Haematological Consequences Of Blood Born Viruses Biology Essay

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The blood-borne parasites described as infectious conditions that reach their target tissue through the blood circulation. These parasites are transmitted from one person's blood to another's (often by an insect vector) and that manifest themselves prominently in the blood elements. There are different parasitic causative agents and malaria being one of the most common blood-borne diseases on earth (Bridges, 2008).

The purposes of this discussion is to focus on the blood born of two parasites genus, Plasmodium and Trypanosoma cruzi as an example their life cycle and the advance laboratory diagnosis.

Malaria is a devastating global disease. Human malaria is caused by a parasite called Plasmodium which is a unicellular protozoan parasite that is transmitted by female Anopheles mosquitoes. The parasite is widely distributed around the world, with varying transmission intensity; it is generally a disease of rural areas, with the significant exceptions of Africa and southern Asia. There are four different species of Plasmodium, including Pl falciparum, vivax, ovale and malariae, however, Plasmodium falciparum is the most lethal form of Plasmodium and is the responsible for the vast majority of deaths associated with malaria, estimated that approximately 500 million clinical cases of malaria are reported and between 1-2 million death annually. Symptoms of malaria start to appear between 10 days to 4 weeks after the initial bite. However, in some plasmodium species, symptoms may develop a year after the bite. In benign malaria symptoms include fever (with temperatue upto 40°C), chills, headaches, muscules aches, vomiting and diarrhoea. Malignant malaria usually begins with similar symptoms to benign malaria, However, complications may advance to, liver failure, breathing problems and shock. It can also affect the brain and central nervous system (Ben, 2008).

Haematological consequences

Malaria infection occurs during pregnancy poses substantial risks to the mother, her fetus and the newborn. Severe malaria caused by Plasmodium falciparum is commonly associated with severe anemia, thrombocytopaenia and alterations in the fibrinolytic and coagulation mechanism. Anaemia in pregnant women infected with malaria has been described to be associated with iron status in pregnancy. P. falciparum may affect iron status through reducing intestinal iron absorption, consuming iron for its own metabolism and releasing iron into the circulation during intravascular hemolysis. Young women of child-bearing are known to be more susceptible to malaria than older women as they are still in the process of acquiring natural immunity. A package of interventions has been recommended since 2000 by the World Health to prevent malaria during pregnancy and its consiquencies (Kabanywanyi et al., 2008).

Severe falciparum malaria in children is mostly present with severe anaemia or coma. However, striking feature of these syndromes is the difference in age distributions of infected children. It has been observed that severe malarial anaemia occurs in children with the median age of 1 to 3 years, while coma occurs to children with the median age of 3 to 5 years. Actually, pathogenesis of severe anaemia in malaria is complex. However, it has been suggested that the destruction of uninfected red cells play is a significant role; it is estimated that about 8 to 10 uninfected erythrocytes are destroyed on each lyses infected erythrocyte. The destruction of uninfected red cells is caused by complement activation during malaria infection. In young children however, due to the lack of proteins such as Complement receptor 1 (CR1 or CD35), decay accelerating factor (DAF or CD55) which are involved in the control of complement activation increase red cells susceptibility to complement immune complexes, the opsimized RBC are then removed by the liver and spleen resulting in severe anaemia (Kai and Roberts, 2008: Odhiambo et al., 2008).

Cerebral malaria (CM) is a major cause of morbidity and mortality in children and young adults infected with Plasmodium falciparum. In sub-Saharan Africa, incidence of CM is estimated to be 1.12 cases per 1,000 children per year with 18.6% mortality, while 10% of the survivors may develop neurological sequelae. In Asia and South America, however, where P. falciparum incedence is lower, CM have been observed in all age groups. Cerebral malaria is complex syndrome characterized by neurological signs, seizures and coma, it is associated with a loss of cerebrospinal fluid spaces and ischemia, alterations in cerebral blood flow velocity and a decrease in cerebral oxygen consumption. The pathogenesis of CM is still poorly understood, evidence suggests that the host's immune system plays a major role in expressing certain cytokines, e.g. TNF-α and IFN-γ, and activating immunocompetent cells.

