Will anti-malarial bednets for children in developing countries significantly decrease resilience against malaria? Is preventing infection really a better social solution than adaptable immune systems?

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Bednets

‘Will anti-malarial bednets for children in developing countries significantly decrease resilience against malaria? Is preventing infection really a better social solution than adaptable immune systems?‘

Short answer: Truly prodigious in its parasitic capabilities, with >100 malaria parasite species capable of infecting a stupendous range of animals from primates to rodents to birds, even lizards and snakes, malaria is estimated to have co-evolved with humans for ~half a million years, cutting a swath through human populations all through history (1).

Given this history, framing one approach (human-made interventions) versus another (natural anti-malaria immunity) fails to get to grips with how to manage such an ancient and wily parasite. It’s also important to keep in mind that natural resistance to malaria builds up over time after multiple infections.

Maternal malaria during any stage of pregnancy can and often does adversely impact the fetus and newborn while babies are disproportionately prone to malaria death. This is why a major focus of public health interventions is preventing malaria during pregnancy and in babies.

Insecticide-treated bed nets (ITNs) are deployed to break the malaria transmission cycle by not just preventing infection but also killing mosquitoes. ITN isn’t the only large scale public health intervention in malaria-endemic African countries, which are presently the principal site of malaria morbidity and mortality. Rather, it is part of a four-pronged approach with the other three being Artemisinin-based combination therapy (ACT), intermittent preventive treatment in pregnancy (IPTp) and indoor residual spraying (IRS).

Problem is a single class of insecticide (pyrethroids) is approved for ITN use while prohibitive cost of the other three classes of insecticide also restricts IRS to mainly pyrethroids. Such mono insecticide use has led to development of insecticide resistance in Anopheles mosquitoes, resistance that is being reported from more and more countries. It also appears to drive mosquito behavior modification, changing indoor feeding to outdoors.

Longer answer expands on the known pros & cons of ITNs.

Important to note that currently, Africa, specifically sub-Saharan Africa, remains the main redoubt for malaria morbidity and mortality (see below from 2). For this reason, sub-Saharan Africa is the epicenter of malaria control.

Insecticide-treated Bed Nets (ITNs): Pros

Cheap and durable, commercially manufactured ITNs are considered a cost-effective public health intervention capable of serving as both a physical barrier as well as a mosquito killer. The WHO recommends using long-lasting commercial ITNs where the insecticide is either coated around or even incorporated into the net fibers, allowing for the insecticide’s biological activity to withstand multiple washes (3). Obviously ITN are most effective in areas where the mosquitoes feed indoors and where maximal biting occurs at night.

ITN breaks the malaria transmission cycle by preventing both a malaria-laden mosquito from biting a malaria-free human host as well as a malaria-free mosquito from biting a malaria-infected human host. Studies in the 1980s showing pyrethroids being able to repel and kill mosquitoes even as they were safe for humans (4) opened the door for their widespread use.

For these reasons the WHO has recommended widespread ITN use across malaria-endemic regions since at least 2000 (5). Antenatal clinics made large numbers of ITNs available to pregnant women at greatly subsidized prices as part of mass distribution campaigns launched by the ministries of health in various malaria-endemic countries (6).

Starting in 2003, a stream of studies have reported ITNs being able to kill substantial numbers of anopheline mosquitoes and reduce malaria transmission (4, 7, 8, 9, 10). Given such results and the large scale push by both the WHO and various health ministries, the proportion of households owning at least one such bed net in sub-Saharan Africa increased dramatically in just a handful years (see below left from 11). However, such a bird’s eye analysis glosses over the extremely wide variation in ITN coverage between different countries and even regions within the same country (see below right from 11).

Insecticide-treated Bed Nets (ITNs): Cons

On its face, a commendable aim is being achieved through economical means within the reach of millions across malaria-endemic African countries. Problem is only one class of insecticide, the Pyrethroid – Wikipedia, has been approved for use in ITNs. TB and HIV have already shown time and again that monotherapy antimicrobial use is a gateway to drug resistance. Likewise, intense monotherapy with insecticide imposes strong selection pressure leading to mosquito insecticide resistance, which has skyrocketed in recent years (12, 13, 14, 15, 16, 17, see below from 11), the biggest danger stemming from reports of mosquito populations being found resistant to all four classes of insecticide currently available for mosquito control (18, 19).

The other three insecticide classes being prohibitively expensive (2, 20) renders them beyond reach of most individuals in malaria-endemic countries and indeed even beyond reach of local public health authorities.

In its 2015 report, the WHO notes that only 52 of 97 countries with ITN and IRS vector control programs reported insecticide resistance in 2014 (11). Many malaria-endemic countries failing to conduct routine malaria vector surveillance means insecticide resistance can be easily missed.

Insecticide resistance develops not abruptly but gradually over a number of years, and so can be and indeed is easily missed. This happened in Mexico where sentinel sites reported very low levels of resistance between 2000 and 2003 and yet recorded >80% resistance frequency by 2007, which is why some authors consider insecticide resistance entails a tipping point (see below from 20).

Research also shows mosquito behavior modification in response to ITNs, mosquitoes previously known to be indoor feeders showing up instead in outdoor feeding (21).

Given the high likelihood that monotherapy would lead to resistance, clearly, widespread deployment of pyrethroid-based ILNs was ill-conceived. Scrambling to push out new classes of insecticide is underway. Will it undo the damage already done remains an open question.

Bibliography

1. Amazon.com: Mosquito: The Story of Man’s Deadliest Foe (9780786886678): Andrew Spielman Sc.D., Michael D’Antonio: Books

2. World Health Organization. “Global plan for insecticide resistance management in malaria vectors.” (2012). http://apps.who.int/iris/bitstre…

3. Hamel, Mary J., and Umberto D’Alessandro. “Control of malaria during pregnancy: preventive strategies. Intermittent preventive treatment and insecticide-treated nets.” Encyclopedia of Malaria (2014): 1-10.

4. Lengeler, Christian. “Insecticide‐treated bed nets and curtains for preventing malaria.” The Cochrane Library (2004). https://pdfs.semanticscholar.org…

5. World Health Organization. “Achieving and maintaining universal coverage with long-lasting insecticidal nets for malaria control.” (2017). http://apps.who.int/iris/bitstre…

6. Bhatt, Samir, et al. “The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.” Nature 526.7572 (2015): 207. https://www.researchgate.net/pro…

7. Hawley, William A., et al. “Community-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western Kenya.” The American journal of tropical medicine and hygiene 68.4_suppl (2003): 121-127. http://citeseerx.ist.psu.edu/vie…

8. Feng, Gaoqian, et al. “Decreasing burden of malaria in pregnancy in Malawian women and its relationship to use of intermittent preventive therapy or bed nets.” PloS one 5.8 (2010): e12012. http://journals.plos.org/plosone…

9. Boudová, Sarah, et al. “The prevalence of malaria at first antenatal visit in Blantyre, Malawi declined following a universal bed net campaign.” Malaria journal 14.1 (2015): 422. https://malariajournal.biomedcen…

10. Escamilla, Veronica, et al. “Effects of community-level bed net coverage on malaria morbidity in Lilongwe, Malawi.” Malaria journal 16.1 (2017): 142. https://malariajournal.biomedcen…

11. World Health Organization. “World malaria report 2015.” (2015). http://apps.who.int/iris/bitstre…

12. Glunt, Katey D., et al. “Long-lasting insecticidal nets no longer effectively kill the highly resistant Anopheles funestus of southern Mozambique.” Malaria journal 14.1 (2015): 298. https://malariajournal.biomedcen…

13. Bass, Chris, and Christopher M. Jones. “Mosquitoes boost body armor to resist insecticide attack.” Proceedings of the National Academy of Sciences 113.33 (2016): 9145-9147. http://www.pnas.org/content/pnas…

14. Churcher, Thomas S., et al. “The impact of pyrethroid resistance on the efficacy and effectiveness of bednets for malaria control in Africa.” Elife 5 (2016). https://www.ncbi.nlm.nih.gov/pmc…

15. Glunt, Katey D., et al. “Empirical and theoretical investigation into the potential impacts of insecticide resistance on the effectiveness of insecticide‐treated bed nets.” Evolutionary Applications. http://onlinelibrary.wiley.com/d…

16. Alout, Haoues, et al. “Consequences of insecticide resistance on malaria transmission.” PLoS pathogens 13.9 (2017): e1006499. http://journals.plos.org/plospat…

17. Fouet, Caroline, Peter Atkinson, and Colince Kamdem. “Human Interventions: Driving Forces of Mosquito Evolution.” Trends in parasitology (2018).

18. Kisinza, William N., et al. “Multiple insecticide resistance in Anopheles gambiae from Tanzania: a major concern for malaria vector control.” Malaria journal 16.1 (2017): 439. https://malariajournal.biomedcen…

19. Ranson, Hilary, and Natalie Lissenden. “Insecticide resistance in African Anopheles mosquitoes: a worsening situation that needs urgent action to maintain malaria control.” Trends in parasitology 32.3 (2016): 187-196.

20. McCoy, Amanda, et al. “Towards an economics policy framework to combat malaria, in an era of insecticide resistance.” (2017). https://strathprints.strath.ac.u…

21. Russell, Tanya L., et al. “Increased proportions of outdoor feeding among residual malaria vector populations following increased use of insecticide-treated nets in rural Tanzania.” Malaria journal 10.1 (2011): 80. https://malariajournal.biomedcen…

https://www.quora.com/Will-anti-malarial-bednets-for-children-in-developing-countries-significantly-decrease-resilience-against-malaria-Is-preventing-infection-really-a-better-social-solution-than-adaptable-immune-systems/answer/Tirumalai-Kamala

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How does methylene blue’s mode of action differ from chloroquine in treating malaria?

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Methylene blue

‘How does methylene blue’s mode of action differ from chloroquine in treating malaria?‘

References the news article, https://newatlas.com/methylene-blue-dye-malaria/53280/?utm_source=quora&utm_medium=referral

While Chloroquine is chemically derived from Methylene Blue (1, see below from 2), their anti-malarial actions appear to be quite different.

This answer briefly outlines

• What’s currently known (circa 2018) of the mechanisms of action (MOA) of Chloroquine and Methylene Blue.
• Shared history of Chloroquine and Methylene Blue, the latter a precursor to the former.

Chloroquine & Methylene Blue: Brief Look at What’s Known About How They Work

Chloroquine targets the asexual erythrocyte stages of the malaria parasite while latest studies suggest Methylene Blue is very effective against its post-erythrocytic sexual gametocyte stages (see below from 3).

