TRANSACTIONSOF THE ROYALSOCIETYOF TROPICALMEDICINEAND HYGIENE(2003) 97, 551-553
Case reports: pernicious complications of benign tertian malaria Stephen D. Lawn, Sanjeev Krishna, Joseph N. Jarvis, Thierry Joet and Derek C. Macallan Department of Cellular and Molecular Medicine, Infectious Diseases, St George's Hospital Medical School, London SW17 ORE, UK Abstract We describe 2 patients with complications ofPlasmodium vivax malaria. Both patients developed marked intravascular haemolysis and haemoglobinuria despite normal levels of glucose-6-phosphate dehydrogenase activity in blood. One required mechanical ventilation because of life-threatening hypoxia due to acute respiratory distress syndrome.
Keywords: malaria, Plasmodium vivax, respiratory distress syndrome, pulmonary oedema, intravascular haemolysis, haemoglobinuria, travel medicine
Introduction While fulminant complications of Plasmodium falciparum malaria are well described (WHO, 2000), complications of P. vivax malaria are rarely reported-hence the term 'benign' tertian malaria. Here we describe 2 patients with complicated P. vivax malaria in whom P. falciparum or other co-infection was carefully excluded.
Patient 1 A previously healthy 52-year-old male U K resident presented at St George's Hospital, London, U K with a 2-week history of increasing fever, myalgia, headache, and dark urine. Two months previously he had developed a febrile illness while working in French Guiana. He had not taken antimalarial chemoprophylaxis and P. vivax infection was diagnosed by blood film examination. A course of oral chloroquine, but no primaquine, was prescribed and he made an uncomplicated recovery. However, his fever recurred 1 month after returning to the UK. On admission he was unwell, sweaty, dehydrated and mildly jaundiced. He was febrile (39.4 °C), hypotensive (70/40 m m H g lying), and was tachycardic (100 bpm). His peripheries were cool, although he was fully alert and orientated. Respiratory examination was normal and arterial blood oxygen saturations were 97% while breathing air. The tip of the spleen was palpable. Blood investigations revealed a low haemoglobin concentration (11.2 g/dL; normal range 13-17 g/dL), a normal white cell count, and thrombocytopenia (71 × 109/L; normal range 150-450 × 109/L). The serum bilirubin was raised (44 pmol/L; normal range < 17 Bmol/L) but serum creatinine and hepatic transaminase concentrations were normal. Urinalysis showed haemoglobinuria and proteinuria without casts. Blood, sputum, and urinary cultures were sterile and a chest radiograph was normal. Early and late trophozoites and schizonts of P. vivax were seen in the blood film with < 1.0% parasitaemia. A commercially available immunochromatographic test (ParaSight-F TM, Becton Dickinson, Franklin Lakes, NJ, USA) for P. falciparum histidinerich protein-2 (HRP-2) was negative. The Malaria Reference Laboratory (MRL) at the London School of Hygiene and Tropical Medicine, U K confirmed the parasitological diagnosis. The patient received fluid resuscitation and i.v. quinine (10 mg/kg at 8 h intervals) during the first 24 h until P. falciparum co-infection had been definitively excluded. By day 2 of admission, the blood pressure and urine output had both improved. The i.v. quinine was substituted by oral chloroquine (25 mg/kg total dose over 3 d). The patient had a mild tachypnoea and Address for correspondence: Dr S. D. Lawn, Department of Cellular and Molecular Medicine, Infectious Diseases, St George's Hospital Medical School, London SW17 ORE, UK; phone +44 (0)20 8672 1255, fax +44 (0)20 8725 3487, e-mail
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scanty inspiratory crepitations at the lung bases and so i.v. fluids were discontinued. On day 3 of admission, however, the patient developed increasing breathlessness at rest without cough, sputum production, or chest pain. Chest auscultation revealed poor air entry and inspiratory crepitations at both lung bases. The patient was afebrile and there were no clinical signs of cardiac failure or deep vein thrombosis. The total and differential white cell counts were normal. There were no electrocardiographic abnormalities. Arterial blood gas measurement while breathing air revealed marked hypoxia (PaO2 = 4.74 kPa, normal range l l . l - 1 4 . 