- Email: [email protected]
The case for outpatient treatment of Plasmodium falciparum malaria in a selected UK immigrant population
Journal of Infection (2009) 59, 259e263
www.elsevierhealth.com/journals/jinf
The case for outpatient treatment of Plasmodium falciparum malaria in a selected UK immigrant population Mark Melzer a,*, Sandra Lacey a, Greta Rait b a
King George and Queen’s Hospitals, Barking, Havering and Redbridge Trust, Barley Lane, Goodmayes, Essex IG3 8YB, UK Medical Research Council General Practice Research Framework, Stephenson House, 158-160 North Gower St., London NW1 2ND, UK b
Accepted 19 August 2009 Available online 23 August 2009
KEYWORDS Outpatient; Out of hospital; Plasmodium falciparum; Treatment
Summary UK guidance recommends that all patients with falciparum malaria be admitted to hospital, although a number of cohort studies in the developed world demonstrate that outpatient treatment of falciparum malaria is feasible and safe in selected patients. We review the literature on outpatient treatment in developed countries and present local data from East London where a selected immigrant population were successfully treated as outpatients. Although it is premature to claim that outpatient treatment of falciparum malaria is safe in all selected patients, we conclude it is time for a large UK-based safety study or randomised trial to dispel the belief that all patients with uncomplicated Plasmodium falciparum must be admitted to hospital. ª 2009 Published by Elsevier Ltd on behalf of The British Infection Society.
Introduction Plasmodium falciparum malaria, in its severest form, is a lifethreatening illness. Within the UK, approximately 2000 cases of malaria are notified per annum and 15 deaths reported annually.1 Selecting patients with potentially life-threatening infections for outpatient treatment is accepted practice for diseases such as community-acquired pneumonia and neutropenic sepsis but remains controversial for falciparum malaria. Despite recent UK guidance2 that recommends all * Corresponding author. Tel.: þ44 20 8970 4032; fax: þ44 20 8970 5784. E-mail address: [email protected] (M. Melzer).
patients be admitted to hospital, outpatient treatment of selected patients with falciparum malaria is practiced in most developing countries and some parts of the developed world.3e7 We review the literature of outpatient treatment of uncomplicated falciparum malaria in the developed world and then describe our experience of treating a selected immigrant population in an area bordering East London.
Studies outside the UK In developing countries, adults and children with uncomplicated falciparum malaria are routinely managed as outpatients. In Africa, there is one published trial of inpatient versus outpatient treatment.8 Patients, including children,
0163-4453/$36 ª 2009 Published by Elsevier Ltd on behalf of The British Infection Society. doi:10.1016/j.jinf.2009.08.010
260 were randomised to supervised (inpatient) versus outpatient treatment with artemetherelumefantrine and, at 28 days, cure rates were 296/303 (97.7%) and 603/615 (98.0%) respectively. In general, in developing countries, inpatient treatment does not occur due to lack of resources and clinical trials have generally focused on the effectiveness of different anti-malarial regimes.9,10 Where treatment with artemisinin combination therapy has been adopted as national policy, audits of prescribing practice have been published.11,12 Other researchers have described where antimalarials are accessed,13,14 point of care diagnostics in the outpatient setting15 and the consequences of over diagnosis and over prescribing anti-malarials.16 In developing countries, further clinical trials of inpatient versus outpatient treatment are unlikely to occur in the future. In developed countries, inpatient admission and observation of patients with uncomplicated falciparum malaria is the preferred option. Outpatient treatment remains controversial despite clinical trials that suggest it can be performed safely in selected patients. In the largest European cohort study published to date, 214 patients in Belgium with parasitaemia counts <1% were treated predominantly with atovoquoneeproguanil (malarone) as outpatients.5 Ten patients were readmitted, five within three days because of vomiting, four after three days because of persistent fever and parasitaemia and one after 14 days because of recrudescence. No fatalities occurred. In an earlier European study, the Swiss cohort study,3 82/113 (73%) were treated with mefloquine and sulfadoxine/pyrimethamine. Three patients were readmitted to hospital, two with drug intolerance and one with adult respiratory distress syndrome. Two further patients were reviewed with dizziness before their scheduled follow up, probably due to an adverse drug event. Again, no fatalities occurred. Two Australian cohort studies have also recorded successful outcomes. In a 30-month retrospective analysis of West African adult migrants, 52/57 (91.2%) were treated out of hospital, most commonly with atovoquoneeproguanil. Of the 27 (51.9%) patients seen at four weeks all had negative blood films.6 In a paediatric study, 56/90 (62.2%) African refugee children, fulfilling criteria including previous malaria, were treated out of hospital with atovoquoneeproguanil or mefloquine. Of the 88 patients attending for follow up at 28 days, 85 had blood films and one, previously an inpatient, had a positive blood film.7 Despite rare cases of drug intolerance, treatment failure and malaria related complications, the authors conclude that selected outpatient treatment of falciparum malaria is practicable and safe (Table 1).