In its human host’s red blood cells, the malaria parasite’s asexual stages (ring, trophozoite, schizont) stages survive by using essential amino acids released from degrading hemoglobin. To tap its essential nutrients, malaria trophozoites take in large amounts of hemoglobin into their digestion vacuoles when they are cycling through the red blood cell phase (intraerythrocytic cycle). Parasite hemoglobin degradation releases hematin (ferriprotoporphyrin), a heme byproduct found lethal to the parasites themselves, which they neutralize by biocrystallizing (polymerizing) heme into an insoluble polymer called hemozoin.

Chloroquine is a weak base and thus easily diffuses into lysosomes where it becomes protonated and is thus unable to diffuse out (4, 5, 6). Once inside malaria parasite lysosomes, Chloroquine is hypothesized to prevent parasite digestion of heme by inhibiting hemozoin biocrystallization by binding hematin gamma-oxodimers. This ends up killing the parasite (7, 8; also see below from 9).

OTOH, Methylene Blue‘s MOA isn’t yet as clearly outlined. Interest in the 1990s focused on its effect on malarial parasite’s Glutathione reductase – Wikipedia enzyme.

The tripeptide Glutathione – Wikipedia is a Thiol – Wikipedia that widely functions as a reducing agent in myriad cellular biochemical pathways. Studies suggest Glutathione can directly degrade hematin, which would help the malaria parasite and work against Chloroquine (10, 11).

Studies found Methylene Blue to apparently selectively block malarial, but not human, glutathione reductase (12, 13) when tested at therapeutic doses (14). Such Methylene Blue activity could even reverse Chloroquine resistance, a finding of undeniably important clinical relevance (15).

However, Methylene Blue‘s effect on malarial glutathione reductase alone couldn’t explain its anti-malarial effect since glutathione reductase knockout malaria parasites were found equally susceptible to it (16).

Recent reports showed Methylene Blue specifically targets all sexual gametocyte stages of malaria parasites both in vitro (17, 18) and in vivo (19, 20). Though how it does this isn’t yet clear, this opens the possibility of preventing transmission back to mosquitoes and thereby help break malaria’s life cycle (21, 22, 23).

Being cheap and easy to make at scale adds to Methylene Blue‘s value as an anti-malarial, especially in combination treatments which could overcome its ineffectiveness as a monotherapy as well as mitigate its side effects since lower doses would suffice.

Problem is Methylene Blue can be toxic to Glucose-6-phosphate dehydrogenase – Wikipedia (G6PD) deficient people by increasing hemolysis and triggering anemia (24), a problem exacerbated by malaria selection pressure that manifests as G6PD deficiency and leads to abnormal hemoglobins variably protected from malaria. Thus G6PD deficiency tends to be higher in malaria-endemic regions. Safety in G6PD-deficient patients needs to be established first. A Thai clinical trial funded by the University of Oxford studied this issue but hasn’t posted or published results from it yet (25).

Brief History Of Methylene Blue & Chloroquine

Methylene Blue is an aniline dye. It and others like it were 19th century synthetic products when scientists such as William Henry Perkin – Wikipedia ended up synthesizing dyes such as Mauve in their attempt to try to synthesize the antimalarial Quinine (1, 26) as an alternative to this ancient natural anti-malarial derived from the South American cinchona tree. Called by some ‘the unrivalled hero of 19th century chemical industry’, Heinrich Caro – Wikipedia synthesized Methylene Blue (27). The likes of Robert Koch and Paul Ehrlich then began using such dyes as biological stains.

• In 1887 Polish pathologist, Czesław Chęciński, first reported that a combination of eosin and Methylene Blue applied to blood smears specifically stained what we now know to be malaria parasites (28).
• In 1890, Dmitri Leonidovich Romanowsky – Wikipedia also published a study where he reported staining malaria parasites in blood smears using a mixture of eosin and Methylene Blue (27).
• Ehrlich took this further by hypothesizing that if Methylene Blue could selectively stain malaria parasites, maybe it could also be selectively toxic to it (9, 29)
• Indeed, Ehrlich reported successfully treating two malaria patients with Methylene Blue (28, 30).

Being a natural extract, Quinine was hobbled by limited supply so a synthetic alternative such as Methylene Blue was considered a boon. However, this perceived advantage proved short-lived, given its many more disadvantages,

• Not as effective as Quinine.
• Discolored skin, eyes, mucous membranes, urine.
• GI tract disturbances.

Following Ehlrich‘s anti-malaria research, many scientists at Bayer IG Farbenindustrie A.G. in Germany began synthesizing a wide variety of compounds. Some such as atabrine (quinacrine or Mepacrine – Wikipedia) had anti-malarial activity though it too stained skin and eyes.

Johann ‘Hans’ Andersag (Hans Andersag – Wikipedia) synthesized a 4-amino-quinoline in 1934 by replacing atabrine’s acridine ring with a quinoline (28). Called Resochin® for RESOrcinate of a 4-aminoCHINolin, IG Farben shelved it in 1935 as being slightly more toxic than atabrine after a test on just 4 neurosyphilis patients who were deliberately infected with malaria at a psychiatric clinic in Dusseldorf. Reoschin® thus languished for >10 years (28).

Licensed to the US Winthrop Chemical Company (6), Resochin®’s potent antimalarial properties were rediscovered by chance during WW II in a variation of the adage, ‘necessity is the mother of invention’. The Japanese invasion of Pearl Harbor blocked Allied access to Quinine. With Atabrine the only synthetic alternative, intense search for alternatives spurred the American Board for the Coordination of Malarial Studies (5) to screen some 16000 compounds, one being SN-7618 (SN=Survey Number). With trials that started in early 1944, by early 1946, tests on >5000 individuals clearly showed SN-7618 as far superior to atabrine. No coloring of skin nor eyes nor GI tract upsets. In November 1945 EK Marshall renamed it Chloroquine (31) and it soon made its way the world over as a pre-eminent anti-malarial and the rest is history.

Bibliography

1. Wainwright, Mark, Harald Mohr, and Wolfram H. Walker. “Phenothiazinium derivatives for pathogen inactivation in blood products.” Journal of Photochemistry and Photobiology B: Biology 86.1 (2007): 45-58. http://www.cytoluminator.com/can…

2. Wainwright, M. “The use of dyes in modern biomedicine.” Biotechnic & Histochemistry 78.3-4 (2003): 147-155.

3. Cowman, Alan F., and Brendan S. Crabb. “Invasion of red blood cells by malaria parasites.” Cell 124.4 (2006): 755-766. https://ac.els-cdn.com/S00928674…

4. Mackenzie, Allen H. “An appraisal of chloroquine.” Arthritis & Rheumatology 13.3 (1970): 280-291. An appraisal of chloroquine

5. Jensen, Markus, and Heinz Mehlhorn. “Seventy-five years of Resochin® in the fight against malaria.” Parasitology research 105.3 (2009): 609.

6. Baker, Nancy C., et al. “A bibliometric review of drug repurposing.” Drug discovery today (2018).

7. Hawley, Shaun R., et al. “Relationship between antimalarial drug activity, accumulation, and inhibition of heme polymerization in Plasmodium falciparum in vitro.” Antimicrobial agents and chemotherapy 42.3 (1998): 682-686. Relationship between Antimalarial Drug Activity, Accumulation, and Inhibition of Heme Polymerization in Plasmodium falciparum In Vitro

8. O’Neill, Paul M., et al. “4-Aminoquinolines—Past, present, and future; A chemical perspective.” Pharmacology & therapeutics 77.1 (1998): 29-58.

9. Schlitzer, Martin. “Malaria chemotherapeutics part I: History of antimalarial drug development, currently used therapeutics, and drugs in clinical development.” ChemMedChem 2.7 (2007): 944-986.

10. Ginsburg, Hagai, et al. “Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action.” Biochemical pharmacology 56.10 (1998): 1305-1313.

11. Famin, Oleg, Miriam Krugliak, and Hagai Ginsburg. “Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs.” Biochemical pharmacology 58.1 (1999): 59-68.

12. Schirmer, R. Heiner, et al. “Methylene blue as an antimalarial agent.” Redox report 8.5 (2003): 272-275. http://www.tandfonline.com/doi/p…

13. Sarma, G. N., et al. “Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development.” Journal of molecular biology 328.4 (2003): 893-907.

14. Färber, P. M., et al. “Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue.” FEBS letters 422.3 (1998): 311-314. http://onlinelibrary.wiley.com/d…

15. Meierjohann, Svenja, Rolf D. Walter, and Sylke Müller. “Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum.” Biochemical journal 368.3 (2002): 761-768. http://www.biochemj.org/content/…

16. Pastrana-Mena, Rebecca, et al. “Glutathione reductase-null malaria parasites have normal blood stage growth but arrest during development in the mosquito.” Journal of Biological Chemistry 285.35 (2010): 27045-27056. Glutathione Reductase-null Malaria Parasites Have Normal Blood Stage Growth but Arrest during Development in the Mosquito

17. Adjalley, Sophie H., et al. “Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue.” Proceedings of the National Academy of Sciences 108.47 (2011): E1214-E1223. http://www.pnas.org/content/pnas…

18. Lelièvre, Joël, et al. “Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence “transmission blocking” assay.” Malaria journal 11.1 (2012): P7. https://malariajournal.biomedcen…

19. Coulibaly, Boubacar, et al. “Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomised controlled trial.” PloS one 4.5 (2009): e5318. http://journals.plos.org/plosone…

20. Dicko, Alassane, et al. “Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial.” The Lancet infectious diseases (2018). http://www.thelancet.com/pdfs/jo…

21. Abdul-Ghani, Rashad, and John C. Beier. “Strategic use of antimalarial drugs that block falciparum malaria parasite transmission to mosquitoes to achieve local malaria elimination.” Parasitology research 113.10 (2014): 3535-3546. https://www.researchgate.net/pro…

22. Wadi, Ishan, et al. “Methylene blue induced morphological deformations in Plasmodium falciparum gametocytes: implications for transmission-blocking.” Malaria journal 17.1 (2018): 11. https://malariajournal.biomedcen…

23. Price, Ric N., and Nicholas J. White. “Drugs that reduce transmission of falciparum malaria.” The Lancet Infectious Diseases (2018). https://www.sciencedirect.com/sc…

24. Müller, Olaf, et al. “Haemolysis risk in methylene blue treatment of G6PD‐sufficient and G6PD‐deficient West‐African children with uncomplicated falciparum malaria: a synopsis of four RCTs.” Pharmacoepidemiology and drug safety 22.4 (2013): 376-385.

25. Pharmacokinetic and in Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD Normal and G6PD Deficiency – Full Text View – ClinicalTrials.gov

26. Oz, Murat, et al. “Cellular and molecular actions of Methylene Blue in the nervous system.” Medicinal research reviews 31.1 (2011): 93-117.

27. Cooksey, C. J. “Quirks of dye nomenclature. 8. Methylene blue, azure and violet.” Biotechnic & Histochemistry 92.5 (2017): 347-356.

