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Respiratory Manifestations of MalariaLung in Malaria FREE TO VIEW

Walter R. J. Taylor, MBBS, MD; Josh Hanson, MBBS; Gareth D. H. Turner, BM, BCh, DPhil; Nicholas J. White, DsC, MD; Arjen M. Dondorp, MD, PhD
Author and Funding Information

From the Mahidol Oxford Tropical Medicine Research Unit (Drs Taylor, Turner, White, and Dondorp), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; the Centre for Tropical Medicine (Drs Taylor, Turner, White, and Dondorp), Nuffield Department of Medicine, Oxford University, The Churchill Hospital, Headington, England; the Service de la Médicine Internationale et Humanitaire (Dr Taylor), Hôpitaux Universitaires de Genève, Geneva, Switzerland; and Cairns Base Hospital (Dr Hanson), Cairns, QLD, Australia.

Correspondence to: Walter R. J. Taylor, MD, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok, 10400, Thailand; e-mail: bob@tropmedres.ac


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Chest. 2012;142(2):492-505. doi:10.1378/chest.11-2655
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Respiratory distress develops in up to 25% of adults and 40% of children with severe falciparum malaria. Its diverse causes include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary edema, concomitant pneumonia, and severe anemia. Patients with severe falciparum, vivax, and knowlesi malaria may develop acute lung injury (ALI) and ARDS, often several days after antimalarial drug treatment. ARDS rates, best characterized for severe Plasmodium falciparum, are 5% to 25% in adults and up to 29% in pregnant women; ARDS is rare in young children. ARDS pathophysiology centers on inflammatory-mediated increased capillary permeability or endothelial damage leading to diffuse alveolar damage that can continue after parasite clearance. The role of parasite sequestration in the pulmonary microvasculature is unclear, because sequestration occurs intensely in P falciparum, less so in P knowlesi, and has not been shown convincingly in P vivax. Because early markers of ALI/ARDS are lacking, fluid resuscitation in severe malaria should follow the old adage to “keep them dry.” Bacteremia and hospital-acquired pneumonia can complicate severe malaria and may contribute to ALI/ARDS. Mechanical ventilation can save life in ALI/ARDS. Basic critical care facilities are increasingly available in tropical countries. The use of lung-protective ventilation has helped to reduce mortality from malaria-induced ALI/ARDS, but permissive hypercapnia in unconscious patients is not recommended because increased intracranial pressure and cerebral swelling may occur in cerebral malaria. The best antimalarial treatment of severe malaria is IV artesunate .

Figures in this Article

Human malaria, caused by five plasmodium species, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and the monkey malaria Plasmodium knowlesi,1 is transmitted by the female anopheline mosquito. Estimated annual malaria cases are 550 million for P falciparum and 80 to 300 million for P vivax.24 African children account for most of the estimated 655,000 deaths.5 Malaria in temperate zones is also important, with 10,000 cases per year in Western Europe and 1,300 to 1,500 in the United States.68

Clinical malaria is caused by the asexual blood stages of the parasite, maturing within infected erythrocytes from ring stages to trophozoites to schizonts. The sexual forms (gametocytes) are taken up by mosquitoes to complete the parasite life cycle. P falciparum asexual forms invade RBCs of all ages, sometimes resulting in a high parasite biomass in the nonimmune patient. The central pathophysiologic feature of severe falciparum malaria is the adherence of erythrocytes containing the mature stages of P falciparum to endothelium in the microcirculation of vital organs, causing their sequestration and impairing microcirculatory flow.9

Without treatment in the nonimmune patient, falciparum malaria can progress to severe disease in days, characterized by multiorgan dysfunction and a mortality of up to 20% to 35%, even with adequate antimalarial treatment.1015 Cerebral malaria (coma) and metabolic acidosis are the most common manifestations of severe disease in all age groups and have the strongest prognostic significance.1619 Severe anemia, hypoglycemia, and convulsions are more common in children, whereas renal failure, severe jaundice, acute lung injury (ALI), and ARDS are more frequent in adults.

