosquito vectors are limited to  the islands and peninsulas south-east Asia. It has been hypothesized, based on genetic diversity, that P. knowlesi has caused human malaria as long as  humans, macaques and the Anopheles vectors have all been on the islands of south-east Asia.

Source: Singh, B., & Daneshvar, C. (2013). Human Infections and Detection of Plasmodium knowlesi. Clinical Microbiology Reviews, 26(2), 165–184. doi:10.1128/CMR.00079-12

Difficulty in diagnosis has made it made it challenging to study the full spectrum of knowlesi malaria across the population. What studies have been done show that it produces a full spectrum of malarial disease from mild to fatal. Most cases reported to-date are in adult males, making an occupational exposure a significant possibility.

Symptoms are representative of other malarial infections: fever, chills and rigor, headache, along with a cough, abdominal pain and diarrhea. Gastrointestinal symptoms correlate with high levels of the parasite in the blood. Thrombocytopenia (low platelet counts) is the most common clinical finding and more severe than in either vivax or falciparum malaria, while anemia appears to be mild in knowlesi malaria. In the few pediatric cases that have been observed, they all responded to anti-malarial therapy. In the few cases of severe disease reported, abdominal symptoms have been so severe in some that malaria was not initially suspected. Acute Respiratory Distress Syndrome (ARDS) has been reported in about 50% of severe cases and acute renal failure in approximately 40%. There have not yet been enough confirmed cases of knowlesi malaria to accurately determine the case fatality rate. Although it appears to respond to a wide range of anti-malarial drugs, an optimized treatment based on a sufficient number of cases was not yet available in 2013.

The discovery of Plasmodium knowlesi in humans comes in the context of increasingly successful control of vivax and falciparum malaria in southeastern Asia. Some of the latest epidemiology from Malaysia suggest that 50-60% of the cases of malaria are now knowlesi. There are fears that knowlesi will jeopardize regional malaria elimination efforts. Is the rate really increasing or is it only apparent as levels of falciparum and vivax decrease? Does a real increase represent an opening niche for knowlesi as vivax and falciparum decrease? Only time and more data will answer our questions.

Primary Reference:

Singh, B., & Daneshvar, C. (2013). Human Infections and Detection of Plasmodium knowlesi. Clinical Microbiology Reviews, 26(2), 165–184. doi:10.1128/CMR.00079-12

For additional epidemiology from Malaysia:

Yusof, R., Lau, Y. L., Mahmud, R., Fong, M. Y., Jelip, J., Ngian, H. U., et al. (2014). High proportion of knowlesi malaria in recent malaria cases in Malaysia, Malaria Journal 13(1), 1–9. doi:10.1186/1475-2875-13-168

William, T., Jelip, J., Menon, J., Anderios, F., Mohammad, R., Mohammad, T. A. A., et al. (2014). Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi, Malaria Journal 13(1), 1–11. doi:10.1186/1475-2875-13-390

Syndemics and Historic Diseases

I’ve been looking for a model or framework to bring together interdisciplinary evidence on diseases of the past. There are a variety of disciplinary approaches but few that can readily incorporate very different types of evidence well.

Apart from past discussions of discrete co-morbidities, the most common framework for understanding historic disease ecology has been pathocoenosis or ‘disease pools’ originated by M. D. Grmek in 1969 and popularized as ‘disease pools’ through McNeill’s Plagues and Peoples (1976). While this concept has proven popular among historians of medicine in high level overviews of human history, the concept begins to break down when practically applied to specific problems, as outlined by Robert Sallares (2004). It is hard enough to identify all of disease-causing microbes in a modern environment, much less a historic environment or population. It is often the minor or chronic disease-causing agents that make the most difference during a co-infection; malaria being a prime contender for the most important.  Pathocoenosis doesn’t adequately take into account the dynamic complexity of microbes in any population (however defined) and the idea that epidemics are disruptions in the equilibrium of pathogens in the population caused by new entrants to the population often doesn’t hold up.

Syndemics is a related concept emerging among biologists and medical anthropologists as a way to understand the diverse complex outcomes of diseases in populations. Syndemic comes from the terms synergistic and epidemic; it is a synergistic epidemic. A synergism exists when two conditions together produce a much greater effect than either individually added together ( ex. 1 +1 = 5 not 2).

