InternalMed_Harrison

InternalMed_Harrison. 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. Molecular diagnosis by polymerase chain reaction (PCR) amplification of parasite nucleic acid is more sensitive than microscopy or rapid diagnostic tests for detecting malaria parasites and defining malarial species. While currently impractical in the standard clinical setting, PCR is used in reference centers in endemic areas. In epidemiologic surveys, sensitive PCR detection may prove very useful in identifying asymptomatic infections as control and eradication programs drive parasite prevalence down to very low levels. Serologic diagnosis with either indirect fluorescent antibody or enzyme-linked immunosorbent assays may prove useful as measures of transmission intensity in future epidemiologic studies. Serology has


InternalMed_Harrison

InternalMed_Harrison. diagnosis with either indirect fluorescent antibody or enzyme-linked immunosorbent assays may prove useful as measures of transmission intensity in future epidemiologic studies. Serology has no place in the diagnosis of acute illness.


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InternalMed_Harrison. Normochromic, normocytic anemia is usual. The leukocyte count is generally normal, although it may be raised in very severe infections. There is slight monocytosis, lymphopenia, and eosinopenia, with reactive lymphocytosis and eosinophilia in the weeks after the acute infection. The erythrocyte sedimentation rate, plasma viscosity, and levels of C-reactive protein and other acute-phase proteins are high. The platelet count is usually reduced to ~105/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 are 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,


InternalMed_Harrison

InternalMed_Harrison. 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 cerebrospinal fluid (CSF) opening pressure at lumbar puncture is ~160 mm; usually the CSF content is normal or there is a slight elevation of total protein level (<1.0 g/L [<100 mg/dL]) and cell count (<20/μL).


InternalMed_Harrison

InternalMed_Harrison. (Table 248-6) When a patient in or from a malarious area presents with fever, thick and thin blood smears should be prepared and examined immediately to confirm the diagnosis and identify the species of infecting parasite (Figs. 248-4 through 248-9). Repeat blood smears should be performed at least every 12–24 h for 2 days if the first smears are negative and malaria is strongly suspected. Alternatively, a rapid antigen detection card or stick test should be performed. Patients with severe malaria or those unable to take oral drugs should receive parenteral antimalarial therapy. If there is any doubt about the resistance status of the infecting organism, it should be considered resistant. Antimalarial drug susceptibility testing can be performed but is rarely available, has poor predictive value in an individual case, and yields results too slowly to influence the choice of treatment. Several drugs are available for oral treatment. The choice of drug depends on the likely sensitivity


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InternalMed_Harrison. value in an individual case, and yields results too slowly to influence the choice of treatment. Several drugs are available for oral treatment. The choice of drug depends on the likely sensitivity of


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InternalMed_Harrison. Type of Disease or Treatment Regimen(s) Known chloroquine-Chloroquine (10 mg of base/kg stat followed by 5 mg/ sensitive strains of kg at 12, 24, and 36 h or by 10 mg/kg at 24 h and Plasmodium vivax, 5 mg/kg at 48 h) P. malariae, P. ovale, or P. knowlesi, Amodiaquine (10–12 mg of base/kg qd for 3 days) P. falciparumb Radical treatment In addition to chloroquine or amodiaquine as detailed for P. vivax or P. ovale above, primaquine (0.5 mg of base/kg qd in tropical infection regions and 0.25 mg/kg for temperate-origin P. vivax) 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 8 weeks. Primaquine should not be given in severe G6PD deficiency. P. falciparum (25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single malariac dose Artesunated (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)e Multidrug-resistant Either artemether-lumefantrined (1.5/9 mg/kg bid for


InternalMed_Harrison

InternalMed_Harrison. Artesunated (4 mg/kg qd for 3 days) plus amodiaquine (10 mg of base/kg qd for 3 days)e Multidrug-resistant Either artemether-lumefantrined (1.5/9 mg/kg bid for P. falciparum malaria 3 days with food) Artesunated (4 mg/kg qd for 3 days) plus mefloquine (24–25 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)e Dihydroartemisinin-piperaquined (2.5/20 mg/kg qd for 3 days) Second-line treat-Either artesunated (2 mg/kg qd for 7 days) or quinine ment/treatment of (10 mg of salt/kg tid for 7 days) plus 1 of the following 3: imported malaria 1. 2. 3. Atovaquone-proguanil (20/8 mg/kg qd for 3 days with food) Artesunated (2.4 mg/kg stat IV followed by 2.4 mg/kg at 12 and 24 h and then daily if necessary)h or, if unavailable, Artemetherd (3.2 mg/kg stat IM followed by 1.6 mg/ kg qd) or, if unavailable, Quinine dihydrochloride (20 mg of salt/kgi infused over 4 h, followed by 10 mg of salt/kg infused over 2–8 h q8hj) or, if unavailable,


InternalMed_Harrison

InternalMed_Harrison. Quinidine (10 mg of base/kgi infused over 1–2 h, followed by 1.2 mg of base/kg per hourj with electrocardiographic monitoring) aIn endemic areas, except in pregnant women and infants, a single dose of primaquine (0.25 mg of base/kg) should be added as a gametocytocide to all falciparum malaria treatments to prevent transmission. This addition is considered safe even in G6PD deficiency. bVery few areas now have chloroquine-sensitive P. falciparum malaria (Fig. 248-2). cIn areas where the partner drug to artesunate is known to be effective. dArtemisinin derivatives are not readily available in some temperate countries. eFixed-dose coformulated combinations are available. The World Health Organization now recommends artemisinin combination regimens as first-line therapy for falciparum malaria in all tropical countries and advocates use of fixed-dose combinations. fTetracycline and doxycycline should not be given to pregnant women or to children <8 years of age. gOral treatment should be


InternalMed_Harrison

InternalMed_Harrison. in all tropical countries and advocates use of fixed-dose combinations. fTetracycline and doxycycline should not be given to pregnant women or to children <8 years of age. gOral treatment should be substituted as soon as the patient recovers sufficiently to take fluids by mouth. hArtesunate is the drug of choice when available. The doses in children weighing <20 kg should be 3 mg/kg. The data from large studies in Southeast Asia showed a 35% lower mortality rate than with quinine, and very large studies in Africa showed a 22.5% reduction in mortality rate compared with quinine. iA loading dose should not be given if therapeutic doses of quinine or quinidine have definitely been administered in the previous 24 h. Some authorities recommend a lower dose of quinidine. jInfusions can be given in 0.9% saline and 5–10% dextrose in water. Infusion rates for quinine and quinidine should be carefully controlled.


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InternalMed_Harrison. Abbreviation: G6PD, glucose-6-phosphate dehydrogenase. the infecting parasites. Despite increasing evidence of chloroquine resistance in P. vivax (from parts of Indonesia, Oceania, eastern and southern Asia, and Central and South America), chloroquine remains a first-line treatment for the non-falciparum malarias (P. vivax, P. ovale, P. malariae, P. knowlesi) except in Indonesia and Papua New Guinea, where high levels of resistance in P. vivax are prevalent.


InternalMed_Harrison

InternalMed_Harrison. The treatment of falciparum malaria has changed radically in recent years. In all endemic areas, the World Health Organization (WHO) now recommends artemisinin-based combinations (ACTs) as first-line treatment for uncomplicated falciparum malaria. These combinations are also highly effective for the other malarias. These rapidly and reliably effective drugs are sometimes unavailable in temperate countries, where treatment recommendations are limited by the registered available drugs. Fake or substandard antimalarials are commonly sold in many Asian and African countries. Thus, careful attention is required at the time of purchase and later, especially if the patient fails to respond as expected. Characteristics of antimalarial drugs are shown in Table 248-7.


InternalMed_Harrison

InternalMed_Harrison. In large studies, parenteral artesunate, a water-soluble artemisinin derivative, has reduced mortality rates in severe falciparum malaria among Asian adults and children by 35% and among African children by 22.5% compared with mortality rates with quinine treatment. Artesunate has therefore become the drug of choice for all patients with severe malaria everywhere. Artesunate is given by IV injection but can also be given by IM injection. Artemether and the closely related drug artemotil (arteether) are oil-based formulations given by IM injection; they are erratically absorbed and do not confer the same survival benefit as artesunate. A rectal formulation of artesunate has been developed as a community-based pre-referral treatment for patients in the rural tropics who cannot take oral medications. Pre-referral administration of rectal artesunate has been shown to decrease mortality risk among severely ill children in communities without access to immediate parenteral treatment.


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InternalMed_Harrison. medications. Pre-referral administration of rectal artesunate has been shown to decrease mortality risk among severely ill children in communities without access to immediate parenteral treatment. Although the artemisinin compounds are safer than quinine and considerably safer than quinidine, only one formulation is available in the United States. IV artesunate has been approved by the U.S. Food and Drug Administration for emergency use against severe malaria and can be obtained through the Centers for Disease Control and Prevention (CDC) Drug Service (see end of chapter for contact information). The antiarrhythmic quinidine gluconate is as effective as quinine and, as it was more readily available, replaced quinine for the treatment of malaria in the United States. The administration of quinidine must be closely monitored if dysrhythmias and hypotension are to be avoided. If total plasma levels exceed 8 μg/mL or the QTc interval exceeds 0.6 s or the QRS complex widens by more than


InternalMed_Harrison

InternalMed_Harrison. quinidine must be closely monitored if dysrhythmias and hypotension are to be avoided. If total plasma levels exceed 8 μg/mL or the QTc interval exceeds 0.6 s or the QRS complex widens by more than 25% of baseline, then infusion rates should be slowed or infusion stopped temporarily. If arrhythmia or saline-unresponsive hypotension develops, treatment with this drug should be discontinued. Quinine is safer than quinidine; cardiovascular monitoring is not required except when the recipient has cardiac disease.


InternalMed_Harrison

InternalMed_Harrison. Severe falciparum malaria constitutes a medical emergency requiring intensive nursing care and careful management. The patient should be weighed and, if comatose, placed on his or her side. Frequent evaluation of the patient’s condition is essential. Adjunctive treatments such as high-dose glucocorticoids, urea, heparin, dextran, desferrioxamine, antibody to tumor necrosis factor α, high-dose phenobarbital (20 mg/kg), mannitol, or large-volume fluid or albumin boluses have proved either ineffective or harmful in clinical trials and should not be used. In acute renal failure or severe metabolic acidosis, hemofiltration or hemodialysis should be started as early as possible.