P vivax, infecting only reticulocytes and young erythrocytes, produces lower parasite burdens, generally < 2% of the RBC population, and does not sequester. However, in vitro adherence has been demonstrated by P vivax-infected erythrocytes to immbolized chondroitin sulfate A and hyaluronic acid and fresh placental cells20 as well as to condroitin sulfate A and intracellular adhesion molecule-1 receptors on human lung endothelial cells, Saimiri brain endothelial cells, and placental cryosections,21 albeit to a much lesser degree than P falciparum. Sequestration in the lung circulation has also been suggested in vivax-infected patients.22 Severe clinical features in vivax malaria have been described, particularly with chloroquine-resistant P vivax in New Guinea island, and these include severe anemia, respiratory distress, ALI/ARDS, and, rarely, coma.2327

P knowlesi has a 24-h erythrocytic life cycle. It may cause high parasitemias and severe disease (7% of cases), most commonly respiratory distress, anemia, jaundice, and renal failure.1,28

A dry cough may be present in 20% to 50% of patients with malaria.2933 Tachypnea may result from high fever, anemia, and lung involvement. Lung function tests have demonstrated small airways obstruction and a decrease in diffusion capacity in uncomplicated falciparum and vivax malaria.22,30,34 The reduced diffusion capacity is attributed to a reduction in the pulmonary capillary vascular component of gas transfer, which could be related to sequestration of parasitized erythrocytes in the pulmonary microcirculation, although this has never been shown directly in patients with vivax malaria. In the same studies, the alveolar-capillary membrane component of gas transfer was reduced progressively in the days following treatment, consistent with the development of pulmonary interstitial and alveolar edema. This posttreatment inflammatory pattern was more prominent in vivax compared with falciparum malaria and was detectable for up to 14 days.

A number of terms have been used to describe respiratory symptoms and signs in clinical series of severe malaria caused by P falciparum, P vivax, or P knowlesi (Table 1).3549 Respiratory distress is commonly used (Table 1) and may differ from the World Health Organization (WHO) definition, which includes only deep breathing and increased respiratory rate for age in children.13 Respiratory distress has many causes, including respiratory compensation for a severe metabolic acidosis, concomitant pneumonia, aspiration pneumonia, fluid overload, ALI/ARDS, and severe anemia (which is more important in young children).10,11,35,46

Table Graphic Jump Location
Table 1 —Summary of the Frequencies and Nature of Respiratory Features Reported in Studies of Severe Vivax and Falciparum Malaria

ALI = acute lung injury; CFR = case fatality rate; CXR = chest radiograph; D0 = day of admission; NA = not applicable; ND = no data; O2 = oxygen; P falciparum = Plasmodium falciparum; P vivax = Plasmodium vivax; RR = respiratory rate; WHO = World Health Organization.

a 

Any one of severe anemia, coma, respiratory distress.

b 

Independent of other organ dysfunction.

c 

Seven deaths due to multiorgan dysfunction syndrome.

d 

Species breakdown not stated.

Severe falciparum malaria in both adults and children is frequently associated with metabolic acidosis, which has a strong prognostic significance for mortality. In both adults and children, respiratory distress can be used as a proxy measure for metabolic acidosis. In falciparum-infected African children, respiratory distress, regardless of the presence of anemia, is associated with a fourfold (3.9 [95% CI, 2.0-7.7]) increased risk of death.46 Data from the African Quinine vs Artesunate in Severe Malaria (AQUAMAT) trial of young African children showed that there was a significant correlation between respiratory distress, respiratory rate, deep breathing, and metabolic acidosis (base excess).49 All four were risk factors for death in univariate analyses but only metabolic acidosis was an independent risk factor for death in a multivariate analysis. In adults, coma and metabolic acidosis are the two main, independent risk factors for death.18 When used in the coma acidosis malaria (CAM) score (0 to 4), a higher CAM score was associated with a higher risk of death.18 Using the respiratory rate instead of the base deficit, a higher respiratory CAM score was also associated with a higher risk of death, although less robust than the CAM score. In Papua, Indonesia, coma (57-fold), respiratory distress (14-fold), and severe anemia (2.8-fold) were significant predictors of death in adults and children infected with vivax and/or falciparum malaria, but metabolic acidosis was not assessed in this study.23 In resource-poor settings where metabolic acidosis cannot be measured, patients with respiratory distress or tachypnea need more intensive care than those without these signs. Coma, hyperparasitemia, and older age were the only independent risk factors for death in imported severe malaria in France.35