4 k P a ) , normocapnia (PaCO2 = 4.75 kPa; normal range 4.3-6.4 kPa), a low oxygen saturation (76.7%), and a blood pH of 7.47. A chest radiograph (Fig. 1) revealed extensive bilateral patchy alveolar shadowing consistent with adult respiratory distress syndrome (ARDS). The patient was transferred to the intensive treatment unit (ITU) for respiratory support, careful fluid management, and empiric broad-spectrum antimicrobial treatment using cefotaxime and erythromycin. The central venous pressure was normal (5 cm water) and serum albumin concentration was 29 g/L (normal range 3 5 - 4 8 g/L). Blood cultures and tracheal secretions were sterile. Legionella and pneumococcal antigens were not present in urine and subsequent serology for atypical respiratory pathogens was negative. No malarial trophozoites were present in the blood film after day 3. However, on day 4 the patient required endotracheal intubation and mechanical ventilation. Oesophageal Doppler studies i
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Fig. 1. Chest radiograph of patient 1 taken on day 4 of admission following endotracheal intubation. The bilateral interstitial infiltrates are consistent with a diagnosis of adult respiratory distress syndrome.
552 revealed a normal cardiac output (5.7 L/min), cardiac index (3.3 L / m i n / m ~) and systemic vascular resistance, confirming the diagnosis of non-cardiogenic pulmonary oedema and ARDS. During his admission the patient's haemoglobin concentration progressively decreased to a nadir of 8.3 g/ dL on day 6 and this was accompanied by sustained hyperbilirubinaemia, a reticulocytosis, and development of 'cola'-coloured urine due to haemoglobinuria. Plasma creatinine was not elevated and normal blood levels of glucose-6-phosphate dehydrogenase (G6PD) activity were detected during the acute illness and following complete recovery. The patient required mechanical ventilation for 3 d. The haemoglobin concentration increased without the need for transfusion and the patient made a full, uncomplicated recovery. He was discharged home on day 11 with a course of primaquine. One month later he was well with a haemoglobin of 13.9 g/dL and normal serum bilirubin concentration. Patient 2 A previously healthy 29-year-old Indian man who had lived in the U K for over 5 years presented with a 10 d history of fever, sweats, headache, and iaundice. He had travelled to India 1 year earlier without taking antimalarial chemoprophylaxis. On admission he was pyrexial, jaundiced, and the liver and spleen were just palpable. His initial investigations revealed a normal haemoglobin (15.4g/dL), a normal clotting screen, and thrombocytopenia (35 × 109/L). There was marked hyperbilirubinaemia (102 mmol/L) but liver transaminase concentrations were not increased. Plasmodium vivax parasites at all stages were seen in the blood film with < 1% parasitaemia. The MRL confirmed the blood film findings. No other infection was identified. The patient was treated with i.v. fluids and oral chloroquine (25 mg/kg total dose over 3 d). The hyperbilirubinaemia persisted and the haemoglobin decreased from 15.4 to 11.9 g/dL over the course of 4 d. The urine became 'cola'-coloured, haemoglobinuria was detectable but the serum creatinine concentration did not increase. Normal blood levels of G6PD activity were detected during the acute illness and following complete recovery. To definitively exclude P. falciparurn co-infection we carried out polymerase chain reaction (PCR) analysis on DNA extracted from this patient's admission blood sample with primers designed to amplify the full-length sequence encoding hexose transporters of P. falciparum and P. vivax (Fig. 2). This confirmed that P. vivax DNA only was present. By day 6 of admission, the patient was apyrexial, no malarial trophozoites were present in the blood film,
Fig. 2. Polymerase chain reaction (PCR) verification of Plasrnodium vivax infection in patient 2. PCR was carried out with the following templates: water control (track 1); DNA extracted from whole blood from patient 2 (tracks 2 and 4); P. falciparum DNA (clone 3D7) (tracks 3 and 5). Primers were designed for full-length amplification ofP. vivax hexose transporter gene (PvHT, 1509 bp, accession no. AJ488939) (tracks 1, 2 and 3) or P. falciparum hexose transporter gene (/ffHT, 1515 bp, accession no. AJ131457) (tracks 4 and 5). PCR conditions were 30 s at 94 °C, 45 s at 53 °C and 3 rain at 68 °C for 35 cycles. This confirms infection with P. vivax alone.