Local UK experience From June 2003 to December 2006, at King George Hospital, part of Barking, Havering and Redbridge University (BHRU) Hospitals, we encouraged physicians to treat selected patients with P. falciparum as outpatients. Patients were eligible for outpatient treatment if they were aged 16 years and over, non-pregnant, non-UK born, alert and orientated, able to tolerate their first dose of oral treatment, normotensive, had normal renal function and a parasitaemia
M. Melzer et al. count of 2% or less. Patients were advised to return to A&E or their GP if vomiting occurred or their symptoms worsened within 48 h. All cases were laboratory confirmed. An antigen detection assay, Malaria-ICT-now, Binax (Portland, USA) was used as a screening assay and thin blood films used for speciation and parasitaemia counts. Two clinical microbiologists collected demographic, clinical and laboratory data on all patients within 72 h of admission. Attending physicians were advised to treat patients with atovoquoneeproguanil, four tablets once daily for three days or quinine 600 mg every 8 h for five to seven days followed by doxycycline (200 mg once daily for seven days), in accordance with UK guidance.2 Some outpatients were switched from oral quinine to atovoquoneeproguanil to aid compliance. At least seven days after treatment, patients were reviewed in an outpatient setting or contacted by telephone to ensure successful completion of treatment. Blood films were repeated if patients were symptomatic. Twentyeight days post-treatment, the hospital’s patient administration computer system was checked to ensure there were no hospital readmissions. Data was analysed using Stata 10.17 Univariate associations were tested using two-tailed Chisquare tests. Where the smallest expected value was less than five, Fisher’s exact test was used. The study was registered as a clinical audit at Barking, Havering and Redbridge Trust and the standards used were a modified version of a Swiss cohort study (2002)3 and the World Health Organisation’s severity criteria for P. falciparum.18 Advice was taken from the NE London ethics committee. It was noted that as this study was registered as an audit, ethical approval was not required. 142 cases of falciparum malaria were diagnosed between June 2003 and December 2006. Parasitaemia counts ranged from <0.1 to 26% (median value 1%; IQR: <0.1e2.0%). Threequarters of cases had a parasitaemia of 2% or less, 106/142 (74.6%). Among these patients, 28/142 (19.7%) patients were not eligible for outpatient treatment as 24 were aged <16 years, two were pregnant and two UK born (Fig. 1). Seventy-eight (54.9%) patients were eligible for out of hospital treatment. Almost two-thirds, 47/78 (60.3%), were male and most had travelled to Nigeria or Ghana, 65/78 (83.3%), their country or origin. Over half the patients, 47/78 (60.3%) had a previous history of malaria. Few had taken prophylaxis, 11/78 (14.1%), and only three had taken appropriate prophylaxis. Most patients were treated with atovoquoneeproguanil, 53/78 (68.0%), and the others quinine/doxycycline, 10/78 (12.8%), quinine/atovoquonee proguanil, 8/78 (10.3%) and quinine alone, 7/78 (9.0%). At presentation, median haemoglobin was 12.7 g/dl (IQR: 11.7e14.0), white cell count 5.2 109/l (IQR: 4.3e6.6) and platelet count 106 109/l (IQR: 79e134). Fifty-two (66.7%) out of 78 patients were treated out of hospital. More than three-quarters of the patients, 41/52 (78.8%) were diagnosed in A&E, commenced on treatment and sent home. The remaining were treated by their GP’s, following advice from the microbiologists, 11/52 (21.2%). In those treated as outpatients, 37 out of 52 (71.2%, 95% CI 58.8e83.5%) were contactable at least 7 days posttreatment and all had successfully completed treatment. The remaining 15 patients were not contactable. Twentyeight days post-treatment, no patients were readmitted to the Trust.