The malaria life cycle

Figure 1: Shows the life cycle of malaria in humans (Jones and Good, 2006).

Malaria life cycle is started when sporozoites are injected into human dermis during a mosquito bite. After inoculation, sporozoites migrate to liver cells to establish an infection inside hepatocytes (exoerythrocytic phase) which will generate to merozoites. Merozoites invade erythrocytes (RBCs) to start the erythrocytic stage in which severe conditions of malaria occur. In the circulation some of the parasites will transform to sexual stages (gametocytes) which are then ingested by a mosquito during a blood meal. Within the mosquito vector the gametocytes will form gametes and fertilisation resulting zygote. Zygote will develop and differentiates into several stages to reach sporozoites which will move, mature and stored inside the salivary glands ready for transmission to the host upon the next blood meal; thus, the life cycle is starting again (Lasonder et al., 2008).

Clinical Diagnosis

Malaria presents a diagnostic challenge to laboratories in most countries. Its early accurate diagnosis and prompt effective treatment are vital, as a few hours delay in treatment can mean the difference between life and death. Clinical diagnosis of malaria is based on the patient's symptoms and physical examination, which have never been validated, have very low accuracy and non-specific. As such, clinical diagnosis needs to be confirmed by a laboratory test to reduce unnecessary use of antimalarials. This inappropriate treatment can result in increase transmission of drug-resistant parasite strains which may results in increase in morbidity and mortality. In many areas however, where parasitological diagnosis is not currently available, The World Health Organisation (WHO) recommendations for clinical diagnosis are still considered valid. Theses clinical diagnosis are based on two categories; In areas where the risk of malaria is low, clinical diagnosis should be based on the degree of exposure to malaria and a history of fever in the previous 3 days where no other severe diseases are suspected. While in areas where the risk of malaria is high, the diagnosis should be based on a history of fever in the previous 24 h and/or the presence of anaemia, which is characterised by pallor of the palms and it is considered to be the most reliable sign in young children (WHO, 2006).

Microscopic Diagnosis

For over a century, light microscopy remained the golden standard for routine malaria diagnosis. It is the most widely used method due to its cost effective, relatively sensitive and can easily be applied. Microscopic examinations of Giemsa-stained thick and thin blood smears allowing the detection of 50 to 500 parasites/μl respectively, and enable identification of plasmodial species and quantification of parasites, in which, both are important to assess disease severity and to prescribe adequate therapy. However, microscopic examination requires a laboratory set-up with a good microscope, reagents, and slides. Moreover, interpretation of blood smears require considerable expertise, particularly in cases of mixed infection or low parasitemia. This and the current lack of standardized, can potentially contribute to false negative results or unreliable species determination. In 2002, 262 laboratories were cross-checked for the results of microscopic species identification by the United Kingdom National External Quality Assessment Scheme (UKNEQAS) on which the accuracy varied from 64% to 95% (Rougemont et al., 2004; Kyabayinze et al., 2008).

For microscopically diagnosis of malaria parasites both thick and thin blood smears are prepared, most often from a finger prick, and stained by Giemsa-stained. Thick blood smears allow a larger volume of blood to be examined, as such; it is more sensitive and mostly used in detecting infection, and estimate parasite concentration. Unfortunately thick blood smears are more difficult to read. Thin blood smears, however, are most useful in examining plasmodia morphology which determines the type of malaria species causing the infection. Due to its low sensitivity at low parasite densities, and the time required for it to be screened, the thin blood films are rarely examined in the developing world and frequently not even made. On the other hand, in the Western world, laboratory technicians relying more on the thin blood film for a definitive diagnosis as it is felt to be easier to make and interpret. A standard reference suggests that thin blood film is 30 fold less sensitive than the thick b lood film, while 1917 a reference reported that thin film is 1-4 fold less sensitive. Dowling and Shute reported that the thin film read for 10 minutes was similar to the thick smear read for 3 minutes however; they suggested that, thin film is much more efficient for identification of Plasmodium ovale. Common errors which may lead to false positive are caused by platelets overlying a red blood cell, and misreading artifacts as parasites. Moreover, if a persons is suspected of having malaria but no parasites are indicated, should have blood smears repeated every 12--24 hours for 3 days (CDC, 1998; Ohrt et al., 2008).