28. Krafts, Kristine, Ernst Hempelmann, and Agnieszka Skórska-Stania. “From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy.” Parasitology research 111.1 (2012): 1-6.

29. Schirmer, R. Heiner, et al. “Lest we forget you—methylene blue….” Neurobiology of aging 32.12 (2011): 2325-e7. http://www.mpasmb-hamburg.mpg.de…

30. Teixeira, Cátia, et al. ““Recycling” classical drugs for malaria.” Chemical reviews 114.22 (2014): 11164-11220. https://repositorio-aberto.up.pt…

31. Coatney, G. Robert. “Pitfalls in a discovery: the chronicle of chloroquine.” The American journal of tropical medicine and hygiene 12.2 (1963): 121-128. https://www.astmh.org/ASTMH/medi…

https://www.quora.com/How-does-methylene-blue-s-mode-of-action-differ-from-chloroquine-in-treating-malaria/answer/Tirumalai-Kamala

How did scientists figure out the Plasmodium life cycle?

Not one or two but the efforts of many over centuries led to the deciphering of the Plasmodium life cycle. Malaria histories point to Giovanni Maria Lancisi – Wikipedia, Charles Louis Alphonse Laveran – Wikipedia, Vasily Danilewsky – Wikipedia, Patrick Manson – Wikipedia, Ronald Ross – Wikipedia, Amico Bignami – Wikipedia, Giuseppe Bastianelli – Wikipedia, Angelo Celli – Wikipedia, Raimondo Feletti – Wikipedia, Giovanni Battista Grassi – Wikipedia, Camillo Golgi – Wikipedia and Ettore Marchiafava – Wikipedia as the most notable of these scientists.

This answer summarizes key discoveries related to the Plasmodium life cycle,

• How focus shifted from bad air to mosquitoes.
• How the Malaria causing organism was identified to be a protozoan, not bacterium.
• How the protozoan parasite gets into human blood in the first place.
• The role of the insect vector, mosquito, in transmitting Malaria between people.

What causes Malaria, Bad Air or Animalcule – Wikipedia?

Combining two Latin words, mal (bad) and aria (air), and originally written as ‘mal’aria’, obviously Malaria was associated with marsh air so much so that simply breathing it was for long thought sufficient to cause the disease. Ague, Cattivara, Intermittent fever, Paludism, Periodic Fever, Swamp miasmata, the various names used through history to describe this disease thus allude to two of its cardinal features, fever and proximity to swamps.

While speculating on the connection between swamps and Malaria epidemics in his 1717 treatise, De Noxiis Palodum Effloriis (On the Noxious Emanations of Swamps), the 17th century Italian physician, Giovanni Maria Lancisi, theorized that swamps produced two types of emanations, animate and inanimate, both potentially capable of causing Malaria. Africans and Indians had long recognized the link between Malaria and mosquitoes (2). Lancisi thus theorized animate emanations were mosquitoes that could carry Malaria-causing animalcules (1). Did such animalcules actually exist?

Are there Malaria causing organisms, and if yes, what are they? Bacteria or Protozoa?

Long before the discovery of the Malaria parasite, Plasmodium, careful observers had already discerned something different about the blood and often also the spleen and liver of Malaria patients. Specifically, autopsies showed some type of heavy pigmentation in these cells and organs. For example, Professor Joseph Jones of the University of Louisiana testified in an 1876 court case that (see below from 2)

‘certain stains on the coat and shirt of an accused prisoner were not paint, as had been affirmed, but were the blood ‘of a human being who had suffered and was probably suffering at the moment when the blood was abstracted, with malaria or paroxysmal fever…many of the particles of melanic pigment were spherical, others irregular and angular, some entirely free, others encased in a hyaline mass’

Today we know this pigment to be Hemozoin – Wikipedia, a product of Malaria parasite metabolism inside red blood cells.

Having already observed such pigmented cells in the autopsied tissues of Malaria patients as well as in fresh blood drawn from those known to have the disease, Charles Louis Alphonse Laveran, a French army physician posted to Constantine, Algeria, in 1878, was already determined to in his own words ‘follow the pigment‘ (3). Looking for pigment in fresh Malaria patient blood with the additional advantage of using a microscope objective with a maximum magnification of 400X, Laveran meticulously examined blood smears of 200 patients, and found in 148 not just the characteristic pigment associated with Malaria blood but also crescent-shaped ‘spherical motionless bodies with pigment, spherical moving bodies with pigment and bodies that extruded flagella-like structures‘ (3), reporting his breakthrough on 6 November 1880 thus (see below from 2),

‘I had suspected for a long time the parasitic nature of these bodies when on November 6th, 1880, while examining one of the spherical pigmented elements in a preparation of fresh blood, I noticed with joy at the periphery motile filaments [probably exflagellation] of the animated nature of which there was no room for doubt’

Laveran obviously (see below from 1)

‘was astonished to observe, [in a soldier’s blood specimen] . . . a series of fine, transparent filaments that moved very actively and beyond question were alive’

Laveran‘s key findings were (3)

• Crescent-shaped bodies present in blood smears of 148 Malaria patients but never in those without Malaria, and
• That Quinine removed these stages from the blood.

Realizing he’d found a parasitic protozoan, Laveran called it Oscillaria malariae and presented his findings to the French Academy of Medical Sciences in December 1880 (4). Though Laveran did win the Nobel Prize in 1907 for identifying the Malaria parasite as a protozoan, his discovery was without precedent since no protozoan had ever been reported inside a human blood cell and thus his findings were initially greeted with skepticism. After all this was the heyday of the bacterium and scientific luminaries such as Robert Koch – Wikipedia and Louis Pasteur – Wikipedia ruled the roost with their discovery of important disease causing bacteria.

Even the eminence grise of physicians, William Osler – Wikipedia, was skeptical at first and only became convinced by looking at blood smears of Malaria patients himself over several weeks (see below from 2).

‘When I first read Laveran’s papers nothing excited my incredulity more than his description of the ciliated bodies. It seemed so improbable and so contrary to all past experience, that flagellate organisms should occur in the blood…The work of the past six months has taught me a lesson on the folly of skepticism based on theoretical conceptions, and of pre-conceived notions drawn on limited experience’

Unknown to Laveran, the Russian physiologist, Vasily Danilewsky, had already discovered a number of parasites in the blood of birds and reptiles (3). Calling them ‘pseudovacules’, by 1885, Danilewsky had identified Plasmodium – Wikipedia, https://en.wikipedia.org/wiki/Ha… and https://en.wikipedia.org/wiki/Le…. Since most of his work was published in Russian, only the French publication of his 3-volume book, La Parasitologie Comparée du Sang, in 1889, made his discoveries widely known.

How the protozoan Malaria parasites get into patients’ blood in the first place: Discovery of the insect-to-human cycle

Laveran‘s discovery connected Malaria to a microscopic protozoan organism. However, how did the protozoan parasite get into Malaria patients’ blood in the first place?

A key figure in parasitic diseases, Scottish parasitologist Patrick Manson was born in Aberdeenshire, Scotland, in 1844, and practiced medicine in Formosa (now Taiwan), where he saw many cases of https://en.wikipedia.org/wiki/Fi…. While on leave in London in 1874, Manson searched the medical literature and found several reports of microfilariae in blood of filarial patients. While wondering how such parasites could spread from one person to another, Manson hit upon the notion of a bloodsucking insect. Back in Formosa, Manson researched and cross-referenced the distribution of bloodsucking insects with filariasis cases. He found mosquitoes to be the best fit. Manson then tried to carefully reconstruct the human-to-insect transmission cycle. First, he fed mosquitoes on active filarial patients and then dissected the mosquitoes at varying lengths of time. This way Manson was able to

• Identify filariae in mosquito gut post-human feeding.
• Observe filarial development and migration into mosquito thoracic muscle where they continued growing.

However, Manson erred in his final conclusion, thinking infected mosquitoes returned to die in water and that humans got accidentally infected after drinking infected water. Shortly afterward, https://en.wikipedia.org/wiki/Jo… in Australia and https://en.wikipedia.org/wiki/Ge… in England (in Patrick Manson‘s lab) independently proved that infected mosquitoes transmitted filaria into humans when they bit them to take their blood meal.

Following in Manson’s footsteps, in the final decade of the 19th century, studies of various tropical diseases were leading scientists to a common notion, that of an insect-to-human cycle (1, 2).

• While local Texas ranchers had long believed ticks were somehow responsible for spreading Texas cattle fever, https://en.wikipedia.org/wiki/Th… and F.L. Kilbourne finally proved that the local ‘hard tick’, https://en.wikipedia.org/wiki/Rh…, transmitted the parasite, https://en.wikipedia.org/wiki/Ba….
• Working in then-Zululand, https://en.wikipedia.org/wiki/Da… showed that https://en.wikipedia.org/wiki/Ts… transmitted nagana or https://en.wikipedia.org/wiki/An…. However, Bruce made a mistake, correct about how insects became infected from taking blood meal on an infected person/animal but incorrect in being unable to decipher that infected insect biting uninfected host could transmit disease back.
• While the Cuban epidemiologist, https://en.wikipedia.org/wiki/Ca…, had suggested mosquitoes might spread https://en.wikipedia.org/wiki/Ye…, there was no proof yet. Already back in 1804, observing that doctors and nurses who cared for yellow fever patients seemed to not get the disease, https://en.wikipedia.org/wiki/St… had subjected himself to some remarkable self-experiments by exposing himself to the ‘hemorrhagic vomitus, other excretions, and blood of patients dying of yellow fever‘ (1). Unable to transmit infections through these methods, Ffirth had concluded that yellow fever was not directly transmitted from person to person. During the 1898 https://en.wikipedia.org/wiki/Sp…, a yellow fever commission led by https://en.wikipedia.org/wiki/Wa… was tasked to investigate. Using human volunteers, the commission found yellow fever could be transmitted to humans by Stegomyia fasciata (now called Aedes aegypti) mosquitoes, with one volunteer Jesse W. Lazear (1866-1900) succumbing to yellow fever from a mosquito bite (5).

Though never awarded the Nobel prize, Manson‘s groundbreaking insight has led to him being labeled the ‘father’ of tropical medicine. Most importantly, Manson‘s observations of Malaria patients in London had shown him that flagellated forms of the Malaria parasite only appeared after blood taken from Malaria patients cooled, i.e., at a temperature far below that of human body temperature. From this he concluded other stages of parasite development occurred outside the human body, perhaps in mosquitoes. Thus, by the time British medical doctor Ronald Ross entered the picture, the time was ripe for connecting all the dots in the Malaria transmission cycle.

Meantime, by 1884 Laveran had convinced the leading Italian malariologists Amico Bignami, Giuseppe Bastianelli, Angelo Celli, Giovanni Battista Grassi, Camillo Golgi, Ettore Marchiafava, as well as the ‘more cynical’ microbiologists Louis Pasteur, Charles Eouard Chamberland and Pierre Paul Emile Roux that Malaria was caused by a protozoan, not a bacterium (3). Only Robert Koch, perhaps the pre-eminent microbiologist of the time, still remained a holdout against the protozoa-Malaria idea.