0
0
25 (43.9%)
2 (2.2%)
Discussion
Two patients had drug intolerance, one developed ARDS. Two further patients were assessed as outpatients before scheduled follow up. a
56 (62.2%) 90 Children Ref7
Australia
52 (91.2%) 57 Adults Ref6
Australia
82 (72.6%) 214 (55.3%) 113 387 Adults Adults Ref3 Ref5
Switzerland Belgium
One third of patients, 26/78 (33.3%) eligible for outpatient treatment, were admitted to hospital and treated as inpatients. Five (6.4%) were intolerant of oral treatment and 21 (26.9%) were admitted for reasons not stated. Their median length of stay was 3-days (IQR: 2e4). There was no significant difference in age, gender, country of birth, parasitaemia, haemoglobulin content and platelet count between those treated as inpatients and outpatients.
28 days
28 days 28 days
28 days
3a 10
0 15 (10.6%) 7 days
Atovoquoneeproguanil Quinine/atovoquoneeproguanil Quinine/doxycycline Quinine Mefloquine/fansidar Atovoquoneeproguanil Halofantrine Quinine Mefloquine Atovoquoneeproguanil Quinine/doxycycline Atovoquoneeproguanil Mefloquine 52 (36.6%) 142 Adults Present study
UK
Drug treatment No. treated as outpatients No. of patients with falciparum malaria Age group
Country
261
Study
Table 1
Treatment of falciparum malaria in patients eligible for outpatient treatment in the developed world.
End point
Loss to follow up
Hospital readmissions
Outpatient treatment of P. falciparum
Within the UK, there remains opposition to outpatient treatment of falciparum malaria due to a perceived risk of complications occurring despite country of origin, ethnicity and parasitaemia <2%. In a recent prospective study from London,19 25 (25.2%) out of 99 consecutive patients with falciparum malaria were classified as having severe disease, in accordance with WHO criteria.18 When compared to the other 74 patients with mild disease, there were no significant differences in ethnicity, residential history and previous malaria, factors associated with immunity to disease. Admission to ITU was high, 6%, and mortality 1%, probably a consequence of selection bias due to referrals to this tertiary centre. If our selection criteria were applied to these 25 severe cases, only three (two Africans and one Southern Asian) had parasitaemia counts of 2% or less and, of these, two had elevated creatinine levels. In accordance with our criteria, one patient, potentially suitable for outpatient treatment, may have developed out of hospital malaria-associated complications and required readmission. If, as the authors conclude, it is unsafe to assume that patients from a malaria endemic area have clinical immunity, one might infer from this paper that all patients with falciparum malaria should be admitted to hospital. In contrast, Phillips et al.,20 recently demonstrated in a West London cohort that patients of ‘black ethnicity’, presenting with a parasitaemia of <2%, are significantly less likely to develop ‘severe malaria’ compared to ‘non-blacks’. Unlike Jennings et al., where ethnicity was not considered to protect against severe disease, Phillip et al.’s paper adds weight to the argument that, in a selected immigrant population, patients with uncomplicated falciparum malaria might be safely treated out of hospital. There were limitations to our study. The numbers treated as outpatients were small but comparable to other published work (Table 1). Approximately a quarter were lost to follow up seven days after starting treatment. Patients, however, had been advised to return to A&E or their GP’s if symptoms persisted and cross-referencing of trust patient administration system at 28 days failed to demonstrate any hospital readmissions. We did not perform end of treatment blood films at 28 days, which would have provided laboratory evidence of cure. Despite the fore-mentioned studies and our own clinical observations, we do not claim that the case for outpatient treatment of falciparum malaria in selected patients has been proven beyond doubt. Measures to further reduce risk might include a safety leaflet outlining the necessity to return if symptoms worsened or vomiting occurred, emergency hotlines and the necessity of being accompanied
