Fever Profile - Malaria - Typhoid

What is Fever

In a healthy individual, the optimum body temperature for regulation and proper functioning is around 37C (98.6F). Fever also called as pyrexia or controlled hyperthermia, is characterized by elevated body temperature, which is a defense mechanism against infections and other foreign substances. Fever is induced by pyrogenic substances that can be endogenous or exogenous, external foreign substances like viruses and bacteria are examples of exogenous pyrogens. Fever also develops due to the production of prostaglandins, which are needed to fight germs.

Persistent fever could be an underlying cause of several infectious diseases such as chikungunya, malaria, typhoid??, dengue and many more diseases. It is the first major symptom that helps to recognize diseases. The fever profile consists of blood tests that screens for the presence of causative factors.

Malaria

Malaria is a parasitic infection caused by Plasmodium species and transmitted by female Anopheles mosquitoes. Malarial parasites present in the infected mosquito's saliva are transmitted to human blood through mosquito bites.

Malarial Antigen A blood test examines the presence of malarial antigen in the blood released by the malarial parasite. Positive result may indicate the risk and type of malaria.

Typhoid

Fever is majorly caused by Salmonella typhi (gram negative bacterium), Salmonella paratyphi A and Salmonella paratyphi B. It spreads through contaminated food and water or through close contact with someone who is infected. Signs and symptoms usually include high fever, headache, abdominal pain, and either constipation or diarrhea.

Typhoid Test This test determines the presence of antibodies produced by immune system of a person exposed to typhoid bacterial proteins or typhoid DNA in the blood.

Dengue Dengue virus belongs to the family of Flaviviridae, which is transmitted by the bite of infected Aedes mosquitoes. It manifests as mild asymptomatic illness, or severe dengue hemorrhagic fever/ dengue shock syndrome.

Dengue Antibody Test-IgG and IgM A blood test that determines the presence of antibodies produced by immune system of a person exposed to dengue viruses.

Complete Hemogram Test A complete blood count test evaluates the overall health of an individual.

Malaria - Jinx to Mankind Just a Fever! It always begins from here and we presume it isn't a cause for concern.

Malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. It is caused by parasitic protozoans belonging to Plasmodium family. Infected female anopheles mosquito is the transmission vector in Malaria. Although rare, malarial parasites can also be transmitted by blood transfusion. The females of the anopheles genus of mosquito prefer to feed on blood at night .

In humans, malaria is caused by
1.Plasmodium vivax
2.Plasmodium falciparam
3.Plasmodium malariae
4. Plasmodium ovale

Malaria Lifecycle The Vicious Circle The malarial parasite life cycle involves two hosts, humans and female anopheles mosquitoes. In humans, during a blood meal, malaria-infected mosquito injects sporozoites (found in infected mosquito's salivary glands) into the blood gametocytes stream. Sporozoites rapidly leave the circulation and infect the liver cells, reproduce asexually and produce daughter cells (merozoites) which are released into the circulation. These merozoites invade the red blood cells and undergo Early asexual multiplication in the erythrocytes, mosquito producing 8 to 24 new infective merozoites, stage at which point the infected erythrocyte bursts and releases more merozoites and the infective cycle continues. Blood stage parasite manifest the disease in human.

In female mosquitoes, the parasites multiplication is known as sporogonic Late cycle. The gametocytes of male and female mosquito which are produced from the merozoites are stage taken in during the blood meal. In the mosquito's stomach, male and female gametes fertilize with each other to form zygote. These oocyst zygotes transform into cokinetes and cross the midgut wall of the mosquito, where these ookinetes develop into oocysts. Further, oocysts mature and divide many times to produce large numbers of small, elongated sporozoites that migrate to the mosquito's salivary glands. Injection of sporozoites in another human host continues the malarial life cycle.

