ETIOLOGY AND PATHOGENESIS
Four species of the genus Plasmodium cause nearly all malaria infections in humans (although rare infections involve species normally affecting other primates). These are Plasmodium falciparum, Plasmodium vivax , Plasmodium ovale, and malariae. Almost all deaths are caused by falciparum malaria. Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal. These microscopic motile forms of the malarial parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction. By this amplification process ( known as intrahepatic or preerythrocytic schizogony or merogony), a single sporozoite eventually may produce from 10000 to >30000 daughter merozoites. The swollen infected liver cell eventually bursts, discharging motile merozoites into the bloodstream. These then invade the red blood cells (RBCs) and multiply six- to twentyfold every 48-72 h. When the parasites reach densities of ~50/μL of blood, the symptomatic stage of the infection begins. In Plasmodium vivax and Plasmodium ovale infections , a proportion of the intrahepatic forms do not divide immediately but remain dormant for a period ranging from 3 weeks to a year or longer reproduction begins. These dormant forms, or hypnozoites , are the cause of the relapses that characterize infection with these two species.
After entry into the bloodstream, merozoites rapidly invade erythrocytes and become trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. In the case of Plamodium vivax, this receptor is related to Duffy blood group antigen Fya or Fyb. Most West Africans and people with origins in that region carry the Duffy-negative FyFy phenotype and are therefore resistant to Plasmodium vivax, malaria. During the early stage of intraerythrocytic development, the small ring forms of the four parasites enlarge, species-specific characteristics become evident, pigment become visible, and the parasite assumes an irregular or ameboid shape. By the end of the 48-h intraerythrocytic life cycle (72 h for Plasmodium malariae), the parasite has consumed nearly all the hemoglobin and grown to occupy most of the RBC. It is now called a schozont.
Multiple nuclear divisions have taken place (schizogony or merogony), and the RBC then ruptures to release 6-30 daughter merozoites, each potentially capable of invading new RBC and repeating the cycle. The disease in human being is caused by the direct effects of RBC invasion and destruction by the asexual parasite and the host's reaction. After a series of asexual cycles (Plasmodium falciparum) or immediately after release from the liver (Plasmodium vivax, Plasmodium ovale, Plasmodium malariae), some of the parasites develop into morphologically distinct, longer-lived sexual forms (gametocytes) that can transmit malaria.
ERYTHROCYTE CHANGES IN MALARIA
In the other three ("benign") malarias, sequestration does not occur, and all stages of the parasite's development are evident on peripheral blood smears. Whereas Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae show a marked predilection for either young RBCs (Plasmodium vivax, Plasmodium ovale) or old cells (Plasmodium malariae) and produce a level of parasitemia that is seldom>2%, Plasmodium falciparum can invade erythrocytes of all ages and may be associated with very high levels of parasitemia.HOST RESPONSE
Initially, the host responds to plasmodial infection by activating nonspecific defense mechanisms. Splenic immunologic and filtrative clearance functions are augmented in malaria, and the removal of both parasitized and uninfected erythrocytes is accelerated. The parasitized cells escaping splenic removal are destroyed when the schozont ruptures. The material released induces the activation of macrophages and the release of proinflammatory mononuclear cell-derived cytokines, which cause fever and exert other pathologic effects. Temperatures of ≥40℃ damage mature parasites; in untreated infections, the effect of such temperatures is to further synchronize the parasitic cycle, with eventual production of the regular fever spikes and rigors that originally served to characterize the different malarias. These regular fever patterns (tertian, every 2 days; quartan, every 3 days) are seldom seen today in patients who receive prompt and effective antimalarial treatment.
The geographic distributions of sickle cell disease, ovalocytosis, thalassemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency closely resemble that of malaria before the introduction of control measures. This similarity suggests that these genetic disorders confer protection against death from falciparum malaria. For example, HbA/S heterozygotes (sickle cell trait) have a sixfold reduction in the risk of dying from severe falciparum malaria. This decrease risk appears to be related to impaired parasite growth at low oxygen tensions. Parasite multiplication in HbA/E heterozygotes is reduced at high parasite densities. In Melanesia, children with α-thalassemia appear to have more frequent malaria (both vivax and falciparum) in the early years of life, and this pattern of infection appears to protect against severe disease. In Melanesian ovalocytosis, rigid erythrocytes resist merozoite invasion, and the intraerythrocytic milieu is hostile.