InternalMed_Harrison

InternalMed_Harrison. In severe malaria, parenteral antimalarial treatment should be started immediately. Artesunate, given by either IV or IM injection, is the agent of choice; it is simple to administer, safe, and rapidly effective. It does not require dose adjustments in liver dysfunction or renal failure, and it should be used in pregnant women with severe malaria. If artesunate is unavailable and artemether, quinine, or quinidine is used, an initial loading dose must be given so that 1379 therapeutic concentrations are reached as soon as possible. Both quinine and quinidine will cause dangerous hypotension if injected rapidly; when given IV, they must be administered carefully by rate-controlled infusion only. If this approach is not possible, quinine may be given by deep IM injections into the anterior thigh. The optimal therapeutic range for quinine and quinidine in severe malaria is not known with certainty, but total plasma concentrations of 8–15 mg/L for quinine and 3.5–8.0 mg/L for quinidine are


InternalMed_Harrison

InternalMed_Harrison. The optimal therapeutic range for quinine and quinidine in severe malaria is not known with certainty, but total plasma concentrations of 8–15 mg/L for quinine and 3.5–8.0 mg/L for quinidine are effective and do not cause serious toxicity. The systemic clearance and apparent volume of distribution of these alkaloids are markedly reduced and plasma protein binding is increased in severe malaria, so that the blood concentrations attained with a given dose are higher. If the patient remains seriously ill or in acute renal failure for >2 days, maintenance doses of quinine or quinidine should be reduced by 30–50% to prevent toxic accumulation of the drug. The initial doses should never be reduced. If safe and feasible, exchange transfusion may be considered for patients with severe malaria, although the precise indications for this procedure have not been agreed upon and there is no clear evidence that this measure is beneficial, particularly with artesunate treatment. Convulsions should


InternalMed_Harrison

InternalMed_Harrison. the precise indications for this procedure have not been agreed upon and there is no clear evidence that this measure is beneficial, particularly with artesunate treatment. Convulsions should be treated promptly with IV (or rectal) benzodiazepines. The role of prophylactic anticonvulsants in children is uncertain. If respiratory support is not available, then a full loading dose of phenobarbital (20 mg/kg) to prevent convulsions should not be given as it may cause respiratory arrest.


InternalMed_Harrison

InternalMed_Harrison. When the patient is unconscious, the blood glucose level should be measured every 4–6 h. All patients should receive a continuous infusion of dextrose, and blood concentrations ideally should be maintained above 4 mmol/L. Hypoglycemia (<2.2 mmol/L or 40 mg/ dL) should be treated immediately with bolus glucose. The parasite count and hematocrit level should be measured every 6–12 h. Anemia develops rapidly; if the hematocrit falls to <20%, then whole blood (preferably fresh) or packed cells should be transfused slowly, with careful attention to circulatory status. Renal function should be checked daily. Children presenting with severe anemia and acidotic breathing require immediate blood transfusion. Accurate assessment is vital. Management of fluid balance is difficult in severe malaria, particularly in adults, because of the thin dividing line between overhydration (leading to pulmonary edema) and underhydration (contributing to renal impairment). As soon as the patient can take


InternalMed_Harrison

InternalMed_Harrison. particularly in adults, because of the thin dividing line between overhydration (leading to pulmonary edema) and underhydration (contributing to renal impairment). As soon as the patient can take fluids, oral therapy should be substituted for parenteral treatment.


InternalMed_Harrison

InternalMed_Harrison. Infections due to sensitive strains of P. vivax, P. knowlesi, P. malariae, and P. ovale should be treated with oral chloroquine (total dose, 25 mg of base/kg) or with an ATC known to be efficacious. In much of the tropics, drug-resistant P. falciparum has been increasing in distribution, frequency, and intensity. It is now accepted that, to prevent resistance, falciparum malaria should be treated with drug combinations and not with single drugs in endemic areas; the same rationale has been applied successfully to the treatment of tuberculosis, HIV/AIDS, and cancers. This combination strategy is based on simultaneous use of two or more drugs with different modes of action. ACT regimens are now recommended as first-line treatment for falciparum malaria throughout the malaria-affected world. These regimens are safe and effective in adults, children, and after the first trimester of pregnancy (uncertainty regarding safety currently precludes their use in the first trimester). The rapidly


InternalMed_Harrison

InternalMed_Harrison. These regimens are safe and effective in adults, children, and after the first trimester of pregnancy (uncertainty regarding safety currently precludes their use in the first trimester). The rapidly eliminated artemisinin component is usually an artemisinin derivative (artesunate, artemether, or dihydroartemisinin) given for 3 days, and the partner drug is usually a more slowly eliminated antimalarial to which


InternalMed_Harrison

InternalMed_Harrison. P. falciparum is sensitive. Five ACT regimens are currently recommended by the WHO. In areas with multidrug-resistant falciparum malaria (parts of Asia and South America, including those with mefloquine-resistant parasites; Fig. 248-10), artemether-lumefantrine, artesunate-mefloquine, or dihydroartemisinin-piperaquine should be used; these regimens provide cure rates of >90%. In areas with sensitive parasites, the aforementioned combinations, artesunatesulfadoxine-pyrimethamine, or artesunate-amodiaquine also may be aHalofantrine should not be used by patients with long ECG QTc intervals or known conduction disturbances or by those taking drugs that may affect ventricular repolarization—e.g., quinidine, quinine, mefloquine, chloroquine, neuroleptics, antiarrhythmics, tricyclic antidepressants, and some antihistamines. bTetracycline and doxycycline should not be given to pregnant women or to children <8 years of age.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: Cl, systemic clearance; ECG, electrocardiogram; G6PD, glucose-6-phosphate dehydrogenase; Vd , total apparent volume of distribution. Andaman Sea Gulf of Thailand ChinaMyanmarThailandCambodiaBhutanIndiaBangladeshVietnamLaosMalaysiaFIGuRE 248-10 Mefloquine and artemisinin resistance in Plasmodium falciparum in Southeast Asia: high-level mefloquine resistance (dark red), low-level mefloquine resistance (pink), and mefloquine sensitivity (failure rate, <20%; green). There is insufficient information for other areas. Artemisinin resistance is now prevalent in areas where mefloquine resistance has been reported (pink areas).


InternalMed_Harrison

InternalMed_Harrison. used. Pyronaridine-artesunate is still under evaluation. Atovaquoneproguanil is highly effective everywhere, although it is seldom used in endemic areas because of its high cost and the propensity for rapid emergence of resistance. Of great concern is the emergence of artemisinin-resistant P. falciparum in western Cambodia and eastern Myanmar. Infections with these parasites are cleared slowly from the blood, with clearance times typically exceeding 3 days, and cure rates with ACTs are reduced.


InternalMed_Harrison

InternalMed_Harrison. The 3-day ACT regimens are all well tolerated, although mefloquine is associated with increased rates of vomiting and dizziness. As second-line treatments for recrudescence following first-line therapy, a different ACT regimen may be given; another alternative is a 7-day course of either artesunate or quinine plus tetracycline, doxycycline, or clindamycin. Tetracycline and doxycycline cannot be given to pregnant women or to children <8 years of age. Oral quinine is extremely bitter and regularly produces cinchonism comprising tinnitus, high-tone deafness, nausea, vomiting, and dysphoria. Adherence is poor with the required 7-day regimens of quinine.


InternalMed_Harrison

InternalMed_Harrison. Patients should be monitored for vomiting for 1 h after the administration of any oral antimalarial drug. If there is vomiting, the dose should be repeated. Symptom-based treatment, with tepid sponging and acetaminophen administration, lowers fever and thereby reduces the patient’s propensity to vomit these drugs. Minor central nervous system reactions (nausea, dizziness, sleep disturbances) are common. The incidence of serious adverse neuropsychiatric reactions to mefloquine treatment is ~1 in 1000 in Asia but may be as high as 1 in 200 among Africans and Caucasians. All the antimalarial quinolines (chloroquine, mefloquine, and quinine) exacerbate the orthostatic hypotension associated with malaria, and all are tolerated better by children than by adults. Pregnant women, young children, patients unable to tolerate oral therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evaluated carefully and hospitalization considered. If there is any doubt as to


InternalMed_Harrison

InternalMed_Harrison. patients unable to tolerate oral therapy, and nonimmune individuals (e.g., travelers) with suspected malaria should be evaluated carefully and hospitalization considered. If there is any doubt as to the identity of the infecting malarial species, treatment for falciparum malaria should be given. A negative blood smear makes malaria unlikely but does not rule it out completely; thick blood films should be checked again 1 and 2 1381 days later to exclude the diagnosis. Nonimmune patients receiving treatment for malaria should have daily parasite counts performed until the thick films are negative. If the level of parasitemia does not fall below 25% of the admission value in 48 h or if parasitemia has not cleared by 7 days (and adherence is assured), drug resistance is likely and the regimen should be changed.


InternalMed_Harrison

InternalMed_Harrison. To eradicate persistent liver stages and prevent relapse (radical treatment), primaquine (0.5 mg of base/kg or, in infections acquired in temperate areas, 0.25 mg/kg) should be given daily for 14 days to patients with P. vivax or P. ovale infections after laboratory tests for G6PD deficiency have proved negative. If the patient has a mild variant of G6PD deficiency, primaquine can be given in a dose of 0.75 mg of base/kg (45 mg maximum) once weekly for 8 weeks. Pregnant women with vivax or ovale malaria should not be given primaquine but should receive suppressive prophylaxis with chloroquine (5 mg of base/kg per week) until delivery, after which radical treatment can be given.


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InternalMed_Harrison. COMPLICATIONS Acute Renal Failure If the plasma level of BUN or creatinine rises despite adequate rehydration, fluid administration should be restricted to prevent volume overload. As in other forms of hypercatabolic acute renal failure, renal replacement therapy is best performed early (Chap. 334). Hemofiltration and hemodialysis are more effective than peritoneal dialysis and are associated with lower mortality risk. Some patients with renal impairment pass small volumes of urine sufficient to allow control of fluid balance; these cases can be managed conservatively if other indications for dialysis do not arise. Renal function usually improves within days, but full recovery may take weeks.


