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Treat Respir Med 2006; 5 (6): 419-428

THERAPY IN PRACTICE 1176-3450/06/0006-0419/$39.95/0

 2006 Adis Data Information BV. All rights reserved.

Pulmonary Manifestations of Malaria
Recognition and Management
Walter R.J. Taylor,1 Viviam Cañon2 and Nicholas J. White3,4
1 Travel and Migration Medicine Unit, Department of Community Medicine, Geneva University Hospital,
Geneva, Switzerland
2 Servicio de Medicina Interna, Hospital Militar Central, Bogota, Colombia
3 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
4 Centre of Vaccinology and Tropical Medicine, The Churchill Hospital, Headington, England

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
1. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
1.1 Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) in Adult Malaria: Focus on Pulmonary Edema . . . . . . . . 421
1.1.1 Pulmonary Edema in Benign Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
1.1.2 Pulmonary Edema in Pregnant Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
1.2 ALI/ARDS in Pediatric Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
1.3 ALI/ARDS Related to Concomitant Bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
2.1 Parasite Counts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
2.2 Radiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
3.1 Chemotherapy: Focus on Plasmodium falciparum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
3.1.1 Artemisinin-Based Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
3.1.2 Quinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
3.1.3 Quinidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
3.2 Malaria Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
3.2.1 Respiratory Compromise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
3.2.2 Fluid Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3.2.3 Acute Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3.2.4 Concomitant Bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3.2.5 Anemia and Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3.3 Other Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427

Abstract Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its
pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement.
Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysi-
ologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS).
Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum
infections as part of a severe systemic illness or as the main feature of acute malaria. P. vivax and P. ovale have
also rarely caused pulmonary edema.
Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure
either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the

[10] There are certain Therefore. Human malaria is a parasitic disease caused by four plasmodi.g. Saharan Africa. ovale produce liver hypnozoites (a dormant P. P. i. acute leaving a malaria-endemic area. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. ovale. and P. However. baum and Shrager[9] later described malaria pneumonitis. species differentiation is not possible um species. resulting in organ damage and dysfunc- with pulmonary symptoms. vivax in Latin America. Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications. P. but descriptions are of historical value attesting to the clinical acumen range generally from 7 to 16 days. and pernicious fever organs (cytoadherence). the risk of developing acute pulmonary tant illness in temperate zones. vivax. of severe malaria in adults. falciparum malaria in adults (table I). falciparum has two distinguishing pathologic fea. ALI/ARDS may also be related to a coincidental bacterial sepsis that may not be clinically obvious. parasitemia is falling. falciparum and P. wheeze or inspiratory crepitations. Pregnant women are particularly prone to developing pulmonary edema. cytes) are necessary to complete the parasite life-cycle in the mosquito.420 Taylor et al. cycle. but current choices are few: e. 1. Whilst this is increasingly being recognized in malaria-endemic countries. with tachypnea. malaria may be the cause of fever months or years after differences in symptoms between adults and children. However. of bygone physicians. and P. and do not cytoadhere. The WHO has defined severe and compli- (relapse) after successful treatment of the blood stage infection. All rights reserved. A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Plasmodium falciparum. The other species cause acute febrile illnesses that rarely or months after mosquito inoculation or further clinical disease cause severe morbidity. clinicians in temperate zones should be aware that malaria may be a possible cause of ’pneumonia’ in a visiting or returning child. schizonts) of the cause of fever in a traveler or visitor from a malaria-endemic parasites cause clinical disease. renal failure and pulmonary edema are rare in children. vivax and P. Clinical Features tures. and some 1400 in the US. Malaria must be treated with effective drugs. and In the past. Despite optimal management. after taking pertinent microbiologic specimens. Clinicians should employ a low threshold for starting broad spectrum antibacterials in such patients. Treat Respir Med 2006.