http://www.malaria.org.za/Malaria_Risk/General_Information/general_information.html

Serological detection:

Despite that microscope is considered to be a gold standard for malaria diagnosis, and has several advantages over other diagnostic approaches, it requires laboratory skills. Rapid diagnostic tests (RDTs) however, requires less expertise, potentially safe, cost-effective, offer the possibility for accurate and accessible detection of malaria parasites, RDTs play important role in limiting malaria over-diagnosis and over-treatment. The WHO has issued recommendations on uses of RDT, as such numerous malaria RDTs are now commercially available. However, the selection of the most suitable RDT remains difficult for some users, as a number of factors related to qualities of RDT itself, such as target antigen, shelf-life, heat sensitivity, cost, sensitivity and specificity, have to be considered. In addition, RDTs diagnostic accuracy can vary on the geographical and epidemiological circumstances of the areas where the tests are to be deployed, which make it difficult to compare results from other conducted studies (Lubell et al., 2008; Mariette et al., 2008).

RDT based on the detection of malaria antigen when patient's blood flowing along a membrane containing specific anti-malaria antibodies. Most of RDTs focusing on the detection of histidine rich protein-2 (HRP-2) and Plasmodium lactate dehydrogenase (pLDH). HRP2 antigen is uniquely synthesized by P. falciparum, thus, the test can distinguish P. falciparum from other plasmodium species and have been recommended in areas where P falciparum is dominant. However, HRP-2 may persist in the blood stream for days or weeks after treatment. An alternative type of RDT detects the enzyme parasite lactate dehydrogenase (pLDH) which is produced by sexual and asexual stages of all four human Plasmodium species, as such, can not differentiate between the Plasmodium species. LDH, however, can only be detected if live parasites are present. Some types of RDT such as BinaxNOW is able to detect both HRP2 and malaria aldolase and so can identify P. falciparum from other P species but unfortunately cannot distinguish between the other three. A part of variation in antigen detection, RDT tests are available in many formats including plastic cassettes, cards or dipsticks, and their quality depends on manufacturer and storage conditions (Endeshaw et al., 2008).

http://www.malariasite.com/MALARIA/rdts.htm

Molecular Diagnosis

Diagnosis of malaria parasites by PCR technique exhibits sensitivity and specificity superior to those of microscopy, and rapid diagnostic tests (RDTs). It has greatly expanded the capability to understand malaria parasite parasitism beyond the blood smear sensitivity limits. It is estimated that PCR-based technique is able to detect malaria parasite from whole blood at the concentration of 1 to 5 parasitized erythrocytes/5 - 106 erythrocytes/μl, which is equivalent to a parasitemia level of 0.0001%. These results obtained are often useful in making specific treatment decisions to kill species that are capable of establishing dormant liver stages and subsequent malarial relapses. These consistently low-level infection reported by PCR detection suggests that the prevalence of malaria parasite infection is higher than that estimated by evaluation of blood smears. Due to its increased sensitivity, PCR diagnostic assays is also used to detect the persistence of chronic infection during the time when malaria parasite transmission level is low to reveal different epidemiological patterns from those understood prior to PCR technique. The disadvantages of PCR technique however, is that, it is unlikely to be useful outside of well-equipped laboratories, failure to differentiate developmental stages of the parasite's erythrocytic life cycle and difficult to determine the levels of parasitemia due to the factors influencing sample collection, storage, and processing. Finally, the limits of detection, based on the amount of sample that required to evaluated in a single reaction (McNamara et al., 2004).