A syndemic, in short, involves a set of enmeshed and mutually enhancing health problems that, working together in a context of deleterious social and physical conditions that increase vulnerability, significantly affect the overall disease status of a population (Singer, 2014).

The theory of syndemics is still evolving. The CDC’s definition refers specifically to two epidemics in the same population that produce a synergistic adverse outcome in human health. Consequently biology and medicine focus primarily on coinfections with an occasional look at nutrition. So far they are beginning to find some fascinating insights into how the immune system copes with two or more disease-causing microbes at once. We have to really take in that we are all coinfected all of the time. It comes down to if there is a significant interaction between multiple microbial species and the immune system. (It should be also said that coinfection can occasionally be protective as well.) Not surprisingly medical anthropologists insist on there always being a social component like malnutrition causing events, human behaviors like drug abuse and sexual practices,  or social disorder and inequality. So far from what I’ve read, these different focuses are complementing each other pretty well.

Some of the well-recognized syndemics include:

  • malaria + malnutrition
  • influenza + bacterial pneumonia
  • HIV + TB
  • HIV + HCV
  • HIV + HCV + IV drug use
  • Lyme disease + other Tick Borne Diseases
  • malnutrition + war (social disruption) + infectious disease (mostly diarrhea)

HIV has had a critical role in recognizing syndemics. Not unexpectedly, HIV coinfection with multiple organisms causes recognized synergetically worse outcomes. In many parts of the world, liver disease is a leading cause of HIV+ patient deaths due to Hepatitis C (HCV). It has also highlighted social conditions and behaviors that increase risk and vulnerability. The massive size, duration and amount of research done on AIDS is what has really allowed syndemic theory to become established.

Syndemics is just beginning to look at zoonotic disease but the future is already promising. As has already been suggested by work on pathocoenosis, malaria is a leading candidate to understand the syndemics of zoonoses. Syndemic effects have been suggested for malaria plus malnutrition, HIV and influenza.  Patients with long-term and serious health outcomes from Lyme disease are often coinfected with other less common tick born infectious diseases that are often undiagnosed (Singer & Bulled, 2014).

From what I have read so far, syndemics appears to take the best parts of the pathocoenosis paradigm, while jettisoning the unsupportable, over-reaching baggage. As we can already see for HIV and malaria, the syndemics approach has the potential to build up a foundation to understand the multifaceted outcomes of disease causing agents in different environments and provide insights into how the human microbiome and immune system interact. While its not perfect and doesn’t incorporate all of the disciplines needed to understand historic disease, it may provide a basis to build upon.

References and further reading:

Sallares, R. (2005). Pathocoenoses ancient and modern. History and Philosophy of the Life Sciences, 27 (2): 201–220. [Malaria]

Singer, M. (2014). Pathogen-pathogen interaction.Virulence, 1(1), 10–18. doi:10.4161/viru.1.1.9933

Singer, M., & Clair, S. (2003). Syndemics and public health: reconceptualizing disease in bio-social context. Medical Anthropology Quarterly, 17(4), 423–441.

Rock, M., Buntain, B. J.,Hatfield, J. M., & HallgrImsson, B. (2009). Animal–human connections, “‘one health,’” and the syndemic approach to prevention. Social Science & Medicine (1982), 68(6), 991–995. doi:10.1016/j.socscimed.2008.12.047

Singer, M. C. (2009). Doorways in nature: Syndemics, zoonotics, and public health. A commentary on Rock, Buntain, Hatfield & Hallgrı ́msson. Social Science & Medicine (1982), 68(6), 996–999. doi:10.1016/j.socscimed.2008.12.041

Ostrach, B., & Singer, M. (2013). Syndemics of War: Malnutrition-Infectious Disease Interactions and the Unintended Health Consequences of International War Policies.  Annals of Anthropological Practice, 36(2), 257–273. doi:10.1111/napa.12003

Morano, J. P., Gibson, B. A., & Altice, F. L. (2013). The Burgeoning HIV/HCV Syndemic in the Urban Northeast: HCV, HIV, and HIV/HCV Coinfection in an Urban Setting. PLoS ONE, 8(5), e64321. doi:10.1371/journal.pone.0064321.t003

Kwan, C. K., & Ernst, J. D. (2011). HIV and Tuberculosis: a Deadly Human Syndemic. Clinical Microbiology Reviews, 24(2), 351–376. doi:10.1128/CMR.00042-10