[7.4] When malaria presents as pregnant women with severe malaria. a malaria blood film must be examined. and coma P. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. This results in diagnostic confusion and suboptimal treatment. ALI/ARDS in pediatric malaria appears to be rare. the prognosis of severe malaria with ARDS is poor. These The incubation periods of the four species vary somewhat. In a prospective case series clinical cases worldwide.8] Appel- generally <2% of the red cell population. and included such quaint diagnoses as bilious remittent fever. country. parenteral artemisinins. ed falciparum malaria.[11-13] In uncomplicat- many areas of mixed species transmission. 5 (6) . trophozoites. intravenous quinine or quinidine (in the US only). falciparum malaria with severe metabolic acidosis or acute pulmonary edema may present with a clinical picture of pneumonia. P. Respiratory compromise should be managed on its merits and may require mechanical ventilation. The latter was classified further as the tion. e. Its asexual forms have a much higher propensity to parasit- ize red blood cells and produce heavy parasite burdens. P. There are also and acute renal failure in 28% of the patients.  2006 Adis Data Information BV. P.[3. falciparum predominates in sub.6] Malaria must always be suspected as a possible The asexual blood stages (rings.[2] Malaria is an impor. fascinating descriptions and classifications of mala- parasitized red cells adhere to the post-capillary venules of vital ria were used based on the clinical picture. pulmonary edema occurred in 9–21%. The other malarias produce lower parasite burdens that are bronchitic. and many other febrile illnesses fall into the differential malariae that is transmitted by the female Anopheline mosquito. an acute febrile illness. notably coma and acute renal failure. Accordingly.g.e. as part of their life.1% in a cohort of 3300 American soldiers. Recent data suggest that the edema was 0. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness.[5.[1] diagnosis. vivax account for the vast majority of is common to both adults and children. falciparum malaria causes severe disease that may lead to tissue parasitic stage) that may produce a first clinical attack weeks death. cated P. intercostal recession. clinically.[14] Pulmo- estimated number of cases of malaria in Western Europe is 10 000 nary edema and hypoglycemia are both particularly common in per year. pneumonic and bronchopneumonic types. whereas the sexual forms (gameto.

In severely hypoxic patients. Shortness of breath and cough are the main symptoms of disseminated intravascular coagulation (DIC). pulmonary edema. death occurred in 7 of 10 ARDS patients poor response to diuretics and oxygen (refractory hypoxemia) is compared with none in 15 with non-ARDS pulmonary edema. ≥4% in a non-immune individual) The most significant malaria-induced lung pathology is acute pulmonary edema. in contrast to cardiogenic pulmonary edema.[23.2 mmol/L) does not participate in gas exchange. However. malaria-induced lung disease.35/plasma bicarbonate <15 mmol/L) after parasite reduction and general clinical improvement. In the absence of artificial ventilation – a not uncommon when parasitemia is falling and patients are improving clinical- situation in many developing countries – mortality in severe ly.[32]  2006 Adis Data Information BV. Dyspnea may start abruptly and progress rapidly. involv. even with appropriate respiratory support. 5 (6) . some patients also report chest and bacterial sepsis. confusion and agita. neutrophil and macro. Malaria-induced pulmonary edema is generally associated with falciparum malaria may exceed 80% (White NJ. recovery is often rapid. after the development of central cyanosis.1 Acute Lung Injury (ALI)/Acute Respiratory Distress Table I. mortality rates when ARDS is a ly the first features of impending pulmonary edema. unpublished severe disease in which respiratory compromise is part of the observations). for falciparum malaria. pulmonary edema. inspiratory crepitations. the additional role of red cell Shock sequestration in the lung. and unrousable coma. Pulmonary edema ing pro.