InternalMed_Harrison

InternalMed_Harrison. Acute Pulmonary Edema (Acute Respiratory Distress Syndrome) Patients should be positioned with the head of the bed at a 45° elevation and given oxygen and IV diuretics. Pulmonary artery occlusion pressures may be normal, indicating increased pulmonary capillary perme ability. Positive-pressure ventilation should be started early if the immediate measures fail (Chap. 326). Hypoglycemia An initial slow injection of 50% dextrose (0.5 g/kg) should be followed by an infusion of 10% dextrose (0.10 g/kg per hour). The blood glucose level should be checked regularly thereafter as recurrent hypoglycemia is common, particularly among patients receiving quinine or quinidine. In severely ill patients, hypoglycemia commonly occurs together with metabolic (lactic) acidosis and carries a poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. Other Complications Patients who develop spontaneous bleeding should be given fresh blood and IV vitamin K. Convulsions should be treated with IV or rectal benzodiazepines and, if necessary, respiratory support. Aspiration pneumonia should be suspected in any unconscious patient with convulsions, particularly with persistent hyperventilation; IV antimicrobial agents and oxygen should be administered, and pulmonary toilet should be undertaken. Hypoglycemia or gram-negative septicemia should be suspected when the condition of any patient suddenly deteriorates for no obvious reason during antimalarial treatment. In malaria-endemic areas where a high proportion of children are parasitemic, it is usually impossible to distinguish severe malaria from bacterial sepsis with confidence. These children should be treated with both antimalarials and broad-spectrum antibiotics from the outset. Because nontyphoidal Salmonella infections are particularly common, empirical antibiotics should be


InternalMed_Harrison

InternalMed_Harrison. children should be treated with both antimalarials and broad-spectrum antibiotics from the outset. Because nontyphoidal Salmonella infections are particularly common, empirical antibiotics should be selected to cover these organisms. Antibiotics should be considered for severely ill patients of any age who are not responding to antimalarial treatment.


InternalMed_Harrison

InternalMed_Harrison. In recent years, considerable progress has been made in malaria prevention, control, and research. Distribution of insecticide-treated 1382 bed-nets (ITNs) has been shown to reduce all-cause mortality in African children by 20%. New drugs have been discovered and developed, and one vaccine candidate (the RTS,S vaccine) will soon be considered for registration. Highly effective drugs, long-lasting ITNs, and insecticides for spraying dwellings are being purchased for endemic countries by the Global Fund to Fight AIDS, Tuberculosis, and Malaria; the President’s Malaria Initiative (funded by the U.S. Agency for International Development and managed by the CDC in partnership with endemic countries); UNICEF; and other organizations. Malaria research and control are being strongly supported by the National Institute of Allergy and Infectious Diseases, the CDC, the Wellcome Trust, the Bill & Melinda Gates Foundation, the Multilateral Initiative on Malaria, the Roll Back Malaria Partnership,


InternalMed_Harrison

InternalMed_Harrison. the National Institute of Allergy and Infectious Diseases, the CDC, the Wellcome Trust, the Bill & Melinda Gates Foundation, the Multilateral Initiative on Malaria, the Roll Back Malaria Partnership, and the WHO among others. While a laudable goal, the global eradication of malaria is not feasible in the immediate future because of the widespread distribution of Anopheles breeding sites; the great number of infected persons; the continued use of ineffective antimalarial drugs; and inadequacies in human and material resources, infrastructure, and control programs. The call for and commitment to ultimate eradication of malaria by the Gates Foundation in 2007— seconded by Margaret Chan, Director General of the WHO—added great impetus to all malaria initiatives, especially those aimed at discovery and implementation of new interventions. Malaria may be contained by judicious use of insecticides to kill the mosquito vector, rapid diagnosis, patient management, and—where effective and


InternalMed_Harrison

InternalMed_Harrison. discovery and implementation of new interventions. Malaria may be contained by judicious use of insecticides to kill the mosquito vector, rapid diagnosis, patient management, and—where effective and feasible—administration of intermittent preventive treatment, seasonal malaria chemoprevention, or chemoprophylaxis to high-risk groups such as pregnant women, young children, and travelers from nonendemic regions. Malaria researchers are intensifying their efforts to gain a better understanding of parasite-human-mosquito interactions and to develop more effective control and prevention interventions. Despite the enormous investment in efforts to develop a malaria vaccine and the 30–60% efficacy in African children of a recombinant protein sporozoite-targeted adjuvanted vaccine (RTS,S) in field trials, no safe, highly effective, long-lasting vaccine is likely to be available for general use in the near future (Chap. 148). Indeed, protection from RTS,S in the very youngest recipients


InternalMed_Harrison

InternalMed_Harrison. field trials, no safe, highly effective, long-lasting vaccine is likely to be available for general use in the near future (Chap. 148). Indeed, protection from RTS,S in the very youngest recipients dropped to 16% only 4 years after vaccination. While there is great promise for one or several malaria vaccines on the more distant horizon, prevention and control measures continue to rely on antivector and drug-use strategies. Furthermore, recent gains are threatened by increasing insecticide resistance and behavioral changes (to avoid ITN contact) in anopheline mosquito vectors and by spreading artemisinin resistance in P. falciparum.


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InternalMed_Harrison. Simple measures to reduce the frequency of infected-mosquito bites in malarious areas are very important. These measures include the avoidance of exposure to mosquitoes at their peak feeding times (usually dusk to dawn) and the use of insect repellents containing 10–35% DEET (or, if DEET is unacceptable, 7% picaridin), suitable clothing, and ITNs or other insecticide-impregnated materials. Widespread use of bed nets treated with residual pyrethroids reduces the incidence of malaria in areas where vectors bite indoors at night. (Table 248-8; wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3infectious-diseases-related-to-travel/malaria) Recommendations for prophylaxis depend on knowledge of local patterns of Plasmodium species drug sensitivity and the likelihood of acquiring malarial infection. When there is uncertainty, drugs effective against resistant


InternalMed_Harrison

InternalMed_Harrison. P. falciparum should be used (atovaquone-proguanil [Malarone], doxycycline, or mefloquine). Chemoprophylaxis is never entirely reliable, and malaria should always be considered in the differential diagnosis of fever in patients who have traveled to endemic areas, even if they are taking prophylactic antimalarial drugs.


InternalMed_Harrison

InternalMed_Harrison. Pregnant women traveling to malarious areas should be warned about the potential risks. All pregnant women at risk in endemic areas should be encouraged to attend regular antenatal clinics. Mefloquine is the only drug advised for pregnant women traveling to areas with drug-resistant malaria; this drug is generally considered safe in the second and third trimesters of pregnancy, and the data on first-trimester exposure, although limited, are reassuring. Chloroquine and proguanil are regarded as safe. The safety of other prophylactic antimalarial agents in pregnancy has not been established. Antimalarial prophylaxis has been shown to reduce mortality rates among children between the ages of 3 months and 4 years in malaria-endemic areas; however, it is not a logistically or economically feasible option in many countries. The alternative—to give intermittent preventive treatment or seasonal malaria chemoprevention—shows promise for more widespread use in infants, young children, and


InternalMed_Harrison

InternalMed_Harrison. feasible option in many countries. The alternative—to give intermittent preventive treatment or seasonal malaria chemoprevention—shows promise for more widespread use in infants, young children, and pregnant women. Children born to nonimmune mothers in endemic areas (usually expatriates moving to malaria-endemic areas) should receive prophylaxis from birth.


InternalMed_Harrison

InternalMed_Harrison. Travelers should start taking antimalarial drugs 2 days to 2 weeks before departure so that any untoward reactions can be detected and so that therapeutic antimalarial blood concentrations will be present when needed (Table 248-8). Antimalarial prophylaxis should continue for 4 weeks after the traveler has left the endemic area, except if atovaquone-proguanil or primaquine has been taken; these drugs have significant activities against the liver stage of the infection (causal prophylaxis) and can be discontinued 1 week after departure from the endemic area. If suspected malaria develops while a traveler is abroad, obtaining a reliable diagnosis and antimalarial treatment locally is a top priority. Presumptive self-treatment for malaria with atovaquoneproguanil (for 3 consecutive days) or another drug can be considered under special circumstances; medical advice on self-treatment should be sought before departure for malarious areas and as soon as possible after illness begins. Every


InternalMed_Harrison

InternalMed_Harrison. another drug can be considered under special circumstances; medical advice on self-treatment should be sought before departure for malarious areas and as soon as possible after illness begins. Every effort should be made to confirm the diagnosis by parasitologic studies.


InternalMed_Harrison

InternalMed_Harrison. Atovaquone-proguanil (Malarone; 3.75/1.5 mg/kg or 250/100 mg, daily adult dose) is a fixed-combination, once-daily prophylactic agent that is very well tolerated by adults and children, with fewer adverse gastrointestinal effects than chloroquine-proguanil and fewer adverse central nervous system effects than mefloquine. It is proguanil itself, rather than the antifolate metabolite cycloguanil, that acts synergistically with atovaquone. This combination is effective against all types of malaria, including multidrug-resistant falciparum malaria. Atovaquone-proguanil is best taken with food or a milky drink to optimize absorption. There are insufficient data on the safety of this regimen in pregnancy.


InternalMed_Harrison

InternalMed_Harrison. Mefloquine (250 mg of salt weekly, adult dose) has been widely used for malarial prophylaxis because it is usually effective against multidrug-resistant falciparum malaria and is reasonably well tolerated. The drug has been associated with rare episodes of psychosis and seizures at prophylactic doses; these reactions are more frequent at the higher doses used for treatment. More common side effects with prophylactic doses of mefloquine include mild nausea, dizziness, fuzzy thinking, disturbed sleep patterns, vivid dreams, and malaise. The drug is contraindicated for use by travelers with known hypersensitivity to mefloquine or related compounds (e.g., quinine, quinidine) and by persons with active or recent depression, anxiety disorder, psychosis, schizophrenia, another major psychiatric disorder, or seizures; mefloquine is not recommended for persons with cardiac conduction abnormalities although the evidence that it is cardiotoxic is very weak. Confidence is increasing with regard


InternalMed_Harrison

InternalMed_Harrison. disorder, or seizures; mefloquine is not recommended for persons with cardiac conduction abnormalities although the evidence that it is cardiotoxic is very weak. Confidence is increasing with regard to the safety of mefloquine prophylaxis during pregnancy; in studies in Africa, mefloquine prophylaxis was found to be effective and safe during pregnancy. However, in one study from Thailand, treatment of malaria with mefloquine was associated with an increased risk of stillbirth; this effect was not seen subsequently.


