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Non-falciparum Malaria (P Vivax, P Ovale, P Malariae)

Clinical Findings

Signs and Symptoms

Patients with nonfalciparum malaria invariably develop fever and chills that may become cyclic. Initially, patients experience chills, which are followed by fever (Box 1). Patients with malaria often manifest many nonspecific symptoms such as weakness, malaise, headache, and myalgias. As the disease progresses, signs of anemia, such as pale conjunctiva, may be seen.

Splenomegaly and mild hepatomegaly may also be present. After hours of fever, defervescence occurs with marked diaphoresis. Patients are weakened and exhausted from the severity of the disease. In established infections caused by P vivax and P ovale, a periodicity may occur approximately every 48 h. P vivax and P ovale infections are clinically indistinguishable. Although similar, disease caused by P ovale is usually less severe, relapses less frequently, and more often spontaneously resolves. Both of these Plasmodium species produce latent disease and may produce relapses months after the initial infection.

Malaria from P malariae has a longer incubation period and possibly more severe paroxysms than are seen with P vivax and P ovale. The clinical periodicity of P malariae may become regular and occur in 72-h intervals. This is termed benign quartian malaria. Some infections with P malariae may be subclinical and persist for years, but P malariae does not produce latent disease.

Malaria treatment non falciparum infections

Laboratory Findings

Three thick blood smears, spaced ~ 12 h apart, should detect any of the Plasmodium species. In instances of subclinical P malariae infection, parasitemia is extremely low and may be difficult to identify even in thick preparations.

Blood smears and urinalysis reveal evidence of hemolysis, but usually to a lesser degree than with infections caused by P falciparum. Elevated albumin levels are present in the urine of patients with P malariae-associated nephrotic syndrome.

Imaging

Hepatosplenomegaly and splenic complications, such as rupture, may be visualized by computed tomography scans or magnetic resonance imaging.

Complicatons

Complications with P vivax are rare, although coma and sudden death have been reported. Individuals with splenomegaly are at higher risk for splenic rupture. Infections with P malariae may be indolent and mild, but immune complex-associated glomerulonephritis and nephrotic syndrome may occur.

Differential Diagnosis

Nonfalciparum malaria

Many of the signs and symptoms of nonfalciparum malaria are nonspecific. There are many causes of anemia and hepatosplenomegaly. Malaria is endemic in many underdeveloped areas; indigenous people in these countries may suffer from protein-calorie malnutrition and are exposed to a wide variety of infectious agents. Impoverished children with dietary deficiencies may be anemic, and those with protein deficiencies may have protuberant abdomens. Numerous infectious diseases may present with hepatomegaly, splenomegaly, or both. Liver enlargement, spleen enlargement, or both may be seen in patients with amebic liver abscesses, Chaga's disease, visceral leishmaniasis, schistosomiasis, echinococcosis, clonorchiasis, and typhoid fever. Noninfectious causes of hepatosplenomegaly, anemia, or both include thalassemias and other hemoglobinopathies, myelofibrosis, and hematopoietic malignancies.

The symptoms of nonfalciparum malaria may also be nonspecific and may be present in a wide variety of diseases. This is especially true early in the course of malaria, before any synchronization of the erythrocytic cycle. Many tropical diseases, such as visceral leishmaniasis, filariasis, and dengue fever, may present with nonspecific symptoms similar to those present in malaria. If cyclic symptoms occur, filariasis should be considered. Pneumonia, urinary tract infections, and other less exotic causes of fever and chills must also be considered. Fever, chills, and night sweats are constitutional symptoms that may be seen with hematopoietic malignancies. P malariae has been associated with nephrotic syndrome, but other etiologies, such as post-infectious immune-complex glomerulonephritis and systemic lupus erythematosis, must be also be considered. The differential diagnosis of nonfalciparum malaria is extensive and may only be successfully narrowed by history, careful physical examination, and laboratory studies.

