MicrobiologyBytes

Malaria is a major global health problem responsible for more than one million deaths annually. Severity of malaria disease is associated with the inability of host immune cells to efficiently eliminate malaria parasites from the blood. Little is known about immune regulatory factors controlling the onset of severe and potentially fatal malaria. Regulatory T (Treg) cells are a small specialized subset of immune cells that suppress the activation and expansion of effector immune cells which partake in parasite elimination. Scientists have now investigated the relationship between Treg cells, parasite burden, and disease severity in adult malaria patients with either uncomplicated or severe malaria.

They were able to demonstrate that Treg cell frequency was elevated in malaria patients and associated with high parasite burden in severe malaria but not in uncomplicated malaria. This type of cell turns off the immune system and can allow the parasite to grow uncontrollably. Comparison of Treg cell characteristics allowed them to identify a new highly suppressive subset of Treg cells that was elevated in severe malaria patients. When comparing Treg cell characteristics, the team was able to identify elevated levels of a new highly suppressive subset of Treg cells in those patients with severe malaria. The regulatory (Treg) cell subset associated with severe disease in humans expresses a unique combination of surface markers, including TNFRII. Regulatory T (Treg) cells are a small specialized subset of immune cells that suppress the activation and expansion of effector immune cells, which partake in parasite elimination.

These results indicate that severe malaria is accompanied by the induction of highly suppressive Treg cells that can promote parasite growth and caution against the induction of these Treg cells when developing effective malaria vaccines. It is estimated that 500 million people live in areas where there is a risk of getting malaria. The severe form of the disease causes death in 1-3 million people each year. Until now it had been largely unknown what bodily factors enable some patients to fight and survive the disease, while other patients contract the severe form of the disease and sometimes die. Targeting this cell type may lead to new drugs and immunotherapeutics against malaria. Further studies are needed to determine if this new cell may also be promoting severe forms of other inflammatory diseases.

Parasite-Dependent Expansion of TNF Receptor II–Positive Regulatory T Cells with Enhanced Suppressive Activity in Adults with Severe Malaria. 2009 PLoS Pathog 5(4): e1000402
Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4+CD25+ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4+CD25+Foxp3+CD127lo Treg cells were significantly elevated in patients with uncomplicated and severe malaria relative to exposed asymptomatic controls. In patients with SM, Treg cell frequency correlated positively with parasitemia and total parasite biomass, both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII+ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum–infected red blood cells dose dependently induced TNFRII+Foxp3hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII2 Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII+Foxp3hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII+Foxp3hi Treg cells when developing effective malaria vaccines.

Related:

• Malaria: now you see me, now you don’t
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine

H5, H7, and H9 avian influenza subtypes top the World Health Organization’s list of strains with the greatest pandemic potential. A transition from avian-like 2,3-linked sialic acid (SA2,3) receptors to human-like 2,6-linked sialic acid (SA2,6) receptors appears to be a crucial step for avian influenza viruses to replicate efficiently and transmit in humans. An increasing number of contemporary avian H9N2 viruses contain leucine (L) at position 226 in the hemagglutinin (HA) receptor-binding site (RBS), supporting the preferential binding to SA2,6 receptors and the ability to replicate efficiently in human respiratory epithelial cells and in the ferret model, an in vivo model which closely resembles human airway epithelium and clinical infection. Since the mid-1990’s, H9N2 influenza viruses have become endemic in poultry throughout Eurasia and have occasionally transmitted to humans and pigs. In addition to possessing human virus-like receptor specificity, avian H9N2 viruses induce typical human flu-like illness, which can easily go unreported, and therefore have the opportunity to circulate, undergo reassortment, and increase in transmissibility.

Seroepidemiological studies in Asia suggest that the incidence of human H9N2 infections could be more prevalent than what has been reported and possible human-to-human transmission cannot be completely excluded. These direct infections with avian H9N2 confirm that interspecies transmission of H9N2 from avian species to mammalian hosts occurs and it is not uncommon. Reassortment between the current human epidemic strain and an avian virus of a different subtype is postulated to generate the next pandemic strain. Given the receptor specificity of avian H9N2 viruses and their repeated introduction into humans, as recent as December 2008, the opportunity for their reassortment and/or adaptation for human-to-human transmission is ever present. However the question remains what is missing for the H9N2 virus to transmit from human-to-human and possibly lead to the next pandemic.