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InternalMed_Harrison. Daily administration of doxycycline (100 mg daily, adult dose) is an effective alternative to atovaquone-proguanil or mefloquine. Doxycycline is generally well tolerated but may cause vulvovaginal thrush, diarrhea, and photosensitivity and cannot be used by children <8 years old or by pregnant women. Chloroquine can no longer be relied upon to prevent P. falciparum infections in most areas but is used to prevent and treat malaria due to the other human Plasmodium species and for P. falciparum malaria in Central American countries west and north of the Panama Primaquine For prevention of malaria 30 mg of base 0.5 mg of base/kg (0.8 mg of Begin 1–2 days before travel to malarious areas. in areas with mainly (52.6 mg of salt) salt/kg) PO qd, up to adult dose; Take daily at the same time each day while in


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InternalMed_Harrison. P. vivax PO qd should be taken with food the malarious areas and for 7 days after leaving such areas. Primaquine is contraindicated in persons with G6PD deficiency. It is also contraindicated during pregnancy and in lactation unless the infant being breast-fed has a documented normal G6PD level. Primaquine Used for presumptive 30 mg of base 0.5 mg of base/kg (0.8 mg of This therapy is indicated for persons who have antirelapse therapy (52.6 mg of salt) PO salt/kg), up to adult dose, PO qd had prolonged exposure to P. vivax and/or (terminal prophylaxis) to qd for 14 days after for 14 days after departure from P. ovale. It is contraindicated in persons with G6PD decrease risk of relapses departure from the the malarious area deficiency as well as during pregnancy and in of P. vivax and P. ovale malarious area lactation unless the infant being breast-fed has a documented normal G6PD level.


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InternalMed_Harrison. aAn adult tablet contains 250 mg of atovaquone and 100 mg of proguanil hydrochloride. bA pediatric tablet contains 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride. cVery few areas now have chloroquine-sensitive malaria (Fig. 248-2). Source: CDC: www.cdc.gov/malaria/travelers/drugs.html.


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InternalMed_Harrison. Canal, Caribbean countries, and some countries in the Middle East. potential problem with protracted prophylactic use; such myopathy is Chloroquine-resistant P. vivax has been reported from parts of eastern more likely to occur at the high doses used in the treatment of rheuma-Asia, Oceania, and Central and South America. This drug is gener-toid arthritis. Neuropsychiatric reactions and skin rashes are unusual. ally well tolerated, although some patients cannot take it because of When used continuously, amodiaquine, a related aminoquinoline, is malaise, headache, visual symptoms (due to reversible keratopathy), associated with a high risk of agranulocytosis (~1 person in 2000) and gastrointestinal intolerance, or pruritus. Chloroquine is considered hepatotoxicity (~1 person in 16,000); thus this agent should not be safe in pregnancy. With chronic administration for >5 years, a char-used for prophylaxis. acteristic dose-related retinopathy may develop, but this condition is Primaquine


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InternalMed_Harrison. this agent should not be safe in pregnancy. With chronic administration for >5 years, a char-used for prophylaxis. acteristic dose-related retinopathy may develop, but this condition is Primaquine (daily adult dose, 0.5 mg of base/kg or 30 mg taken rare at the doses used for antimalarial prophylaxis. Idiosyncratic or with food), an 8-aminoquinoline compound, has proved safe and allergic reactions are also rare. Skeletal and/or cardiac myopathy is a effective in the prevention of drug-resistant falciparum and vivax 1384 malaria in adults. This drug can be considered for persons who are traveling to areas with or without drug-resistant P. falciparum and who are intolerant to other recommended drugs. Abdominal pain and oxidant hemolysis—the principal adverse effects—are not common as long as the drug is taken with food and is not given to G6PDdeficient persons, in whom it can cause serious hemolysis. Travelers must be tested for G6PD deficiency and be shown to have a level in the normal


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InternalMed_Harrison. the drug is taken with food and is not given to G6PDdeficient persons, in whom it can cause serious hemolysis. Travelers must be tested for G6PD deficiency and be shown to have a level in the normal range before receiving primaquine. Primaquine should not be given to pregnant women or neonates. Primaquine, given in a single dose of 0.25 mg/kg as a gametocytocide, together with an ACT is recommended in falciparum malaria treatment regimens in malaria elimination programs. In the past, the dihydrofolate reductase inhibitors pyrimethamine and proguanil (chloroguanide) were administered widely, but the rapid selection of resistance in both P. falciparum and P. vivax has limited their use. Whereas antimalarial quinolines such as chloroquine (a 4-aminoquinoline) act on the erythrocyte stage of parasitic development, the dihydrofolate reductase inhibitors also inhibit preerythrocytic growth in the liver (causal prophylaxis) and development in the mosquito (sporontocidal activity). Proguanil


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InternalMed_Harrison. parasitic development, the dihydrofolate reductase inhibitors also inhibit preerythrocytic growth in the liver (causal prophylaxis) and development in the mosquito (sporontocidal activity). Proguanil is safe and well tolerated, although mouth ulceration occurs in ~8% of persons using this drug; it is considered safe for antimalarial prophylaxis in pregnancy. The prophylactic use of the combination of pyrimethamine and sulfadoxine is not recommended because of an unacceptable incidence of severe toxicity, principally exfoliative dermatitis and other skin rashes, agranulocytosis, hepatitis, and pulmonary eosinophilia (incidence, 1:7000; fatal reactions, 1:18,000). The combination of pyrimethamine with dapsone (0.2/1.5 mg/kg weekly; 12.5/100 mg, adult dose) has been used in some countries. Dapsone may cause methemoglobinemia and allergic reactions and (at higher doses) may pose a significant risk of agranulocytosis. Proguanil and the pyrimethamine-dapsone combination are not available in


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InternalMed_Harrison. may cause methemoglobinemia and allergic reactions and (at higher doses) may pose a significant risk of agranulocytosis. Proguanil and the pyrimethamine-dapsone combination are not available in the United States. Because of the increasing spread and intensity of antimalarial drug resistance (Figs. 248-2 and 248-10), the CDC recommends that travelers and their providers consider their destination, type of travel, and current medications and health risks when choosing antimalarial chemoprophylaxis. There is an increasingly appreciated problem of counterfeit and substandard antimalarial drugs (and other medicines) on the shelves of pharmacies in Southeast Asia and sub-Saharan Africa; hence, travelers should purchase their preventive drugs from a reputable source before going to a malarious country. Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and local health departments and the CDC Malaria Hotline (770-488-7788) or the CDC


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InternalMed_Harrison. country. Consultation for the evaluation of prophylaxis failures or treatment of malaria can be obtained from state and local health departments and the CDC Malaria Hotline (770-488-7788) or the CDC Emergency Operations Center (770-488-7100).


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InternalMed_Harrison. Edouard G. Vannier, Peter J. Krause Babesiosis is an emerging tick-borne infectious disease caused by protozoan parasites of the genus Babesia that invade and eventually lyse red blood cells (RBCs). Most cases are due to Babesia microti and occur in the United States, particularly in the Northeast and upper Midwest. The infection typically is mild in young and otherwise healthy individuals but can be severe and sometimes fatal in persons >50 years of age and in immunocompromised patients. Sporadic cases have been reported in Europe and the rest of the world.


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InternalMed_Harrison. ETIOLOGY AND EPIDEMIOLOGY Geographic Distribution More than 100 Babesia species are found in wild and domestic animals; a few of these species cause infection in humans (Fig. 249-1). B. microti, a parasite of small rodents, is the most common etiologic agent of human babesiosis and is endemic in the northeastern and upper midwestern United States. Seven states in these two regions (Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, and Wisconsin) account for >95% of the reported cases. Other etiologic agents include Babesia duncani and B. duncani–type organisms on the West Coast and Babesia divergens–like organisms in Kentucky, Missouri, and Washington State. The primary causative agent of human babesiosis in Europe is


InternalMed_Harrison

InternalMed_Harrison. The primary causative agent of human babesiosis in Europe is B. divergens, but Babesia venatorum and B. microti also have been reported. In Asia, cases due to B. microti–like organisms have been documented in Japan, Taiwan, and the People’s Republic of China. A case caused by B. venatorum also has been reported from the People’s Republic of China. A case of B. microti infection was described in Australia. Sporadic cases due to uncharacterized species have been reported in Colombia, Egypt, India, Mozambique, and South Africa.


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InternalMed_Harrison. Incidence More than 1100 cases were reported in the United States in 2011, the year the disease became nationally notifiable. This figure represents a fivefold increase in incidence over the past decade. The incidence of babesiosis is markedly underestimated because symptoms are nonspecific and because young healthy individuals typically experience a mild or asymptomatic infection and may not seek medical attention. Fewer than 50 cases of B. divergens, B. divergens–like, and B. venatorum infections have been reported. Babesiosis caused by B. duncani and B. duncani–type organisms has also been sporadic, with fewer than 10 reported cases.


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InternalMed_Harrison. B. duncani and B. duncani–type organisms has also been sporadic, with fewer than 10 reported cases. Modes of Transmission In the United States, B. microti is transmitted to humans primarily by the nymphal stage of the deer tick (Ixodes scapularis), the same tick that transmits the causative agents of Lyme disease (Chap. 210) and human granulocytotropic anaplasmosis (Chap. 211). Transmission generally occurs from May through October, with three-fourths of cases presenting in July and August. The vectors for transmission of B. duncani and B. divergens– like organisms are thought to be Ixodes pacificus and Ixodes dentatus, respectively. In Europe, Ixodes ricinus is the vector for B. divergens and B. venatorum. In Japan, B. microti–like organisms have been found in Ixodes ovatus ticks.


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InternalMed_Harrison. Babesiosis occasionally is acquired through transfusion of blood or blood products. B. microti is the most common transfusion-transmitted pathogen reported to the U.S. Food and Drug Administration, and more than 170 such cases have been identified. Three transfusion-transmitted cases caused by B. duncani have been documented. Transfusion-transmitted cases occur year-round, although most cases occur from June through November. More than 80% of cases occur in endemic areas. Transfusion-transmitted babesiosis occurs in nonendemic areas when unrecognized Babesia-contaminated blood products are imported from endemic areas: asymptomatically infected residents of endemic areas donate blood in nonendemic areas, or residents of nonendemic areas travel to endemic areas, become infected, and donate blood after they return home. Approximately three-quarters of the transfusion-transmitted babesiosis cases reported between 1979 and 2009 occurred in the last decade of this period, and about


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InternalMed_Harrison. donate blood after they return home. Approximately three-quarters of the transfusion-transmitted babesiosis cases reported between 1979 and 2009 occurred in the last decade of this period, and about one-fifth of patients died.