Clinical Presentation and Epidemiology

ALI and ARDS have well-defined criteria for diagnosis based on reduced Pao2/Fio2 ratios, bilateral infiltrates on the chest radiograph, and absence of left atrial hypertension (Table 2).50 ARDS is the most severe pulmonary manifestation of severe malaria, irrespective of the infecting species. ALI/ARDS may be seen as part of a severe multisystem illness or may be the main clinical feature and often occurs within a few days of starting treatment when parasitemia is falling.15,34 This is illustrated well by Krishnan and Karnad,15 who showed that at presentation, 84 of 301 patients (28%) had mild hypoxia (Pao2/Fio2 < 400 mm Hg), 18 ALI, and 10 ARDS. ARDS developed in a further 33 patients within 48 h and in 36 patients after 48 h.15

Table Graphic Jump Location
Table 2 —Defining Criteria for ALI and ARDS

PA = posteroanterior. See Table 1 legend for expansion of other abbreviations.

a 

Irrespective of the level of positive end-expiratory pressure.

b 

Abnormal chest radiograph findings may appear after functional disturbances.

Dyspnea in patients developing ARDS may start abruptly, progress rapidly, and cause death within hours of onset.5153 Physical signs include sweating, tachypnea, labored breathing, peripheral and central cyanosis, inspiratory crepitations, expiratory wheezes, and frothy sputum. An increased respiratory rate and dyspnea are usually the earliest signs.13 The jugular venous pulse is not raised unless there is concomitant fluid overload. Hypoxia-related confusion and agitation may also be seen.

The risk of developing ARDS/pulmonary edema in patients presenting with uncomplicated falciparum malaria is low: 0.1% (3 of 3,300) in US Army soldiers in Vietnam.54 In severe malaria, reported incidence rates vary widely between < 2% to about 25% (Table 1). This > 10-fold difference mainly reflects differences in the applied definitions of ARDS.36,37,55

In the large South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) study of adult severe malaria, 175 patients (12%) had respiratory distress (respiratory rate > 32/min).10 In France, 25% (101 of 400) of patients admitted with severe malaria were mechanically ventilated; 76 (19%) for ARDS (n = 58) or ALI (n = 18).35 This high ventilation rate is probably related to the higher availability of mechanical ventilators and an older patient population with comorbidities.

Prognosis

ARDS has grave prognostic significance. In settings without mechanical ventilation, ARDS mortality was 81% in Rajasthan, India, and 100% in Vietnam.36,37 Even with availability of mechanical ventilation, ARDS accounts for circa 10% to > 40% of malaria deaths but reached an astonishing 95% (70 of 74) in Krishnan and Karnad15 ICU series, in which the risk of death was some 50-fold higher with ARDS (89% [70 of 79] vs 1.8% [four of 222]) compared with a threefold higher risk in France for those with respiratory distress: 69.1% (29 of 42) vs 20.1% (72 of 358).35 The independent risk of ARDS-associated death was not examined by Krishnan and Karnad.15 It was not an independent prognosticator in Bruneel et al’s35 French series but was associated with a relative risk increase of 14-fold in African adults compared with 44-fold increase for coma and sevenfold increase for acute renal failure.39

In African children presenting with severe falciparum malaria, the incidence of respiratory distress varies between 7%46 and 16%11 in large series of hospitalized patients. This is a considerably lower rate compared with falciparum-infected (41%) or vivax-infected (60%) children below the age of 5 years reported from a rural clinic in Papua New Guinea.24 In a Kenyan series, 52% of the reported 64 deaths from severe falciparum malaria presented with respiratory distress either alone or together with other clinical features, translating to a fourfold independent relative risk of death in children with respiratory distress compared with 3.3-fold for impaired consciousness, 3.3-fold for hypoglycemia, and 2.6-fold for jaundice.46 Respiratory distress at presentation was found in 867 (16%, n = 5425) African children with severe falciparum malaria in the AQUAMAT study, of whom 145 died. After admission, an additional 101 children developed respiratory distress, 60 of whom died. Respiratory distress-related deaths accounted for 205 of the 527 deaths (38.9%).11 In Senegal, a retrospective series identified 502 children with WHO-defined severe falciparum malaria; 83 were ventilated but only four (0.8%) because of ALI/ARDS.47

It is no longer disputed that ALI/ARDS occurs in pure vivax malaria. Data have come mostly from case reports, making it difficult to estimate its frequency.20,27,53,5658 In one case series, ARDS occurred in one of 38 (2.6 [0.06%-13.8%]) US soldiers with otherwise uncomplicated vivax malaria acquired in Afghanistan.59 In severe vivax, rates have varied between about 1% to 10% (Table 1) and were one of 11 (9%)60 and four of 10 (10%)26 in two well-described small series from India. Case reports have also documented ARDS in P ovale61 and P malariae.62