A new study describes respiratory droplet transmission of an avian–human H9N2 influenza virus in ferrets and pinpoints the minimal changes necessary for respiratory droplet transmission in this model. After only 10 passages of nasal washes researchers were able to establish infection and sustain respiratory droplet transmission that was reproducible in multiple studies. This adaptation required only 5 amino acid changes in the entire influenza virus genome, implying that little is needed for currently circulating avian H9N2 viruses to transmit human-to-human following reassortment with a human strain. Studies to identify the minimal changes necessary indicated three changes in the surface HA and NA as the key point mutations essential for respiratory droplet transmission. The scientists also identified and located a change that dramatically alters the antigenicity of the virus, bringing to light the inherent limitations in the selection of vaccine seed stocks for avian H9N2 viruses and the possible inefficiency regarding the seed stock selection of other avian influenza strains. Whether these changes can affect transmission phenotypes of additional avian H9N2 strains and possibly other influenza subtypes, most notably H5 and H7, remains to be determined.

Minimal molecular constraints for respiratory droplet transmission of an avian–human H9N2 influenza A virus. PNAS USA April 20, 2009
Pandemic influenza requires interspecies transmission of an influenza virus with a novel hemagglutinin (HA) subtytpe that can adapt to its new host through either reassortment or point mutations and transmit by aerosolized respiratory droplets. Two previous pandemics of 1957 and 1968 resulted from the reassortment of low pathogenic avian viruses and human subtypes of that period; however, conditions leading to a pandemic virus are still poorly understood. Given the endemic situation of avian H9N2 influenza with human-like receptor specificity in Eurasia and its occasional transmission to humans and pigs, we wanted to determine whether an avian–human H9N2 reassortant could gain respiratory transmission in a mammalian animal model, the ferret. Here we show that following adaptation in the ferret, a reassortant virus carrying the surface proteins of an avian H9N2 in a human H3N2 backbone can transmit efficiently via respiratory droplets, creating a clinical infection similar to human influenza infections. Minimal changes at the protein level were found in this virus capable of respiratory droplet transmission. A reassortant virus expressing only the HA and neuraminidase (NA) of the ferret-adapted virus was able to account for the transmissibility, suggesting that currently circulating avian H9N2 viruses require little adaptation in mammals following acquisition of all human virus internal genes through reassortment. Hemagglutinin inhibition (HI) analysis showed changes in the antigenic profile of the virus, which carries profound implications for vaccine seed stock preparation against avian H9N2 influenza. This report illustrates that aerosolized respiratory transmission is not exclusive to current human H1, H2, and H3 influenza subtypes.

Related:

• The Biology of Influenza
• Influenza pandemic – when?
• The Pathogenicity of Pandemic Influenza Viruses
• H5N1 and 1918 pandemic influenza virus infection and the lungs

Approximately 50 years ago the Pillsbury Company was asked to develop protocols to ensure that astronauts would be free from food-borne illness during space travel. The entire process of production, harvesting, processing, and preparation of food was critically analyzed in order to identify control points that might be susceptible to the introduction of microbial contamination. Thus, Hazard Analysis of Critical Control Point (HACCP) was born. Risk assessment within HACCP was used to bypass end-product testing, which was deemed to be too expensive and essentially impractical for both NASA and the food industry. Global recognition of standardized protocols to eliminate risk at every step from “farm to fork” has translated into our national food safety policy. Unfortunately, raw foods have thrown a major linchpin into this vastly effective policy because of the lack of a verifiable kill step to ensure the elimination of food-borne disease transmission. Salmonella outbreaks in leafy greens, tomatoes, and other produce exemplify food safety issues related to the consumption of raw foods. Produce at harvest will contain indigenous bacteria and viruses, but their numbers are presumed to be relatively low and devoid of human pathogens. These assumptions have kept raw foods under the HACCP radar, and problems are exacerbated by low infectious dose for some strains and the establishment of Salmonella in environmental reservoirs. Issues with trace-back, such as co-mingling of produce lots from multiple farms before retail sale, globalization of food markets, and the short shelf-life of fresh-cut products further exacerbate the problem. These issues are complex, and easy solutions are not in sight.