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InternalMed_Harrison. Seven cases of probable or confirmed congenital B. microti infection have been described. Other cases of neonatal babesiosis have been acquired by transfusion or tick bite. CLINICAL MANIFESTATIONS Asymptomatic B. microti Infection At least 20% of adults and 40% of children do not experience symptoms following B. microti infection. Asymptomatic infection, whether treated or not, may persist for >1 year after acute babesial illness. There is no evidence of long-term complications following asymptomatic infection; however, people who are asymptomatically infected may transmit the infection when they donate blood. Mild to Moderate B. microti Illness Symptoms typically develop following an incubation period of 1–4 weeks after tick bite and 1–9 weeks (but as long as 6 months) after transfusion of blood products. Patients experience a gradual onset of malaise, fatigue, and weakness. Fever I. persulcatus B. duncani I. scapularis B. microti B. divergens I. ricinus I. ovatus


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InternalMed_Harrison. FIGuRE 249-1 Worldwide distribution of human babesiosis. Dark colors designate areas where human babesiosis is either endemic or sporadic (as defined by more than three tick-borne cases reported in a country or state). Isolated cases of babesiosis are denoted by circles. Colors designate causative Babesia species: Babesia microti and B. microti–like organisms in red, Babesia duncani and B. duncani–type organisms in orange, Babesia divergens and B. divergens–like organisms in blue, Babesia venatorum in purple, KO1 in black, and unspeciated Babesia organisms in white. Due to space constraints, the 10 cases reported from Montenegro are denoted by a single white circle, and those from Australia, Mozambique, and South Africa are not shown. Light colors denote areas that are enzootic for Ixodes tick species known to transmit one or several Babesia species but where human babesiosis has yet to be documented. (Adapted from E Vannier, PJ Krause: N Engl J Med 366:2397, 2012.) can reach 40.9°C


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InternalMed_Harrison. tick species known to transmit one or several Babesia species but where human babesiosis has yet to be documented. (Adapted from E Vannier, PJ Krause: N Engl J Med 366:2397, 2012.) can reach 40.9°C (105.6°F) and is accompanied by one or more of the following: chills, sweats, headache, myalgia, arthralgia, nausea, anorexia, and dry cough. Less common symptoms include sore throat, photo-phobia, abdominal pain, vomiting, weight loss, shortness of breath, and depression. On physical examination, fever is the salient feature. Ecchymoses and petechiae have been reported. An erythema migrans rash signifies concurrent Lyme disease (Chap. 210). Splenomegaly and hepatomegaly occasionally are noted. Lymphadenopathy is absent. Jaundice, slight pharyngeal erythema, and retinopathy with splinter hemorrhages and retinal infarcts rarely occur. Symptoms typically last 1–2 weeks, but fatigue may persist for several months.


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InternalMed_Harrison. Severe B. microti Illness Severe babesiosis requires hospital admission and typically occurs in patients with one or more of the following: age of >50 years, neonatal prematurity, male gender, asplenia, HIV/AIDS, malignancy, hemoglobinopathy, and immunosuppressive therapy. More than one-third of hospitalized patients develop complications, including acute respiratory distress syndrome, disseminated intra-vascular coagulation, congestive heart failure, renal failure, splenic infarcts, and splenic rupture. Patients who develop complications tend to have severe anemia (hemoglobin, ≤10 g/L). Laboratory prognostic factors for severe outcome—defined by hospitalization for >14 days, an intensive care unit stay of >2 days, or death—include an elevated alkaline phosphatase level (>125 U/L) and parasitemia of >4%. The fatality rate is 5–9% among hospitalized patients but is ~20% among immunocompromised patients and patients with transfusion-transmitted babesiosis.


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InternalMed_Harrison. Other Babesia Infections Cases of B. duncani infection range in severity from asymptomatic to fatal. Clinical manifestations are similar to those reported for B. microti infection. All three patients infected with B. divergens–like organisms in the United States required hospitalization; one died. Most cases of B. divergens infection in Europe have occurred in people lacking a spleen. The incubation period is 1–3 weeks. Symptoms appear suddenly and consist of fever (>41°C or 105.8°F), shaking chills, drenching sweats, headache, myalgia, and lumbar and abdominal pain. Hemoglobinuria and jaundice are commonly noted, and mild hepatomegaly may occur. If the infection is not treated, patients often develop pulmonary edema and renal failure. All four patients infected with B. venatorum in Europe had been splenectomized; their illness ranged from mild to severe, and none died. A child in China who developed B. venatorum illness had an intact spleen and survived the infection.


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InternalMed_Harrison. Anemia is a key feature of the pathogenesis of babesiosis. Hemolytic anemia caused by rupture of infected RBCs generates cell debris that may accumulate in the kidney and cause renal failure. Anemia also results from the clearance of intact RBCs as they pass through the splenic red pulp and encounter resident macrophages. Babesia antigens expressed at the RBC membrane promote opsonization and facilitate uptake by splenic macrophages. In addition, RBCs are poorly deformable as a result of oxidation generated by the parasite and the host immune response and are filtered out as they attempt to squeeze across the venous vasculature. Bone marrow suppression due to cytokine production may also contribute to anemia.


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InternalMed_Harrison. An appropriate immune response is necessary for the control and clearance of Babesia. However, several lines of evidence suggest that an excessive response contributes to pathogenesis. Studies using laboratory mice have clearly established that CD4+ T cells are critical for resistance to and resolution of B. microti infection. CD4+ T cells are a major source of interferon γ (IFN-γ), and lack of this cytokine causes resistant mice to become highly susceptible to B. microti. IFN-γ is central to host resistance in B. duncani infection, but natural killer cells are its main source. B. duncani infection is more severe than B. microti infection in rodents and is characterized by pulmonary inflammation. Tumor necrosis factor α is expressed around alveolar septa, whereas IFN-γ is detected around pulmonary vessels. Blockade of either cytokine promotes the survival of mice infected with B. duncani.


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InternalMed_Harrison. A diagnosis of babesiosis should be considered for any patient who lives or travels in a Babesia-endemic area and presents with a febrile illness in the late spring, summer, or early autumn or within 6 months after a blood transfusion. Co-infection with Babesia should be considered in cases of Lyme disease or human granulocytotropic anaplasmosis when symptoms are more severe or prolonged than usual. Screening laboratory tests can help support the diagnosis of babesiosis. A complete blood count often shows anemia and thrombocytopenia. Low hematocrit, hemoglobin, and haptoglobin levels and elevated reticulocyte counts and lactate dehydrogenase levels are consistent with hemolytic anemia. Liver enzyme tests often reveal elevated levels of alkaline phosphatase, aspartate and alanine aminotransferases, and bilirubin. Urinalysis may show hemoglobinuria, excess urobilinogen, and proteinuria. Elevated levels of blood urea nitrogen and serum creatinine indicate renal compromise.


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InternalMed_Harrison. A specific diagnosis usually is established by microscopic examination of Giemsa-stained thin blood smears (Fig. 249-2). Babesia trophozoites appear round, pear-shaped, or ameboid. The ring form is most common and lacks the central brownish deposit (hemozoin) typical of Plasmodium falciparum trophozoites (see Fig. 250e-1C). Other distinguishing features are the absence of schizonts and gametocytes and the occasional presence of tetrads (“Maltese cross”). FIGuRE 249-2 Giemsa-stained thin blood films showing Babesia microti parasites. B. microti are obligate parasites of erythrocytes. Trophozoites may appear as ring forms (A) or as ameboid forms (B). Merozoites can be arranged in tetrads and are pathognomonic (C). Extracellular parasites can be noted, particularly when parasitemia is high (D). (Adapted from E Vannier, PJ Krause: N Engl J Med 366:2397, 2012.)


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InternalMed_Harrison. Tetrads are characteristic of B. microti, B. duncani, and B. divergens–like organisms in human erythrocytes. Because the number of parasitized RBCs may be low, particularly at the onset of symptoms, identification of the parasite may require multiple blood smears over several days. Parasitemia levels can range from 1% to 20% in immunocompetent hosts and can be as high as 85% in immunocompromised patients. If parasites cannot be identified by microscopy and the disease is still suspected, amplification of the babesial 18S rRNA gene by polymerase chain reaction (PCR) is recommended. Quantitative PCR has greatly lowered the threshold for detection of B. microti DNA.


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InternalMed_Harrison. Serology can suggest or confirm the diagnosis of babesiosis. An indirect immunofluorescent antibody test for B. microti is most commonly used. IgM titers of ≥1:64 and IgG titers of ≥1:1024 suggest active or recent infection. Titers typically decline over 6–12 months. Antibodies to B. microti do not cross-react with B. duncani or B. divergens antigen. In B. divergens infection, serology is of limited use because symptoms often appear before antibodies can be detected. Sera from patients infected with B. divergens–like organisms or B. venatorum are reactive against B. divergens antigen. ASYMPTOMATIC B. MICROTI INFECTION


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InternalMed_Harrison. B. venatorum are reactive against B. divergens antigen. ASYMPTOMATIC B. MICROTI INFECTION People who experience asymptomatic B. microti infection often are not diagnosed and treated. Current guidelines recommend antibiotic therapy for asymptomatic carriers only if parasitemia persists for >3 months. Laboratory-based tests are being developed for the purpose of screening the blood supply and will result in the identification of a greater number of asymptomatic B. microti carriers, raising the question of whether they should be treated. MILD TO MODERATE B. MICROTI ILLNESS Atovaquone plus azithromycin, given orally for 7–10 days, is the recommended antibiotic treatment combination for mild to moderate B. microti Infection (Mild to Moderate Illnessa,b) Atovaquone (750 mg q12h PO) Atovaquone (20 mg/kg q12h PO; maximum, 750 mg/dose)


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InternalMed_Harrison. B. microti Infection (Mild to Moderate Illnessa,b) Atovaquone (750 mg q12h PO) Atovaquone (20 mg/kg q12h PO; maximum, 750 mg/dose) Azithromycin (500 mg/d PO on day 1, 250 mg/d PO thereafter) Azithromycin (10 mg/kg qd PO on day 1 [maximum, 500 mg/dose], 5 mg/kg qd PO thereafter [maximum, 250 mg/dose]) B. microti Infection (Severe Illnessc,d) B. divergens Infection Clindamycin (7–10 mg/kg q6–8h IV or 7–10 mg/kg q6–8h PO; maximum, 600 mg/dose) Quinine (8 mg/kg q8h PO; maximum, 650 mg/dose) Clindamycin (600 mg q6–8h IV) Clindamycin (7–10 mg/kg q6–8h IV; maximum, 600 mg/dose)


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InternalMed_Harrison. Quinine (8 mg/kg q8h PO; maximum, 650 mg/dose) Clindamycin (600 mg q6–8h IV) Clindamycin (7–10 mg/kg q6–8h IV; maximum, 600 mg/dose) Quinine (650 mg q8h PO) Quinine (8 mg/kg q8h PO; maximum, aTreatment duration, 7–10 days. bA high dose of azithromycin (600–1000 mg) combined with atovaquone has been recommended for immunocompromised hosts. cTreatment typically is given for 7–10 days, but its duration may vary. In severely immunocompromised patients, therapy should be continued for at least 6 weeks, including 2 weeks after parasites are no longer detected on blood smear. dSeveral alternative regimens have been used in a limited number of cases of B. microti infection, and their efficacy is uncertain. These regimens include atovaquone, azithromycin, and clindamycin; atovaquone, azithromycin, and doxycycline; atovaquone, clindamycin, and doxycycline; atovaquone, doxycycline, and artemisinin; atovaquone-proguanil; azithromycin and quinine; and azithromycin, clindamycin, and doxycycline.