Moving full speed ahead on their independent studies to decipher the role of mosquitoes in Malaria transmission set the British and Italians on a famous collision course where the rightful recognition for discovery became a casualty of politics.

Deciphering the role of the insect vector in Malaria transmission: Independent discovery by British and Italians

The British side of the Malaria story

Meeting Manson for the first time in 1894 when he was home in London on leave, Ross, then a low ranking physician in the Indian Medical Service, became his student. Convinced Malaria was spread by mosquitos and that India was the ideal place to finally crack the case, Manson taught Ross the basics, showing him human blood smears containing Malaria parasites.

With Manson supervising his studies long-distance, and heeding his dictate to ‘follow the flagellum‘ (3) over the next four years, Ross tried to connect the dots between Plasmodium, mosquitoes and Malaria. First, Ross fed different types of mosquitoes on Malaria patients. Ross had three different types of mosquitoes to choose from, common grey or barred-back, less common ‘brindled’, and much rarer ‘dappled-winged’ (3).

On two consecutive days in August 1897, Ross was fortunate to have supply of the rarer ‘mosquitoes whose wings were dappled and had four dark spots‘ (2). Today, we call such mosquitoes anopheline. After feeding such mosquitoes on a Malarial patient with crescent-shaped bodies in their red blood cells, Ross observed cysts growing on the mosquitoes’ stomachs, and that when these cysts ruptured, they released ‘rods’ that invaded the mosquitoes’ salivary glands. Indeed he found mosquito salivary glands to be packed with Plasmodium rods, a discovery he marked by calling August 20, 1897, ‘mosquito day’, a date that’s been commemorated as such ever since, https://en.wikipedia.org/wiki/Wo….

Unfortunately, before Ross could pursue the next logical step in the discovery process and experimentally show Malaria transmission from diseased to healthy people through the bite of Malaria-infected mosquito, he was transferred to Calcutta, a city with little human Malaria, to instead work on kala-azar, https://en.wikipedia.org/wiki/Vi…. Luckily, Manson had suggested to Ross the possibility of studying Malaria in birds as well. Thus, in Calcutta, Ross began work on Proteosoma relictum (now called Plasmodium relictum), a common Malaria parasite in crows and sparrows.

Here he found that rather than ‘dappled-winged’, the more common ‘grey’ (now called culicine) mosquitoes did the trick. Specifically, he found that 178 of 242 ‘grey’ mosquitoes fed on infected birds developed ‘pigmented spores’ (3). Ross was then able to follow all of the parasite’s developmental steps within the mosquito, from exflagellation and fertilization in its gut to oocyst formation and sporogony to final migration of sporozoites in its salivary glands (2). The final proof came when Ross could infect healthy sparrows by inoculating them with sporozoites isolated from experimentally infected mosquitoes.

Writing to Manson on July 6, 1898, Ross memorialized his discovery thus (see below from 1, emphasis mine),

‘I think that this, after further elaboration, will close at least one cycle of proteosoma, and I feel that I am almost entitled to lay down the law by direct observation and tracking the parasite step by step—Malaria is conveyed from a diseased person or bird to a healthy one by the proper species of mosquito and is inoculated by its bite. Remember, however, that there is virtue in the “almost.” I don’t announce the law yet. Even when the microscope has done its utmost, healthy birds must be infected with all due precaution. . . . In all probability it is these glands which secrete the stinging fluid which the mosquito injects into the bite. The germinal rods . . . pass into the ducts . . . and are thus poured out in vast numbers under the skin of the man or bird. Arrived there, numbers of them are probably instantly swept away by the circulation of the blood, in which they immediately begin to develop into malaria parasites, thus completing the cycle. No time to write more’

Manson presented these results to the British Medical Association in Edinburgh in July 1898 (1).

The Italian side of the Malaria story

In the 1890s, Italian scientists such as Bastianelli, Bignami, Golgi, Marchiafeva reported how the protozoan parasite invaded blood cells, grew within them, and produced daughter cells that invaded other blood cells (3). By 1898, Bignami and Grassi had access to Malaria sites in Rome and Siciliy. Over the next two years, the Italians methodically filled in the blanks (6, 7),

• Showed only female Anopheles mosquitoes could transmit Malaria.
• Described the entire lifecycle of Plasmodium vivax, P. falciparum and P. malariae. Feeding local Anopheles claviger mosquitoes on infected patients transmitted infection to uninfected individuals via the bite of such infected mosquitoes.
• In a classic experiment, Grassi sent 112 volunteers to a malarious region in the Capaccio Plains, protecting them from mosquito bites between dusk and dawn. Only 5 of these volunteers succumbed to Malaria compared to 415 unprotected volunteers, all of whom contracted it.

Thus, by 1898, Grassi, Bastianelli and Bignami had not only resolved the entire life cycle of the human Malaria parasite, Plasmodium falciparum, but also demonstrated that Malaria could not exist without Anopheles mosquito. Yet, only Ross was awarded the Nobel Prize for this discovery in 1902. Why this discrepancy? Politics, which is never pure nor simple (Nobel Prize controversies – Wikipedia).

This is when Robert Koch enters the picture, ostensibly at the invitation of the Italian government to ‘solve the malaria problem‘ (8). Apparently this is when the Italians rushed to publish their results, with Grassi first publishing his initial report on the P. falciparum lifecycle in November 1898, citing Ross‘ work only at the very end, and then publishing a fuller report a month later not citing Ross at all (2). Thus ensued a battle royale between Ross and Grassi with Koch apparently eagerly adding the kindling. Rich irony there that of all the world famous microbiologists of his time, Koch was perhaps the last to begrudgingly acknowledge only by 1887 that Malaria was caused not by a bacterium but by a protozoan. When the committee considered splitting the 1902 Nobel Prize between Ross and Grassi, it was apparently Koch‘s vehement opposition that led to the prize going to Ross alone (1), more proof, not that we need more, that human society rewards aren’t merit-based as a matter of course, even though we or at least some of us fervently wish they were.

Bibliography

1. Nelson, Kenrad E., et al. “Infectious disease epidemiology theory & practice.” (2001): 205.

2. Esch, Gerald. Parasites and Infectious disease: discovery by serendipity and otherwise. Cambridge University Press, 2007.

3. Cox, Francis EG. “History of the discovery of the malaria parasites and their vectors.” Parasites & vectors 3.1 (2010): 5. https://parasitesandvectors.biom…

4. Laveran, Alphonse. Un nouveau parasite trouvé dans le sang des malades atteints de fièvre palustre: origine parasitaire des accidents de l’impaludisme. 1881.

5. Reed, Walter, and James Carroll. “The prevention of yellow fever.” Public health papers and reports 27 (1901): 113. https://www.ncbi.nlm.nih.gov/pmc…

6. Grassi, Battista, Amico Bignami, and Giuseppe Bastianelli. Ulteriori ricerche sul ciclo dei parassiti malarici umani nel corpo del zanzarone. tip. della R. Accademia dei Lincei, 1898.

7. Grassi, Giovanni Battista. Studio di uno zoologo sulla malaria. Vol. 3. R. Accademia dei lincei, 1900.

8. Harrison, Gordon. “Mosquitoes, malaria and man: a history of the hostilities since 1880.” Mosquitoes, malaria and man: a history of the hostilities since 1880. (1978).

https://www.quora.com/How-did-scientists-figure-out-the-Plasmodium-life-cycle/answer/Tirumalai-Kamala

How did the Zika virus get to the US?

A Vector (epidemiology) – Wikipedia -borne disease spread by bites of infected Aedes – Wikipedia species, Zika’s recent trajectory suggests it was only a matter of time before it got to the US.

This is because

• Its most prominent vector, Aedes aegypti – Wikipedia, is widespread across the southern US (1).

• Locally infected mosquitoes sustain local Zika infection (see below from 2).

Little known for 60 years since its original isolation from a monkey in Zika forest in Uganda in 1947, < 20 human cases of Zika infection were confirmed over the next 60 years (3). However, a quick succession of outbreaks across Polynesia, first in Yap island in 2007 then in French Polynesia in 2013, suggested Zika had somehow quietly spread beyond Africa sometime during those decades. 2015-2016 outbreaks in Brazil and Colombia signaled it had spread to the Americas (see below from 2 and 4).

Keep in mind, Zika could keep coming to the US through other means as well. While it was primarily considered mosquito-borne, data from these successive large-scale outbreaks showed that it could also be transmitted sexually, vertically (from mother to fetus) and through blood (2). This means that some degree of local infection could be sustained by returning infected travelers as well. After all, sexual transmission was suspected in what was perhaps the very first documented case of Zika infection in mainland US all the way back in 2008, when a US researcher, infected while working in the field in Senegal, apparently infected his wife but not his children after he returned to the US (5).

Bibliography

1. http://www.usd338.com/vimages/sh…

2. Basu, Rupsa, and Ebenezer Tumban. “Zika Virus on a Spreading Spree: what we now know that was unknown in the 1950’s.” Virology journal 13.1 (2016): 165. https://virologyj.biomedcentral….

3. Musso, Didier, and Duane J. Gubler. “Zika virus.” Clinical microbiology reviews 29.3 (2016): 487-524. Zika Virus

4. Baud, David, et al. “An update on Zika virus infection.” The Lancet.

5. Foy, Brian D., et al. “Probable non–vector-borne transmission of Zika virus, Colorado, USA.” Emerging infectious diseases 17.5 (2011): 880. https://www.ncbi.nlm.nih.gov/pmc…

https://www.quora.com/How-did-the-Zika-virus-get-to-the-US/answer/Tirumalai-Kamala

Is there any evidence that the Zika virus hurts the brain development of infants or young children if they’re infected after they’re born?

Tags

Microcephaly

Most reported Zika-associated microcephaly cases are from intrauterine first trimester infection. Among perinatal, specifically third trimester and immediate post-birth, Zika cases, there are only a few case reports of brain development issues.

Reported Outcomes Of Perinatal Zika Infection

Though a mouse model of Zika infection (1), where embryos were infected in utero at embryonic age 14.5 days (mouse gestation is ~21 days), reported post-natal microcephaly, only a handful of human perinatally infected Zika-associated brain development or neurologic issues have been reported in the biomedical literature so far.