Vivax malaria-related ARDS was often the only severe clinical feature but has also been described in the context of multiorgan disease.26,55,60 Pulmonary edema has been documented at presentation and up to 4 days posttreatment, with a median time of onset of 2.5 days.27 Patient management has included oxygen delivery by mask, noninvasive positive pressure ventilation, CPAP, or mechanical ventilation (duration 4-13 days). Interpreting mortality rates in severe vivax requires caution, because series are generally small, and coinfections, particularly bacterial infections, may not have been excluded convincingly. In an Indonesian series of severe vivax malaria, mortality was 27 of 700 patients (3.6%), of which 12 of 27 deaths (44%) were related to respiratory distress.23

In a pediatric series reported from Papua New Guinea, reported incidence rates of respiratory distress were 41%, 60%, and 66.7% for falciparum, vivax, and mixed vivax/falciparum malaria, respectively (Table 1).24 In a similar clinical series from southern Papua, Indonesia, of adults and children, incidence rates of respiratory distress were highest in falciparum-infected patients. Patients with clinically defined severe malaria had a respiratory distress-related mortality of 4% for vivax and 7% for mixed species or falciparum malaria.23

Two interesting case series from Malaysian Borneo describe polymerase chain reaction-confirmed, severe P knowlesi.1,45 In the small number of patients (n = 33) who were classified as having severe disease, using WHO falciparum criteria, rates of respiratory distress or ALI/ARDS were high (Table 1). A postmortem study was only able to document macroscopic lung findings; lungs were described as heavy and congested and looked “beefy red.”28

Falciparum malaria in pregnancy causes substantial maternal morbidity and mortality in low transmission settings. It was responsible for about one-third of all-cause maternal mortality in Sudanese women.63 Data on malaria-related pulmonary edema are extremely limited (Table 1).14,37,49,6466 Reported incidence rates vary between about 2.9% and about 29% and case fatality rates from between 0% and 8% to 33%.15,49,64,67,68 Acute pulmonary edema may also occur just after delivery, especially in the presence of peripartum severe anemia or fluid overload.13,37

Although clinical experience might suggest that pregnant women are particularly prone to pulmonary edema/ARDS, this has yet to be proven. Kochar et al69 hinted at an increased risk: 4.4% ARDS rate in two of 45 pregnant women vs 1.6% (four of 243) nonpregnant women (P = .2). Whether pregnancy is an independent risk factor for death is unclear. Some studies report no mortality differences,15,25 but mortality rates from Kochar et al69 suggest otherwise (P = .0002): 37.7% (17 of 45 pregnant women) vs 14.8% (36 of 243 nonpregnant women). These rates were significantly higher compared with men: 7.6% (24 of 314 men).69

One series describes 118 pregnant Ethiopian women with severe malaria: 36 (30.5%) had cerebral malaria, 14 (11.9%) were shocked, 12 (10.2%) had pulmonary edema, and nine (7.6%) had acidotic breathing. Intensive care facilities were unavailable, and the overall mortality was 33%; eight of 12 women with pulmonary edema died.49

The pathogenesis of ALI/ARDS in severe falciparum malaria is not understood. There are multiple potential causes that may result in lung injury during malaria, which may also be interrelated. These include the effects of sequestration of parasitized erythrocytes, host immunologic reactions to lung-specific sequestration or systemic malaria infection, superimposed pulmonary infections (community acquired, nosocomial, or opportunistic in immunocompromised patients), aspiration, coexistent sepsis and bacteremic-induced ARDS, or the effects of treatment such as fluid resuscitation. The sequestration of parasitized RBCs (PRBCs) in the pulmonary microcirculation may initiate lung damage via direct endothelial activation and recruitment of host inflammatory responses, but these can continue after treatment with antimalarial drugs. The occurrence of ALI/ARDS when a parasite is declining or has been cleared suggests a posttreatment inflammatory effect as a contributory cause, although parasite products such as malaria hemozoin pigment can persist in the vessels either bound to endothelial cells in ghosted ruptured erythrocyte membranes postschizogony or phagocytosed by host leukocytes. Supporting evidence comes from the observed progressive reduction in the alveolar-capillary membrane component of gas transfer as well as the occurrence of ALI/ARDS in P vivax and P knowlesi infections, albeit in a much smaller number of recorded cases, which show much less microvascular sequestration than P falciparum.28 A combination of parasitized erythrocyte sequestration and lung inflammatory changes, similar to those proposed for the pathogenesis of bacterial sepsis ARDS (reviewed in detail elsewhere70,71), are considered the main cause of falciparum malaria-induced ALI/ARDS.

