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Case Report: Acute Respiratory Distress Syndrome in a Case of Plasmodium
ovale Malaria
Gerardo Rojo-Marcos,* Juan Cuadros-González, José María Mesa-Latorre, Ana María Culebras-López, and
Raúl de Pablo-Sánchez
Department of Internal Medicine, Department of Microbiology and Parasitology, and Department of Intensive Care, University
Hospital “Príncipe de Asturias”, Alcalá de Henares, Madrid, Spain
Abstract. Acute respiratory distress syndrome is a well-known complication in Plasmodium falciparum infection. It
is less frequently described in Plasmodium vivax, and only one case is reported in Plasmodium ovale. Here we present
the second description of this pulmonary complication in a P. ovale acute infection.
INTRODUCTION
Malaria is the most frequent parasitic disease in the world,
with 500 million cases and > 1 million deaths every year over-
all in children younger than 5 years of age in Africa. It can be
caused by four Plasmodium species: P. falciparum, P. vivax, P.
ovale, and P. malariae. The prevalence rate of P. ovale infection
may be 0.5–10.5% of all malaria cases and is restricted to sub-
Saharan Africa, the islands of the western Pacific, and rarely on
the mainland of southeast Asia.
1
Acute respiratory distress Syn-
drome (ARDS) is a well known complication in P. falciparum
infection and less frequently described in P. vivax.P. ovale
usually causes mild disease without complications, and only
one case of ARDS has been reported up to now in the medi-
cal literature.
2
Here we present the second description of this
pulmonary complication in a P. ovale acute infection.
CASE REPORT
A 43-year-old Nigerian man returned from a 3-month trip
to Nigeria visiting relatives without taking malaria prophy-
laxis. He had been living for 5 years in Spain, and he had a
history of hypertension and diabetes mellitus for 13 years. His
daily treatment was irbesartan and insulin. Three days after
returning, he began with fever, chills, headache, malaise, and
vomiting. On admission, he was febrile (40.5°C), supine blood
pressure was 104/62 mm of Hg, cardiac rate was 88/min, and
oxygen saturation breathing room air was 96% assessed by
pulsoximetry, with a normal respiratory rate. Physical exami-
nation showed only mucosal dryness, and lung auscultation
was clear.
Laboratory results showed a white blood cell count of
5,700/L (56% neutrophils, 1% bands, 41% lymphocytes, 2%
monocytes), hemoglobin of 9.8 g/dL, and platelet count of
56,000/L. Serum creatinine was 1.8 mg/dL, glucose was 243
mg/dL, albumin was 2.7 g/dL, aspartate aminotransferase was
77 IU/L, alanine aminotransferase was 77 IU/L, gamma
glutamyl transpeptidase was 88 IU/L, lactate dehydrogenase
was 950 IU/L, total bilirubin was 1.9 mg/dL, and ferritin was
2,462 ng/mL. Serum electrolytes, coagulation, creatine phos-
phokinase, haptoglobin, and urine analysis were within nor-
mal range. Chest radiography was normal without cardiome-
galy. An electrocardiogram showed an incomplete left bundle
block.
Trophozoites and gametocytes of P. ovale with a parasitemia
of 6,000/L were detected by an expert microscopist in the thick
film, and a malaria antigen test (NOW Malaria KT test, Binax
Inc., Scarborough, ME) was positive for the aldolase (malaria
antigen common to the four species) band and negative for
HRPf-2. Multiplex polymerase chain reaction (PCR)
3
per-
formed in a reference laboratory (Laboratorio de Malaria del
Centro Nacional de Microbiología, Spain) confirmed this diag-
nosis and was negative for other Plasmodium species.
The patient was started on oral chloroquine therapy for 3
days, paracetamol, and insulin. During the first 2 days, 1,500
and 2,500 mL of 0.9% saline were infused, respectively. Forty-
eight hours after admission, fever continued, creatinine wors-
ened to 2.4 mg/dL with sodium fractional excretion of 0.09%,
and he developed progressive dyspnea, tachypnea, and he-
moptysis. Bibasal crackles were heard on auscultation, and
jugular venous pressure was not elevated. Arterial blood gases
showed pH 7.52, pCO
2
of 26.7 mm of Hg, pO
2
of 38 mm of Hg,
bicarbonate of 22.3 mmol/L, and hemoglobin dropped to 7.8
g/dL. Bilateral extensive alveolar infiltrates were seen in chest
radiography (Figure 1). He was admitted to the intensive care
unit (ICU) and was intubated and ventilated. Ceftriaxone and
levofloxacin were added as empirical treatment, and two
packed red cell units were transfused. Arterial blood gases
during mechanical ventilation with 50% oxygen and 10 cm
H
2
O PEEP were pH 7.43, pCO
2
of 36 mm of Hg, pO
2
of 90
mm of Hg, and bicarbonate of 24.4 mmol/L. The PaO
2
/FiO
2
ratio remained < 200 for 10 days. Central venous pressure
(CVP) was 20 cm H
2
O initially. Pulmonary capillary wedge
pressure (PCWP) was not measured. Noradrenalin infusion
was needed for 48 hours because of a hypotensive episode on
the fourth day of ICU, which did not respond to fluids and the
development of progressive generalized edema. Negative
fluid balance was achieved on Day 5 in the ICU after being
hemodynamically stabilized. Echocardiogram performed on
Day 30 from admission showed an important left ventricular
hypertrophy with normal systolic function. Thick film per-
formed on the second day of chloroquine treatment showed
only gametocytes and 5 days later was negative. Multiple
urine and blood cultures were negative. Bronchoscopy on the
first day in the ICU showed diffuse inflammatory signs with
intense bloody secretions. Bronchoalveolar aspirate was
negative for bacteria, mycobacteria, and fungi. Lactic acid
and rheumatoid factor were normal. Antineutrophil, anti-
nuclear, and antibasal membrane antibodies were negative.