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InternalMed_Harrison. Sources: (1) ME Falagas, MS Klempner: Clin Infect Dis 22:809, 1996. (2) PJ Krause et al: N Engl J Med 343:1454, 2000. (3) PJ Krause et al: Clin Infect Dis 46:370, 2008. (4) CM Shih, CC Wang: Am J Trop Med Hyg 59:509, 1998. (5) CP Stowell et al: N Engl J Med 356:2313, 2007. (6) JM Vyas et al: Clin Infect Dis 45:1588, 2007. (7) GP Wormser et al: Clin Infect Dis 50:381, 2010.


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InternalMed_Harrison. babesiosis (Table 249-1). Clindamycin plus quinine is a second choice. Symptoms usually begin to resolve within 48 h of therapy initiation, but complete resolution may take weeks to months. An atypical or poor response to therapy should raise concern about the possibility of concurrent Lyme disease (Chap. 210) or human granulocytotropic anaplasmosis (Chap. 211). In the first prospective trial of antibabesial therapy, the combination of atovaquone plus azithromycin was compared with clindamycin plus quinine in adults. These two drug combinations were equally effective in resolving symptoms and clearing parasitemia. Adverse effects were reported in 15% of trial participants who received atovaquone plus azithromycin but in 72% of those who received clindamycin plus quinine. Adverse reactions were so severe that treatment had to be stopped in about one-third of participants taking clindamycin plus quinine but in only 2% of those taking atovaquone plus azithromycin.


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InternalMed_Harrison. SEVERE B. MICROTI ILLNESS Clindamycin given intravenously plus quinine given orally for 7–10 days constitute the recommended treatment for severe babesiosis. Intravenous quinidine may be used instead of oral quinine but requires cardiac monitoring because of the risk of QT prolongation and polymorphic ventricular tachycardia.


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InternalMed_Harrison. Standard antimicrobial therapy is sometimes insufficient to resolve symptoms and clear parasitemia, especially in patients with marked immunosuppression due to splenectomy, HIAIDS, malig-13 nancy, andor immunosuppressive therapy (including rituximab for cell lymphomas). In such patients, antimicrobial therapy should be administered for at least weeks, including 2 weeks after parasites are no longer observed on blood smear. High-dose azithromycin (00–1000 mgd) plus atovauone have been successfully used in immunocompromised patients. esistance to atovauone plus azithromycin has occurred in a few cases. In patients who are unresponsive to atovauone plus azithromycin or who do not tolerate clindamycin plus uinine, alternative regimens have been used (Table 21).


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InternalMed_Harrison. Partial or complete C exchange transfusion is recommended in patients with high-grade parasitemia (0, severe anemia (hemoglobin, 0 gdL), or pulmonary, hepatic, or renal compromise. Parasitemia and hematocrit should be monitored daily until symptoms recede and the parasitemia level is The regimen for B. duncani infections typically consists of intravenous clindamycin (00 mg tidid or 1200 mg bid) plus oral uinine (00–50 mg tid) for 7–10 days. A regimen often used for B. divergens–like infections is intravenous clindamycin (00 mg tidid, 0 mg tid, or 1200 mg bid) plus oral uinine or uinidine (50 mg tid). In Europe, B. divergens infection is considered a medical emergency. The recommended treatment is immediate complete blood exchange transfusion and therapy with intravenous clindamycin plus either oral uinine or intravenous uinidine. Some cases have been cured with exchange transfusion and clindamycin monotherapy. Anemia may persist for month and reuire additional transfusion.


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InternalMed_Harrison. No vaccine is available for human use. There is no role for antibiotic prophylaxis. Individuals who reside in endemic areas, especially those at risk for severe babesiosis, should wear clothing that covers the lower part of the body, apply tick repellents (such as DEET) to clothing, and limit outdoor activities where ticks may abound from May through October. The skin should be thoroughly examined after outdoor activities, and ticks should be removed with tweezers. Individuals with a history of symptomatic babesiosis or with positive Babesia serology are indefinitely deferred from donating blood.


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InternalMed_Harrison. Atlas of Blood Smears of Malaria and Babesiosis Nicholas J. White, Joel G. Breman Six species of blood protozoan parasites cause human malaria (Chap. 248): the potentially lethal and often drug-resistant Plasmodium falci-parum; the relapsing parasites Plasmodium vivax and Plasmodium ovale 250e (with what appear to be two morphologically identical sympatric species of P. ovale); Plasmodium malariae, which can persist at low densities for years; and, in infections in individuals living in or close to tropical forests in Southeast Asia, Plasmodium knowlesi, a monkey parasite that microscopically resembles P. falciparum (young forms) and P. malariae (older forms) but is identified definitively by molecular methods.


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InternalMed_Harrison. The malaria parasites are readily seen under the microscope (×1000 250e-1 magnification) in thick and thin blood smears stained with supravital dyes (e.g., Giemsa’s, Field’s, Wright’s, Leishman’s). The morphologic characteristics of the parasites are summarized in Table 250e-1. In the thick film, lysis of red blood cells by water leaves the stained white cells and parasites, allowing detection of densities as low as 50 parasites/μL. This degree of sensitivity is up to 100 times greater than that of the thin film, in which the cells are fixed and the malaria parasites are seen inside the red cells. The thin film is better for speciation and provides useful prognostic information in severe falciparum malaria. Several findings are associated with increased mortality risk: high parasite counts, more mature parasites (>20% containing visible malaria pig ment), and phagocytosed malaria pigment in >5% of neutrophils. Babesia microti (Chap. 249) appears as a small ring form resembling


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InternalMed_Harrison. P. falciparum. Unlike Plasmodium, Babesia does not cause the production of pigment in parasites, nor are schizonts or gametocytes formed. aThe early trophozoites of Plasmodium knowlesi resemble those of P. falciparum. The late and mature trophozoites and schizonts of P. knowlesi appear very similar to those of P. malariae. The differences are that (1) P. knowlesi trophozoites may have double chromatin dots, with two or three parasites per RBC, and may cause higher-level parasitemia; and (2) P. knowlesi mature schizonts have 16 merozoites rather than the 8–10 found with P. malariae. bTwo morphologically identical sympatric species, according to recent evidence. Abbreviation: RBC, red blood cell. CHAPTER 250e Atlas of Blood Smears of Malaria and Babesiosis


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InternalMed_Harrison. Abbreviation: RBC, red blood cell. CHAPTER 250e Atlas of Blood Smears of Malaria and Babesiosis Figure 250e-1 Thin blood films of Plasmodium falciparum. A. Young trophozoites. B. Old trophozoites. C. Pigment in polymorphonuclear cells and trophozoites. D. Mature schizonts. E. Female gametocytes. F. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) Figure 250e-2 Thin blood films of Plasmodium vivax. A. Young trophozoites. B. Old trophozoites. C. Mature schizonts. D. Female gametocytes. E. Male gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)


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InternalMed_Harrison. Figure 250e-3 Thin blood films of Plasmodium ovale. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) Figure 250e-4 Thin blood films of Plasmodium malariae. A. Old trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) Figure 250e-5 Thick blood films of Plasmodium falciparum. A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) CHAPTER 250e Atlas of Blood Smears of Malaria and Babesiosis


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InternalMed_Harrison. CHAPTER 250e Atlas of Blood Smears of Malaria and Babesiosis Figure 250e-6 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) Figure 250e-7 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) Figure 250e-8 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Gametocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.)


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InternalMed_Harrison. Figure 250e-9 Thin blood film showing trophozoites of Babesia. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2nd ed, with the permission of the World Health Organization.) 1387 Leishmaniasis Shyam Sundar DEFINITION Encompassing a complex group of disorders, leishmaniasis is caused by unicellular eukaryotic obligatory intracellular protozoa of the genus Leishmania and primarily affects the host’s reticuloendothelial system. 251 Leishmania species produce widely varying clinical syndromes ranging from self-healing cutaneous ulcers to fatal visceral disease. These syndromes fall into three broad categories: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucosal leishmaniasis (ML).


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InternalMed_Harrison. Leishmaniasis is caused by ~20 species of the genus Leishmania in the order Kinetoplastida and the family Trypanosomatidae (Table 251-1). Several clinically important species are of the subspecies Viannia. The organisms are transmitted by phlebotomine sandflies of the genus Phlebotomus in the “Old World” (Asia, Africa, and Europe) and the genus Lutzomyia in the “New World” (the Americas). Transmission may be anthroponotic (i.e., the vector transmits the infection from infected humans to healthy humans) or zoonotic (i.e., the vector transmits the infection from an animal reservoir to humans). Human-tohuman transmission via shared infected needles has been documented in IV drug users in the Mediterranean region. In utero transmission to the fetus occurs rarely.


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InternalMed_Harrison. Leishmania organisms occur in two forms: extracellular, flagellate promastigotes (length, 10–20 μm) in the sandfly vector and intracellular, nonflagellate amastigotes (length, 2–4 μm; Fig. 251-1) in vertebrate hosts, including humans. Promastigotes are introduced through the proboscis of the female sandfly into the skin of the vertebrate host. Neutrophils predominate among the host cells that first encounter and take up promastigotes at the site of parasite delivery. The infected neutrophils may undergo apoptosis and release viable parasites that are taken up by macrophages, or the apoptotic cells may themselves be taken up by macrophages and dendritic cells. The parasites multiply as amastigotes inside macrophages, causing cell rupture with subsequent invasion of other macrophages. While feeding on infected hosts, sand-flies pick up amastigotes, which transform into the flagellate form in the flies’ posterior midgut and multiply by binary fission; the promastigotes then migrate to


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InternalMed_Harrison. feeding on infected hosts, sand-flies pick up amastigotes, which transform into the flagellate form in the flies’ posterior midgut and multiply by binary fission; the promastigotes then migrate to the anterior midgut and can infect a new host when flies take another blood meal.