High-risk population for malaria Some population groups are at considerably higher risk of contracting malaria, and developing severe disease than others. These include the following
Infants Infants born in regions prone to malaria are highly exposed to this disease from approximately 3 months of age, as the immunity obtained from the mother starts to decrease.
Children under 5 years of age In high transmission areas, children under 5 years of age acquire partial immunity to the disease. Majority of the malarial disease occur in these children without acquired immunity.
Patients with HIV/AIDS HIV infection increases the risk of malarial infection, especially patients with immunosuppress ion (reduction in the activation of the immune system). HIV infected adults in high transmission areas may lead to complicated and severe malaria and death.
Pregnant women Malaria in pregnant women is a major public health problem increasing the risk to maternal and fetal health. This can lead to stillbirth, miscarriage, anemia, low birth weight and fetal death.
Migrants, Mobile populations and Frequent travelers Migrants, refugees and other mobile population groups often lack partial immunity to malaria, and have limited access to prevention, diagnostic testing and treatment services.

Signs and Symptoms of malaria

The signs and symptoms of malaria usually begin around 9 to 14 days after the bite by an infected mosquito. The most common symptoms are Paroxysm i.e. cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every two days (tertian fever) in P. vivax and P. ovale infections, and every three days (quartan fever) for P. malariae and P. falciparum infection High fever over 38C for more than few hours
Headache
Vomiting
Chills and rigors
Fatigue

Symptoms for severe and complicated malaria
High Fever
Prostration (inability to sit)
Breathing difficulties
Severe anemia
Generalized convulsions/fits
Inability to drink or vomiting Dark or limited production of urine

Malaria, sometimes called the "King of Diseases" is a complex disease that, even under the most optimistic scenario, will continue to be a major health threat for decades. Relapses are important contributors to illness and morbidity in P. vivax and P. ovale infections. The malaria parasite is able to evade and modulate the immune response. Therefore, immunity against the malaria parasite is suboptimal. Complete eradication of malaria is a big challenge.

Different species of mosquito respond differently to medicines, exhibit drug resistance in different ways, creating a foolproof vaccine against all malarial infections, are several challenges making the attempts complex and difficult. Malaria, caused by single-cell parasite has the capacity to invade and evolve in varied ways that can escape the immune system.

A person recovered from malaria is not assured of protection from malarial infections in the later stage of life. As the body cannot develop immunity because of the continuous change of malaria parasite makes it very complex to create a vaccination. Even prolonged exposure to insecticides can develop resistance towards insecticides by the mosquitoes.

Though it seems to be a daunting condition, there are various ways to be optimistic and bring change in the environment. Educating and taking action on hygiene and sanitation can control malaria. Travelers being aware of malaria risk and taking efforts for protective measures and malarial prevention can help reduce its attributable mortality and morbidity. Regions with limited financial resources face problems in preventing the infection, but implementing chemoprophylaxis and permethrin-impregnated bed nets have helped against malaria in these regions. Therefore, as such fever is a threat to one's life, do not leave your sickness ignored.

Thyrocare offers Fever Profile Testing for the qualitative analysis of malaria antigen using advanced and sophisticated automated technology using immunoassay at highly affordable rates.

Malarial Biomarkers

Malaria is one of the most common zoonotic transmissions reported in tropical and subtropical zones of the globe. The protozoan causing this ancient disease belongs to the family of genus Plasmodium. The Center for Disease Control (CDC) has declared malaria to be an endemic, spreading the infection in more than 100 countries. In 2019, India reported 3,38,494 malariarelated morbidity cases.

There are five species of Plasmodium that can cause this illness
- Plasmodium falciparum (P. falciparum)
- Plasmodium malariae (P. malariae)
- Plasmodium vivax (P. Vivax)
-Plasmodium ovale (P. ovale)
-Plasmodium knowlesi(P. knowlesi)

Although all of them are being transferred via Anopheles mosquito, P. falciparum accounts for the highest mortality rate. Investigations suggest that the in vivo proliferation of the pathogen is associated with intracellular structural modifications and hijacking other healthy red blood cells for survival.

Cerebral malaria is considered to be the most severe neurological complication of infection with Plasmodium falciparum. It is a clinical syndrome characterized by the clinical hallmark of coma which is usually caused by parasitized red blood cells (PRBCs) sequestered in cerebral microcirculation and the finding of asexual forms of the parasite on peripheral blood smears. Mortality rate for this syndrome is high and some surviving patients perpetuate brain injury that reflects as long-term neurocognitive impairments

Moreover, the parasite has exhibited tremendous resistivity towards various drugs, urging medical professionals and technologists to come up with better advances in diagnosis and treatment that may help in right choice of prophylaxis.