Several molecular methods which utilise PCR have been developed for the detection of malarial parasite; these include Nested PCR, Real-time quantitative PCR, Loop-mediated isothermal amplification (LAMP) and Multiplex PCR methods. These techniques can give valuable information when difficult morphological problems arise during attempts to identify parasites to the species level. Various polymorphic molecular markers are used in these techniques as targets for the differentiation of Plasmodium spp. These markers include circumsporozoite protein (CSP), apical membrane antigen 1 (AMA1), merozoite surface protein 1 (MSP1), small-subunit 18S rRNA. The CS gene for instant has been used for species-specific regions and has been coupled with specific fluorescein or radiolabeled probes for detection of P. vivax (Yang et al., 2006).

http://www.fda.gov/Cber/blood/malaria071206sk2.htm

Fluorescence Microscope

Fluoresce microscope was introduced in an attempt to reduce the visual task and to enhance the detection of malaria parasites in blood films. The technique uses type of fluorescent dyes that have an affinity for the nucleic acid and will attach to the parasite nuclei. When these parasite nuclei excited by an appropriate wavelength of UV light they fluoresce strongly. As such, the malaria parasites can then be easily examined in a markedly reduced length of time. Two types of fluorochromes, acridine orange (AO) and benzothiocarboxypurine (BCP) are commonly used for this technique, and they both excited at 490 nm and exhibit apple green or yellow fluorescence. Another type of fluorochromes is called Rhodamine-123, and is useful for assessing the viability of parasites, since its uptake relies on an intact, working parasitic membrane (Moody, 2002).

An acridine orange (AO) method used either as a direct-staining technique or combined with a concentration method such as a thick blood film. A centrifugal quantitative buffy coat (QBC) combines an AO-coated capillary tube, while WBC and platelets are separated by centrifugation. The fluorescence-stained parasites can be viewed through the capillary tube using a special fluorescence microscope. AO staining is able to detect malaria parasites at the levels of <100 parasites/μl (0.002% parasitemia), with an excellent specificity for P. falciparum (>93%). Despite that AO is a very intense fluorescent stain, it is nonspecific and stains nucleic acids from all cell types. As such it required a microscopist who is able to distinguish fluorescence-stained parasites from other cells and cellular debris containing nucleic acids, Particular in the presence of Howell-Jolly bodies from patients with hemolytic anemia (Moody, 2002).

The specimen is a smear of human blood containing the malarial parasite stained with acridine orange

Treatment

Adequate diagnosis and prompt treatment are two important factors in management of malaria disease. In rural areas in sub-Sahara Africa, for instance, more than 70% of individuals with symptoms received anti-malarial drugs without visiting health sectors. Due to the lack of accurate diagnosis facilities in these areas, malaria diagnosis is based on clinical symptoms that are known to lack specificity which lead to over-treatment and unnecessary exposure to antimalarials resulting in increase transmission of drug-resistant parasite. Drugs such as Chloroquine and sulphadoxine-pyrimethamine (SP) once were commonly used, have become largely ineffective as monotherapy for the treatment of Plasmodium falciparum. As such, The World Health Organization (WHO) has recently recommended artemisinin-based combination therapy (ACT) as first-line treatment for all falciparum malaria, as they are safe, well-tolerated and rapidly acting, generally, given over three days. In addition, ACT is effective against both asexual and early sexual parasite stages. Recent studies have shown that efficacy and effectiveness of ACT provides cure rates of over 90% (Pongtavornpinyo et al.,2008; Saulo et al.,2008).

Despite of its recommendation and increasingly uses, the ACT remains in unaffordable cost to many communities and governments in poorer countries. Although a co-formulated ACT consisting of artesunate and amodiaquine (announced in 2007) is available at prices as low as US$ 0.5 per child dose and US$ 1.0 per adult dose, it is still 5 - 10 times higher than the prices of chloroquine or SP in Africa. Studies done in animal modals have shown that artemisinin derivatives is associated with neuronal damage, particularly in areas of the brainstem involved in hearing and gait control while in human, clinical studies including thousands of patients confirmed that artemisinin-based combination therapies were safe and well tolerated (Carrara et al., 2008; Saulo et al., 2008).