Pathogens in raw foods: what the salad bar can learn from the raw bar. Curr Opin Biotechnol. Apr 14 2009
Recent Salmonella outbreaks associated with consumption of fresh produce have increased public concern for the safety of raw food products, perhaps signaling a paradigm shift in approaches to food safety. Limitations to our capacity to ensure that raw foods are safe for the consumer include the availability of sufficiently rapid and reliable technology for prevention, intervention, and risk assessment. Other food products, such as shellfish, with greater historical precedent for real or perceived public health risk may offer perspective and insight into strategies for meeting these challenges. This review documents current practices for pathogen prevention and detection in raw oysters and presents technological advances and impediments that determine the application of these methods.

Related:

• E. coli O157:H7 Spinach Outbreak
• Food Biosafety & Disgruntled Teenagers

A study conducted by Johns Hopkins University in the USA suggests that Human Papillomavirus (HPV) poses a greater risk in contracting cancer than smoking or alcohol. The study of 300 people also found that that those with more than six partners were almost nine times at greater risk of contracting the disease. And those who had already experienced a previous oral HPV infection were 32 times more likely to develop cancer. HPV is the cause of roughly 70 per cent of cervical cancers. Researchers believed oral sex was the main mode of transmission of HPV but could not rule out that it could also be passed through kissing. During the study, men and women who had been recently diagnosed with oropharyngeal cancer had blood and saliva samples taken and were also asked about their sexual practices and family history. They found HPV16 – one of the most common cancer-causing strains of the virus – was present in the tumours of 72 per cent of cancer patients. Scientists said the majority of HPV infections had no symptoms and often did not require treatment, but a small percentage of those who contracted high-risk strains may go on to develop cancer.

Oral Sexual Behaviors Associated with Prevalent Oral Human Papillomavirus Infection. J Infect Dis. Mar 25 2009
Oral human papillomavirus (HPV) infection is a cause of oropharyngeal cancer. We investigated whether sexual behaviors that elevated the odds of oropharyngeal cancer developing in a case-control study similarly elevated the odds of oral HPV infection developing among control patients. HPV infection was detected in 4.8% of 332 control patients from an outpatient clinic and in 2.9% of 210 college-aged men (age range, 18-23 years). Among control patients, the odds of infection developing independently increased with increases in the lifetime number of oral or vaginal sex partners. Among college-aged men, the odds of oral HPV infection developing increased with increases in the number of recent oral sex partners or open-mouthed kissing partners but not vaginal sex partners. Oral sex and open-mouthed kissing are associated with the development of oral HPV infection.

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• Should we cure cancer?
• HPV vaccines: prospects for eliminating ano-genital cancer
• Dumb and Dumber

Bluetongue is a disease of ruminants caused by Bluetongue virus (BTV) and it is transmitted by biting midges. In sheep, clinical signs of BTV infection can include fever, vasodilation, swelling and, in severe cases, death, although the severity of symptoms varies with the breed of sheep, the individual animal and the strain of virus involved. Cattle are a major reservoir host for BTV infection, primarily because of the less obvious clinical signs in these animals. After an exhaustive search for a natural agent of transmission, Culicoides midges were shown to be the vectors for Bluetongue virus (Culicoides and the emergence of bluetongue virus in northern Europe. Trends Microbiol 2009 17(4): 172-178).

Although BTV infection was initially centred in Africa, the virus was first detected in Greece in 1989, from where it has spread steadily north. Since the disease is spread exclusively by insects, and because the virus is quite specific about which midge species can be used as vectors, predictions about the spread of the disease were based on known ranges of different midge species, which in turn depends on climate. However, midges can sometimes be carried over very long distances by weather systems, or by ships or aircraft.

Despite widespread speculation regarding the exact origin of BTV-8 as the strain of the virus found in northern Europe, no single convincing hypothesis has been proposed. Although future full-genome sequencing might assist this task (as was the case in the incursion of West Nile virus into North America), the small number of reference strains of BTV-8 from areas of potential origin collected before the incursion into northern Europe makes it unlikely that this approach will provide unambiguous evidence. As long as our understanding of the potential routes of virus introduction remains poor, we will be unable to accurately estimate the potential for future introductions of BTV, as has been illustrated by the more recent detection of BTV-6 in Europe, or of other midge-borne arboviruses, such as African horse sickness virus (AHSV).