[15-18] Consequently.[22-24] parasitemia. except that right-sided filling sepsis syndrome.[26-28] include labored breathing (’air hunger’). A study of Thai adults. overzealous use of intravenous fluids. antimalarial drug treatment. peripheral and Death may occur rapidly. Important iatrogenic factors are a delay in tightness.g. the possible role of nitric oxide in ischemic Spontaneous bleeding hypoxia. Pulmonary In Colombia. All rights reserved. within hours.and anti-inflammatory cytokines.[19] Lung function is com. Severe anemia (in adults: hemoglobin <7 g/dL or hematocrit <20%) promised because of a ventilation perfusion mismatch whereby Acute intravascular hemolysis with hemoglobinuria blood circulates through collapsed alveoli and edematous lung but Hypoglycemia (whole blood glucose <2. it may also occur as ria are jaundice with acute renal failure. Clinical and laboratory features of severe and complicated Syndrome (ARDS) in Adult Malaria: Focus on falciparum malaria in adults Pulmonary Edema Clinical features Coma (unrousable coma defines cerebral malaria) The definitions of acute lung injury (ALI) and the acute respira. Impaired consciousness tory distress syndrome (ARDS) have now been standardized (table Prostration/extreme weakness II). the permeability of Laboratory features the alveolar capillary membrane increases and protein-rich fluid Hyperbilirubinemia (total bilirubin ≥3 mg/dL) leaks into the lungs (exudative phase). preceding complication appear higher despite artificial ventilation. and expiratory wheezes. Pulmonary edema is associated particularly ture from the 1960s that describe the rapid evolution of pulmonary with cerebral malaria. acidosis. Good clinical descriptions can be found in the litera. cal signs reflect the severity of underlying lung involvement and and the failure to detect and effectively treat bacterial sepsis.30] The jugular venous pulse is not raised unless there is concomitant fluid overload.21] ALI/ARDS may occur Acidemia/acidosis (pH <7. Acute renal failure phage activation. metabolic acidosis. severe metabolic the predominant manifestation of an otherwise unremarkable feb.[29. hypoalbuminemia.31] involvement. Dyspnea and an increased respiratory rate are usual. and. Physi.24] Other poor prognostic features of severe mala- clinical picture of a toxic patient. metabolic acidosis. Although data are not extensive.[23. shock. tachypnea. Malaria-associated ALI/ARDS results from a complex host Multiple convulsions inflammatory response both in the lung and systemically.25] In patients who survive.Pulmonary Manifestations of Malaria 421 1. Treat Respir Med 2006. In one other clinical (e.[20. ing increased lung inflammation. The reported mortality rates of strictly defined. the mortality of severe malaria is approximately edema may occur at presentation or after several days of treatment 20%. inspiratory crepitations) or radiologic signs. this Hyperlactemia (plasma lactate >5 mmol/L) may represent a post-treatment shift in the cytokine balance favor.g. e. and cardiogenic pressures are not elevated unless excess intravenous fluids have been given. adult severe tion may be present and cannot be differentiated from cerebral malaria from tropical countries vary between 15% and 40%. acute renal failure. Parasitemia ≥4% to ≥20% (depends on malaria-acquired immunity.[12] usual. pneumonia.[23] The differential diagnoses are wide and include acute cardiogenic pulmonary edema.[13.[10] Other important associations are high edema and its poor prognosis in US Servicemen. hypoglycemia. It has the same dramatic clinical features as rile illness.

and auscultatory signs of Pulmonary edema is a well described but rare feature in patients consolidation were more likely in radiographically confirmed with P.[33-35] In contrast to falciparum malaria.41] In retrospective studies of adult ty in breathing and a raised respiratory rate. b Abnormal CXR findings may lag behind functional disturbances. and a small proportion (5%) had more than lished data). Prevalence data for bacteremia The clinical overlap of falciparum malaria and pneumonia in a vary widely. Streptococcus pneumoniae. responding to anticonvulsant treatment. and contributes to the overall clinical picture. 