Prevention

Currently, several vaccines against multiple stages are in clinical development including pre-erythrocytic, blood stage and other. Despite that these vaccines vary in their characteristics, it is unlikely that any of them will provide long-lasting sterilizing immunity against the malaria parasite. As long as there is no an official used maliria vaccine, the control of spreading of the vector mosquitoes remains the most affective may of preventing the infection. This can be achieved by preventing mosquito from breeding, such as, avoiding water accumulation, applying larvicides to stagnant water to limit mosquito reproduction and by spraying insecticides to kill the existing mosquitoes. The other affective way is by avoid mosquito bites, this can be achieved by avoiding mosquito-infested areas, by using repellent agents and by wearing long sleeves, long pants, socks and gloves particularly at the time when mosquitoes are most active, furthermore, by prevent the infected person from mosquito bite in order to minimise the viral life cycle (Penny et al., 2008). The public education and awareness of the disease and its vector must be well considered so that the preventing measures are taken particularly by maintain a clean environment

Conclusion

Regardless of whether microscopic or other non microscopic technique is used for malaria diagnosis, education of laboratory staff about malaria diagnosis, quality control and quality assurance systems are very important factors to be put in place to ensure the diagnosis is of a high standard. If clinicians will have low confidence in the tests used, patients will be treated based on clinical symptoms. These clinical symptoms have never been validated and have very low accuracy and less specificity. Continue to do so will be very unlikely that the use of microscopy or other laboratory technique give any benefit and their use. Furthermore, by giving an inappropriate malaria treatment will not just cause unnecessary exposure to antimalarials, but will increase transmission of drug-resistant parasite strains resulting in increase morbidity and mortality (WHO, 2006; Tagbor et al., 2008).

Microscopic Diagnosis

For over a century, light microscopy remained the golden standard for routine malaria diagnosis. It is the most widely used method due to its cost effective, relatively sensitive and can easily be applied. Microscopic examinations of Giemsa-stained thick and thin blood smears allowing the detection of 50 to 500 parasites/μl respectively, and enable identification of plasmodial species and quantification of parasites, in which, both are important to assess disease severity and to prescribe adequate therapy. However, microscopic examination requires a laboratory set-up with a good microscope, reagents, and slides. Moreover, interpretation of blood smears require considerable expertise, particularly in cases of mixed infection or low parasitemia. This and the current lack of standardized, can potentially contribute to false negative results or unreliable species determination. In 2002, 262 laboratories were cross-checked for the results of microscopic species identification by the United Kingdom National External Quality Assessment Scheme (UKNEQAS) on which the accuracy varied from 64% to 95% (Rougemont et al., 2004; Kyabayinze et al., 2008).

For microscopically diagnosis of malaria parasites both thick and thin blood smears are prepared most often from a finger prick, and stained by Giemsa-stained. Thick blood smears allow a larger volume of blood to be examined, as such; it is more sensitive and mostly used in detecting infection, and estimate parasite concentration. Unfortunately thick blood smears are more difficult to read. Thin blood smears, however, are most useful in examining plasmodia morphology which determines the type of malaria species causing the infection. Due to its low sensitivity at low parasite densities, and the time required for it to be screened, the thin blood films are rarely examined in the developing world and frequently not even made. On the other hand, in the Western world, laboratory technicians relying more on the thin blood film for a definitive diagnosis as it is felt to be easier to make and interpret. A standard reference suggests that thin blood film is 30 fold less sensitive than the thick film, while 1917 a reference reported that thin film is 1-4 fold less sensitive. Dowling and Shute reported that the thin film read for 10 minutes was similar to the thick smear read for 3 minutes however, they suggested the thin film is much more efficient for identification of Plasmodium ovale. Common errors which may lead to false positive are caused by platelets overlying a red blood cell, and misreading artifacts as parasites. Moreover, if a persons is suspected of having malaria but no parasites are indicated, should have blood smears repeated every 12--24 hours for 3 days (CDC, 1998; Ohrt et al., 2008).

http://iier.isciii.es/mmwr/preview/mmwrhtml/ss5005a2.htm

Figure A-2

,

Serological detection:

Despite that microscope is considered to be a gold standard for malaria diagnosis, it requires laboratory skills. Rapid diagnostic tests (RDTs) however, requires less expertise, potentially safe, cost-effective, offer the possibility for accurate and accessible detection of malaria parasites, RDTs play important role in limiting malaria over-diagnosis and over-treatment. The WHO has issued recommendations on uses of RDT, as such numerous malaria RDTs are now commercially available. However, the selection of the most suitable RDT remains difficult for some users, as a number of factors related to qualities of RDT itself, such as target antigen, shelf-life, heat sensitivity, cost, sensitivity and specificity, have to be considered. In addition, RDTs diagnostic accuracy can vary on the geographical and epidemiological circumstances of the areas where the tests are to be deployed, which make it difficult to compare results from other conducted studies (Lubell et al., 2008; Mariette et al., 2008).