• Reported Brain And/Or Neurologic Abnormalities
  • Two infants with laboratory-confirmed Zika infection from third trimester exposure during the 2016-16 Brazil Zika outbreak showed not microcephaly but other brain abnormalities such as subependymal cysts in both and lenticulostriate vasculopathy in one (2).
  • Paraguay reported Guillain–Barré syndrome – Wikipedia in one child after post-natal Zika in 2016 (3).
• No Reported Brain And/Or Neurologic Abnormalities
  • Of two cases of perinatal Zika transmission from mothers infected close to delivery during the 2013-14 French Polynesia Zika outbreak, one infant remained asymptomatic while the other was diagnosed with Thrombocytopenia – Wikipedia and diffuse rash but not microcephaly (4).
  • A study (5) of 1501 live births of Zika-infected mothers during the 2015-16 Brazil Zika outbreak found first trimester infection to be most severely affected, based on head circumference z score.
  • Similarly, no apparent anomalies were reported (6) among children born to 1850 pregnant women in Colombia, >90% of them reportedly Zika infected during the third trimester.

Reported Outcomes Of Postnatal Zika Infection In Infants & Children

• The CDC collated and analyzed (7) previously published data (8, 9, 10, 11, 12, 13) on ten 3 to 16 year old Zika-infected children from Africa, Asia, South America and the Pacific. Though none of them developed rash, all had fever, 2 each had conjunctivitis, vomiting or diarrhea while 3 had joint pain (Arthralgia – Wikipedia). No microcephaly.
• All eight cases of travel-related Zika cases among American children as of February 2016 (7) had rash with at least one other symptom (fever, arthralgia, nonpurulent conjunctivitis). Again no microcephaly.
• The 2007 Yap Island, Micronesia Zika virus outbreak included several infants and children. While their symptoms were similar to those in adults, namely, fever, maculopapular rash, arthralgia, Conjunctivitis – Wikipedia, 0 to 19 year olds had fewer probable and confirmed cases of Zika compared to 20 to 59 year olds (14). No microcephaly.
• No single case of microcephaly reported to CDC from US states among 150 probable or confirmed Zika cases among children <18 years of age (15). Ranging from 1 month to 17 years in age with median age of 14 years, all infections were travel-associated.
  • 129 (82%) had rash.
  • 87 (55%) had fever.
  • 45 (29%) had conjunctivitis.
  • 44 (28%) had arthralgia.

Bibliography

1. Shao, Qiang, et al. “Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.” Development 143.22 (2016): 4127-4136.

2. de Souza, Antonio Soares, et al. “Fetal infection by Zika virus in the third trimester: report of 2 cases.” Clinical Infectious Diseases 63.12 (2016): 1622-1625.

3. Lovera, Dolores, et al. “Neurologic syndrome associated with Zika postnatal acquisition. With regard to the first case in Paraguay.” Revista del Instituto de Medicina Tropical 11.2 (2016): 36-41.

4. Besnard, M., et al. “Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014.” Euro surveill 19.13 (2014): 20751. http://www.eurosurveillance.org/…

5. França, Giovanny VA, et al. “Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation.” The Lancet 388.10047 (2016): 891-897. https://www.researchgate.net/pro…

6. Pacheco, Oscar, et al. “Zika virus disease in Colombia—preliminary report.” New England Journal of Medicine (2016). http://www.nejm.org/doi/pdf/10.1…

7. Fleming-Dutra, Katherine E. “Update: interim guidelines for health care providers caring for infants and children with possible Zika virus infection—United States, February 2016.” MMWR. Morbidity and mortality weekly report 65 (2016). https://www.cdc.gov/mmwr/volumes…

8. Macnamara, F. N. “Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria.” Transactions of the royal society of tropical medicine and hygiene 48.2 (1954): 139-145. http://icmr.nic.in/zika/publicat…

9. Olson, J. G., and T. G. Ksiazek. “Zika virus, a cause of fever in Central Java, Indonesia.” Transactions of the Royal Society of Tropical Medicine and Hygiene 75.3 (1981): 389-393. http://www.dtic.mil/cgi-bin/GetT…

10. Heang, Vireak. “Zika Virus Infection, Cambodia, 2010-Volume 18, Number 2—February 2012-Emerging Infectious Disease journal-CDC.” (2012). https://www.ncbi.nlm.nih.gov/pmc…

11. Alera, Maria Theresa, et al. “Zika virus infection, Philippines, 2012.” Emerging infectious diseases 21.4 (2015): 722. https://www.ncbi.nlm.nih.gov/pmc…

12. Dupont-Rouzeyrol, Myrielle. “Co-infection with Zika and Dengue Viruses in 2 Patients, New Caledonia, 2014-Volume 21, Number 2—February 2015-Emerging Infectious Disease journal-CDC.” (2015). https://www.researchgate.net/pro…

13. Arzuza-Ortega, Laura, et al. “Fatal sickle cell disease and Zika virus infection in girl from Colombia.” Emerging infectious diseases 22.5 (2016): 925. https://www.ncbi.nlm.nih.gov/pmc…

14. Duffy, Mark R., et al. “Zika virus outbreak on Yap Island, federated states of Micronesia.” N Engl J Med 2009.360 (2009): 2536-2543. http://www.nejm.org/doi/pdf/10.1…

15. Goodman, Alyson B. “Characteristics of Children Aged< 18 Years with Zika Virus Disease Acquired Postnatally—US States, January 2015–July 2016.” MMWR. Morbidity and Mortality Weekly Report 65 (2016). https://www.cdc.gov/mmwr/volumes…

https://www.quora.com/Is-there-any-evidence-that-the-Zika-virus-hurts-the-brain-development-of-infants-or-young-children-if-theyre-infected-after-theyre-born/answer/Tirumalai-Kamala

Should blood banks be testing for Zika?

Tags

Blood bank, Blood test, Blood transfusion

Recent data suggest blood transfusions could transmit Zika so yes, blood banks in Zika-endemic areas should test for it. The link between maternal Zika infection and baby microcephaly (1) and other serious birth defects (2) is now compelling. Were Zika-infected blood transfused to pregnant women, risk could be unacceptably high for fetuses.

Though Zika fever is a Vector (epidemiology) -borne disease spread by the bite of infected Aedes mosquitoes, a steady drumbeat of data shows it can also spread by other routes.

Zika persists in semen (3, 4), vaginal tract (5, 6) and in circulation of pregnant women (7) for surprisingly long periods of time, and can be transmitted sexually (8, 9, 10, 11). Since Zika’s asymptomatic in ~80% of those infected, Zika-infected blood transfusions could be a risk factor to fetuses not just if given to pregnant women but also if given to their sexual partners.

Preliminary data suggest blood transfusion could transmit Zika

• During the 2013-2014 French Polynesia Zika virus outbreak it was detected by Reverse transcription polymerase chain reaction (RT-PCR) in 42 of 1505 (2.8%) blood donors who were asymptomatic when they donated (12). 11 of these 14 reported having Zika fever-like syndrome about 3 to 10 days later.
• In the US territory of Puerto Rico, a total of 68 of 12777 (~0.5%) blood donations from April 3 to June 11, 2016 were identified as presumptive Zika viremic based on Nucleic acid test (NAT) with rates rising by ~2.2 over a 9 week period during the summer (see figure below from 13).

These studies revealed Zika’s potential for spreading through blood transfusion.

More recently, a couple of case reports suggest blood transfusions could indeed transmit Zika

• In Brazil (14), concentrated Platelet from the blood of an asymptomatic 54 year old man was transfused into a 55 year old liver cancer patient undergoing liver transplant.
  • Four days post-transplant, the transfused recipient was serum Zika virus positive by RT-PCR.
  • Suspicion fell on the platelet donor after he contacted the blood donor facility 3 days after his donation to report he’d just developed dengue-like symptoms. His stored serum sample was then tested and found positive not for Dengue but for Zika virus by RT-PCR.
  • Though source of recipient’s Zika could have been other transplant related tissues and blood products, sequence analysis of 10 partial nucleotide sequences of the Zika virus isolated from the donor compared with the complete genome sequence of that isolated from the recipient matched 99.8%, strongly suggesting Zika transmission through transfusion.
  • Recipient coming from a Zika non-epidemic area and being hospitalized in a mosquito-free area for 5 days before his Zika positive test further increased the likelihood he got Zika from his platelet transfusion.

• In Brazil again (15), an asymptomatic person donated platelets through Apheresis on January 16, 2016. These were transfused into two different patients on January 19.
  • On January 21, the donor called the blood bank to report Zika symptoms (skin rash, eye pain, pain in both knees) starting on January 18.
  • Donor samples before and after donation were negative for related Dengue virus and Chikungunya by RT-PCR. However, donor’s plasma and urine samples were Zika positive 14 days after initial blood donation.
  • Plasma samples from both recipients were Zika positive, 6 and 23 days post-transfusion, respectively.

Given the high risk of newborn microcephaly from maternal Zika infection, far better to err on the side of caution and start screening blood donations for Zika. This may be why on August 26, 2016, the US FDA (16, emphasis mine)

‘issued a revised guidance recommending universal testing of donated Whole Blood and blood components for Zika virus in the U.S. and its territories‘.

Based on the available evidence the FDA concluded (17)

‘ZIKV meets the conditions for an RTTI [relevant transfusion-transmitted infection ] as described in 21 CFR 630.3(h)(2)‘

Specifically (17, emphasis mine),

‘FDA has determined that ZIKV meets the criteria in 21 CFR 630.3(h)(2) for an RTTI because of the sufficient incidence and prevalence of ZIKV to affect the potential donor population in the United States and because of the availability of appropriate screening tests for ZIKV‘ .