27 had pneumonia on the chest shown clearly that pulmonary inflammatory changes occur com.1 Pulmonary Edema in Benign Malaria as observed cough.3 ALI/ARDS Related to Concomitant Bacteremia with malaria and should be looked for actively with regular checks Bacteremia is a well recognized complication/association of of blood glucose levels. none was sufficiently discriminating to confidently other severe clinical features like acute intravascular hemolysis exclude malaria. ria has been studied by Crawley et al. and (iv) In women who are in the second and third trimesters of preg- periodic respiration (n = 14) leading to respiratory arrest and nancy. e. In a small clinical series. The citation with intravenous fluids and/or blood. Gachot et al. pulmonary edema has been seen rarely in both with cerebral malaria.[42] During the high transmission season. vivax and P. chest wall recession.g. respectively. 0. and 12% in two presenting with ‘clinical pneumonia’ defined as cough or difficul. mal respiratory pattern.2 Pulmonary Edema in Pregnant Women subtle status epilepticus. which resolved following resus- normal PaCO2) requiring mechanical ventilation for 2–5 days. Treat Respir Med 2006.’ The majority be rare in the ‘benign’ malarias. Escher-  2006 Adis Data Information BV. an ominous sign demanding careful clinical evaluation. vivax and ovale malaria.[38] an increase in small airways obstruction.[37] Similar results and shock.[10. and ≈11% A broad mix of pathogens have been isolated from studies. pulmonary edema associated with malaria is a particular death. It may not have an obvious clinical source. Although certain objective signs such ing Staphylococcus aureus. and inspiratory crepitations at presentation. severe malaria. (Cañon V. and reductions in gas The respiratory pattern in African children with cerebral mala- transfer. PA = posteroanterior. pneumonia with malaria).[39] Of 295 Kenyan children In Colombia. PaO2 = partial pressure of oxygen in arterial blood. clinic setting was shown in a study of young Gambian children unpublished data ). 1.1.[28. The latter two patterns are compatible with progression of problem that leads to a high mortality. x-ray. especially if the woman is anemic or ever.40. falciparum malaria in France. All rights reserved. on admission to their ICUs. low/ due to severe metabolic acidosis. the prognosis is were reported in a hospital-based study of 200 Kenyan children usually good.[27] and Bruneel et al.1. with nystagmus and salivation (n = 18). due to EEG-confirmed. studies in African children.422 Taylor et al. seven patients had cough. Hypoglycemia is common in pregnant women 1. Although clinically obvious pulmonary edema may with an admission diagnosis of ‘severe pneumonia.5% radiologic evidence of pneumonia (20% pneumonia alone. especially in the wet season. CXR = chest x-ray. Table II. and may be associated with pneumonia. Defining criteria for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) Timing Oxygenation PA chest x-ray Pulmonary artery wedge pressure Acute onset ALI PaO2/FiO2 ≤300mm Hga Bilateral infiltratesb ≤18mm Hg or no clinical evidence of left atrial hypertension Acute onset ARDS PaO2/FiO2 ≤200mm Hga Bilateral infiltratesb ≤18mm Hg or no clinical evidence of left atrial hypertension a Irrespective of the level of positive end-expiratory pressure. Four distinct shortness of breath. and 23 had falciparum malaria and radiologically confirmed monly in falciparum. 6% (10/175) in Thai adults. 1. ovale malaria. FiO2 = concentration of inspired oxygen. ≈40% had malaria only.[16] has (137) had a positive malaria slide. (ii) hypoventilation prognosis was good and there were no deaths. pneumonia. patterns of respiration were observed: (i) deep breathing (n = 80) All were in type I respiratory failure (PaO2 <60mm Hg. one abnormal respiratory pattern during their illness. unpub. (iii) hyperventilation with extensor posturing (n = 20).2% (1/500) in Vietnamese adults (White NJ.36] It may occur after raised intracranial pressure leading to brain stem herniation.2 ALI/ARDS in Pediatric Malaria endemic areas there is undoubted diagnostic overlap. 13% (5/40) and 14% (13/95). How- delivery of the placenta. one-third of 666 children had found rates of community-acquired bacterial infection to be 12. includ- malaria with another illness. 5 (6) . recent work by Anstey et al. In 1. resulting in cough. these suppositions have not been confirmed by autopsy fluid-overloaded before labor. An increase in the respiratory rate is studies. appropriate for age. a substantial minority (40%) had an abnor- vivax and mixed vivax/falciparum malaria. Clinicians should be aware that hypoglycemia also causes tachypnea and should be excluded.