s.D. LAWNETAL. the haemoglobin concentration had started to rise and the serum bilirubin had decreased to 25 mmol/L. The patient was discharged on day 8. One month later the patient's haemoglobin concentration was 15.8 g/dL, having completed a full course of primaquine without further complications.
Discussion Plasmodium vivax causes a debilitating febrile illness, but vital organ damage and severe haemolysis are very unusual. In a recent series of 101 patients with P. vivax malaria in the Republic of Korea, splenic rupture in 1 patient was the only serious complication. The occurrence of severe disease in patients with P. vivax malaria should lead to careful investigation for the presence of concurrent P. falciparum infection, other co-infections or pre-existing disease. As well as seeking the opinion of the MRL, we conducted either an immunochromatographic test or PCR to definitively exclude P. falciparum co-infection in our patients. In previous reports of complicated P. vivax malaria, rigorous exclusion of co-pathology is not always evident. Reported complications of P. vivax malaria include pulmonary pathology, central nervous system dysfunction, nephrotic syndrome, coagulation abnormalities, bone marrow hypoplasia and splenic rupture (reviewed by Pukrittayakamee et al., 1998). Pulmonary complications of P. falciparum malaria are frequently observed (Patel & Kahn, 1991) but there are only a few well-documented reports of ARDS attributable to P. vivax infection (Tortes et al., 1997; Pukrittayakamee et al. 1998; Carlini etal., 1999; Curlin et al., 1999; Tanios et al., 2001). This report demonstrates that life-threatening ARDS may complicate P. vivax malaria in the absence of an unusually high parasitaemia. As in all previous reports, the onset of ARDS followed initiation of antimalarial treatment. Awareness of this complication should encourage caution during i.v. rehydration of patients with P. vivax malaria as is recommended practice with P. falciparum malaria (WHO, 2000). The mechanisms underlying acute lung damage caused by malarial parasites are not well understood. Microvascular sequestration of parasitized erythrocytes is thought to be the principal pathophysiological mechanism underlying most non-pulmonary vital organ damage in P. falciparum infections (WHO, 2000). However, the onset of ARDS in patients with P. falciparum malaria commonly occurs 1-5 d after commencing appropriate treatment when peripheral parasitaemia has often decreased or disappeared. Furthermore, this and previous case reports have established that ARDS may also complicate infections with P. vivax--a parasite that does not cause cytoadherence. These observations suggest that cytoadherence of infected erythrocytes to pulmonary capillaries is not the principal mechanism of pulmonary pathology in patients with malaria. Subclinical impairment of lung function is common in both P. falciparum and non-P, falciparum malaria, with small airways obstruction, impaired alveolar ventilation, reduced gas transfer, and increased pulmonary phagocytic activity (Anstey et al. 2002). It seems likely that common inflammatory mechanisms underlie the lung functional impairment in P. falciparum and P. vivax malaria. It is postulated that the development of ARDS probably reflects increased pulmonary endothelial injury and a transient increase in pulmonary capillary permeability (Anstey et al., 2002). The frequent onset of ARDS after starting treatment may reflect a post-treatment exacerbation of this inflammatory response mediated by local or systemic proinflammatory cytokine release as occurs in the Jarish-Herxheimer reaction (Negussie et al., 1992). Both patients in this report developed significant haemolysis, leading to visible haemoglobinuria. Com-
COMPLICATIONSOF PLASMODIUM VIVAXMALARIA pared to convalescent levels, the haemoglobin concentrations decreased by approximately 5 . S g / d L and 3.5 g/dL in patients 1 and 2, respectively, with maxim u m rates of decline of 1 - 2 g / d L / d . Marked hyperbilirubinaemia but normal liver function and normal G6PD activity were seen in both patients. In contrast, only mild hyperbilirubinaemia was found in 11 (10.9%) of a series of 101 Korean patients with P. vivax malaria, with bilirubin concentrations not rising more than two-fold above the upper limit of the normal range (Oh et al., 2001). While anaemia was a common finding in this cohort, severe rapid haemolysis and haemoglobinuria were not reported (Oh et al., 2001). This report adds further evidence that malaria due to P. vivax is not always 'benign'.