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InternalMed_Harrison. Leishmaniasis occurs in 98 countries—most of them developing—in tropical and temperate regions (Fig. 251-2). More than 1.5 million cases occur annually, of which 0.7–1.2 million are CL (and its variations) and 200,000–400,000 are VL. More than 350 million people are at risk, with an overall prevalence of 12 million. Although the distribution of Leishmania is limited by the distribution of sandfly vectors, human leishmaniasis is on the increase worldwide. VL (also known as kala-azar, a Hindi term meaning “black fever”) is caused by the Leishmania donovani complex, which includes


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InternalMed_Harrison. VL (also known as kala-azar, a Hindi term meaning “black fever”) is caused by the Leishmania donovani complex, which includes L. donovani and Leishmania infantum (the latter designated Leishmania chagasi in the New World); these species are responsible for anthroponotic and zoonotic transmission, respectively. India and neighboring Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil are the four largest foci of VL and account for 90% of the world’s VL burden, with India being the worst affected. Zoonotic VL is reported from all countries in the Middle East, Pakistan, and other countries from western Asia to China. Endemic foci also exist in the independent states of the former Soviet Union, mainly Georgia and Azerbaijan. In the Horn of Africa, Sudan, South Sudan, Ethiopia, Kenya, Uganda, and Somalia report VL. In Sudan and South Sudan, large outbreaks are thought to be anthroponotic, although zoonotic transmission also occurs. VL is rare in West and sub-Saharan Africa.


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InternalMed_Harrison. Organism, Clinical Endemic Region Syndrome Species Vector Reservoir Transmission Setting aL. infantum is designated L. chagasi in the New World. Abbreviations: CL, cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; ML, mucosal leishmaniasis; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis. Mediterranean VL, long an established endemic disease due to on the immune system. IV drug users are at particular risk. Other L. infantum, has a large canine reservoir and was seen primarily in forms of immunosuppression (e.g., that associated with organ trans-infants before the advent of HIV infection. In Mediterranean Europe, plantation) also predispose to VL. In the Americas, disease caused by 70% of adult VL cases are associated with HIV co-infection. The com-L. infantum is endemic from Mexico to Argentina, but 90% of cases in bination is deadly because of the impact of the two infections together the New World are reported from northeastern Brazil.


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InternalMed_Harrison. FIGuRE 251-1 A macrophage with numerous intracellular amasti-gotes (2–4 μm) in a Giemsa-stained splenic smear from a patient with visceral leishmaniasis. Each amastigote contains a nucleus and a char-acteristic kinetoplast consisting of multiple copies of mitochondrial DNA. A few extracellular parasites are also visible. Immunopathogenesis The majority of individuals infected by


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InternalMed_Harrison. L. donovani or L. infantum mount a successful immune response and control the infection, never developing symptomatic disease. Forty-eight hours after intradermal injection of killed promastigotes, these individuals exhibit delayed-type hypersensitivity (DTH) to leishmanial antigens in the leishmanin skin test (also called the Montenegro skin test). Results in mouse models indicate that the development of acquired resistance to leishmanial infection is controlled by the production of interleukin (IL) 12 by antigen-presenting cells and the subsequent secretion of interferon (IFN) γ, tumor necrosis factor (TNF) α, and other proinflammatory cytokines by the T helper 1 (TH1) subset of T lymphocytes. The immune response in patients developing active VL is complex; in addition to increased production of multiple proinflammatory cytokines and chemokines, patients with active disease have markedly elevated levels of IL-10 in serum as well as enhanced IL-10 mRNA expression in lesional tissues.


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InternalMed_Harrison. of multiple proinflammatory cytokines and chemokines, patients with active disease have markedly elevated levels of IL-10 in serum as well as enhanced IL-10 mRNA expression in lesional tissues. The main disease-promoting activity of IL-10 in VL may be to condition host macrophages for enhanced survival and growth of the parasite. IL-10 1389 can render macrophages unresponsive to activation signals and inhibit killing of amastigotes by downregulating the production of TNF-α and nitric oxide. Multiple antigen-presentation functions of dendritic cells and macrophages are also suppressed by IL-10. Patients with such suppression do not have positive leishmanin skin tests, nor do their peripheral-blood mononuclear cells respond to leishmanial antigens in vitro. Organs of the reticuloendothelial system are predominantly affected, with remarkable enlargement of the spleen, liver, and lymph nodes in some regions. The tonsils and intestinal submucosa are also heavily infiltrated with parasites.


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InternalMed_Harrison. system are predominantly affected, with remarkable enlargement of the spleen, liver, and lymph nodes in some regions. The tonsils and intestinal submucosa are also heavily infiltrated with parasites. Bone marrow dysfunction results in pancytopenia.


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InternalMed_Harrison. Clinical Features On the Indian subcontinent and in the Horn of Africa, persons of all ages are affected by VL. In endemic areas of the Americas and the Mediterranean basin, immunocompetent infants and small children as well as immunodeficient adults are affected especially often. The most common presentation of VL is an abrupt onset of moderateto high-grade fever associated with rigor and chills. Fever may continue for several weeks with decreasing intensity, and the patient may become afebrile for a short period before experiencing another bout of fever. The spleen may be palpable by the second week of illness and, depending on the duration of illness, may become hugely enlarged (Fig. 251-3). Hepatomegaly (usually moderate in degree) soon follows. Lymphadenopathy is common in most endemic regions of the world except the Indian subcontinent, where it is rare. Patients lose weight and feel weak, and the skin gradually develops dark discoloration due to hyperpigmentation that is most


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InternalMed_Harrison. regions of the world except the Indian subcontinent, where it is rare. Patients lose weight and feel weak, and the skin gradually develops dark discoloration due to hyperpigmentation that is most easily seen in brown-skinned individuals. In advanced illness, hypoalbuminemia may manifest as pedal edema and ascites. Anemia appears early and may become severe enough to cause congestive heart failure. Epistaxis, retinal hemorrhages, and gastrointestinal bleeding are associated with thrombocytopenia. Secondary infections such as measles, pneumonia, tuberculosis, bacillary or amebic dysentery, and gastroenteritis are common. Herpes zoster, chickenpox, boils in the skin, and scabies may also occur. Untreated, the disease is fatal in most patients, including 100% of those with HIV co-infection.


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InternalMed_Harrison. Leukopenia and anemia occur early and are followed by thrombocytopenia. There is a marked polyclonal increase in serum immunoglobulins. Serum levels of hepatic aminotransferases are raised in a significant proportion of patients, and serum bilirubin levels are elevated occasionally. Renal dysfunction is uncommon. Laboratory Diagnosis Demonstration of amastigotes in smears of tissue aspirates is the gold standard for the diagnosis of VL (Fig. 251-1). The FIGuRE 251-2 Worldwide distribution of human leishmaniasis. CL, cutaneous leishmaniasis; VL, visceral leishmaniasis. FIGuRE 251-3 A patient with visceral leishmaniasis has a hugely enlarged spleen visible through the surface of the abdomen. Splenomegaly is the most important feature of visceral leishmaniasis.


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InternalMed_Harrison. FIGuRE 251-3 A patient with visceral leishmaniasis has a hugely enlarged spleen visible through the surface of the abdomen. Splenomegaly is the most important feature of visceral leishmaniasis. sensitivity of splenic smears is >95%, whereas smears of bone marrow (60–85%) and lymph node aspirates (50%) are less sensitive. Culture of tissue aspirates increases sensitivity. Splenic aspiration is invasive and may be dangerous in untrained hands. Several serologic techniques are currently used to detect antibodies to Leishmania. An enzyme-linked immunosorbent assay (ELISA) and the indirect immunofluorescent antibody test (IFAT) are used in sophisticated laboratories.


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InternalMed_Harrison. In the field, however, a rapid immunochromatographic test based on the detection of antibodies to a recombinant antigen (rK39) consisting of 39 amino acids conserved in the kinesin region of L. infantum is used worldwide. The test requires only a drop of fingerprick blood or serum, and the result can be read within 15 min. Except in East Africa (where both its sensitivity and its specificity are lower), the sensitivity of the rK39 rapid diagnostic test (RDT) in immunocompetent individuals is ~98% and its specificity is 90%. In Sudan, an RDT based on a new synthetic polyprotein, rK28, was more sensitive (96.8%) and specific (96.2%) than rK39-based RDTs. Qualitative detection of leishmanial nucleic acid by polymerase chain reaction (PCR) and quantitative detection by real-time PCR are confined to specialized laboratories and have yet to be used for routine diagnosis of VL in endemic areas. PCR can distinguish among the major species of Leishmania infecting humans.


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InternalMed_Harrison. Differential Diagnosis VL is easily mistaken for malaria. Other febrile illnesses that may mimic VL include typhoid fever, tuberculosis, brucellosis, schistosomiasis, and histoplasmosis. Splenomegaly due to portal hypertension, chronic myeloid leukemia, tropical splenomegaly syndrome, and (in Africa) schistosomiasis may also be confused with VL. Fever with neutropenia or pancytopenia in patients from an endemic region strongly suggests a diagnosis of VL; hypergammaglobulinemia in patients with long-standing illness strengthens the diagnosis. In nonendemic countries, a careful travel history is essential when any patient presents with fever.


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InternalMed_Harrison. Severe anemia should be corrected by blood transfusion, and other comorbid conditions should be managed promptly. Treatment of VL is complex because the optimal drug, dosage, and duration vary with the endemic region. Despite completing recommended treatment, some patients experience relapse (most often within 6 months), and prolonged follow-up is recommended. A pentavalent antimonial is the drug of choice in most endemic regions of the world, but there is widespread resistance to antimony in the Indian state of Bihar, where either amphotericin B (AmB) deoxycholate or miltefosine is preferred. Dose requirements for AmB are lower in India than in the Americas, Africa, or the Mediterranean region. In Mediterranean countries, where cost is seldom an issue, liposomal AmB is the drug of choice. In immunocompetent patients, relapses are uncommon with AmB in its deoxycholate and lipid formulations. Antileishmanial therapy has recently evolved as new drugs and delivery systems have become


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InternalMed_Harrison. In immunocompetent patients, relapses are uncommon with AmB in its deoxycholate and lipid formulations. Antileishmanial therapy has recently evolved as new drugs and delivery systems have become available and resistance to antimonial compounds has emerged.


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InternalMed_Harrison. Except for AmB (deoxycholate and lipid formulations), antileishmanial drugs are available in the United States only from the Centers for Disease Control and Prevention.


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InternalMed_Harrison. Two pentavalent antimonial (SbV) preparations are available: sodium stibogluconate (100 mg of SbV/mL) and meglumine antimoniate (85 mg of SbV/mL). The daily dose is 20 mg/kg by IV infusion or IM injection, and therapy continues for 28–30 days. Cure rates exceed 90% in Africa, the Americas, and most of the Old World but are <50% in Bihar, India, as a result of resistance. Adverse reactions to SbV treatment are common and include arthralgia, myalgia, and elevated serum levels of aminotransferases. Electrocardiographic changes are common. Concave ST-segment elevation is not significant, but prolongation of QTc to >0.5 s may herald ventricular arrhythmia and sudden death. Chemical pancreatitis is common but usually does not require discontinuation of treatment; severe clinical pancreatitis occurs in immunosuppressed patients.