e. while a thin film (figure 2) is tor of the total parasite biomass. Malaria is a parasitologic diagnosis. followed by increasing areas of fluffy shadowing (alveolar pat-  2006 Adis Data Information BV. of parasitized red cells per 1000 red cells is counted and multiplied physical findings.[49] A positive test with negative microscopy in a patient with a consistent clinical picture should be regarded as malaria. plasma lac. especial- ly if there is a history of antimalarial drug ingestion. especially if ALI/ARDS and/or shock are present.2 Radiology A chest radiograph may be helpful in differentiating pneumo- nia. A Giemsa-stained thick blood film showing asexual forms of Plas. modium falciparum.[47. and maintain a low threshold for starting broad spectrum antibiotics. (ii) three blood cultures. 5 (6) .6. blood glucose. therefore. and (iii) blood gases. All rights reserved. a good microscopist will detect low parasite counts down to 1 2. When using the thick film. A blood film is the ’gold Negative blood films should be repeated 12-hourly for 48 hours standard’ for diagnosing malaria.48] Serial count (WCC) divided by 200.[27. 2. A negative slide result does not rule out malaria. a negative result does not exclude malaria. logic signs include a generalized increase in interstitial markings. A thick film (figure 1) has high Quantifying the asexual parasitemia is a very imprecise indica- sensitivity for detecting parasitemia. A Giemsa-stained thin blood film showing showing ring forms of tate. Further investigations will be determined by the history. Clinicians should be wary of the possibility of bacteremia in severely ill patients. and metabolic acidosis. or by the hematocrit ×125.. biochemistry including bicarbonate.[46] Nevertheless. In practice. Fig. because of red cell adherence and better for species differentiation. but makes the diagnosis unlikely. adequacy of the circulation. For the thin film. µL (i. Two films should be examined before malaria can be discounted from the differential diagnosis. They should be viewed as complementing expert microscopy.. A baseline ECG and chest radiograph are useful. Treat Respir Med 2006. it is the convention to parasite counts have some clinical utility in monitoring the pro- approximate the parasitemia by assuming the total WCC is 8000/ gress of disease. Diagnosis The initial assessment of the sick malaria patient should focus on the basics of airway protection. 2. other cultures as clinically indicated. there is a the parasitemia. cardiogenic pulmonary edema.44] More research is required to better define patients who may have coexisting malaria and bacterial sepsis.42.Pulmonary Manifestations of Malaria 423 ichia coli. the number Rapid diagnostic tests (RDTs) are currently available for diag- nosing malaria.[50] RDTs are sometimes less sensitive than microscopy. multiplying the count by 40). routinely in clinical practice. and the differential diagnosis by the total red cell count. Falciparum schizonts and/or malaria pigment in ≥5% of per 200 white cells is counted and multiplied by the total white cell neutrophils on a blood film are poor prognostic signs. 1. but are particularly useful if microscopy is unavaila- ble. Venous access should be obtained and the following routine laboratory tests performed: (i) hematology.[43. Klebsiella spp.45] 2. the number of parasites disease. This is a scenario increasingly being seen in travelers who are able to buy artemisinin-based derivatives over the counter in many malaria- endemic countries. and the level of consciousness. Both may be used for quantifying sequestration from the circulation. and non-typhoid salmonellae. Radio- Fig. Plasmodium falciparum. However. which is reported as the number of parasites per rough correlation between parasitemia and the severity of clinical microliter (µL).1 Parasite Counts parasite per 500 white blood cells on a thick film. Acinetobacter spp.

shortness of breath (pneumonia). All rights reserved. and risk of convulsions and psychosis. ratio is normal unless there is coincidental severe anemia or Artesunate for injection is prepared by adding sodium bicarbonate underlying heart disease. Detailed recommendations for severe malaria hypoglycemia has to be balanced against the relative lack of safety 1 The use of trade names is for product identification purposes only and does not imply endorsement. Once the diagnosis of malaria is estab. the dose is 3.1.g. parenteral artemisinins are better options choice for the other species. Therefore. The fissures. trine) and Artekin (a fixed combination of dihydroartemisinin and piperaquine).[54] Oral preparations include artesunate.51. e.[56] Quinine was also associated with a 3-fold higher risk of lished. respiratory failure. nine. developing hypoglycemia. Infectious disease services need to be involved include artemether/lumefantrine (6 doses over 48 hours). Treat Respir Med 2006. 