Conant, K. L., Marinelli, A., & Kaleeba, J. A. R. (2013). Dangerous liaisons: molecular basis for a syndemic relationship between Kaposi’s sarcoma and P. falciparum malaria. Frontiers in Microbiology, 4(article 35), 1–14. doi:10.3389/fmicb.2013.00035/abstract

Faure, E. (2014). Malarial pathocoenosis: beneficial and deleterious interactions between malaria and other human diseases. Frontiers in Physiology, 5. doi:10.3389/fphys.2014.00441/abstract

Herring, D. Ann, & Sattenspiel, L. (2007). Social contexts, syndemics, and infectious disease in northern Aboriginal populations. American Journal of Human Biology, 19(2), 190–202. doi:10.1002/ajhb.20618   [1918 influenza]

Singer, M., & Bulled, N. (2014). Ectoparasitic Syndemics: Polymicrobial Tick-borne Disease Interactions in a Changing Anthropogenic Landscape.Medical Anthropology Quarterly, n/a–n/a. doi:10.1111/maq.12163

Plague in Surat: 20 Years Later

I can’t let 2014 pass in a few weeks without mentioning that this fall was the twentieth anniversary of the plague outbreak in Surat, India — a major turning point in modern plague history and in the development of the (re)emerging infectious disease paradigm.

In the final accounting, 53 people died of plague, mostly pneumonic, but there are over 5000 cases classified as suspected and at least half a million people fled across India. Compared to other pneumonic plague outbreaks in Africa within the last twenty years, the number of deaths was small and the mortality rate tiny (1% of suspected cases). The government response was not only woefully inadequate but also exacerbated the damage within India and scared the rest of the world.

The lessons learned from Surat are really what is important.

  • The need for a national database to keep track of seemingly isolated cases and the need for surveillance of rodents, even when there haven’t been any human cases in many years. Better surveillance established since 1994 has identified several more plague outbreaks in India and enough evidence of enduring plague foci in the country.
  • The need for transparency, willingness to accept foreign help and the futility of trying to hide the epidemic from the press.
  • The costs of unsupported allegations of biological warfare or terrorism are too high to make unless there is certainty. It ultimately does not deflect responsibility away from the government for the response. The political costs for governments who make official erroneous allegations are greater than accepting responsibility for the outbreak.

In this month’s issue of the Indian Journal of Microbiology, the full genomic sequence of Yersinia pestis collected at Surat in 1994 and at a 2002 outbreak in India was released. Four samples were sequenced and they are all four different strains. Unfortunately, they did not do a phylogenetic analysis to indicate where they fit on the Y. pestis tree.

Twenty years ago it was the double hit of plague in Surat in 1994 and the discovery of antibiotic resistant plague in Madagascar in 1995 that raised concern about re-emerging infection diseases. Antibiotic resistant strains of Yersinia pestis have continued to appear in Madagascar and now insecticide resistant fleas are a problem as well. While public health processes and surveillance are better than in 1994, there has been no improvement plague incidence or concerning resistant strains.

Ebola is currently extracting the toll that was feared of plague in Surat two decades ago. If Surat was the warning that acute pandemics are still possible, Ebola is showing how far we still have to go 20 years later. Both plague in Surat and Ebola in 2014 are also reminding us that knowing what to do to stop an epidemic is not enough, execution is everything.

Further reading on Surat:

Barrett, Ron. (2008) “The 1994 Plague in Western India: Human Ecology and the Risks of Misattribution” p. 49-71 in Terrorism, War, or Disease? Unraveling the Use of Biological Weapons. Edited by A.L. Clunan, P.B. Lavoy, and S. B. Martin. Stanford Security Studies. Stanford University Press. This is the best analysis of the Surat outbreak that I have found.

Ziegler, Michelle (2014) The Black Death and the Future of the Plague. The Medieval Globe, 1: 183-199 for an overview of plague since 1994.

Mahale, K. N., Paranjape, P. S., Marathe, N. P., Dhotre, D. P., Chowdhury, S., Shetty, S. A., et al. (2014). Draft Genome Sequences of Yersinia pestis Strains from the 1994 Plague Epidemic of Surat and 2002 Shimla Outbreak in India. Indian Journal of Microbiology, 54(4), 480–482. doi:10.1007/s12088-014-0475-7

For more on antibiotic resistant plague, see this past post and on the most recent reported pneumonic plague outbreak in Madagascar.