Bibliography

1. Johansson, Michael A., et al. “Zika and the Risk of Microcephaly.” New England Journal of Medicine (2016). http://www.nejm.org/doi/pdf/10.1…

2. Rasmussen, Sonja A., et al. “Zika virus and birth defects—reviewing the evidence for causality.” New England Journal of Medicine 374.20 (2016): 1981-1987. http://www.nejm.org/doi/pdf/10.1…

3. Mansuy, Jean Michel, et al. “Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen.” Lancet Infect Dis 16.405 (2016): 00138-9. https://www.researchgate.net/pro…

4. Barzon, L., et al. “Infection dynamics in a traveller with persistent shedding of Zika virus RNA in semen for six months after returning from Haiti to Italy, January 2016.” Euro surveillance: bulletin Européen sur les maladies transmissibles= European communicable disease bulletin 21.32 (2016). http://www.eurosurveillance.org/…

5. Davidson, Alexander. “Suspected female-to-male sexual transmission of Zika virus—New York City, 2016.” MMWR. Morbidity and Mortality Weekly Report 65 (2016). http://www.cdc.gov/mmwr/volumes/…

6. Prisant, N. et al. Zika virus in the female genital tract. Lancet Infectious Diseases, 2016, July 11. http://www.thelancet.com/pdfs/jo…

7. Meaney-Delman, Dana, et al. “Prolonged Detection of Zika Virus RNA in Pregnant Women.” Obstetrics & Gynecology (2016). Prolonged Detection of Zika Virus RNA in Pregnant Women. : Obstetrics & Gynecology

8. Foy, Brian D., et al. “Probable non-vector-borne transmission of Zika virus, Colorado, USA.” Emerg Infect Dis 17.5 (2011): 880-2. https://www.researchgate.net/pro…

9. Coelho, Flávio Codeço, et al. “Sexual transmission causes a marked increase in the incidence of Zika in women in Rio de Janeiro, Brazil.” bioRxiv (2016): 055459. http://www.biorxiv.org/content/b…

10. D’Ortenzio, Eric, et al. “Evidence of sexual transmission of Zika virus.” New England Journal of Medicine 374.22 (2016): 2195-2198. http://www.nejm.org/doi/pdf/10.1…

11. Fréour, Thomas, et al. “Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016.” Eurosurveillance 21.23 (2016). http://www.e-sciencecentral.org/…

12. Musso, D., et al. “Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014.” Euro Surveill 19.14 (2014): 20761. http://www.eurosurveillance.org/…

13. Kuehnert, Matthew J. “Screening of blood donations for Zika virus infection—Puerto Rico, April 3–June 11, 2016.” MMWR. Morbidity and Mortality Weekly Report 65 (2016). https://www.cdc.gov/mmwr/volumes…

14. Barjas‐Castro, Maria L., et al. “Probable transfusion‐transmitted Zika virus in Brazil.” Transfusion 56.7 (2016): 1684-1688. http://onlinelibrary.wiley.com/d…

15. Motta, Iara JF, et al. “Evidence for Transmission of Zika Virus by Platelet Transfusion.” New England Journal of Medicine (2016). http://www.nejm.org/doi/pdf/10.1…

16. FDA advises testing for Zika virus in all donated blood and blood components in the US

17. http://www.fda.gov/downloads/Bio…

https://www.quora.com/Should-blood-banks-be-testing-for-Zika/answer/Tirumalai-Kamala

If a child is conceived while the father has Zika, but the mother never gets infected, can the fetus be affected?

Tags

Sexual transmission

Though bite of infected Aedes – Wikipedia mosquito is its primary mode of spread, since 2011, several case reports have

• Suggested Zika can be sexually transmitted.
• Documented Zika’s prolonged presence in semen of infected men.

In August 2016, the WHO (1) listed a total of 17 published reports on possible sexual transmission of Zika and 8 others on its presence in semen. Thus, as of Oct 2016, there’s plenty of scientific evidence that it’s possible for a Zika-infected man to infect a previously uninfected woman during sexual intercourse, in which case a fetus could also be affected. In other words, counting on a woman remaining uninfected following sex with a Zika-infected man is highly risky, especially for the fetus.

Reports Of Sexual Transmission From Symptomatic Males To Females

In each of these cases, the previously uninfected women developed symptoms suggestive of Zika even though they hadn’t been exposed to Zika-infected mosquitoes, i.e., highly likely they were infected through sexual transmission.

Cases reported from Argentina and France (2), Canada (3), Chile (4), France, where in one case the suspected route was oral sex (5) while the other case suggested male to female sexual transmission occurred 32 to 41 days after the man got infected with Zika (6), Germany (7), Italy (8), a case where Zika virus RNA was found in the man’s semen even 62 days after first symptoms of infection, New Zealand (9), a case where semen samples from the man tested positive for Zika virus RNA even 76 days after symptom onset and only tested negative on days 99 and 117, Peru (10), Spain (11), USA (12, 13, 14, 15).

Other Reports Of Sexual Transmission Include

• Asymptomatic male to female, one each in France (16) and USA (17). Since ~80% of Zika-infected people remain asymptomatic (18), prolonged presence of potentially infectious Zika in semen makes its sexual transmission a very important means of spreading through the population. Data also shows a pregnant woman being asymptomatic doesn’t preclude Zika virus from affecting the fetus.
• One case of male to male transmission (anal sex), in Texas, USA (19).
• One case of female to male transmission in New York City, USA (20).

Documented Cases Of Zika’s Presence In Semen

Live virus: Researchers were able to isolate Zika virus from semen

• In one case from the 2013 French Polynesia – Wikipedia Zika outbreak (21) two weeks after self-reported symptoms started.
• In a French case where semen virus load was 100000 times that in blood (22) two weeks after self-reported symptoms started.
• Even 62 days after first fever symptom in a case from Scotland (23).

Virus RNA: Detectable in a Netherlands patient up to 47 days after symptom onset (24), 80 (25) and 93 days (26) from two cases in France, and even 181 (27) and 188 days (28) in two cases from Italy.

These data suggest live virus is not only present in semen of Zika-infected men but can also stay there for extended periods of time. This is why the WHO recommends (1) that

• In regions with active Zika virus transmission,

‘Pregnant women should practice safer sex or abstain from sexual activity for at least the whole duration of the pregnancy. Their partners should also be informed about this recommendation.’

• And in regions with no active Zika virus transmission,

‘a. Men and women returning from areas where transmission of Zika virus is known to occur should adopt safer sex practices or consider abstinence for at least 6 months upon return to prevent Zika virus infection through sexual transmission.

b. Couples or women planning a pregnancy, who are returning from areas where transmission of Zika virus is known to occur, are advised to wait at least 6 months before trying to conceive to ensure that possible Zika virus infection has cleared.

c. Sexual partners of pregnant women, returning from areas where transmission of Zika virus is known to occur, should be advised to practice safer sex or abstain from sexual activity for at least the whole duration of the pregnancy.’

Bibliography

1. World Health Organization. “Prevention of sexual transmission of Zika virus: interim guidance update.” World Health Organization, Geneva, Switzerland (2016). http://apps.who.int/iris/bitstre…

2. Zika virus infection – Argentina and France

3. Statement from the Chief Public Health Officer of Canada and Ontario’s Chief Medical Officer of Health on the first positive case of sexually transmitted Zika Virus – Canada News Centre

4. Zika virus infection – Chile

5. D’Ortenzio, Eric, et al. “Evidence of sexual transmission of Zika virus.” New England Journal of Medicine 374.22 (2016): 2195-2198. http://www.nejm.org/doi/pdf/10.1…

6. Turmel, Jean Marie, et al. “Late sexual transmission of Zika virus related to persistence in the semen.” The Lancet (2016). http://ac.els-cdn.com/S014067361…

7. Frank, Christina, et al. “Sexual transmission of Zika virus in Germany, April 2016.” Eurosurveillance 21.23 (2016). http://www.eurosurveillance.org/…

8. Venturi, G., et al. “An autochthonous case of Zika due to possible sexual transmission, Florence, Italy, 2014.” Euro Surveill 21.8 (2016): 30148. http://www.eurosurveillance.org/…

9. Harrower, Jay, et al. “Sexual transmission of Zika virus and persistence in semen, New Zealand, 2016.” Emerging Infectious Diseases 22.10 (2016): 1855. http://wwwnc.cdc.gov/eid/article…

10. Zika virus infection – Peru

11. Spain records first case of sexually transmitted Zika virus

12. Foy, Brian D., et al. “Probable non–vector-borne transmission of Zika virus, Colorado, USA.” Emerging infectious diseases 17.5 (2011): 880. http://www.ncbi.nlm.nih.gov/pmc/…

13. Sex After a Field Trip Yields Scientific First. Martin Enserink, Science, April 6, 2011. Sex After a Field Trip Yields Scientific First

14. Zika Infection Transmitted by Sex Reported in Texas. The New York Times, Donald G. McNeil Jr., Sabrina Tavernise, Feb 2, 2016. Log In – New York Times

15. Hills, Susan L. “Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission—continental United States, 2016.” MMWR. Morbidity and mortality weekly report 65 (2016). http://www.cdc.gov/mmwr/volumes/…

16. Fréour, Thomas, et al. “Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016.” Eurosurveillance 21.23 (2016). http://www.eurosurveillance.org/…

17. Brooks, Richard B. “Likely sexual transmission of Zika virus from a man with no symptoms of infection—Maryland, 2016.” MMWR. Morbidity and Mortality Weekly Report 65 (2016). http://www.cdc.gov/mmwr/volumes/…

18. Duffy, Mark R., et al. “Zika virus outbreak on Yap Island, federated states of Micronesia.” New England Journal of Medicine 360.24 (2009): 2536-2543. http://www.nejm.org/doi/pdf/10.1…

19. Deckard, D. Trew. “Male-to-male sexual transmission of Zika virus—Texas, January 2016.” MMWR. Morbidity and mortality weekly report 65 (2016). https://www.cdc.gov/mmwr/volumes…

20. Davidson, Alexander. “Suspected female-to-male sexual transmission of Zika virus—New York City, 2016.” MMWR. Morbidity and mortality weekly report 65 (2016). http://www.cdc.gov/mmwr/volumes/…

21. Musso, Didier, et al. “Potential sexual transmission of Zika virus.” Emerg Infect Dis 21.2 (2015): 359-61. https://www.researchgate.net/pro…

22. Mansuy, Jean Michel, et al. “Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen.” Lancet Infect Dis 16.405 (2016): 00138-9. https://www.researchgate.net/pro…

23. Atkinson, Barry, et al. “Detection of Zika virus in semen.” Emerg Infect Dis 22.5 (2016). Emerging Infectious Disease journal

24. Reusken, Chantal, et al. “Longitudinal follow-up of Zika virus RNA in semen of a traveller returning from Barbados to the Netherlands with Zika virus disease, March 2016.” Eurosurveillance 21.23 (2016). http://www.eurosurveillance.org/…

25. Matheron, Sophie, et al. “Long-lasting persistence of Zika virus in semen.” Clinical Infectious Diseases 63.9 (2016): 1264-1264. Long-Lasting Persistence of Zika Virus in Semen

26. Mansuy, Jean Michel, et al. “Zika virus in semen of a patient returning from a non-epidemic area.” The Lancet Infectious Diseases 16.8 (2016): 894-895. http://www.thelancet.com/pdfs/jo…

27. Barzon, Luisa, et al. “Infection dynamics in a traveller with persistent shedding of Zika virus RNA in semen for six months after returning from Haiti to Italy, January 2016.” Eurosurveillance 21.32 (2016). http://www.eurosurveillance.org/…

28. Nicastri, Emanuele, et al. “Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016.” Eurosurveillance 21.32 (2016). http://www.eurosurveillance.org/…

 

https://www.quora.com/If-a-child-is-conceived-while-the-father-has-Zika-but-the-mother-never-gets-infected-can-the-fetus-be-affected/answer/Tirumalai-Kamala

What are the chances that there’s something else like Zika coming soon?

Tags

Aedes, Zoonosis

Global Zika-like outbreaks are increasingly inevitable largely due to unprecedented rates of

• Population mobility and density
• Rapid global transport
• Human ecosystem alteration
• Climate change

existing cheek by jowl with

• Vast health and wealth disparities
• Vast global differences in public health infrastructure including sanitation and active disease surveillance capacity
• Surfeit of neglected and/or little known diseases, many of them tropical, that lack drugs or vaccines to treat or prevent them and whose geographic reach spreads as climate change expands the range of the vectors capable of transmitting them.