RDT based on the detection of malaria antigen when patient's blood flowing along a membrane containing specific anti-malaria antibodies. Most of RDTs focusing on the detection of histidine rich protein-2 (HRP-2) and Plasmodium lactate dehydrogenase (pLDH). HRP2 antigen is uniquely synthesized by P. falciparum, thus, the test can distinguish P. falciparum from other plasmodium species and have been recommended in areas where P falciparum is dominant. However, HRP-2 may persist in the blood stream for days or weeks after treatment. An alternative type of RDT detects the enzyme parasite lactate dehydrogenase (pLDH) which is produced by all four human Plasmodium species, as such, can not differentiate between the Plasmodium species. LDH, however, can only be detected if live parasites are present. Some types of RDT such as BinaxNOW is able to detect both HRP2 and malaria aldolase and so can identify P. falciparum from other P species but unfortunately cannot distinguish between the other three. A part of variation in antigen detection, RDT tests are available in many formats including plastic cassettes, cards or dipsticks, and their quality depends on manufacturer and storage conditions (Endeshaw et al., 2008).

Molecular Diagnosis

Diagnosis of malaria parasites by PCR technique exhibits sensitivity and specificity superior to those of microscopy, and rapid diagnostic tests (RDTs). It has greatly expanded the capability to understand malaria parasite parasitism beyond the blood smear sensitivity limits. It is estimated that PCR-based technique is able to detect malaria parasite from whole blood at the concentration of 1 to 5 parasitized erythrocytes/5 - 106 erythrocytes/μl, which is equivalent to a parasitemia level of 0.0001%. These results obtained are often useful in making specific treatment decisions to kill species that are capable of establishing dormant liver stages and subsequent malarial relapses. These consistently low-level infection reported by PCR detection suggests that the prevalence of malaria parasite infection is higher than that estimated by evaluation of blood smears. Due to its increased sensitivity, PCR diagnostic assays is also used to detect the persistence of chronic infection during the time when malaria parasite transmission level is low to reveal different epidemiological patterns from those understood prior to PCR technique. The disadvantages of PCR technique however, is that, it is unlikely to be useful outside of well-equipped laboratories, failure to differentiate developmental stages of the parasite's erythrocytic life cycle and difficult to determine the levels of parasitemia due to the factors influencing sample collection, storage, and processing. Finally, the limits of detection, based on the amount of sample that required to evaluated in a single reaction (McNamara et al., 2004).

Several molecular methods which utilise PCR have been developed for the detection of malarial parasite; these include Nested PCR, Real-time quantitative PCR, Loop-mediated isothermal amplification (LAMP) and Multiplex PCR methods. These techniques can give valuable information when difficult morphological problems arise during attempts to identify parasites to the species level. Various polymorphic molecular markers are used in these techniques as targets for the differentiation of Plasmodium spp. These markers include circumsporozoite protein (CSP), apical membrane antigen 1 (AMA1), merozoite surface protein 1 (MSP1), small-subunit 18S rRNA. The CS gene for instant has been used for species-specific regions and has been coupled with specific fluorescein or radiolabeled probes for detection of P. vivax (Yang et al., 2006).

Microarray Test

Conclusion

Regardless of whether microscopic or other non microscopic technique is used for malaria diagnosis, education of laboratory staff about malaria diagnosis, quality control and quality assurance systems are very important factors to be put in place to ensure the diagnosis is of a high standard. If clinicians will have low confidence in the tests used, patients will be treated based on clinical symptoms which has never been validated and has very low accuracy and less specificity. Continue to do so will be very unlikely that the use of microscopy or other laboratory technique give any benefit and their use. Furthermore, by giving an inappropriate treatment will not just cause unnecessary exposure to antimalarials, but will increase transmission of drug-resistant parasite strains resulting in increase morbidity and mortality (WHO, 2006).(Tagbor et al., 2008).

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