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Although the technology to produce safe, effective, inactivated vaccines existed, no coordinated action was taken by any Member State of the European Union (EU) to begin production of a BTV-8 vaccine until late 2007, when the full damage began to become evident. This was in part due to the assumption that the virus would not overwinter under northern European conditions (despite the fact that BTV had been documented overwintering successfully in other areas with far cooler winter temperatures). In the absence of an available vaccine, knowledge concerning the entomology of the insects involved in BTV transmission became paramount.

The spread of BTV has provided a severe test of the way in which the movement of vector-borne pathogens is predicted, identified and controlled in Europe. There are many arobovirus diseases (spread by arthropod vectors such as midges, mosquitos and ticks), affecting human as well as animal health. Whether BTV represents a herald for future incursions by other arboviruses into Europe remains difficult to know. It is clear that there exists a similar potential for emergence of other insect-borne pathogens on grounds of climate alone, but where different vectors are used – for example, in the case of AHSV – the dynamics of the current BTV outbreak cannot easily be used to estimate risk. What has been shown by this outbreak is that arbovirus–vector relationships are highly dynamic and extremely difficult to combat. Unless regions that are potentially at risk of transmission are prepared to invest the resources required to provide adequate information regarding vectors and suitable control methods, this will remain the case.

Related:

• Bluetongue virus
• How does bluetongue virus survive the winter?
• Bluetongue virus polymerase

Acute gastroenteritis (AGE) is a common illness affecting all age groups worldwide, causing an estimated three million deaths annually. However, in many patients a causal agent cannot be found despite extensive diagnostic testing. Proposing that novel viruses are the reason for this diagnostic gap, researchers screened fecal samples from symptomatic children using a molecular degenerate amplification technique and detected the presence of a novel parvovirus, Human Bocavirus species 2 (HBoV2). The genome of HBoV2 is 23% variant from its closest relative, the human bocavirus, a member of the Bocavirus genus of the Parvovirinae. Using specific amplification assays, they found HBoV2 was the third most prevalent virus detected in samples from symptomatic children in a case control study of AGE. Further, they found virus presence was associated with symptoms. During this screening, they detected a second related parvovirus, now named Human Bocavirus species 3 (HBoV3), but the prevalence was low and not associated with symptoms. The discovery of HBoV2 has reduced the diagnostic gap, but more studies are required to further investigate its role in AGE.

A Novel Bocavirus Associated with Acute Gastroenteritis in Australian Children. 2009 PLoS Pathog 5(4): e1000391
Acute gastroenteritis (AGE) is a common illness affecting all age groups worldwide, causing an estimated three million deaths annually. Viruses such as rotavirus, adenovirus, and caliciviruses are a major cause of AGE, but in many patients a causal agent cannot be found despite extensive diagnostic testing. Proposing that novel viruses are the reason for this diagnostic gap, we used molecular screening to investigate a cluster of undiagnosed cases that were part of a larger case control study into the etiology of pediatric AGE. Degenerate oligonucleotide primed (DOP) PCR was used to non-specifically amplify viral DNA from fecal specimens. The amplified DNA was then cloned and sequenced for analysis. A novel virus was detected. Elucidation and analysis of the genome indicates it is a member of the Bocavirus genus of the Parvovirinae, 23% variant at the nucleotide level from its closest formally recognized relative, the Human Bocavirus (HBoV), and similar to the very recently proposed second species of Bocavirus (HBoV2). Fecal samples collected from case control pairs during 2001 for the AGE study were tested with a bocavirus-specific PCR, and HBoV2 (sequence confirmed) was detected in 32 of 186 cases with AGE (prevalence 17.2%) compared with only 15 controls (8.1%). In this same group of children, HBoV2 prevalence was exceeded only by rotavirus (39.2%) and astrovirus (21.5%) and was more prevalent than norovirus genogroup 2 (13.4%) and adenovirus (4.8%). In a univariate analysis of the matched pairs (McNemar’s Test), the odds ratio for the association of AGE with HBoV2 infection was 2.6 (95% confidence interval 1.2–5.7); P = 0.007. During the course of this screening, a second novel bocavirus was detected which we have designated HBoV species 3 (HBoV3). The prevalence of HBoV3 was low (2.7%), and it was not associated with AGE. HBoV2 and HBoV3 are newly discovered bocaviruses, of which HBoV2 is the thirdmost-prevalent virus, after rotavirus and astrovirus, associated with pediatric AGE in this study.

