Category Archives: Asia

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:
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

Multi-Drug Resistant Tuberculosis in Former Soviet States

It has been known for some time that the former Soviet Union had a huge tuberculosis problem. The problem was so big that no one really knew how bad it was in the Soviet Union or is now in its successor states. Over the last couple months, three reports have appeared in Euro Surveillance  and Emerging Infectious Diseases that begin to quantitate the problem.

In  the first report, France sent out a warning to states accepting immigrants from the former Soviet Union. Over the last two complete years 2010 and 2011, France has experienced a surge in multi-drug resistant (MDR) tuberculosis.

MDR-TB in France 2006-2012 [1]
MDR-TB in France 2006-2012 [1]
XDR-TB by country of birth in France 2006-2012
XDR-TB in France 2006-2012 [1]
 When they examined the country of birth for these cases, almost all of the surge came from countries of the former Soviet Union (fig. 1) [1]. When they looked for more regionalism, they discovered that the majority of the increase came from the country of Georgia and the Russian Federation.[1] For the more worrisome extensively drug resistant (XDR) tuberculosis, the vast majority of the French cases have come from the former Soviet Union going back to 2008; 14 of 17 cases in 2012 came from Georgia (fig. 3) [1]. Genetic analysis of the MDR-TB and XDR-TB strains in France showed variation indicating that transmission did not occur in France but was brought into France by immigration [1].

A survey of MDR-TB in Uzbekistan yielded even more grim results. In the first national TB survey, 23% of all newly diagnosed cased of TB and 62% of previously treated cases were resistant to at least two antibiotics; only 3.8% of MDR-TB cases were co-infected with HIV [2].  The XDR-TB rate was 5.3% with no HIV co-infections [2].  Demographics analysis yielded three primary risk factors or groups: adults under age 45, institutionalization in prisons or previous anti-TB treatment centers, and not owning their own home [2].

The news out of Siberia is no better. A survey published last month showed MDR-TB rates in Siberia are over 25% of primary TB cases with a a mean age of 33 [3]. The two regions, Irkutsk and Yakutia had strains of different origins. The Irkutsk MDR-TB were primarily a common Beijing lineage. On the other hand, the more isolated community of Yakutia had the MDR-TB S256 strain that has been linked with a strain only found among Canadian aboriginal population [3]. The linkage between these the Siberian and Canadian strains have not yet been fully investigated. While these strains are related they are not identical so it is possible that these are a previously undetected ancient lineage that has developed antibiotic resistance in Russia. This was the first isolation of this strain in Russia. The Siberian strains had uncommon mutations in the resistance genes that would not have been picked up well by commercial tests. Zhdanova and co-authors stress the importance of investigating regional strains and developing tests that will adequately detect local strains.

MDR-TB rates from the former Soviet Union are higher than anywhere else in the world [5]. These surveys show that it is even worse than the WHO estimated in 2010. It is far worse than any survey coming out of South Africa, a country often mentioned as being a particular concern for MDR-TB. For comparison, the MDR-TB rate for the United States in 2011 was 1% for MDR-TB and far less than 1% for XDR-TB [4].  Given the vast size and population of the former Soviet Union, migration out of former Soviet states could jump-start a new white plague, strains of TB that even the best medical care will have difficulty keeping under control.

References:

  1. Bernard, C., Brossier, F., Sougakoff, W., Veziris, N., Frechet-Jachym, M., Metivier, N., et al. (2013). A surge of MDR and XDR tuberculosis in France among patients born in the Former Soviet Union. Euro Surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin, 18(33).
  2. Ulmasova, D. J., Uzakova, G., Tillyashayhov, M. N., Turaev, L., van Gemert, W., Hoffmann, H., et al. (2013). Multidrug-resistant tuberculosis in Uzbekistan: results of a nationwide survey, 2010 to 2011. Euro Surveilliance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin, 18(42).
  3. Zhdanova, S., Heysell, S. K., Ogarkov, O., Boyarinova, G., Alexeeva, G., Pholwat, S., et al. (2013). Primary Multidrug-Resistant Mycobacterium tuberculosis in 2 Regions, Eastern Siberia, Russian Federation. Emerging Infectious Diseases, 19(10), 1649–1652. doi:10.3201/eid1910.121108
  4. Centers for Disease Control and Prevention. (2013). Antibiotic Resistance Threats in the United States, 2013 (pp. 1–114). Department of Health and Human Services.
  5. World Health Organization. (2010)  Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 Global Report on Surveillance and Response.   http://whqlibdoc.who.int/publications/2010/9789241599191_eng.pdf

Western Iranian Plague Foci Still Active, 2011-2012

In a letter in this month’s Emerging Infectious Diseases, an Iranian and French team of epidemiologists report that the old plague focus in western Iran bordering Kurdistan is still active. Between 1947 and 1966 there were nine human plague epidemics causing 156 human deaths.  The last recorded human case occurred in 1966 and in animals in 1978. No surveys for plague were conducted for the following 30 years. It is unlikely to be a coincidence that the Iranian Revolution also began in 1978.

During the summers of 2011 and 2012, the team captured and tested for the plague F1 antibody 98 rodents and counted their fleas, finding only one rodent with antibodies (1.08%). They also tested 117 sheepdogs finding 4 positive dogs or 3.42%.  In dogs, plague antibodies only last about six months suggesting that these sheepdogs must have had recent infections.  This is enough to suggest that the plague foci is still present in western Iran. Moreover, they believe the number of reservoir rodents and fleas per rodent (Xenopsylla species index 4.10) is “most favorable” circumstances for an epizootic. With plague antibodies found in the only area surveyed in 30 years, it is clear that surveillance needs to not only continue but expand extensively.

Reference:

Esamaeili S, Azadmanesh K, Naddaf SR, Rajerison M, Carniel E, & Mostafavi E (2013). Serologic survey of plague in animals, Western Iran. Emerging infectious diseases, 19 (9) PMID: 23968721