Severe falciparum malaria is characterized by an upregulation of proinflammatory cytokines (eg, tumor necrosis factor [which causes an increase in endothelial intracellular adhesion molecule-1 expression], IL-1, IL-6, and IL-872), which have also been implicated in the pathogenesis of ARDS. Antiinflammatory cytokines such as IL-4 and IL-10 are also upregulated, and an imbalance between IL-10 and the proinflammatory cytokine IL-6 has prognostic significance for death.72 However, none of the cytokine profiles in severe falciparum malaria are specifically associated with capillary leakage in the lung.

A decrease in pulmonary nitric oxide (NO) production in adults with severe malaria73 could be significant for pulmonary capillary leakage, because pulmonary NO is central in the modulation of pulmonary vascular tone and pulmonary hypertension.74 A relative l-arginine deficiency (the precursor of NO) with increased levels of asymmetric dimethylarginine (an inhibitor of NO synthase) and an increase in free hemoglobin caused by intravascular hemolysis all contribute to this decrease in NO bioavailability.75 Data from a murine model of severe malaria caused by Plasmodium berghei indicate that vascular endothelial growth factor (VEGF) may also be involved in damaging alveolar capillary endothelium,76 but levels of plasma VEGF in patients with human falciparum malaria are significantly lower in severe vs uncomplicated cases77 and in patients with fatal cerebral malaria in India,78 arguing against high levels of VEGF being directly associated with lung injury in severe human falciparum malaria.

The Pathology of the Lung in Malaria

Most pathology studies are autopsy series in patients who have died of severe falciparum malaria. These are open to the problems of postmortem artifact and a snapshot effect of examining single patients at different stages of disease and treatment. However, some common findings at autopsy have been described.

The lungs are often heavy and edematous, with occasional serous pleural and pericardial effusions. Pleural or intrapulmonary punctuate hemorrhages are common. Microscopically, alveolar capillaries demonstrate the sequestration of PRBCs, causing congestion of pulmonary capillaries, and large numbers of monocytes and neutrophils, often containing phagocytosed malaria pigment (Fig 1A).

Figure Jump LinkFigure 1. A, Histopathology of the lung in a fatal case of adult falciparum malaria. There is expansion of alveolar capillaries by sequestered parasitized erythrocytes and host inflammatory leukocytes. Monocytes and neutrophils within alveolar septal capillaries contain phagocytosed hemozoin pigment (hematoxylin and eosin [H&E] staining, magnification × 400, scale bar 200 μm). B, A more severe histologic picture from a fatal case of falciparum malaria, with sequestration of parasitized erythrocytes and host leukocytes expanding the alveolar septae, intraalveolar hemorrhage and pulmonary edema, and hyaline membrane formation as part of a picture of diffuse alveolar damage (H&E staining, magnification × 200, scale bar 200 μm)Grahic Jump Location

Overall, the histologic appearances are of thickened, congested alveolar septa, patchy intraalveolar hemorrhage, and pulmonary edema.79 In individual cases, more severe changes can be seen, including hyaline membrane formation as an indicator of diffuse alveolar damage (Fig 1B). There is generally a lack of vascular thrombosis and lung infarction. Individual cases may show a complicating pyogenic pneumonia acquired during recovery from severe malaria. Ultrastructural studies report marked interstitial edema of the alveolar septa dissociating the matrix substance and fibrils, swollen capillary endothelial cells causing narrowing of the capillary lumen, alveolar septal capillaries occluded by PRBCs, leukocytes, and pigment-containing macrophages.80,81

Cytoadherence, the pathologic hallmark of severe falciparum malaria, varies between organs, being greatest in the brain but occurring also in the lungs. The host leukocyte response in adults is greater in the lung than the brain, but a direct association between PRBC or leukocyte sequestration and lung pathology has not been established in the human. In the P berghei-ANKA murine experimental malaria model, CD36-mediated sequestration of PRBC within the lung has been linked to the development of ALI; a host inflammatory reaction is suggested to be a likely source of capillary endothelial damage and subsequent lung pathology.82,83 Similar pathologic features are reported in the lung in simian models infected with Plasmodium coatneyi, Plasmodium fragile, and P knowlesi.84,85