Elements of the Parasitic Lifecycle Responsible for Transmission On this World Mosquito Day, CDC has urged people to pay attention to the mosquito Anopheles stephensi, responsible for the quick spread of infections in many man-made habitats.

Earlier there was an urgent need to understand the parasitic lifecycle and its mode of transmission but now scientists have diverted their attention towards the relevance of finding specific biomarkers for quick diagnosis.

Symptomatic Assessment in a ResourceLimited Setting
Traditional diagnostic methods were mostly dependant on the symptomatic exhibition of a condition; such as fever, chills, extreme headache, fatigue, muscular pain, nausea, vomiting, and loss of appetite.

These symptoms, if ignored for a longer period, turn out to be fatal within a short time. However, at the same time, they are also found to be overlapping with other common health challenges like pneumonitis, tuberculosis, and other gastrointestinal issues. At the same time, in areas that are declared with endemic species by world health authorities; some people can often go asymptomatic, further escaping the clinical evaluation of malaria. Some patients have reported severe health challenges like respiratory distress due to pulmonary edema, severe anemia, acute kidney failure, hypoglycemia,etc

Previously, it was challenging to diagnose malaria on time, causing significant morbidity and mortality associated with the same. Estimates have suggested that the numbers of clinical illnesses reported are above five billion episodes. The data has further pinpointed the fact that more than 60% of the reported cases are from the poor, underdeveloped parts of the world that are still struggling to get better diagnostic facilities and medical support.

Thus, while poverty struck areas of the world are still looking for better medical facilities, clinical scientists are working on game changing biomarkers as tools in diagnosis and treatment.

Available Biomarkers
Although, science and technology have experienced vast advancements over time, and diagnosing malaria is not an exception, it is undeniable that the majority of diagnostic procedures available today are still dependent on the age-old process of blood smear analysis. Accordingly, current biomarker testings available for rapid detection of malaria parasites are listed

Nucleic Acid Amplification Testing
Fortunately, with aggressive scientific research, contemporary methods are now available based on nucleic acid amplification of circulating pathogenic DNA that is more sensitive, faster, and accurate as compared to classic methods. Studies have further supported that genomic assessment methods are very accurate in detecting even the lowest pathogenic load, such as 5 parasites per microlitre.

Rapid Testing Using Immunological Lateral Flow Devices
It is possible to detect pathogenic parasites from circulating blood using lateral flow immunochromatography assay. Theoretically, this approach has been proposed to be more rapid, sensitive, and accurate in detecting the very minute level of parasitic antigen. The method has also gained high scientific acknowledgment due to its ability to detect antigenic receptors for many parasitic generations that have been difficult earlier using a light microscope. Moreover, with this method it is possible to detect the parasite from saliva and/ or urine of the infected person; and hence, can resolve major challenges associated with sampling of blood even, with a reported sensitivity of around 73% that can be increased to 83% in highly infected patients.

Urine Malaria Rapid Detection Method
It is a recently developed technique that can detect the histidine-rich protein II (HRP-II) biomarker of P. falciparum. The method requires urine sample and hence has been acknowledged as non-invasive method of detection. Investigations have indicated that the method is highly efficient with high sensitivity and specificity as compared to other existing methods. Some other studies have further suggested that with the current method, it is possible to detect 120 parasites/L; and is found to be 50% higher in comparison to other methods from a similar domain. However, further optimization is still mandatory to avoid false positive detection due to void sampling, like morning urine with a higher antigenic titer.

Loop-Mediated Isothermal Amplification (LAMP)
This is one of the most promising and widely assessed diagnostic techniques, capable of detecting even the minutest concentration of human Plasmodium spp. The method is also commercially available in the form of LAMP kits and can detect direct as well as indirect infections associated with P. falciparum as well as P. vivax, and is further classified as one of the high-throughput techniques. Studies have indicated that from any given sample including blood, saliva, and/or urine; the technique can help detect low as 2.5 parasites/uL in a very cost-efficient manner.

Multiplex Biomarkers & Future Prospects
With technological evolution, it is now possible to sense presence of pathogenic parasites from any given sample i.e. blood and/or urine, using self-contained analytical devices without the need for any processing steps. The technology incorporates nanoscience; which further enables the detection of monoclonal antibodies against the pathogenic antigen. The assay is found to be highly sensitive with the detection limit at 0.00005%. Scientists are relying on these one-step detection techniques to overcome traditional diagnostic challenges due to the paucity of specific biomarkers.