Several of these factors also increase human-wildlife interactions, which in turn increase risk of Zoonosis – Wikipedia, diseases transmissible between animals and humans.

Originally discovered in 1947 in the Zika forest adjacent to Lake Victoria in Uganda, for decades Zika was but one of several RNA viruses known only to a handful of aficionados. Its obscurity began changing starting in 2007 when it caused an outbreak on the Micronesian island of Yap (1) followed by a larger 2013-2014 outbreak in French Polynesia (2) culminating of course in the global headlines of the 2015-2016 outbreak in Brazil and beyond (3).

So, clearly a case of a virus that until quite recently remained confined to a remote African forest and yet in less than a decade it’s spread across the globe, not only infecting large swaths of previously unexposed human populations but also expanding its capability in terms of disease outcomes from GBS (Guillain–Barré syndrome – Wikipedia) to fetal abnormalities (Microcephaly – Wikipedia). While less than a decade may sound shocking, not being unprecedented is even more so since Zika’s only following in the footsteps of related viruses, Chikungunya – Wikipedia and Dengue virus – Wikipedia, all zoonoses. Having similarly triumphantly marched across the globe in recent decades, their spread eerily echoes that of their carrier mosquito, Aedes – Wikipedia.

A 2008 study (4) estimated 335 emerging infectious diseases (EID) between 1940 and 2004. Averaging yields a very deceptive ~5 per year, deceptive because frequency between Pandemic – Wikipedia has steadily shrunk in recent years. Consider for example the high-profile global outbreaks of SARS (Severe acute respiratory syndrome – Wikipedia) in 2003, Bird flu (Influenza A virus subtype H5N1 – Wikipedia) in 2007, Swine flu (2009 flu pandemic – Wikipedia) in 2009, MERS (Middle East respiratory syndrome – Wikipedia) in 2012, Ebola virus disease – Wikipedia in 2014 and Zika fever – Wikipedia in 2015.

~60% of EIDs are primarily zoonotic. For e.g., Chikungunya, Dengue Ebola, HIV, Lyme, SARS, West Nile, Zika, to mention just a few.

• The 2008 analysis (4) concluded majority arose from wildlife and that human population density was the single common predictor for all types of EIDs (zoonotic or not, drug-resistant or not, vector-borne or not).
• EIDs seem to be a ‘hidden’ cost of human economic development (see below from 4, 5).

Population Mobility & Rapid Global Transport

Practically anywhere in the world is today a mere plane ride away even as these anywheres remain vastly different in basic public health infrastructure and active disease surveillance capacity. One sick person is all it takes for infectious diseases to spread beyond borders, i.e., vastly expanded potential for diseases to rapidly spread globally.

Consider for example how global air travel has exponentially expanded in <100 years. A paltry 1205 total global plane tickets sold in 1914 had increased to a whopping 2,595,448,927 in 2010. Yet large swaths of the world still lack adequate sanitation (see below from 6 and 7).

Human-driven Ecosystem Alterations & Climate Change Tilt The Balance In Favor Of Increased Pandemic Risk

More than ever before, massive human -driven ecosystem alterations have become the norm since the Industrial Revolution – Wikipedia with this process only further globalizing in the current era (8; see below from 9, emphasis mine).

‘With roughly half the temperate and tropical forests cut down, nearly half the icefree, desert-free terrestrial landscape converted to croplands or pasture, and more than 800,000 dams impeding the flow through more than 60% of the world’s rivers, alterations to our planet’s land use and land cover represent some of the most pervasive changes humanity has made to Earth’s natural systems‘

Human-driven ecological changes increase human encroachments into wildlife habitat. Such human-wildlife interactions increase zoonoses risk.

• For example, studies suggest such processes may have kick-started the initial Ebola and HIV outbreaks (10).
• No surprise then that ~75% of EIDs are zoonoses (4, 5, 11).
• New disease outbreaks become more inevitable when previously unimaginable mobility and enormous human-driven ecological changes exist alongside crippling poverty consisting of acute food scarcity and no sanitation, hygiene or running water since the more malnourished are weaker and likelier to get sick, especially with new EIDs.
• A corollary is increased hunting and consumption of wild meat, Bushmeat – Wikipedia (12).
  • For example, ‘ground zero’ for the 2013-2016 West African Ebola outbreak is suspected to be hungry children living in the remote Meliandou – Wikipedia village in southern Guinea – Wikipedia who killed and ate infected fruit bats (13, 14).
  • Something so seemingly inconsequential and yet it triggered a global public health emergency with a total of 28616 cases and 11310 fatalities from 10 countries according to West African Ebola virus epidemic – Wikipedia.
• Mapping such outbreaks only emphasizes that infectious disease transmissions have become that much easier given how fluidly, rapidly and easily humans can traverse the globe these days, and the increasingly porous divides between previously more strongly demarcated divisions such as affluence and poverty, sanitation and filth.

Thus, since lack of hygiene, sanitation and running water are today only a plane ride away so is pandemic risk.

The rapid, global expansion of mosquito species such as Aedes aegypti – Wikipedia and Aedes albopictus – Wikipedia is but one example of how climate change effects place greater selection pressures on vast numbers of species to adapt to these rapid changes, many of which end up increasing infectious disease risk not just in humans but for all types of life forms (see some other examples below from 15).

A 2009 analysis (16) concluded climate change may influence different arthropod-transmitted Arbovirus – Wikipedia diseases differently.

• Chikungunya: A single mutation in the Chikungunya virus facilitated its adaptation to the fast expanding mosquito species, A. albopictus, i.e., Chikungunya’s spreading by latching on to this mosquito’s coat-tails, whose spread is facilitated by climate change. Human travel simply augments spread even more.
• Rift Valley fever – Wikipedia, Bluetongue disease – Wikipedia: According to these authors, climate change helps mosquitoes spread in newly flooded areas while human activities such as irrigation projects, movements of herded animals and animal imports to feed large numbers of humans, for example during Mecca pilgrimages, also contribute to Rift Valley virus outbreaks.

Bibliography

1. Duffy, Mark R., et al. “Zika virus outbreak on Yap Island, federated states of Micronesia.” New England Journal of Medicine 360.24 (2009): 2536-2543. http://www.nejm.org/doi/pdf/10.1…

2. Cao-Lormeau, V. M., et al. “Zika virus, French polynesia, South pacific, 2013.” Emerging infectious diseases 20.6 (2014): 1085-1086. http://wwwnc.cdc.gov/eid/article…

3. Campos, Gubio S., Antonio C. Bandeira, and Silvia I. Sardi. “Zika virus outbreak, Bahia, Brazil.” Emerging infectious diseases 21.10 (2015): 1885. https://www.ncbi.nlm.nih.gov/pmc…

4. Jones, Kate E., et al. “Global trends in emerging infectious diseases.” Nature 451.7181 (2008): 990-993.

5. World Organisation for Animal Health

6. In flight

7. Total population: access to sanitation

8. Foley, Jonathan A., et al. “Global consequences of land use.” science 309.5734 (2005): 570-574. https://www.researchgate.net/pro…

9. Myers, Samuel S., et al. “Human health impacts of ecosystem alteration.” Proceedings of the National Academy of Sciences 110.47 (2013): 18753-18760. https://www.researchgate.net/pro…

10. Hahn, Beatrice H., et al. “AIDS as a zoonosis: scientific and public health implications.” Science 287.5453 (2000): 607-614. https://www.researchgate.net/pro…

11. Taylor, Louise H., Sophia M. Latham, and E. J. Mark. “Risk factors for human disease emergence.” Philosophical Transactions of the Royal Society of London B: Biological Sciences 356.1411 (2001): 983-989. http://rstb.royalsocietypublishi…

12. Wolfe, Nathan D., et al. “Naturally acquired simian retrovirus infections in central African hunters.” The Lancet 363.9413 (2004): 932-937. http://www.jhsph.edu/research/af…

13. Vogel, Gretchen. “Bat-filled tree source of Ebola epidemic?.” Science 347.6218 (2015): 142-143. Bat-filled tree may have been ground zero for the Ebola epidemic

14. Bausch, Daniel G., and Lara Schwarz. “Outbreak of Ebola virus disease in Guinea: where ecology meets economy.” PLoS Negl Trop Dis 8.7 (2014): e3056. http://journals.plos.org/plosntd…

15. Altizer, Sonia, et al. “Climate change and infectious diseases: from evidence to a predictive framework.” science 341.6145 (2013): 514-519. http://www.colorado.edu/eeb/facu…

16. Gould, Ernest A., and Stephen Higgs. “Impact of climate change and other factors on emerging arbovirus diseases.” Transactions of the Royal Society of Tropical Medicine and Hygiene 103.2 (2009): 109-121. http://www.idpublications.com/jo…

https://www.quora.com/What-are-the-chances-that-theres-something-else-like-Zika-coming-soon/answer/Tirumalai-Kamala

Can we assume that no dengue epidemic in the U.S. implies little chance of a Zika epidemic? (both diseases are transmitted by the same mosquito)

Tags

Aedes aegypti, Aedes albopictus, Mosquito control, Vertically transmitted infection

Not too long back Dengue epidemics were part and parcel of life in certain parts of the US (1). Florida had its last Dengue epidemic in 1934. Keeping mosquito-borne diseases at bay in the lush, warm, wet sub-tropical Florida climate is a constant tug-of-war and recent history ominously suggests that laxity in stringent, community-wide mosquito control could deliver net advantage to mosquitoes and the diseases they carry. Florida’s climate allows year-around residence of Aedes aegypti, the mosquito species that transmits Dengue and Zika in Central and South America. Thus, there’s no guarantee Dengue won’t make a comeback or that Zika can’t gain a foothold in the state. Exploring chances of Dengue and Zika in Florida helps appraise their capacity to spread into continental US and suggests that holding them at arm’s length is a fragile standoff at the best of times.

The Three Mosquiteers* In Florida’s History: Dengue, Malaria, Yellow Fever

Since at least the 1970s, Florida’s become one of the foremost global tourist destinations but a 2013 article on the history of mosquito-borne diseases in Florida (2) reminds us just how recent that transformation is. For long Florida was sparsely inhabited, its entire population numbering just 34730 in 1830 (3). As recently as the 1950s, Florida was a place to flee from in summer (4), of course only by those who could afford to do so.