Abdominal ultrasound was normal, and abdominothoracic
* Address correspondence to Gerardo Rojo-Marcos, Department of
Internal Medicine, University Hospital “Príncipe de Asturias,” Ctra.
Alcalá-Meco s/n. Alcalá de Henares, 28805 Madrid, Spain. E-mail:
grojo.hupa@salud.madrid.org
Am. J. Trop. Med. Hyg., 79(3), 2008, pp. 391–393
Copyright © 2008 by The American Society of Tropical Medicine and Hygiene
391
CT with intravenous contrast on Day 13 in the ICU showed
bilateral alveolar infiltrates with pseudonodular appearances,
pleural effusions, and atelectasia in the lower lobules. Urinary
Legionella antigen and human immunodeficiency virus
(HIV), hepatitis C virus, hepatitis A virus immunoglobulin M,
syphilis, Brucella, and Leishmania serology were all negative,
and serologic evidence of a previous infection by hepatitis B
virus was seen. Stool parasites were negative. Mansonella per-
stans was detected in the blood. Acinetobacter bowmannii
grew in another bronchoalveolar aspirate taken 15 days after
ICU admission, and intravenous colistin and amikacin were
added. A 14-day oral primaquine treatment was completed
after confirming a normal level of glucose-6-phosphate-
dehydrogenase.
Sustained fever persisted for 14 days after chloroquine ini-
tiation, but infiltrates, oxygenation, and renal function im-
proved progressively. Extubation was achieved on Day 21 in
the ICU, and he was transferred to the internal medicine
ward. Finally he was discharged 40 days after admission. Ten
months later, he was asymptomatic, and a thoracic computed
tomography scan showed normal lungs.
DISCUSSION
In this patient, pulmonary edema is consistent with criteria
of ARDS after a P. ovale infection with acute onset of bilat-
eral infiltrates on chest radiography, absence of clinical evi-
dence of left atrial hypertension, and a PaO
2
/FiO
2
ratio
ⱕ200.
4
Fluid infusion during the first 48 hours to improve
prerenal acute renal failure might have worsened the pulmo-
nary distress, adding a component of fluid overload to a pa-
tient with hypertensive cardiomyopathy and possible diastolic
dysfunction beside a lung with enhanced vascular permeabil-
ity injured by P. ovale infection. Renal function deteriorated
initially because of low intravascular volume and saline ex-
pansion, and vasopressure drugs were necessary. CVP is not a
reliable method to measure left atrial pressure overall on me-
chanical ventilation with PEEP. PCWP would have given
complementary information in this case but was not used. The
radiographic feature and slow infiltrates resolution were also
more consistent with ARDS. Other factors that might have
contributed to pulmonary edema were anemia, fever, and hy-
poalbuminemia with low oncotic pressure.
The possibility of mixed infection with P. falciparum was
ruled out by PCR analysis. Community acquired pneumonia
or sepsis from another source were unlikely because of initial
negative microbiological analysis including results from the
first bronchoscopy. Ventilator-associated pneumonia by
Acinetobacter was not related with the acute lung injury but a
late nosocomial infection with favorable outcome. Diffuse
pulmonary hemorrhage is described in ARDS, and other eti-
ologies may be excluded by the absence of connective tissue
disease signs, negative laboratory tests, and good evolution
without immunosuppressive drugs.
The clinical evolution of this patient was similar to previous
reports of P. vivax and P. ovale ARDS. Almost none had
significant respiratory symptoms or x-ray abnormalities at
presentation,
5
and worsening resulted several days after ini-
tiation of specific treatment of malaria. A better clinical evo-
lution and lower mortality has been described in P. virax than
in P. falciparum–related ARDS. Mortality of ARDS without
mechanical ventilation may exceed 80% in falciparum ma-
laria, but in those patients who survive, clinical recovery is
often rapid.