Falciparum Malaria

The differential diagnosis of falciparum malaria is also extensive. The focus of the differential diagnosis is usually based on the most severely affected organ system. If only generalized fever and chills are present, the differential is broad. These symptoms may be seen in a wide variety of infections (see above) or may represent the constitutional symptoms that may accompany some lymphoproliferative disorders. The mental status changes present in cerebral malaria may also be seen in patients with brain abscesses, meningitis, tumor, or cerebral or subdural hemorrhage. Gastrointestinal symptoms, such as abdominal pain and diarrhea, may be present in patients with bacterial or viral gastroenteritis, chronic colitis, or ischemic colitis. Similarly, involvement of the liver may suggest viral hepatitis, typhoid fever, or other hepatic disorders. The pulmonary edema and adult respiratory distress syndrome that may occur in falciparum malaria are clinically indistinguishable from those caused by many other etiologies. The astute cytologist, however, may detect the presence of a Plasmodium species in RBCs present in respiratory tract samplings (sputa or bronchoalveolar lavage) and may thereby identify the etiology of the respiratory pathology. The hemolytic anemia present in malaria may be clinically indistinguishable from other causes of hemolytic anemia but is usually readily distinguished by an examination of a peripheral blood smear.

When ring forms are present, the possibility of babesiosis must also be considered. Recent travel to Plasmodium- or Babesia-endemic areas is important supportive information. Babesia species may be excluded by the presence of advanced amoeboid or schizont forms and by the presence of malarial pigment. Babesia species do not produce amoeboid forms or schizonts, and they do not metabolize hemoglobin to form pigment. These criteria usually readily differentiate Babesia species from P vivax, P ovale, and P malariae. The differentiation of Babesia species and P falciparum is more difficult, because RBCs infected with either Babesia species or P falciparum usually contain only small, delicate ring forms. Furthermore, infections with both these organisms may show more than one ring form per RBC and high degrees of parasitemia.

A useful approach to the differentiation of Babesia and P falciparum is to search for pathognomonic forms, to perform an exhaustive search for advanced plasmodial forms and malarial pigment, and to obtain a detailed clinical and travel history. The pathognomonic forms of Babesia spp. and P falciparum are the tetrad of merozoites (Maltese cross) and the crescent-shaped gametocyte, respectively. Unfortunately, these forms are not always present in the blood smear. An exhaustive search may demonstrate a rare amoeboid or schizont form in P falciparum infections, especially in patients with severe disease, but this is not guaranteed. The presence of malarial pigment also differentiates Plasmodium species from Babesia species. In morphologically indeterminate instances, historical information may be the most helpful information available. Alternatively, molecular methods may be used to differentiate these organisms. These, however, are not routinely available in many areas.

Diagnosis

The first clue to clinicians of the possibility of malaria is often from a history of travel to a malaria-endemic area. Patients should be asked about their travel history, and the clinician should probe for any information about travel to malaria-endemic areas in either the recent or distant past. If patients have traveled to malaria-endemic areas, they should be asked if they received chemoprophylaxis and if they ever contracted malaria. Specific questioning concerning any travel to endemic areas in the past may reveal the possibility of infections with nonfalciparum Plasmodium species, which may cause disease months to years after the initial infection and return from endemic areas.

Non falciparum malaria

Mosquito-based transmission in naturally endemic areas is the most frequent mode of transmission, but less common modes of transmission may also occur. Plasmodial organisms in the erythrocytic phase may also be parenterally transmitted, through intravenous drug abuse (shared needles) or blood transfusion. This mode of transmission is infrequent in the United States and other nonendemic locales and is directly related to the frequency of infected donors. Historical information regarding having contracted malaria and recent travel to malaria-endemic areas is useful for screening potential blood donors. As mentioned earlier in this chapter, another group of individuals who may contract malaria are those who live in close proximity to an international airport.

The signs and symptoms of malaria depend somewhat on the infecting Plasmodium species. Early in the course of disease, nonsynchronized fever and chills may be present with other nonspecific symptoms such as fatigue, malaise, myalgia, and headache. The classic, nonfalciparum malarial cycle consists of shaking chills, followed by high, spiking fever, and finally defervescence with exhaustion. This cycle is most commonly seen with infections by P vivax but is also common with infections caused by P ovale and P malariae. The cyclic nature of the symptoms reflects the synchronization of the erythrocytic malarial cycle and is a clinical clue to malaria. When highly synchronized, this cycle occurs approximately every 48 h for infections caused by P vivax and P ovale and every 72 h for infections caused by P malariae.