3. because this carries an increased fever and confusion or coma (meningitis or encephalitis). Less typical features include interstitial to artesunate powder. and a number of loose or fixed combinations. A chest x-ray of a male patient ventilated for malaria-induced artesunate and amodiaquine. 3.  2006 Adis Data Information BV. tern) that may become extensive (figure 3). artesunate and mefloquine. associated with a higher risk of recurrent hypoglycemia. parenteral preparations have to be used. person with an imported fever or someone residing close to or In adults with severe malaria.1 Artemisinin-Based Derivatives Artemisinin-based derivatives are not currently available in the US. There is bilateral shadowing in the mid.2 mg/kg followed 24 hours later by 1. doxy- early. in Indonesia and New Guinea.[53] tion (anterior thigh). artemisinin. e. Artemether can only be given by intramuscular injec- mediastinum. and unilateral or bilateral pleural effusions. 3.g. They are the most potent antimalarial drugs and act rapidly to kill substantial numbers of parasites. There may also be radiologic signs later by 2. Chloroquine is the treatment of In pregnant women. fever and jaundice (hepatitis). ill patients should be managed in an first trimester of pregnancy. but are used widely in many parts of the world. In the In well resourced settings. followed 12 and 24 hours occasionally the reverse is true.[22.g. The cardiothoracic For severe malaria.4 mg/kg daily until oral treatment can be of the complications of ventilation. intravenous artesunate tance of P. intravenous artesunate reduced working in an international airport must have a blood film done the case fatality rate by 35% compared with intravenous qui- with or without an RDT.4 mg/kg loading dose. 5 (6) . but these are orientated more to- wards tropical environments.6 mg/kg daily.[10] We highlight below practical points regarding the management of severe falciparum malaria. Mefloquine should not be used.g. the lower risk of quinine-induced intensive care unit. and may be given by a slow push intrave- infiltrates alone.1 Chemotherapy: Focus on Plasmodium falciparum 3.[55] Chloroquine or sulfadoxine/ fever and acute renal failure (leptospirosis). artesunate is a 2. Malaria mimics many diseases and may present with fea. e. falciparum to chloroquine and sulfadoxine/ should be used as the first-line drug for treating severe malaria in pyrimethamine. There is widespread resis. because of parasite resistance. Fig. Therefore. thickening of interlobular septal lines and lung nous injection or by the intramuscular route (anterior thigh). adults. vivax. are available from the WHO. thereafter. and focal areas of quinine and mefloquine resis. fever and every 8 hours for 7 days) may be used in pregnant women.424 Taylor et al. Treatment Both drugs are given until the patient is able to eat and drink Malaria in Western clinical practice is relatively uncommon normally. pneumothorax or pneumo- substituted. clindamycin (5 mg/kg tures strongly suggestive of a localized infection. every pyrimethamine should not be used. cognizant that there are areas of focal than quinine in the second and third trimesters because quinine is chloroquine-resistant P. The key to successful treatment is to complete a course of 7 days. Alternatives to oral artesunate early recognition. cycline (100mg every 12 hours for 7 days).52] Radio- currently recommended intravenous or intramuscular dose of logic signs usually develop 6–24 hours after the onset of dyspnea.to lower lung CoArtemether 1 (a fixed combination of artemether and lumefan- zones. effective treatment is crucial. oral artesunate (2 mg/kg/day) may be given outside of specialist settings.4 mg/kg. then 2. e. tance (mostly Southeast Asia).

At least 24 hours of quinidine gluconate infusion are called ‘permissive hypercapnea.6 seconds.1 Respiratory Compromise 10 mg/kg salt every 8 hours. quinidine gluconate resulting in a low or normal PaCO2.1.2. and a decrease in cardiac out- insert).5mg base/kg ( = 12 mg/kg salt) infused over 4 hours and the concentration of inspired oxygen to reduce the risk of every 8 hours. Metabolic acidosis in malaria results in hyperventilation. should be slowed or stopped for an increase in the QRS complex artesunate should be the artemisinin of first choice. In Colombia. low tidal volume ventilation is used and South America). quinine may also be given as a continuous infusion. Treat Respir Med 2006.” Quinine is the mainstay of treatment in many countries. adjusting PEEP followed by 7.