6
Fever resolution can be delayed from initiation
of therapy despite good parasitologic response,
7
probably as a
consequence of intense inflammatory response post-
treatment. Low parasitemia is nearly a constant in these spe-
cies of Plasmodium. Complications are most often described
in non-immune individuals,
6
which our patient can be consid-
ered because he has been living in a non-malarious country
for 5 years. Diabetes mellitus as a cause of immunosuppres-
sion could have been a factor for more severe infection as
might be seen in HIV patients with malaria.
The pathophysiology of acute pulmonary edema in malaria
is not clear, and the mechanism may be different in P. falci-
parum, vivax, or ovale. In the case of falciparum, infected red
cells cytoadhere to the microvascular endothelium causing
mechanical obstruction of pulmonary vasculature. Inflamma-
tory cells like neutrophils and mononuclears are activated
increasing pulmonary phagocytic cell activity with intense lib-
eration of cytokines. Alveolar capillary permeability increases,
and intravascular fluid is spread into the lungs leading to an
ARDS feature.
8
A possible role of impaired pulmonary NO
bioavailability has been postulated as a cause of higher risk of
developing ARDS.
9
A component of hydrostatic edema may
be facilitated by fluid overload so that the recommendations
in malaria are to maintain the CVP and PCWP at relatively
low levels.
In series of severe falciparum malaria, pulmonary edema
occurred in 9–21%. Pulmonary edema in P. vivax infection is
a rare complication, but in the last years has been more fre-
quently reported.
5
Because of its clinical and microbiological
similarities with P. ovale malaria, it might provide more in-
sights into the pathophysiology of our reported case. It is
known that altered pulmonary function is common in uncom-
plicated falciparum, vivax, and ovale infection.
10
In a recently
published study comparing uncomplicated vivax and falci-
parum malaria, the functional lung alterations suggested that
P. vivax–infected erythrocytes may also be sequestered within
the pulmonary microvasculature,
11
but it is unknown whether
P. ovale can sequester in the lung. Moreover, host response
seems to be stronger at lower parasitemia in vivax and ovale
than in falciparum infection,
12
and progressive alveolar-
FIGURE 1. Chest radiograph 48 hours after admission showing
extensive bilateral alveolar infiltrates.
ROJO-MARCOS AND OTHERS392
capillary dysfunction after treatment of vivax malaria is also
consistent with this greater inflammatory response,
11
a phe-
nomena not seen in uncomplicated falciparum infection.
13
Marked increase in pulmonary phagocytic activity was also
measured in a patient with P. ovale 1–2 days after starting
chloroquine.
10
Some formation of rosettes has also been shown
in vivax and ovale
14
that may support the sequestrating hypoth-
esis. More virulent strain of P. ovale cannot be excluded in this
case. Until now, there were very few autopsy studies in pa-
tients with vivax and ovale infection without clear conclusions
on mechanisms of pulmonary injury.
An increasing number of patients from West Africa is seen
in our area, and P. ovale infections represented 7% of our
malaria cases,
15
including one locally acquired case.
16
Al-
though it is a rare complication, it is important to be aware of
the possibility of developing ARDS in malaria other than
falciparum infection. Careful monitoring of fluid replacement
must be recommended for the treatment of severe malaria of
any species. Finally, it must be stressed that all travelers to
malarious areas and especially African people visiting rela-
tives and friends must be counseled about taking adequate
malaria prophylaxis.
Received March 13, 2008. Accepted for publication June 4, 2008.
Disclosure: The authors state that they have no conflict of interest.
Authors’addresses: Gerardo Rojo-Marcos, Department of Internal
Medicine, University Hospital “Príncipe de Asturias,”Ctra. Alcalá-
Meco s/n. Alcaláde Henares, 28805 Madrid, Spain, Tel: 34-918878100
ext. 2635, Fax: 34-918801825, E-mail: grojo.hupa@salud.madrid.org.
Juan Cuadros-González, Department of Mycrobiology and Parasitol-
ogy, University Hospital “Príncipe de Asturias,”Ctra. Alcalá-Meco
s/n. Alcaláde Henares, 28805 Madrid, Spain, Tel: 34-918878100 ext.
2073, Fax: 34-918801825. JoséMaría Mesa-Latorre, Department of
Internal Medicine, University Hospital “Príncipe de Asturias,”Ctra.
Alcalá-Meco s/n. Alcaláde Henares, 28805 Madrid, Spain, Tel: 34-
918878100 ext. 2656, Fax: 34-918801825. Ana María Culebras-López,
Department of Internal Medicine, University Hospital “Príncipe de
Asturias,”Ctra. Alcalá-Meco s/n. Alcaláde Henares, 28805 Madrid,
Spain, Tel: 34-918878100 ext. 2602, Fax: 34-918801825. Raúl de Pablo-
Sánchez, Department of Intensive Care, University Hospital
“Príncipe de Asturias,”Ctra. Alcalá-Meco s/n. Alcaláde Henares,
28805 Madrid, Spain, Tel: 34-918878100 ext. 2205, Fax: 34-918801825.
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RESPIRATORY DISTRESS IN PLASMODIUM OVALE 393