Nonspecific host defense mechanisms stop the infection's expansion, and the subsequent specific immune response controls the infection. Eventually, exposure to sufficient strains confers protection from high-level parasitemia and disease but not from infection. As a result of this state of infection without illness (premunition), asymptomatic parasitemia is common among adults and older children living in regions with stable and intense transmission (i.e., holo- or hyperendemic areas). Immunity is mainly specific for both the species and the strain of infecting malarial parasite. Both humoral immunity and cellular immunity are necessary for protection, but the mechanisms of each are incompletely understood(Fig. 203-1). Immune individuals have a polyclonal increase in serum levels of IgM, IgG, and IgA, although much of this antibody is unrelated to protection. Antibodies to a variety of parasitic antigens presumably act in concert to limit in vivo replication of the parasite. In the case of falciparum malaria, the most important of these antigens is the surface adhesin--the variant protein PfEMP1 mentioned above. Passively transferred IgG from immune adults has been shown to reduce levels of parasitemia in children; although parasitemia in very young infants can occur, passive transfer of maternal antibody contributes to the relative (but not complete) protection of infants from severe malaria in the first months of life. This complex immunity to disease declines when a person lives outside an endemic area for several months or longer.
Several factors retard the development of cellular immunity to malaria. These factors include the absence of major histocompatibility antigens on the surface of infected RBCs, which precludes direct T cell recognition; malaria antigen-specific immune unresponsiveness; and the enormous strain diversity of malarial parasites, along with the ability of the parasites to express variant immunodominant antigens on the erythrocyte surface that change during the period of infection. Parasites may persist in the blood for months (or, in the case of Plamodium malariae, for many years) if treatment is not given. The complexity of the immune response in malaria, the sophistication of the parasites evasion mechanisms, and the lack of a good in vitro correlate with clinical immunity have all slowed progress toward an effective vaccine.
CLINICAL FEATURES
Malaria is a very common cause of fever in tropical countries. The first symptoms of malaria are nonspecific; the lack of a sense of well-being, headache, fatigue, abdominal discomfort, and muscle aches followed by fever are all similar to the symptoms of a minor viral illness. In some instances, a prominence of headache, chest pain, abdominal pain, arthralgia, myalgia, or diarrhea many suggest another diagnosis. Although headache many be severe in malaria, there is no neck stiffness or photophobia resembling that in meningitis. While myalgia may be prominent, it is not usually as severe as in dengue fever, and the muscles are not tender as in leptospirosis or typhus. Nausea, vomiting, and orthostatic hypotension are common. The classic malarial paroxysms, in which fever spikes, chills, and rigors occur at regular intervals, are relatively unusual and suggest infection with Plasmodium vivax or Plamodium ovale. The fever is irregular at first (that of falciparum malaria may never become regular); the temperature of nonimmune individuals and children often rises above 40℃ in conjunction with tachycardia and sometimes delirium. Although childhood febrile convulsions may occur with any of the malarias, generalized seizures are specifically associated with falciparum malaria and may herald the development of cerebral disease. Many clinical abnormalities have been described in acute malaria, but most patients with uncomplicated infections have few abnormal physical findings other than fever, malaise, mild anemia, and ( in some case) a palpable spleen. Anemia is common among young children living in areas with stable transmission, particularly where resistance has compromised the efficacy of antimalarial drugs. In nonimmune individuals with acute malaria, the spleen takes several days to become palpable, but splenic enlargement is found in a high proportion of otherwise healthy individuals in malaria-endemic areas and reflects repeated infections. Slight enlargement of the liver is also common, particularly among young children. Mild jaundice is common among adults; it may develop in patients with otherwise uncomplicated falciparum malaria and usually resolves over 1-3 weeks. Malaria is not associated with a rash like those seen in meningococcal septicemia, typhus, enteric fever, viral exanthems, and drug reactions. Petechial hemorrhages in the skin or mucous membranes-features of viral hemorrhagic fevers and leptospirosis-develop only rarely in severe falciparum malaria.