The histopathologic findings of a P vivax-infected patient who died with rapidly progressive breathlessness have been published.53P falciparum was excluded by light microscopy and polymerase chain reaction. The main findings were heavy (mean, 470 g) edematous lungs, congestion of alveolar capillaries with mononuclear cells, mostly CD68-positive monocytes/macrophages, and CD3-positive T cells, with some containing phagocytosed pigment; there were few neutrophils. There were early signs of diffuse alveolar damage and focal areas of hyaline membrane formation. Scanty PRBCs were seen, but there was no cytoadherence. The findings in this patient overlap with those found in falciparum-infected patients, but the lack of cytoadherence stands in contrast.

The histopathologic findings support the alveolar septum as the main site of the pulmonary changes seen in falciparum and vivax malaria and that the two species may share similar mechanisms that can proceed independent of PRBC cytoadherence, but are much rarer as a presentation of severe malarial disease than in falciparum malaria. Cytoadherence in P falciparum may have an initiating role in ALI, but more research is needed into the role of host immune responses in augmenting lung pathology in severe falciparum malaria by secondary, parasite-independent mechanisms.

Drugs

Severe malaria can kill within hours of presentation, especially in children.43,46 Prompt diagnosis by microscopy or a rapid diagnostic test and early initiation of parenteral antimalarial treatment are crucial. Effective oral drugs, principally an artemisinin-based combination treatment, are given once patients can swallow normally. Artesunate is unquestionably the drug of choice for adults, pregnant women, and children. Large randomized trials showed a 35% and 22% reduction in case fatality rates in adults and children, respectively, compared with quinine.10,11 Artesunate for injection is prepared by adding sodium bicarbonate to artesunic acid powder and may be given by a slow push IV injection or by the IM route (anterior thigh). The IV/IM dose is 2.4 mg/kg stat, + 12 h, + 24 h, thereafter 2.4 mg/kg daily. Artesunate is remarkably well tolerated and has no significant cardiovascular toxicity.86,87

Artemether can only be given by IM injection (anterior thigh), but absorption from the IM injection depot of fat-soluble artemether is erratic.88 The dose is 3.2 mg/kg followed 24 h later by 1.6 mg/kg/d.

Quinine should only be used if artesunate is unavailable or if artesunate-induced anaphylaxis has occurred.89 It should be administered as either a rate controlled IV infusion or an IM injection. It must never be given as a bolus injection because it may cause death from hypotension and ventricular arrhythmias. Hypoglycemia is common; blood glucose should be monitored intensively. The dose is 20 mg/kg salt followed by 10 mg/kg salt every 8 hours.

In cerebral malaria, high-dose dexamethasone increased morbidity in one trial90 and had no appreciable effect on clinical or parasitologic outcomes in a smaller trial.91 Steroids are not recommended.84 Similarly, high-dose corticosteroids are not indicated in the acute phase of ARDS, but there is controversy over its use in “refractory ARDS.” Whether this may apply to malaria ARDS is unknown.92,93

ARDS

There are no ALI/ARDS treatment trials in malaria, so management strategies follow nonmalaria ARDS guidelines.9496 Mechanical ventilation is often difficult in the severely diseased lung. Lung compliance is markedly reduced and unevenly distributed, ventilation/perfusion is mismatched, and gas diffusion is compromised. Guidelines include the application of volume- or pressure-support ventilation with positive end-expiratory pressure, avoidance of both high tidal volumes (6 mg/kg ideal body weight) and an initial plateau pressure < 30 cm H2O.97 Permissive hypercapnia is not recommended in cerebral malaria because this exacerbates the increased intracranial pressure and brain swelling that may arise from increased intravascular blood volume of sequestered PRBCs.98 For the same reason, rapid-sequence intubation should be done to prevent hypercapnia with a subsequent further rise in intracranial pressure.

In many centers, reversal of the inspiration-expiration ratio is used as a strategy in case of refractory hypoxemia. Putting the patient in the prone position can dramatically improve oxygenation, although a systematic application of this strategy failed to improve mortality in a randomized trial in patients with nonmalaria-related ARDS.99

When available, venovenous extracorporeal membrane oxygenation can be a life-saving method in severe ARDS with severely compromised oxygenation to sustain gas exchange and to provide time for lung tissue to heal.100 Some case studies report the successful treatment with noninvasive positive pressure ventilation in patients with vivax malaria-associated ARDS,56 but it failed in 16 of 32 falciparum-infected patients.35 It is probably only an alternative for milder respiratory compromise.