References Anstey, N. M., Jacups, S. P., Cain, T., Pearson, T., Ziesing, P. J., Fisher, D. A., Currie, B. J., Marks, P. J. & Maguire, G. P. (2002). Pulmonary manifestations of uncomplicated falciparum and vivax malaria: cough, small airways obstruction, impaired gas transfer, and increased pulmonary phagocytic activity.Journal of Infectious Diseases, 185, 1326-1334. Carlini, M. E., White, A. C. Jr. & Atmar, R. L. (1999). Vivax malaria complicated by adult respiratory distress syndrome. Clinical Infectious Diseases, 28, 1182-1183. Curlin, M. E., Barat, L. M., Walsh, D. K. & Granger, D. L. (1999). Noncardiogenic pulmonary oedema during vivax malaria. Clinical Infectious Diseases, 28, 1166-1167.
CD-ROM Review Acute Respiratory Infection. A Topics in International Health CD-ROM. Wallingford: CABI Publishing, 2001. Price: Institutional Rate £120/US$195; Student/Individual Rate £30/US$55; Developing Country Rate £45/US$80; Reduced Developing Country Rate £20/US$35. ISBN 0-85199-495-4. The aim of Topics in International Health is to provide an educational resource for medical and life science students, their teachers, health care professionals, academics, and researchers. The tutorial comes in a CD format, which loaded on to my computer without difficulty. It offered a series of 12 interactive tutorials, which covered the essential information required for the target audience. For each tutorial the objectives were clear and the student had the opportunity of discovering whether they had assimilated the relevant
553 Negussie, Y., Remick, D. G., DeForge, L. E., Kunkel, S. L., Eynon, A. & Griffin, G. E. (1992). Detection of plasma tumor necrosis factor, interleukins 6, and 8 during the Jarisch-Herxheimer reaction of relapsing fever. Journal of ExperimentalMedicine, 175, 1207-1212. Oh, M.-D., Shin, H., Shin, D., Kim, U., Lee, S., Kim, N., Choi, M.-H., Chai, J-Y. & Choe, K. (2001). Clinical features of vivax malaria. American Journal of Tropical Medicine and Hygiene, 65, 143-146. Patel, V. & Kahn, F. A. (1991). Pulmonary complications of malaria. Seminars in RespiratoryDisease, 12, 8-17. Pukrittayakamee, S., Chantra, A., Vanijanonta, S. & White, N. J. (1998). Pulmonary oedema in vivax malaria. Transactions of the Royal Society of TropicalMedicine and Hygiene, 92, 421-422. Tanios, M. A., Kogelman, L., McGovem, B. & Hassoun, P. M. (2001). Acute respiratory distress syndrome complicaring Plasmodium vivax malaria. Critical Care Medicine, 29, 665-667. Torres, J. R., Perez, H., Postigo, M. M. & Silva, J. R. (1997). Acute non-cardiogenic lung injury in benign tertian malaria. Lancet, 350, 31-32. WHO (2000). Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 94, supplement 1, S1/1-S1/90.
Received 17 March 2003; revised 21 M a y 2003; accepted for publication 23 M a y 2003
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