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InternalMed_Harrison. AmB is currently used as a first-line drug in Bihar, India. In other parts of the world, it is used when initial antimonial treatment fails. Conventional AmB deoxycholate is administered in doses of 0.75–1.0 mg/kg on alternate days for a total of 15 infusions. Fever with chills is an almost universal adverse reaction to AmB infusions. Nausea and vomiting are also common, as is thrombophlebitis in the infused veins. Acute toxicities can be minimized by administration of antihistamines like chlorpheniramine and antipyretic agents like acetaminophen before each infusion. AmB can cause renal dysfunction and hypokalemia and, in rare instances, elicits hypersensitivity reactions, bone marrow suppression, and myocarditis, all of which can be fatal.


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InternalMed_Harrison. The several lipid formulations of AmB developed to replace the deoxycholate formulation are preferentially taken up by reticuloendothelial tissues. Because very little free drug is available to cause toxicity, a large amount of drug can be delivered over a short period. Liposomal AmB has been used extensively to treat VL in all parts of the world. With a terminal half-life of ~150 h, liposomal AmB can be detected in the liver and spleen of animals for several weeks after a single dose. This is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of VL; the regimen is 3 mg/kg daily on days 1–5, 14, and 21 (total dose, 21 mg/kg). However, the total-dose requirement for different regions of the world varies widely. In Asia, it is 10–15 mg/kg; in Africa, ~18 mg/kg; and in Mediterranean/American regions, ≥20 mg/kg. The daily dose is flexible (1–10 mg/kg). In a study in India, a single dose of 10 mg/kg cured infection in 96% of patients. Adverse effects of


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InternalMed_Harrison. mg/kg; and in Mediterranean/American regions, ≥20 mg/kg. The daily dose is flexible (1–10 mg/kg). In a study in India, a single dose of 10 mg/kg cured infection in 96% of patients. Adverse effects of liposomal AmB are usually mild and include infusion reactions, backache, and occasional reversible nephrotoxicity.


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InternalMed_Harrison. Paromomycin (aminosidine) is an aminocyclitol-aminoglycoside antibiotic with antileishmanial activity. Its mechanism of action against Leishmania has yet to be established. Paromomycin is approved in India for the treatment of VL at an IM dose of 11 mg of base/kg daily for 21 days; this regimen produces a cure rate of 95%. However, the optimal dose has not been established in other endemic regions. Paromomycin is a relatively safe drug, but some patients develop hepatotoxicity, reversible ototoxicity, and (in rare instances) nephrotoxicity and tetany.


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InternalMed_Harrison. Miltefosine, an alkylphosphocholine, is the first oral compound approved for the treatment of leishmaniasis. This drug has a long half-life (150–200 h); its mechanism of action is not clearly understood. The recommended therapeutic regimens for patients on the Indian subcontinent are a daily dose of 50 mg for 28 days for patients weighing <25 kg, a twice-daily dose of 50 mg for 28 days for patients weighing ≥25 kg, and 2.5 mg/kg for 28 days for children 2–11 years of age. These regimens have resulted in a cure rate of 94% in India. However, recent studies from the Indian subcontinent indicate a decline in the cure rate. Doses in other regions remain to be established. Because of its long half-life, miltefosine is prone to induce resistance in Leishmania. Its adverse effects include mild to moderate vomiting and diarrhea in 40% and 20% of patients, respectively; these reactions usually clear spontaneously after a few days. Rare cases of severe allergic dermatitis, hepatotoxicity, and


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InternalMed_Harrison. to moderate vomiting and diarrhea in 40% and 20% of patients, respectively; these reactions usually clear spontaneously after a few days. Rare cases of severe allergic dermatitis, hepatotoxicity, and nephrotoxicity have been reported. Because miltefosine is expensive and is associated with significant adverse events, it is best administered as directly observed therapy to ensure completion of treatment and to minimize the risk of resistance induction. Because miltefosine is teratogenic in rats, its use is contraindicated during pregnancy and (unless contraceptive measures are strictly adhered to for at least 3 months after treatment) in women of childbearing age.


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InternalMed_Harrison. Multidrug therapy for leishmaniasis is likely to be preferred in the future. Its potential advantages in VL include (1) better compliance and lower costs associated with shorter treatment courses and decreased hospitalization, (2) less toxicity due to lower drug doses and/or shorter duration of treatment, and (3) a reduced likelihood that resistance to either agent will develop. In a study from India, one dose of liposomal AmB (5 mg/kg) followed by miltefosine for 7 days, paromomycin for 10 days, or both miltefosine and paromomycin simultaneously for 10 days (in their usual daily doses) produced a cure rate of >97% (all three combinations). In Africa, a combination of SbV and paromomycin given for 17 days was as effective and safe as SbV given for 30 days.


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InternalMed_Harrison. Recovery from VL is quick. Within a week after the start of treatment, defervescence, regression of splenomegaly, weight gain, and recovery of hematologic parameters are evident. With effective treatment, no parasites are recovered from tissue aspirates at the posttreatment evaluation. Continued clinical improvement over 6–12 months is suggestive of cure. A small percentage of patients (with the exact figure depending on the regimen used) relapse but respond well to treatment with AmB deoxycholate or lipid formulations.


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InternalMed_Harrison. HIV/VL co-infection has been reported from 35 countries. Where both infections are endemic, VL behaves as an opportunistic infection in HIV-1-infected patients. HIV infection can increase the risk of developing VL by severalfold in endemic areas. Co-infected patients usually show the classic signs of VL, but they may present with atypical features due to loss of immunity and involvement of unusual anatomic locations, with, for example, infiltration of the skin, oral mucosa, gastrointestinal tract, lungs, and other organs. Serodiagnostic tests are commonly negative. Parasites can be recovered from unusual sites such as bronchoalveolar lavage fluid and buffy coat. Liposomal AmB is the drug of choice for HIV/VL co-infection—both for primary treatment and for treatment of relapses. A total dose of 40 mg/kg, administered as 4 mg/kg on days 1–5, 10, 17, 24, 31, and 38, is considered optimal and is approved by the FDA, but most patients experience a relapse within 1 year. Pentavalent


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InternalMed_Harrison. dose of 40 mg/kg, administered as 4 mg/kg on days 1–5, 10, 17, 24, 31, and 38, is considered optimal and is approved by the FDA, but most patients experience a relapse within 1 year. Pentavalent antimonials and AmB deoxycholate can also be used where liposomal AmB is not accessible. Reconstitution of patients’ immunity by antiretroviral therapy has led to a dramatic decline in the incidence of co-infection in the Mediterranean basin. In contrast, HIV/VL co-infection is on the rise in African and Asian countries. Ethiopia is worst affected: up to 30% of VL patients are also infected with HIV. Because restoration of the CD4+ T cell count to >200/μL does decrease the frequency of relapse, antiretroviral therapy (in addition to antileishmanial therapy) is a cornerstone for the management of HIV/VL co-infection. Secondary prophylaxis with lipo somal AmB has been shown to delay relapses, but no regimen has been established as optimal.


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InternalMed_Harrison. On the Indian subcontinent and in Sudan and other East African countries, 2–50% of patients develop skin lesions concurrent with or after the cure of VL. Most common are hypopigmented macules, papules, and/or nodules or diffuse infiltration of the skin and sometimes of the oral mucosa. The African and Indian diseases differ in several respects; important features of post–kala-azar dermal leishmaniasis (PKDL) in these two regions are listed in Table 251-2, and disease in an Indian patient is depicted in Fig. 251-4. In PKDL, parasites are scanty in hypopigmented macules but may be seen and cultured more easily from nodular lesions. Cellular infiltrates are heavier in nodules than in macules. Lymphocytes are the dominant cells; next most common are histiocytes and plasma TABLE 251-2 CLInICAL, EPIdEMIOLOgIC, And THERAPEuTIC FEATuREs OF POsT–KALA-AzAR dERMAL LEIsHMAnIAsIs: EAsT AFRICA And THE IndIAn suBCOnTInEnT


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InternalMed_Harrison. TABLE 251-2 CLInICAL, EPIdEMIOLOgIC, And THERAPEuTIC FEATuREs OF POsT–KALA-AzAR dERMAL LEIsHMAnIAsIs: EAsT AFRICA And THE IndIAn suBCOnTInEnT FIGuRE 251-4 Post–kala-azar dermal leishmaniasis in an Indian patient. Note nodules of varying size involving the entire face. The face is erythematous, and the surface of some of the large nodules is discolored.


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InternalMed_Harrison. cells. In about half of cases, epithelioid cells—scattered individually or forming compact granulomas—are seen. The diagnosis is based on history and clinical findings, but rK39 and other serologic tests are positive in most cases. Indian PKDL is treated with pentavalent antimonials for 60–120 days. This prolonged course frequently leads to noncompliance. The alternative—several courses of AmB spread over several months—is expensive and unacceptable for most patients. Oral miltefosine for 12 weeks, in the usual daily doses, cures most patients with Indian PKDL. In East Africa, a majority of patients experience spontaneous healing. In those with persistent lesions, the response to 60 days of treatment with a pentavalent antimonial is good.


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InternalMed_Harrison. CL can be broadly divided into Old World and New World forms. Old World CL caused by Leishmania tropica is anthroponotic and is confined to urban or suburban areas throughout its range. Zoonotic CL is most commonly due to Leishmania major, which naturally parasitizes several species of desert rodents that act as reservoirs over wide areas of the Middle East, Africa, and central Asia. Local outbreaks of human disease are common. Major outbreaks currently affect Afghanistan and Pakistan in association with refugees and population movement. CL is increasingly seen in tourists and military personnel on mission in CL-endemic regions of countries like Afghanistan and as a co-infection in HIV-infected patients. Leishmania aethiopica is restricted to the highlands of Ethiopia, Kenya, and Uganda, where it is a natural parasite of hyraxes. New World CL is mainly zoonotic and is most often caused by Leishmania mexicana, Leishmania (Viannia) panamensis, and Leishmania amazonensis. A wide range of


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InternalMed_Harrison. it is a natural parasite of hyraxes. New World CL is mainly zoonotic and is most often caused by Leishmania mexicana, Leishmania (Viannia) panamensis, and Leishmania amazonensis. A wide range of forest animals act as reservoirs, and human infections with these species are predominantly rural. As a result of extensive urbanization and deforestation, Leishmania (Viannia) braziliensis has adapted to peridomestic and urban animals, and CL due to this organism is increasingly becoming an urban disease. In the United States, a few cases of CL have been acquired indigenously in Texas.