Why? Simply, until recently, life in much of Florida was considered so unbearable (5), much of its population stayed concentrated in the north between Alabama and Georgia, the Florida Panhandle, a largely disease- and poverty-stricken area between Jacksonville and Pensacola, known as the ‘malaria belt’, also home to cholera, dengue, diphtheria, hookworm, influenza, pellagra, pertussis, smallpox, tetanus, typhoid, yellow fever. Though largely forgotten today, mosquito-borne diseases in the form of malaria, dengue and yellow fever thus inform a great deal of Florida’s history. Maurice Provost, the first director of what would become the Florida Medical Entomological Laboratory recalled in 1973 (see below from 6),

“My most vivid memories of malaria-control days in Florida are of the morning-after inspections of so many of the humble shacks we sprayed with DDT. The poor housewife often enough would come to me with tears of joy and show me a basketful of dead bedbugs, roaches, and other vermin, and she would exclaim that her family had spent the first night of their lives without annoyance from biting or creeping things”

Florida’s last dengue epidemic was in 1934. Reads like so much ancient history now. Why? Mosquito control (7), a stupendous achievement pretty much taken for granted not just now but already a generation back in 1981 (see below from 8, emphasis mine).

“Florida would not be where it is today were it not for mosquito control. That alone makes a lot of people mad, but they weren’t around when you could not go outside after dark and most of the coastal communities closed down during the summer. Most of the people who fight your programs are newcomers. A newcomer is now somebody who came here after 1970.”

Complacence Belied, After 1934, In 2009 Locally Acquired (autochthonous) Dengue Returned To Florida

While sporadic travel-related Dengue infections remained, Florida didn’t report any locally acquired (autochthonous) Dengue since 1934, a record broken in 2009. Starting in July 2009 and continuing until April of the following year, a total of 28 locally acquired Dengue cases were reported in Key West, FL (See figure below left from 9). Eventually a total of >90 locally acquired Dengue cases were reported in Key West alone (See figure right from 10).

Starting from tiny Key West in 2009 (see left from 11), by 2013, locally acquired Dengue had expanded upward to encompass at least 8 Florida counties (see right from 12).

Local acquisition means complete local mosquito-to-local human-to-local mosquito cycle, the step necessary for outbreaks and eventually epidemics too. Definitely the opposite of welcome news. The silver lining in this dismaying story was that Maimi-Dade County, a port with heavy traffic from Dengue-endemic countries, doesn’t appear to have conditions sufficient to sustain local Dengue transmission. Puzzling similarities in the Counties with the most number of cases, namely Key West-containing Monroe in 2009-2010 and Martin in 2013, were

• Neither is a major port of entry for either aviation or shipping.
• Both had larger numbers of locally acquired cases compared to other Florida counties.

How did Key West and Martin favor local Dengue transmission? Studies suggest factors they have in common are (12, see table below from 11)

• Tendency to keep open-air water receptacles such as bird-baths without frequently changing them.
• Keep windows open >50% of the time.
• Have >50% vegetation on their property.

OTOH, local Dengue transmission was greatly reduced if

• Empty standing water containers were changed weekly.
• Air-Conditioners (A-Cs) were used >50% of the time.
• Mosquito repellents were used routinely.

Situation in Florida is even more precarious given the fact that one study found local Florida Ae. aegypti mosquitoes capable of Vertically transmitted infection of the Dengue strain isolated from the 2009 Key West outbreak (13). When infected with Dengue virus, ~8% of these Florida mosquitoes were found capable of vertically transferring it to their eggs. Thus, Florida’s just barely keeping Dengue at arm’s length and even the slightest laxity could be all it takes for it to gain a stable foot-hold. Threat of Zika just adds to the strain on public health. Not to mention the really scary scenario if Aedes albopictus also became capable of transmitting Dengue and Zika, something it can’t at present. This would be really scary given how much more widespread this mosquito species is all across the continental US and indeed much of the temperate regions of the world.

Trouble is collective memory’s fickle and easily breeds complacence. When persistent, deeply vexing problems such as the perennial scourge of mosquitoes get intensively abated within just a generation, as happened in Florida, it doesn’t take long for collective, generation-spanning amnesia to dictate the conversation. Already back in 1991, public opinion apparently supported the idea that mosquito control officials greatly exaggerate the threat of disease to justify their jobs (4). What’s easily forgotten in such short-sighted political and economic debates is that mosquito (vector) control is inherently resource and personnel intensive and only works with sustained community support and participation (14). To quote Hribar (2, emphasis mine),

‘Is it too expensive to control Aedes aegypti? Equipment, training, pesticides, and people cost money. To do the job right, a lot of time must be devoted to seeking out larval habitats and eliminating them. Adult emergences must be dealt with promptly. The public must cooperate with public health and mosquito control agencies in the fight against Aedes aegypti. Whatever the cost surely it will be less than the hospitalization, medicines, lost wages, and funeral expenses that may be the alternative ‘

Though climate and location render Florida and other states in the Gulf Coast of the United States vulnerable to Dengue and Zika, common-sense, practical measures can do a great deal to minimize and even prevent them from getting established in the US. Apart from aggressive, community-based mosquito (vector) control, air-conditioning and using screens on doors and windows can greatly stem Ae. aegypti‘s capacity to complete Dengue and Zika‘s transmission cycle. Of course, prevention is greatly facilitated by widespread use of centralized air-conditioning and heating systems, something only to be expected in an advanced economy like the US. Given how important tourism is to Florida’s economy, one would hope the state apparatus wouldn’t hesitate to pull out all stops to prevent mosquito-borne Dengue and Zika from taking root in the state.

*: Defined here as mosquito-borne parasitic and viral diseases.

Bibliography

1. Bouri, Nidhi, et al. “Return of epidemic dengue in the United States: implications for the public health practitioner.” Public health reports 127.3 (2012): 259. http://www.ncbi.nlm.nih.gov/pmc/…

2. Hribar, L. G. “Influence and impact of mosquito-borne diseases on the history of Florida, USA.” Life Excit. Biol 1 (2013): 53-68. https://blaypublishers.files.wor…

3. Cody, Scott K. “Florida’s population center migrates through history.” Florida Focus 2.1 (2006): 1-5) http://www.bebr.ufl.edu/sites/de…

4. Mulrennan, J. A. “Benefits of mosquito control.” Mosquito control pesticides: ecological impacts and management alternatives. Conference Proceedings. Scientific Publishers, Inc. Gainesville, Florida, USA. 1991.

5. Gaiser, D. “The importance of mosquito control to tourism in Florida.” Proceedings of the Florida Anti Mosquito Association (1980).

6. Provost, Maurice W. “Environmental Quality and the Control of Biting Flies.” Symposium on Biting-Fly Control and Environmental Quality. 1973.

7. Mulrennan Jr, John Andrew. “Mosquito control-Its impact on the growth and development of Florida.” Insect Potpourri: Adventures in Entomology (1992): 75.

8. Harden, F.W. 1981. You and the environment. Journal of the Florida Anti-Mosquito Association 52:60-61. http://floridamosquito.org/Archi…

9. Trout, A., et al. “Locally Acquired Dengue-Key West, Florida, 2009-2010.” Morbidity and Mortality Weekly Report 59.19 (2010): 577-581. http://www.cdc.gov/mmwr/pdf/wk/m…

10. Rey, Jorge R. “Dengue in Florida (USA).” Insects 5.4 (2014): 991-1000. Dengue in Florida (USA)

11. Radke, Elizabeth G., et al. “Dengue outbreak in key west, Florida, USA, 2009.” Emerg Infect Dis 18.1 (2012): 135-7. http://wwwnc.cdc.gov/eid/article…

12. Teets, Frank D., et al. “Origin of the dengue virus outbreak in Martin County, Florida, USA 2013.” Virology reports 1 (2014): 2-8. https://www.researchgate.net/pro…

13. Buckner, Eva A., Barry W. Alto, and L. Philip Lounibos. “Vertical transmission of Key West dengue-1 virus by Aedes aegypti and Aedes albopictus (Diptera: Culicidae) mosquitoes from Florida.” Journal of medical entomology 50.6 (2013): 1291-1297. https://www.researchgate.net/pro…

14. Parks, Will, and Linda Lloyd. Planning social mobilization and communication for dengue fever prevention and control: a step-by-step guide. World Health Organization, 2004. https://www.researchgate.net/pro…

https://www.quora.com/Can-we-assume-that-no-dengue-epidemic-in-the-U-S-implies-little-chance-of-a-Zika-epidemic-both-diseases-are-transmitted-by-the-same-mosquito/answer/Tirumalai-Kamala

Mosquito usually carries quite infectious virus like Ebola. Do mosquitoes get infected by viruses they transmit?

Tags

Antiviral immunity, Mosquito-to-mosquito virus transmission

Thus far, ‘There is no evidence that mosquitoes or other insects can transmit Ebola virus‘ (1). However, several other viral diseases are mosquito-borne. These include Chikungunya virus, Dengue virus, Yellow fever virus, Zika virus, to mention a few. These are transmitted through the bite of infected Aedes species mosquitoes.

Mosquitoes do get infected by the viruses they transmit (See figure below from 2).

As the figure highlights, in addition to successfully replicating in the mid gut, viruses taken in during blood meals face several barriers to productive infection of mosquitoes. These include a) a time constraint in infecting mosquito mid gut epithelial cells, b) successful escape from mid gut epithelial cells after they replicate within them, and c) successful infection and replication within mosquito salivary glands.

There is also evidence of mosquito-to-mosquito virus transmission (3). While mosquito immune responses against parasitic Protozoa such as Plasmodium are quite well-studied (4), mosquitoes can also make immune responses against viruses that infect them. Studies have found specific mosquito mid-gut immune responses against Arbovirus such as Chikungunya, Dengue virus and West Nile fever (see summary figure from 5, 6).

Bibliography

1. Transmission | Ebola Hemorrhagic Fever | CDC

2. Franz, Alexander WE, et al. “Tissue barriers to arbovirus infection in mosquitoes.” Viruses 7.7 (2015): 3741-3767. Tissue Barriers to Arbovirus Infection in Mosquitoes

3. Haddow, Andrew D., et al. “First isolation of Aedes flavivirus in the Western Hemisphere and evidence of vertical transmission in the mosquito Aedes (Stegomyia) albopictus (Diptera: Culicidae).” Virology 440.2 (2013): 134-139. https://www.researchgate.net/pro…

4. Jaramillo-Gutierrez, Giovanna, et al. “Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes.” BMC microbiology 9.1 (2009): 1. https://www.researchgate.net/pro…

5. Saraiva, Raúl G., et al. “Mosquito gut antiparasitic and antiviral immunity.” Developmental & Comparative Immunology (2016).

6. Sim, Shuzhen, Natapong Jupatanakul, and George Dimopoulos. “Mosquito immunity against Arboviruses.” Viruses 6.11 (2014): 4479-4504. Mosquito Immunity against Arboviruses

https://www.quora.com/Mosquito-usually-carries-quite-infectious-virus-like-Ebola-Do-mosquitoes-get-infected-by-viruses-they-transmit/answer/Tirumalai-Kamala