SEVER FALCIPARUM MALARIA
Appropriately and promptly treated, uncomplicated falciparum malaria (i.e., the patient can swallow medicines and food) carries a mortality rate of ~0.1%. However, once vital-organ dysfunction occurs or the total proportion of erythrocytes infected increases to >2% (a level corresponding to >1012 parasites in an adult), mortality risk rises steeply.
Cerebral Malaria Coma is a characteristic and ominous feature of falciparum malaria and, despite treatment, is associated with death rates of ~ 20% among adults and 15% among children. Any obtundation, delirium, or abnormal behavior should be taken very seriously. The onset may be gradual or sudden following a convulsion.
Cerebral malaria manifests as diffuse symmetric encephalopathy; focal neurologic signs are unusual. Although some passive resistance to head flexion may be detected, signs of meningeal irritation are lacking. The eyes may be divergent and a pout reflexes are preserved, except in deep coma. Muscle tone may be either increased or decreased. The tendon reflexes are variable, and the plantar reflexes may be flexor or extensor posturing may be seen. Approximately 15% of patients have retinal hemorrhages; with pupillary dilatation and indirect ophthalmoscopy, this figure increases to 30-40%. Other funduscopic abnormalities include discrete spots of retinal opacification (30-60%), papilledema (8% among children, rare among adults), cotton wool spots (<5%), and decolorization of a retinal vessel or segment of vessel (occasional cases). Convulsions, usually generalized and often repeated, occur in up to 50% of children with cerebral malaria. More covert seizure activity is also common, particularly among children, and may manifest as repetitive tonic-clonic eye movements or even hypersalivation. Whereas adults rarely (i.e., in <3% of cases) suffer neurologic sequelae, ~15% of children surviving cerebral malaria-especially those with hypoglycemia, severe anemia, repeated seizures, and deep coma-have some residual neurologic deficit when they regain consciousness; hemiplegia, cerebral palsy, cortical blindness, deafness, and impaired cognition and learning (all of varying cerebral malaria have a persistent language deficit. The incidence of epilepsy is increased and the life expectancy decreased among these children.
Hypoglycemia Hypoglycemia, an important and common complication of severe malaria, is associated with a poor prognosis and is particularly problematic in children and pregnant women. Hypoglycemia in malaria results from a failure of hepatic gluconeogenesis and an increase in the consumption of glucose by both host and , to a much lesser extent, the malaria parasites. To compound the situation, quinine and quinidine-drugs used for the treatment of severe chloroquine-resistant malaria-are powerful stimulants of pancreatic insulin secretion. Hyperinsulinemic hypoglycemia is especially troublesome in pregnant women receiving quinine treatment. In severe disease, the clinical diagnosis of hypoglycemia is difficult; the usual physical signs (sweating, gooseflesh, tachycardia) are absent, and the neurologic impairment caused by hypoglycemia cannot be distinguished from that caused by malaria.
Acidosis An important cause of death from severe malaria, results from accumulation of organic acids. Hyperlactemia commonly coexists with hypoglycemia. In adults, coexisting renal impairment often compounds the acidosis; in children, ketoacidosis may also contribute. Other still-unidentified organic acids are major contributors to acidosis. Acidotic breathing, sometimes called respiratory distress, is a sign of poor prognosis. It is often followed by circulatory failure refractory to volume expansion or inotropic drug and ultimately by respiratory arrest. The plasma concentrations of bicarbonate or lactate are the best biochemical prognostications in severe malaria. Lactic acidosis is caused by the combination of anaerobic glycolysis in tissues where sequestered parasites interfere with microcirculatory flow, hypovolemia, lactate production by the parasites, and a failure of hepatic and renal lactate clearance. The prognosis of severe acidosis is poor.
Renal Impairment Renal impairment is common among adults with severe falciparum malaria but rare among children. The pathogenesis of renal failure is unclear but may be related to erythrocyte sequestration interfering with renal microcirculatory flow and metabolism. Clinically and pathologically, this syndrome manifests as acute tubular necrosis, although renal cortical necrosis never develops. Acute renal failure may occur simultaneously with other vital-organ dysfunction (in which case the mortality risk is high) or may progress as other disease manifestations resolve. In survivors, urine flow resumes in a median of 4 days, and serum creatinine levels return to normal in a mean of 17 days. Early dialysis or hemofiltration considerably enhances the likelihood of a patient's survival, particularly in acute hypercatabolic renal failure.