The erythrocytic cycle of P falciparum becomes synchronized less frequently than malaria caused by other Plasmodium species. Patients with P falciparum infections more commonly demonstrate daily chills and fever spikes. The signs and symptoms of falciparum malaria are highly variable. The ischemic changes produced by the microvascular congestion may manifest in any organ system (see above). Therefore the clinical presentation usually depends on the organ system most severely affected. For this reason, malaria must remain in the differential diagnosis for a wide variety of disorders, especially if patients have recently visited malaria-endemic locales. Most patients demonstrate some degree of anemia and hypoglycemia. Headache, seizures, mental status changes, and coma may be seen in patients with cerebral malaria. Blackwater fever from the excretion of blood, hemoglobin, and malarial pigment is common in patients with renal involvement. The involvement of the gastrointestinal tract may produce nausea, vomiting, diarrhea, and abdominal pain. Hepatic involvement may result in jaundice, with elevations in serum levels of bilirubin and liver enzymes. Not surprisingly, primary gastrointestinal and hepatic manifestations of P falciparum malaria are commonly mistaken for self-limited bacterial or viral enteritis and viral hepatitis, respectively.

Although clinical history and physical examination findings may suggest malaria, the definitive diagnosis is made in the laboratory. Although ELISA and PCR-based assays for the detection of the malarial parasite are available, the examination of thick blood smears remains the most cost-effective method in the United States. Thick blood smears should be performed on the peripheral blood of patients suspected to have malaria. If the first blood smear is negative, two more should be performed at 12-h intervals. When a Plasmodium species is detected in a thick blood smear, thin blood smears should be made for plasmodial speciation.

If available, highly sensitive and specific molecular methods may be used for the detection of Plasmodium species. Molecular assays used for Plasmodium identification include the detection of P falciparum's histidine-rich protein 2 by ELISA and the detection of Plasmodium nucleic acid by PCR. Dipstick technology has been applied to the detection of histidine-rich protein 2. This allows for a sensitive and specific molecular detection system to be available in the field. The detection of Plasmodium nucleic acids by the PCR may soon become the gold standard. PCR-based detection systems offer excellent sensitivity and specificity. This system is extremely useful for patients with low-grade parasitemia. The use of preamplification immunomagnetic separation of Plasmodium species and specific colorimetric detection of PCR products may enhance sensitivity and make this technology more user friendly. The PCR-based assay may use either species-specific DNA primers or broad-range Plasmodium-specific primers. When broad-range primers are used, speciation is accomplished by either DNA sequencing or Southern-blotting/microtiter plate hybridization with species-specific nucleic acid probes. In nonendemic areas, the molecular detection of plasmodia may be impractical, because costly reagents and kits may expire with only minimal use.

Treatment

In the treatment of malaria, specific antiplasmodial therapy and supportive care are essential to reduce morbidity and mortality. The basic principles of antiplasmodial therapy are defined below. Therapeutics and dosages for the most commonly used antimalarial agents are listed in Box 80-2. It should be noted that antimalarial drugs exist in both salt and base formulations, and potentially dangerous dosing errors may occur unless care is taken. Updated information regarding the treatment and prophylaxis of malaria are available through the Centers for Disease Control and Prevention and the World Health Organization.

P vivax, P ovale, P malariae, and chloroquine-sensitive P falciparum. Chloroquine phosphate is given to eradicate the RBC phase. Oral therapy is usually sufficient for infections with P vivax, P ovale, and P malariae and for P falciparum infections that are not severe. Intravenous administration of antiplasmodial agents should be used for patients with severe falciparum malaria. Side effects of chloroquine may include gastrointestinal disturbances, pruritis, dizziness, and headache. Chloroquine resistance is widespread among P falciparum and rarely has been reported for P vivax. Alternative regimens include mefloquine and quinine. Patients infected with either P vivax or P ovale must also be given primaquine phosphate to eradicate hepatic hypnozoites. The failure to use primaquine may result in malarial relapse at a later date. Primaquine phosphate may cause hemolytic anemia in patients with glucose-6-phosphatase deficiency; additional side effects include gastrointestinal and central nervous system disturbances. In infections caused by these organisms during pregnancy, chloroquine is the drug of choice, and quinine is an alternative. Although not yet approved by the Food and Drug Administration, mefloquine is also probably safe during pregnancy; mefloquine should not be used for severe falciparum malaria, since intravenous therapy is required and there is no parenteral formulation for mefloquine. Although quinine may be used in pregnancy, it may cause uterine contractions and contributes to hypoglycemia. Primaquine and halofantrine are contraindicated in pregnancy.