Fluids

The traditional fluid balance advice in adults with severe falciparum malaria has been to “run patients dry” to prevent iatrogenic pulmonary edema. This advice holds true for patients with ARDS. Defining optimal fluid balance for patients without ARDS is difficult. In malaria, vasodilatation and microvascular obstruction reduce effective circulating volume and tissue perfusion, contributing to renal impairment and metabolic acidosis.9,101103

Fluid resuscitation, guided by invasive monitoring with transpulmonary thermodilution, was studied in 28 adult patients with severe malaria in an ICU setting (J. Hanson, MBBS, personal communication, February 2012). Transpulmonary thermodilution allows measurement of global end diastolic volume (GEDVI) (a measure of intravascular volume), extravascular lung water (a measure of pulmonary edema), and pulmonary vascular permeability (PVPI) (a measure of pulmonary capillary leakiness). All 28 patients were hypovolemic (GEDVI < 680 mL/m2) on admission; two had concurrent clinical pulmonary edema and required respiratory support (one had mechanical ventilation, one CPAP), both survived. The remaining 26 received a median (range) of 3.4 (1.0-7.3) L of fluid resuscitation during the first 6 h of their hospitalization. By 72 h, eight of these 26 patients (31%) had developed clinical pulmonary; five of the eight were hypovolemic and three were euvolemic (GEDVI 680-800 mL/m2) when clinical pulmonary edema developed, and five of the eight died despite mechanical ventilation. All but one patient who were able to have a PVPI measured while not receiving CPAP had increased pulmonary vascular permeability (PVPI > 3). The other had a PVPI of 2.97. Five additional patients had a PVPI > 3 at some point during their hospitalization, therefore, 15 of 28 (54%) had clinical pulmonary edema or documented increased pulmonary vascular permeability during their hospitalization. There was no correlation between the volume of fluid resuscitation and development of pulmonary edema, but the patients developing pulmonary capillary leakage could not be identified on admission. In the absence of an early marker for ALI/ARDS, it is, thus, not safe to aggressively fluid resuscitate nonshocked adult patients with severe malaria. Patients should be rehydrated slowly in the first 48 h and more aggressive fluid resuscitation reserved for the minority of patients presenting with shock (3%-12%) and even then the high risk of ALI should be considered.11,35,36,104

A recent study in severely ill African children with severe malaria and shock found a greater mortality rate in those who received a fluid bolus.105 Although the study did not report whether respiratory complications were the cause of this increased mortality, the results support clearly the need for judicious fluid resuscitation in pediatric severe falciparum malaria. More work on fluid therapy in severe malaria is needed addressing similar issues as in nonmalaria ARDS.106,107

Because respiratory symptoms and signs can be caused by severe malaria, pneumonia may be overlooked in the differential diagnosis of respiratory distress. In settings where both diseases are common, both illnesses can be present concomitantly in up to 13%, as reported in two pediatric series.108,109 O’Dempsey et al108 showed that although certain objective signs, such as observed cough, chest wall recession, and crepitations, were more likely in radiographically confirmed pneumonia, none was sufficiently discriminating to exclude malaria.

It is clear that both diseases have to be considered in febrile patients presenting with respiratory distress in malaria-endemic settings. Similarly, clinicians in temperate zones should have malaria on their differential diagnosis in, for example, travelers, visitors of family and friends, and deployed soldiers to tropical countries, who present with a clinical picture suggesting pneumonia.110

The frequencies of concomitant bacteremia in adults vary widely: 0.2% (one of 500) in Vietnamese adults on admission (T. T. Hien, MD, and N. J. White, DsC, MD, unpublished data, February 2012), 4.5% (10 community acquired plus eight nosocomial of 400, France),35 and 13% (39 of 301) in India; 31 of 39 were associated with ventilator-associated pneumonia (VAP).15 Training in the use of sterile techniques in respiratory care of such patients in ICUs in developing countries has the potential to improve this.

