Knocking Out Breakbone Fever: New Mammalian Transmission Model for Dengue Virus

        

A recent study uses several varieties of knockout mice to develop a dengue fever transmission model. This approach could greatly contribute to knowledge of transmission between vertebrate hosts and the dengue virus vector, the Aedes mosquito. 

         Agonizing muscle and joint pains. Measles-like skin rashes. Sudden-onset high fever. Severe headaches. With symptoms such as these there is little wondering why dengue fever is so feared. Even more concerning is that cases of dengue fever have been spreading into new geographic regions; a result of increased population density, international travel, habitat development, environmental change, and a plethora of other factors. Additionally, with no approved vaccine for dengue virus currently on the market, it has become of utmost importance to gain a better knowledge of the entomological, virological and immunological components of infection establishment and transmission to prevent its spread. 

          Dengue fever and the more severe conditions it can cause –like dengue shock syndrome and dengue hemorrhagic fever - are a result of infection by dengue virus, a single positive-stranded RNA flavivirus. It is the most common arboviral (viruses that are transmitted by arthropods) infection of humans. The dengue virus vector - the organism that transmits the virus to another organism - is the mosquito Aedes aegypti, a species that originated in Africa. However, the range of this vector has dramatically spread over the past few decades and can now be found in most tropical and sub-tropical regions. The ability of this vector to move into new regions is one of the primary reasons that dengue fever epidemics are now regularly occurring in southeast Asia, India, the western Pacific and much of South America. 

         Even with dengue fever becoming a severe global threat, the study of the disease has been neglected. This is partially a result because of how difficult dengue virus is to study, as result of the lack of a good vertebrate transmission model. While it has been found that mice can get infected in lab settings, they don't get sick in any way which limits the usefulness of mouse models to the study of dengue virus replication. As a result, much research into dengue vaccines has been limited as few are willing to jump into clinical trials with a product that has yet to be animal tested. 

         However, a lab at the Louisiana State University in Baton Rouge might have found the solution to this problem. Using an array of genetic technologies it is possible to target and "knock out" specific mouse genes, allowing researchers to replace existing genes with altered versions. Using this technique, several varieties of knockout mice deficient in type I and II interferon receptors have been developed. By decreasing the response of interferons, the proteins that drive transcription to activate an antiviral response, researchers suspected that they could increase the permissiveness of cells to dengue fever and allow for increased virus transmission. The knock-out mice were inoculated with a non-mouse adapted dengue virus and tested for viral load and cytokine production daily. In addition, the mice were exposed to mosquitoes that were fed the same virus strain via an artificial membrane feeder. Finally, uninfected mosquitos were allowed to forage on dengue virus infected mice to determine if the mosquitos could contract the virus from the mammalian host. 
    

Why Ignore a Hemorrhagic-Fever-Causing Virus?

           Yet another hemorrhagic viral infection is being added to the queue of potential sicknesses in Western Africa.  Lassa fever is a disease that appears with many different symptoms: fever, vomiting, chest and abdominal pains, sore throat, internal bleeding, seizures, and comas.  When these symptoms first present in a patient, however, Lassa fever is rarely even considered as a potential diagnosis.  The disease is usually mistaken for other problems, such as appendicitis and perforated typhoid ileitis, with which it shares many symptoms.  It is only after dangerous abdominal surgeries that Lassa fever is usually diagnosed, but by that point many of the patients are beyond help and end up passing away.  These surgeries usually involve cutting through the abdomen and accessing very vascular tissue for appendectomies or other procedures.  For patients with a hemorrhagic fever, this is exceptionally dangerous, as these patients bleed incredibly easily and may already be exhibiting internal bleeding.  Even the prick of the needle used to administer anesthetics causes incessant bleeding.  Clearly, Lassa fever needs to be considered as a diagnosis in all patients who exhibit these symptoms in order to prevent risky surgeries and needless deaths.

            Treatment of Lassa fever is very simple.  It involves the administration of the antiviral drug ribavirin^1,2 while supportive care is given to keep the patient comfortable, and that is it.  The treatment is very affective, too.  Normally, Lassa fever has a mortality rate of 20-58%³, but with ribavirin treatment, the mortality rate drops to 5%².  Not only could diagnosing Lassa fever earlier save lives by preventing dangerous surgeries, but it could also save a lot of time in money in other ways by starting this simple and effective treatment.