[59] and recommendations on its use and monitoring are relatively common (Day NPJ and White NJ. Positive pressure ventilation with positive end-expiratory er antimalarial can be given. Quinine is given as a loading dose of 20 mg/kg salt followed by 3. for  2006 Adis Data Information BV.2 Quinine unresponsive to fluid challenge. or hypotension 3. and back on infusion for 4 hours. However. the artemisinins or cause ventricular arrhythmia.[62-64] This may lead to a rise in arterial carbon dioxide. once the parasite density this issue in ventilated patients with severe falciparum malaria. A rise in PaCO2 would result in cerebral available in the US. where non-sequestrating P.” routinely with PEEP.25mg base/kg ( = 10mg salt/kg) of quinidine gluconate infused full of static adherent parasitized red blood cells. It is recommended to give a loading dose of vasodilatation and expansion of an already engorged brain that is 6. doxycycline or anoth- lation. Breathless patients should be assessed and given oxygen ad- off infusion for 4 hours. This combined strategy appears In the US. starting 8 hours after the loading dose (see package barotrauma. hypotension. The following dosage regi. At the dosages required Noninvasive positive pressure ventilation (NPPV) has gained for the treatment of falciparum malaria. a QTc interval >0. If this is not well tolerated.Pulmonary Manifestations of Malaria 425 data of the artemisinins. pressure (PEEP) is used and combined with early hemofiltration 3. All rights reserved. Such an expan- intravenously over 1–2 hours followed by a continuous infusion of sion within the defined space of the cranium would lead to a 0. call for the use of low tidal volume ventilation. but is < 1% and the patient can take oral medication.[60] “Since 1991. and quinine may be used in the first trimester. quinidine/quinine for 7 days in Southeast Asia and 3 days in Africa vivax is a cause of ALI/ARDS. and is These two dose regimens are very different and there is concern effective at the doses used for severe malaria despite areas of focal that the low-dose regimen may be insufficient for a life-threaten- resistance. and frequent blood pressure monitoring.0125mg base/kg/min ( = 0. which should be consulted. which in turn maintains has been the only parenterally administered antimalarial drug cerebral vasoconstriction. It must 3.1. quinidine gluconate may acceptance for the management of respiratory failure due to. regimen is an intravenous loading dose of 15mg base/kg ( = 24mg Current guidelines for the mechanical ventilation of patients salt/kg) of quinidine gluconate infused intravenously over 4 hours. (accessed September 2006). avoid a rise in partial pressure of carbon dioxide in arterial blood mens are a verbatim copy selected from the US CDC web site (PaCO2). Alterna- ministered by the most appropriate method. unpublished observa- available from the US Centers for Disease Control and Prevention tions.3 Quinidine for patients in acute renal failure. as above. The quinidine gluconate infusion advantage of artesunate over quinine in nonpregnant adults. 1992–96). Oral quinine may be used to complete a total of 7 respiratory failure rapidly. oxygen toxicity. The using nasal canulae or a face mask may suffice.[56] Intubation should be smooth and quick to (CDC). it may also be given by intramuscular injection to the anterior thigh.[16] An alternative dramatic rise in intracranial pressure. Because of the clear-cut prolongation of the QTc interval.2 Malaria Complications never be given as a bolus injection. It is more optimal in this setting where both respiratory and renal failure are cardiotoxic.02mg salt/kg/min). Oxygen delivery tively.[58] It should be administered as an intravenous infusion ing disease. Quinidine levels should be maintained in the range of 3–8 put. the patient can hypercapnia may be undesirable in comatose malaria patients complete the treatment course with oral quinine at a dosage of because this will further increase the cranial blood flow and 10mg salt/kg every 8 hours (for a combined treatment course of intracranial pressure.’ There are no studies examining recommended (or 3 intermittent doses). Pending more data. the infusions should be continued until the patient is able to eat and experience from Southeast Asia is that breathless patients develop drink normally. necessitating prompt mechanical venti- days’ treatment. hypoglycemia.[57] by >50%. so- mg/L. quinidine is used instead of quinine. 5 (6) . One potential disadvantage of low tidal “Parenteral quinidine gluconate is cardiotoxic and should be volume ventilation is that deep sedation and sometimes patient administered in an intensive care setting with continuous cardiac paralysis may be required. a QTc interval that is prolonged by more than 25% of the baseline value.[61] (any crystalloid fluid may be used) over 4 hours. because of its cardiotoxicity. Patients are on infusion for 4 hours.