Hematologic Abnormalities Anemia results from accelerated RBC removal by the spleen, obligatory RBC destruction at parasite schizogony, and ineffective erythropoiesis. In severe malaria, both infected and uninfected RBCs show reduced deformability, which correlates with prognosis and development of anemia. Splenic clearance of all RBCs is increased. In nonimmune individuals and in areas with unstable transmission, anemia can develop rapidly and transfusion is often required. As a consequence of repeated malarial infections, children in many areas of Africa may develop severe anemia resulting from both shortened RBC survival and marked dyserythropoiesis. Anemia is a common consequence of antimalarial drug resistance, which results in repeated or continued infection.
Slight coagulation abnormalities are common in falciparum malaria, and mild thrombocytopenia is usual. Of patients with severe malaria, <5% have significant bleeding with evidence of disseminated intravascular coagulation. Hematemesis from stress ulceration or acute gastric erosions may also occur.
Liver Dysfunction Mild hemolytic jaundice is common in malaria. Severe jaundice is associated with P. falciparum infections; is more common among adults than among children; and results from hemolysis, hepatocyte injury, and cholestasis. When accompanied by other vital-organ dysfunction (Often renal impairment), liver dysfunction carries a poor prognosis. Hepatic dysfunction contributes to hypoglycemia, lactic acidosis, and impaired drug metabolism. Occasional patients with falciparum malaria may develop deep jaundice (with hemolytic, hepatitis, and cholestatic components) without evidence of other vital-organ dysfunction.
DEMONSTRATION OF THE PARASITE
The diagnosis of malaria rests on the demonstration of asexual forms of the parasite in stained peripheral-blood smears. After a negative blood smear, repeat smear should be made if there is a high degree of suspicion. Of the Romanowsky stains, Giemsa at pH 7.2 is preferred; Wright's, Field's, or Leishman's stain can also be used. Both thin and thick, and blood smears should be examined. The thin blood smear should be rapidly air-dried, fixed in anhydrous methanol, and stained; the RBCs in the tail of the film should then be examined under oil immersion (x 1000 magnification). The level increasing diagnostic sensitivity. Both parasites and white blood cells (WBCs) are counted, and the number of parasites per unit volume is calculated from the total leukocyte count. Alternatively, a WBC count of 8000/µL is assumed. This figure is converted to the number of parasitized erythrocytes per microliter. A minimum of 200 WBCs should be counted under oil immersion. Interpretation of blood smear films requires some experience because artifacts are common. Before a thick smear is judged to be negative, 100-200 fields should be examined under oil immersion. In high-transmission areas, the presence of up to 10,000 parasites/µL of blood may be tolerated without symptoms or signs in partially immune individuals. Thus the detection of malaria parasites is sensitive but only poorly specific in identifying malaria as the cause of illness.
Rapid, simple, sensitive, and specific antibody-based diagnostic stick or card tests that detect P. falciparum-specific, histidine-rich protein 2 (PfHRP2) or lactate dehydrogenase antigens in finger-prick blood samples have been introduced. Some of these tests carry a second antibody, which allows falciparum malaria to be distinguished from the less dangerous malaria. PfHRP2-based tests may remain positive for several weeks after acute infection. This feature is a disadvantage in high-transmission areas where infections are frequent but is of value in the diagnosis of severe malaria in patients who have taken antimalarial drugs and cleared peripheral parasitemia (but in whom the PfHRP2 test remains strongly positive). The relationship between parasitemia and prognosis is complex; in general, patients with >105 parasites/µL are at increased risk of dying, but nonimmune patients may die with much lower counts, and partially immune persons may tolerate parasitemia levels many times higher with only minor symptoms. In severe malaria, a poor prognosis is indicated by a predominance of more mature P. falciparum parasites(i.e., >20% of parasites with visible pigment) in the peripheral blood film or by the presence of phagocytosed malarial pigment in >5% of neutrophils. In P. falciparum infections, gametocytemia peaks 1 week after the peak of asexual parasites. Because the mature gametocytes of P. falciparum are not affected by most antimalarial drugs, their persistence does not constitute evidence of drug resistance. Phagocytosed malarial pigment is sometimes seen inside peripheral-blood monocytes or polymorphonuclear leukocytes and may provide a clue to recent infection if malaria parasites are not detectable. After the clearance of the parasites, this intraphagocytic malarial pigment is often evident for several days in the peripheral blood or for longer in bone marrow aspirates or smears of fluid expressed after intradermal puncture. Staining of parasites with the fluorescent dye acridine orange allows more rapid diagnosis of malaria (but not speciation of the infection ) in patients with low-level parasitemia.