Related:

• Newly discovered respiratory viruses

Today’s post is from guest blogger Helen Fry, who is a student at the University of Leicester.

MicrobiologyBytes welcomes guest bloggers who would like to contribute occasional posts which conform to the style and content of this site. If you would like to be a guest blogger here, please email your post with a completed copyright release form to me at: alan.cann@gmail.com

A quick glance at the British National Formulary and it’s easy to see just how many antibiotics are licensed for use in the UK. What is more difficult to see is how many antiviral agents are available, and this is because there are much fewer. The only viral diseases with treatments listed in BNF 57 are HSV, VZV, HIV, RSV, viral hepatitis and influenza. Viruses are the most abundant ‘lifeforms’ on the planet and there is a huge diversity of viruses that cause disease in humans. Viral disease, although often milder than bacterial or eukaryotic disease, accounts for a major burden on the health service and is a considerable cause of morbidity and mortality. Some viral diseases cause very severe infections and are a heavy global issue, such as HIV and viral diarrhoea (a major cause of infant and childhood mortality in countries without safe drinking water). So if viruses are so abundant and are such a global health pest, why are there so few antiviral agents?

There are several reasons why this is the case. First there is the difficulty of researching viral disease. Most pathogenic bacteria can be cultured and investigated fairly easily, with some notable exceptions such as TB and Chlamydia trachomatis. Culturing and investigating viruses is a lot harder, as it requires cell culture methods, where the appropriate line of eukaryotic cells is grown up and infected with the virus. This means that the virus cannot be studied directly, as with a growing population of bacteria, and because they are so small they can only be visualised via electron microscopy (The impact of cell culture sensitivity on rapid viral diagnosis: a historical perspective). There are non-culture based detection methods, but these only confirm the presence of the virus, they do not allow it to be studied. Viruses do not release any compounds on their own, any proteins made are produced in the host cell, whereas bacteria release toxins and chemotactic agents, quorum sensing molecules and siderophores, to name a few. This makes them easier to study. The fact that viruses are harder to study means that less is generally known about them, and it is a lot harder to identify potential targets for antivirals. On the other hand, viruses have much smaller genomes (on the whole, with some obvious exceptions), meaning that the genomes can be sequenced easily (Role of Cell Culture for Virus Detection in the Age of Technology).

Once a virus has been fully characterised, despite the difficulties, it is still problematic to make useful antiviral agents, and even the ones licensed in the UK are often quite toxic. This is for several reasons. Since the most important part of the virus life cycle takes part inside host cells antivirals often have to penetrate the cell in order to be effective. This means that the drug has to be highly specific for virally infected cells or risk being toxic to healthy cells. The viruses use host cell machinery to replicate themselves, meaning that a drug targeted against this part of the cycle risks affecting genome replication in healthy cells unless a virus specific target can be identified. Bacteria are prokaryotes, which mean that their cells are highly different to ours and it is often a simple matter of identifying a difference between our cells and theirs, and finding a molecule that interacts with it, such as the beta-lactams and cell wall synthesis. Antivirals have similar issues to antiprotozoals, in that finding a compound active against the microbe is not that hard, the difficulty lies in finding one that does not interact with host processes and is therefore non-toxic.

Finally, however, it all comes down to money. Drug development is now a process that is left exclusively to pharmaceutical companies due to its prohibitive costs, and since they are primarily a business rather than a service, all activity undertaken by them will inevitably be profit driven, rather than need driven. Bringing a drug to market now costs several million US$ and taken over 10 years from target identification to phase IV clinical trials. It is therefore a huge investment, and the drug companies want to be as such as possible that their drug will make it to market and will make as much money as possible before the patent runs out. Since patents last for 20 years, a drug may only have 5 years to make back the money it took to develop before cheaper generics can be made. This has caused companies to focus on drugs that are least likely to fail trials due to toxicity and that will make the most money in a short amount of time. Therefore the focus has been on lifestyle drugs that people will take every day for years on end, such as statins and antihypertensives, that have a low risk of toxicity and are well established in doctors’ prescribing pads. HIV therapy has benefited from this, as HIV+ people will need to take their medication every day for the rest of their lives. This, along with the fact that HIV is a rapidly fatal disease without medication meaning that drug companies can charge almost what they like for them, has meant that the number of effective, less toxic antiretrovirals is increasing and is already fairly big in comparison to other viral illnesses. Drug companies will risk producing drugs that are more likely to be toxic if they can charge a large amount for them once approved. This is usually the case for life-threatening illnesses, explaining why chemotherapy for cancer costs so much (in the tens of thousands for a single cycle in some cases), but is quite good these days, at least for the common cancers.