Bacteremia was not an independent risk factor for death in adults with severe imported falciparum malaria,35 but it may contribute to acidosis and death in patients with shock and/or ALI/ARDS.104,111 In India, sepsis was present in 23 of the 60 patients (38%) with severe malaria who died within 7 days and 12 of 14 patients (85%) who died after day 7 (P = .004).15 Clinicians should have a low threshold for starting antibiotics in patients with clinically suspected bacteremia. Nosocomial infections are also an important complication reported in 66 of 400 (16.5%) cases in severe imported malaria in France,35 of which 48 (12%) were VAPs. VAPs were also reported in 31 of 79 (about 39%) Indian patients with ARDS15 and in 20 of 83 (24%) intubated African children.47

African children with slide-proven severe falciparum malaria and concomitant bacteremia (4%-9%) have up to a threefold increased risk of death compared with children without bacteremia,112115 although this was not confirmed in one study.116 Although enteric bacteria predominate, respiratory pathogens, including Streptococcus pneumoniae and Haemophilus influenzae, account for up to 25% of bacteria isolated from African children with severe falciparum malaria and concomitant bacteremia.113 The administration of broad-spectrum parenteral antibiotics (eg, third-generation cephalosporins), is increasingly advocated as a standard concomitant treatment of children with severe falciparum malaria.

Aspiration pneumonia is another important infectious complication in cerebral malaria. Intubation of the comatose patient to protect the airway (performed often with Glasgow Coma Scores ≤ 8) was needed in 56 (14%) adults35 and 51 of 83 children (about 61%) for either coma, status epilepticus, or abnormal posturing.47 A recent study in a resource-poor setting where intubation was not available showed that 33% of adult patients with cerebral malaria who started nasogastric tube feeding on the day of admission developed aspiration pneumonia, which itself was associated with a 50% mortality rate.117

Risk factors for developing ARDS in severe malaria are poorly defined, and early predictors could guide fluid therapy and respiratory care. Biomarkers for the early detection of ALI and ARDS are currently being explored, and further work on optimizing fluid regimens to prevent iatrogenic pulmonary edema is needed. Data on the immunopathogenesis and the pathology of pulmonary malaria are limited and would be useful for identifying studies of adjunct treatment.

Respiratory distress is a common feature in severe falciparum malaria and has multiple causes, including severe anemia, metabolic acidosis, concomitant pneumonia, fluid overload, and ALI/ARDS. ALI/ARDS, described mainly in adult patients and pregnant women with severe falciparum malaria, can also occur in other malarias, but better and well-defined incidence data for ALI/ARDS are needed in all groups of patients. Its immunopathophysiology is incompletely understood. Mechanical ventilation strategies in severe malaria-associated ARDS are the same as in other conditions with ARDS, except that permissive hypercapnia is not recommended because of increased intracranial pressure frequently present in the patient with cerebral malaria.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Hanson, White, and Dondorp are supported by The Wellcome Trust as part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme.

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Figures

Figure Jump LinkFigure 1. A, Histopathology of the lung in a fatal case of adult falciparum malaria. There is expansion of alveolar capillaries by sequestered parasitized erythrocytes and host inflammatory leukocytes. Monocytes and neutrophils within alveolar septal capillaries contain phagocytosed hemozoin pigment (hematoxylin and eosin [H&E] staining, magnification × 400, scale bar 200 μm). B, A more severe histologic picture from a fatal case of falciparum malaria, with sequestration of parasitized erythrocytes and host leukocytes expanding the alveolar septae, intraalveolar hemorrhage and pulmonary edema, and hyaline membrane formation as part of a picture of diffuse alveolar damage (H&E staining, magnification × 200, scale bar 200 μm)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Summary of the Frequencies and Nature of Respiratory Features Reported in Studies of Severe Vivax and Falciparum Malaria

ALI = acute lung injury; CFR = case fatality rate; CXR = chest radiograph; D0 = day of admission; NA = not applicable; ND = no data; O2 = oxygen; P falciparum = Plasmodium falciparum; P vivax = Plasmodium vivax; RR = respiratory rate; WHO = World Health Organization.

a 

Any one of severe anemia, coma, respiratory distress.

b 

Independent of other organ dysfunction.

c 

Seven deaths due to multiorgan dysfunction syndrome.

d 

Species breakdown not stated.

Table Graphic Jump Location
Table 2 —Defining Criteria for ALI and ARDS

PA = posteroanterior. See Table 1 legend for expansion of other abbreviations.

a 

Irrespective of the level of positive end-expiratory pressure.

b 

Abnormal chest radiograph findings may appear after functional disturbances.

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