LABORATORY FINDINGS
Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it may be raised in very severe infections. These is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte sedimemtation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high. The platelet count is usually reduced to ~105 parasites/µL. Severe infections may be accompanied by prolonged prothrombin and partial thromboplastin times and by more severe thrombocytopenia. Levels of antithrombin III are reduced even in mild infection. In uncomplicated malaria, plasma concentrations of electrolytes, blood urea nitrogen (BUN), and creatinine re usually normal. Findings in severe malaria may include metabolic acidosis, with low plasma concentrations of glucose, sodium, bicarbonate, calcium, phosphate, and albumin together with elevations in lactate, BUN, creatinine, urate, muscle and liver enzymes, and conjugated and unconjugated bilirubin. Hypergammaglobulinemia is usual in immune and semi-immune subjects. Urinalysis generally gives normal results. In adults and children with cerebral malaria, the mean opening pressure at lumbar is ~160 mm of cerebrospinal fluid (CSF); usually the CSF is normal or has a slightly elevated total protein level [<1.0 g/L (<100 mg/dL)] and cell count (<20/μL).
TREATMENT REGIMENS
|
Types of Disease or Treatment |
Regimen(s) |
|
Uncomplicated Malaria |
|
|
Known chloroquine-sensitive strains of Plasmodium vivax, P. malariae, P. ovale, P. falciparum Radical treatment for P. vivax or P. ovale infection Sensitive P. falciparum malaria Multidrug-resistant P. falciparum malaria Second-line treatment/treatment of imported malaria |
Chloroquine (10mg of base/kg stat followed by 5 mg/kg at 12,24,and 36 h or by 10 mg/kg at 24 h and 5 mg/kg at 48 h) Or Amodiaquine (10-12 mg of base/kg qd for 3 days) In addition to chloroquine or amodiaquine as detailed above, primaquine (0.25 mg of base/kg qd; 0.375-0.5 mg of base/kg qd in Southeast Asia and Oceania) should be given for 14 days to prevent relapse. In mild G6PD deficiency, 0.75 mg of base/kg should be given once weekly for 6 weeks. Primaquine should not be given in severe G6PD deficiency. Artesunate ( 4mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days) Either artemether-lumefantrine (1.5/9mg/kg bid for 3 days with food) or artesunate (4 mg/kg qd for 3 days) Plus Mefloquine (25 mg of base/kg-either 8 mg/kg qd for 3 days or 15 mg/kg on day 2 and then 10 mg/kg on day 3) Either artesunate (2 mg/kg qd for 7 days) or quine (10 mg of salt/kg tid for 7 days) Plus 1 of the following 3: 1. Tetracycline (4mg/kg qid for 7 days) 2. Doxycycline (3mg/ qd for 7 days) 3. Clindamycin (10 mg/kg bid for 7 days) Or Atovaquone-proguanil (20/8mg/kg qd for 3 days with food) |
|
Severe Falciparum Malaria |
|
|
|
Artesunate (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary) Or Artemether (3.2 mg/kg stat IM followed by 1.6 mg/kg qd) Or Quinine dihydrochloride (20 mg of salt/kg infused over 4 h, followed by 10 mg of salt/kg infused over 2-8 q8h) Or Quinidine (10 mg of base/kg infused over 1-2 h, followed by 1.2 mg of base/kg per hour with electrocardiographic monitoring) |
No comments:
Post a Comment