Conclusively, despite the evolution of diagnostic techniques for more accurate and better detection of pathogens; people are more inclined towards using traditional technology even with limited sensitivity and specificity. This is further limiting the process of complete eradication of malaria, especially in asymptomatic individuals. Other developed techniques like rapid tests and nucleic acid amplification tests are more confined to the fixed population of people; demanding expert handling and basic biological understanding, further rendering them not suitable for routine implementations. This further compels the implementation of more advanced techniques like multiplex biosensing systems, due to their suitability in off-lab settings, high sensitivity, and specificity. With the new approach provoking to find ultra-sensitive, field ready, and user friendly methods; the scientific world is all set to live in the malaria-free world!

Dengue

Dengue also termed as the Bone break fever", is a febrile illness that can result in fatal outcome in severe cases. Caused by Flavivirus, it is spread by the mosquitoes belonging to Aedes genus majorly the Aedes aegypti and Aedes albopictus. It is a vector borne disease and the status of the host immune system, pathogen virulence, host genetic makeup, etc. greatly influence the rate of progression of disease in an affected individual

Epidemiology and prevalence of dengue
Dengue is never reported as a singular case in any region or population group as its occurrence is always seasonal and as an epidemic. India is believed to have more cases of dengue than any other country in the world, with major outbreaks in recent years. Mumbai is found to be one of the most affected city in Maharashtra in the year 2014 due to erratic rains and weather changes. Many other states all over India have also been reported to be affected with dengue; increased cases majorly from the Northeast region of the country.

Mode of Transmission and Stages of Dengue Viruses are infectious agents which have the ability to infect any host cell, utilise its machinery and multiply to raise an infectious state The causative agent of dengue is transmitted through an infected mosquito bite. When a mosquito bites a dengue infected person, the virus enters into mosquito and undergoes a state of dormancy. Post this phase, the active virions enter the salivary gland of the mosquito and thus result in making the vector highly infectious.

Symptoms of Dengue
- Fever
- Nausea
- Liver enlargement
- Failure of circulatory system
- Damage to blood vessels.

Risk factors of Dengue
1.Dengue virus is found to efficiently survive in tropical climates, and hence, people residing in such regions are always at a higher risk.
2. Presence of filth, stagnant water bodies, unclean surroundings all become active breeding grounds for mosquito larvae.
3. Also lack of awareness in diag nosis leads to an increased risk factor. Differentiation between febrile illness and dengue is very important for appropriate and timely treatment.

Diagnosis of Dengue

On presenting symptoms of fever, headache accompanied by severe body ache, the first test recommended by a physician will be a complete blood count (CBC). This test will highlight clinical status of the count of blood cells and platelets which is extremely important for differential diagnosis of dengue. Reduction in platelet count is one of the major signs of dengue and can aid the doctor to start a preliminary antiviral treatment. However, this condition can arise in other viral conditions as well and hence further specialised tests like Enzyme linked immunosorbent assay (ELISA) may be recommended by the doctor to assess disease prognosis as well as treatment efficiency. Serum IgG and IgM levels are estimated for confirmatory diagnosis of dengue.

Treatment of Dengue
There are no specific and dedicated treatment modalities available for dengue. Treating dehydration and low platelet count condition is the only path to recovery. Treatment with general analgesics like acetaminophen is done to provide relief from fever and pain.

Why is this vicious cycle not breakable?
Poor sanitation is one of the major causes of dengue in India. Unattended garbage and stagnant water bodies become breeding grounds for mosquitoes thus making all classes of people susceptible to this painful condition. The major preventive measures to be taken for dengue are as follows:
Drains should be kept free from choke.
To avoid breeding of larva at home, clean the water in the saucer of potted plants.
Aedes mosquitoes is most active during day time and hence avoid going near shrubs where adult mosquitoes rest during the day.
Dispose all the household garbage into bins which are properly covered.
Wear clothes and shoes which completely cover especially when visiting dengue endemic areas.
Install mosquito screens on the windows and ensure use of repellents.