            There are some problems with diagnosing Lassa fever pre-surgery, though.  As described earlier, the symptoms of Lassa fever are very similar to those of other diseases, so diagnostic mistakes may be made.  Also, there are no known methods for testing for the presence of Lassa fever in the early onset of the disease, as the symptoms are nonspecific before the mucosal bleeding begins.^4,5  Lastly, even when Lassa fever is expected, diagnostic facilities in Western Africa typically lack the equipment necessary to test for its presence.⁵  To solve these problems, a sort of checklist needed to be made to help with the diagnosis of Lassa fever.

            Dongo et al. did a case study on seven different patients diagnosed with Lassa fever after going through abdominal surgery.  They hoped to find certain symptoms that were common among all of the cases, but were also unique to Lassa fever.  The researchers ended up finding many common symptoms throughout the cases, all of which are outlined in Table 1.  Every patient had a fever among admission to the treatment center.  Four out of the seven of them had very low white blood cell counts, and two had very low platelet counts, or thrombocytopenia.  Another four of them had prolonged bleeding times when cut or pricked.  A few of the patients also exhibited ascites, which is the build up of fluid in the abdomen.  Because of the hemorrhagic nature of Lassa fever, the built up fluid consists mainly of blood.  This blood also gets excreted through the urinary tract, causing the patient’s urine to be bloody in a symptom known as hematuria.  Lastly, proteinuria was common in some of the cases, which is the presence of excess protein in a patient’s urine.

            While all of these symptoms are good indicators of Lassa fever, they are not all exclusive to the disease.  Dongo et al. have limited the list of symptoms down to thrombocytopenia, high fever, proteinuria, and hematuria.  Specifically, if a patient presents with thrombocytopenia as well as any of the other three symptoms, then there is a good chance they have Lassa fever, and they should be placed on ribavirin immediately.  One last notable indicator the researchers included was the prolonged bleeding from any cut or prick.  If the prolonged bleeding exists along with the other symptoms, the patient is even more likely to have Lassa fever. 

           Beyond that, this extensive bleeding is associated with a higher rate of transmission of the disease.  In many of the case studies, the surgeons or other medical staff attending to the patients contracted Lassa fever.^6,7  In the instances where this secondary infection occurred, every patient exhibited the prolonged bleeding, and in the instances where there was no prolonged bleeding, no transmission occurred. 

Lassa fever is a highly lethal sickness endemic in Western Africa that does not get the attention that it needs.  New guidelines need to be implemented to help diagnose this disease when it is present.  When thrombocytopenia is present along with hematuria, proteinuria, high fever, or prolonged bleeding, it should be assumed that the patient has Lassa fever and the appropriate precautions should be taken.  Doing so will prevent potentially life threatening surgeries, save time and money, and halt the transmission of the disease to healthcare workers.

Primary Article

Dongo AE, Kesieme EB, Iyamu CE, Okokhere PO, Akhuemokhan OC, Akpede GO: Lassa fever presenting as acute abdomen: a case series.  Virology Journal 2013, 10:123.

Supporting Articles

1. Richmond JK, Baglole DJ: Lassa fever: epidemiology, clinical features, and social

consequences. BMJ 2003, 327:1271-1275.

2. Mccormick JB, King IJ, Webb PA, Scribner CL, Craven RB, Johnson KM, Elliot LH,

Belmont-William R: Lassa fever: Effective therapy with Ribavirin. N Engl J Med 1986, 314:20-26.

3. Khan SH, Goba A, Chu M: New opportunities for research on the pathogenesis and treatment of Lassa fever.  J Antiviral 2008, 78:103-115.

4. CDC Lassa fever fact sheet. CDC infectious disease information. Viral haemorrhagic fever. http://www.cdc.gov/ncidod/dvrd/spb/mnpage/dispages/Lassaf.htm

5. Bausch DG: Viral haemorrhagic fevers. In Clinical Infectious disease. Edited by Schlossberg D. New York, NY: Cambridge University Press; 2008:1319-1332.

6. Bowen GS, Tomori O, Wulff H, Cassals J, Noonan F, Downs WG: Lassa fever in Onitsha,

East Central Nigeria in 1974.Bull World Health Organ 1975, 52:599-604.

7. Fischer-Hoch SP, Tomori O, Nasidi A: Review of cases of nosocomial Lassa fever In Nigeria: The high price of poor medical practice. BMJ 1995, 311:857-859.