The incentive of money can be seen with the influenza drugs. Not many people have the need for influenza antivirals, since there is a pretty good vaccine produced each year for those at risk, and those not in high risk groups do not tend to suffer from severe enough disease to warrant treatment with anything other than blankets and Lemsip. So why are there two good drugs sitting on the market when they are not needed? The answer lies with the government who, fearing an approaching flu pandemic (we are due for one) decided to stockpile the anti-influenza drugs before they were widely used and resistance developed.

The biggest burden of viral disease, as with most infectious diseases, lies in developing countries. They are the worst hit by the HIV pandemic, suffer outbreaks of haemorrhagic fevers, are plagued by water borne viral diarrhoeal diseases and various other viral nasties. However, since they for the most part do not have the capital to fund a national health service and the people cannot afford medications themselves, these countries and their endemic diseases have been largely ignored by the drug companies due to the lack of profit potential. This means that the countries worst affected by HIV are the ones who do not have access to effective antiretroviral therapy, and that children die in the thousands because of viral diarrhoea. Some drug companies are starting to research third world diseases, but progress is slow and funding is not the best. Since we in the west need medications we cannot boycott the companies, and allowing patents to be extended would only put more strain on the already overwrought NHS. However, there needs to be a shift in attitudes towards making the companies more responsible for the drugs they develop.

Related:

• MicrobiologyBytes: Antivirals
• GSK to provide cheap drugs to the developing world
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The spread of dengue (DEN) worldwide combined with an increased severity of the DEN-associated clinical outcomes has made this mosquito-borne virus of great global public health importance. This article reviews the latest findings in the field of DEN pathogenesis, vector control and vaccine development. Atypical clinical manifestations as well as a shift in the age of DEN-infected patients have forced a revisit of the current definitions and classifications of the DEN-associated diseases. The antibody-mediated internalization of DEN virus triggers intracellular pathways that further enhance viral replication and output. A correlation between the human leukocyte antigen system and disease severity was found. The development of tetravalent DEN vaccine candidates is reaching its final stages, though the antibody levels required to protect against the four DEN serotypes are still unknown. Efforts have been devoted to identify the host target cells that are permissive or resistant to DEN virus replication and to decipher the downstream events that would result in either disease enhancement or protection. Strong emphasis has recently been made on genetic polymorphisms that confer DEN protection versus susceptibility to severe DEN. The increasing knowledge gained from basic science should help to better design effective DEN vaccines.

Pathogenesis and prevention of dengue virus infection: state-of-the-art. Curr Opin Infect Dis. Mar 2nd 2009

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• Dengue Virus
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A 46-year-old woman was hospitalized due to fever of up to 39°C of one week’s duration. The patient complained of weakness, night sweats, and weight loss for two weeks prior to admission. The patient had no past medical history, and did not take any medications, supplements, or illicit drugs. She was born and lived all her life in a rural village. She was indirectly exposed to farm animals and pets, yet had no close contact with these, and her family was not engaged in agricultural work. She denied having been bitten by ticks or fleas. There was no history of recent foreign travel or eating raw meat or unpasteurized milk. She reported no rashes, arthralgia, dryness of eyes, mouth ulcers, or mucocutaneous bleeding. On examination she appeared pale and sweaty. The cardiorespiratory examination was unremarkable. A markedly tender and enlarged liver and spleen, 3 cm and 10 cm below the costal margins, respectively, were noted, with no palpable lymph nodes. Periorbital and peripheral extremity edema was also present. What are likely etiologies for this patient’s high fever and organomegaly?

Prolonged Fever, Hepatosplenomegaly, and Pancytopenia in a 46-Year-Old Woman. 2009 PLoS Med 6(4): e1000053