It did not during quinine transfusions. convulsions. The Regular measurements of blood glucose are essential – hourly use of low ‘renal’ dose dopamine is also questionable. blood urea >25–30 mmol/L. and 4-hourly during administration of result in improved renal function in Vietnamese adults with mala- artemisinins.[65] However.[78] and should be consulted. gastrointestinal bleed. a serum creatinine of NPPV requires a cooperative patient and is unsuitable in severely 500–700 µmol/L. children. Studies in Vietnamese adults with severe malaria have shown globin level is suggested in the WHO guidelines.g. 3. dehydrated and/or anemic patients need to be resuscitated Malaria patients may have a concomitant bacteremia on admis- adequately with crystalloids and blood. Clinical data suggest that infusions of albumin com. lations without malaria and before the widespread use of There are data from sepsis patients that hypoproteinemia leukoreduction. and increased tive antimalarial treatment and rehydration. No target hemo- rax.2. e.[66] al pathogens are likely to be resistant to routine antibacterials.[63] Although this recommen- other pressor agents (dopamine. adrenaline is best avoided unless for a hemoglobin level of 7–9 g/dL.[53] There is a fine line between tibacterials to cover both Gram-negative and Gram-positive orga- trying to keep the lungs ‘dry’ and not compromising cardiac and nisms[23. and checking for acidemia/acidosis (blood gases. and include manifest uremia (changes in sensorium. excluding a myocardial infarction (a possibility in elderly The WHO recommendations for commencing a blood transfusion patients). sepsis. Frusemide is often used to ‘rescue’ the kidney from developing Hypoglycemia may go unrecognized in a severely ill patient. they are reasonable targets to aim for pending predicts the development of ARDS and is also a marker of a poor revised. All rights reserved. consideration of obtaining pathogen-free blood. occult gastro. How. (serum bicarbonate <12 mmol/L). ECG signs). ATN. In such patients.70. Nosocomi- 0–5cm H2O. Hypoglycemia is a particular problem in pregnant ARF is hypercatabolic and characterized by rapid increases in women.2. The blood that adrenaline exacerbates lactic acidosis.[68] heart disease. Clinical manifestations include a change in behavior. norepinephrine [noradrenaline]) dation is based on work conducted in non-malaria-endemic popu- have failed.3 Other Therapies causes of acute renal failure.[10] These are based partly on the very important practical intestinal bleeding. ed.4 Concomitant Bacteremia ever. restricting blood transfusion as recommended above appears safe.426 Taylor et al. Malarial acute renal failure (ARF) behaves in a similar way to so strict recommendations cannot be made. require energetic management. should be correct- viewed by Hébert and Fergusson. Treat Respir Med 2006.[71] The clinical indications for dialysis are essentially those for other 3. inflammatory cytokines and  2006 Adis Data Information BV. 5 (6) . as guided by invasive sion. significantly reducing the mortality 3. a finding not associated transfusion recommendations for adult patients with sepsis are to with dopamine.[64. line infections and ventila- the central venous and pulmonary artery occlusion pressures at tor-related pneumonia. evidenced-based recommendations. Exchange transfusion has been suggested as an ancillary treat- ing). ria ARF.3 Acute Renal Failure and concomitant acute myocardial infarction or unstable angina.[73] Attention to fluid balance is an important element in manage- ment because of the risk of exacerbating pulmonary edema. pericarditis. cardiogenic pulmonary edema and COPD. urea.2. fluid overload. uremic pericardial effusion.72] Hemofiltration is the preferred treatment modality. but there is no evidence that this approach is effective.[74] Patients who are in shock despite apparent normovolemia 3. and 12mm Hg. There are no evidenced-based guidelines. The recommendations in malaria are to maintain acquired in the intensive care unit. e. and severe acidemia (blood pH <7. but clinicians hemodynamic monitoring using a central venous pressure (CVP) should employ a low threshold for starting broad spectrum an- line and a Swan Ganz catheter. Using blood transfu- acute tubular necrosis (ATN) of diverse etiology.43] in patients with shock. For patients with stable ischemic merits further evaluation in malaria patients.g.2 Fluid Balance rate compared with peritoneal dialysis in Vietnamese adults. hyperkalemia (>7 mmol/L and/or related ment to remove infected red cells. Unusual causes should also be sought.[70] Established malaria respiratory rate. and a pneumotho. laria patients in endemic countries will otherwise be healthy and bined with frusemide (furosemide) are beneficial. example. flapping tremor.[75.g.76] Most adult ma- prognosis.[67] Because lactic acidosis is an independent risk transfuse when the hemoglobin decreases to <7 g/dL and to aim factor for death in severe malaria. respectively.[77] There are no data on patients with severe malaria 3. and ALI/ARDS.5 Anemia and Hypoglycemia should be evaluated with particular attention to finding a source of Anemia and hypoglycemia are two important complications. dehydration and shock. plasma in the tropics are a hematocrit level of <20% in adults and <15% in lactate).2.1) or acidosis ill patients and those with impaired consciousness. e. Infections renal function. This approach tolerate low hemoglobin levels.24. dialysis should be instituted promptly. Factors leading sions in patients with acute myocardial infarction has been re- to prerenal failure.[69] Most patients with renal impairment respond to effec- deteriorating level of consciousness.

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