Chloroquine-resistant P falciparum. Oral regimens for patients that do not have severe disease or have severe disease and access to only minimal healthcare facilities consist of quinine given with pyrimethamine-sulfadoxine or followed by either tetracycline or clindamycin. Other oral therapies include mefloquine and quinidine gluconate. Injections of artesunate or artemether or suppositories of artemisinin or artesunate may be useful in instances of limited healthcare. If oral therapy is not possible or if severe disease is present, parenteral therapy with quinine hydrochloride or quinidine gluconate may be given. Pregnant women with chloroquine-resistant malaria who do not have severe disease may be treated with intravenous quinine, sulfonamide/ pyrimethamine (in areas such as India and some regions of Africa, where P falciparum is likely to be sensitive) and mefloquine. Mefloquine should not be used for severe falciparum malaria, since intravenous therapy is required, and there is no parenteral formulation for mefloquine. Exchange transfusion may be lifesaving for patients with hyperparasitemia and should be considered if this option exists. The indications for exchange transfusion are a parasitemia of > 10% combined with severe disease, therapeutic failure, or poor prognostic factors or a parasitemia of > 30%, even in the absence of clinical complications.

Prognosis

The prognosis of nonfalciparum malaria is generally good. These organisms are usually responsive to therapy. Relapses of P vivax or P ovale malaria can be avoided with appropriate therapy. P malariae responds well to therapy; however, rare renal involvement may contribute to morbidity and mortality.

The prognosis in falciparum malaria, especially for the nonimmune, is guarded. Malaria caused by P falciparum constitutes a medical emergency until proven otherwise. Multisystem organ damage may occur with extreme morbidity and high mortality. Death may occur rapidly from microvascular compromise and subsequent hypoxemia. Involvement of the central nervous system, lungs, and kidneys is especially devastating. Prompt administration of appropriate antimalarial agents, possible exchange transfusion and supportive care significantly reduce morbidity and mortality.

Prevention & Control

Vector Control. An understanding of the habit and behavior of the female Anopheles mosquito is useful in disease prevention. Marshlike areas and even microenvironments with standing water serve as breeding areas for the Anopheles mosquitos. Avoidance of mosquito-infested areas and elimination of standing water decrease the likelihood of being bitten. If these areas cannot be avoided, insect repellent should be used. Anopheles mosquitoes are evening and nighttime feeders; therefore a combination of mosquito netting and insect repellent at bedtime is encouraged. Mosquito netting impregnated with insecticides is optimal for nighttime barrier protection. The large-scale use of insecticides for vector control usually provides only a short-term solution; insecticide-resistant mosquito strains develop rapidly.

Chemoprophylaxis. Chloroquine is still a useful chemoprophylactic agent in areas without a high prevalence of chloroquine-resistant strains (Box 3). The emergence of chloroquine resistance in P falciparum and more recently in P vivax has limited the usefulness of this drug as a chemoprophylactic agent. In areas where chloroquine resistance is found, mefloquine, doxycycline, or chloroquine plus proguanil may be used for prophylaxis.

Months before departure, travelers to endemic areas should consult physicians experienced in tropical disease prevention. Chemoprophylaxis must begin weeks before departure to ensure an absence of drug hypersensitivity and adequate serum levels. Records should be kept during travel of any failure to maintain the dosing schedule. Chemoprophylaxis should continue for 4 weeks after leaving endemic areas. If episodes of noncompliance have occurred and the patient has not become ill, they are still at risk for malaria if they visited P vivax- or P ovale-endemic areas.

Information regarding various aspects of malaria, including treatment and prophylaxis, is regularly updated by the World Health Organization and Centers for Disease Control and Prevention. Respective World Wide Web sites are http://www.who.ch/ and http://www.cdc.gov/cdc.htm. Information on various aspects of malaria and other diseases is available from the Centers for Disease Control and Prevention via fax, toll free, at 1-888-232-3228.

Vaccine Development. A highly effective malaria vaccine is yet to be developed. This will likely remain a difficult task, particularly because of the antigenic variability characteristic of Plasmodium species. Vaccine targets currently being studied include the sporozoite, the merozoite, and the gametocyte. The respective goals of these vaccine targets are to prevent infection, to decrease the severity and complications of disease, and to arrest development in the mosquito and prevent the production of infective sporozoites.

Links

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209815/

https://clinicaltrials.gov/ct2/show/NCT00725777

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