262
M. Melzer et al.
172 cases of malaria
142 patients with falciparum malaria
36 patients with a parasitaemia count >2%
30 patients with non-falciparum malaria
106 patients with a parasitaemia count <2%
28 patients failed to fulfil criteria for outpatient treatment
78 patients fulfilled criteria for outpatient treatment
52 patients treated out of hospital
39 patients treated in A&E and discharged same day
Figure 1
26 patients treated as in hospital
13 patients treated by GP’s
In or out of hospital environment where patients with falciparum malaria were treated.
home by a friend or family member. Other laboratory criteria, used as markers of severity, included anaemia, (Hb < 8 g/dl) and hyperbilirubinaemia, as outlined by WHO.18 Consideration of the likelihood of ‘malarial immunity’ might also reduce risk. For this reason we excluded all UK born patients but additional inclusion criteria such as residence in a malaria endemic area or a past history of malaria may improve safety. The majority of our patients, although resident in the UK, frequently returned to their country of origin and re-exposure to malaria may have boosted their pre-existing immunity. Another concern is a rapidly rising parasitaemia. This was observed in one of our inpatients, eligible for outpatient treatment, but no complications occurred and a 3-day course of oral atovoquoneeproguanil was completed without changing treatment. The successful treatment of our cohort, in and around East London, may have been due to patients born in Ghana and Nigeria, returning to their country of origin, 60% of whom had a past history of malaria. This contrasts with 42% of patients with falciparum malaria, seen in travel clinics throughout Europe, who are either European born travellers or Western expatriates.21 We, therefore, cannot say that our findings are applicable to all ethnic groups or populations, living in other countries.
Conclusion Our findings and results from other cohort studies in developed countries challenge UK national guidance and add weight to those advocating a review of national policy. We do not claim to have proven that outpatient treatment of selected patients is safe in every circumstance. It is, however, time for an appropriately powered UK-based safety study or a randomised trial to dispel the belief that all patients with P. falciparum malaria must be admitted to hospital.
Conflicts of interest The authors declare there were no conflicts of interest.
References 1. Smith AD, Bradley DJ, Smith V, Blaze M, Behrens RH, Chiodini PL, et al. Imported malaria and high risk groups: observational study using UK surveillance data 1987e2006. BMJ 2008;337:103e6. 2. Lalloo DG, Shingadia, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, et al. UK malaria treatment guidelines. J Infect 2007;54:111e21.
Outpatient treatment of P. falciparum 3. D’Acremont V, Landry P, Darioli R, Stuerchler D, Pecoud A, Genton B, et al. Treatment of imported malaria in an ambulatory setting: prospective study. BMJ 2002;324:875e7. 4. Toovey S. Effectiveness of co-artemether in an unsupervised outpatient setting for the treatment of falciparum malaria. Travel Med Infect Dis 2008;6:29e31. 5. Bottieau E, Clerinx J, Colebunders R, Van den Enden E, Wouter R, Demey H, et al. Selective ambulatory management of imported falciparum malaria: a 5-year prospective study. Eur J Clin Microbiol Dis 2006;26:181e8. 6. Chih DT, Heath CH, Murray RJ. Outpatient treatment of malaria in recently arrived African migrants. Med J Aust 2006;185: 598e601. 7. Cherian S, Burgner D. Selective ambulatory management of Plasmodium falciparum malaria in paediatric refugees. Arch Dis Child 2007;92:983e6. 8. Piola P, Fogg C, Bajunirwe F, Biraro S, Grandesso F, Ruzagira E, et al. Supervised versus unsupervised intake of six-dose artemetherelumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial. Lancet 2005;365(9469):1467e73. 9. Achan J, Tibenderana JK, Kyabayinze D, Wabwire Mangen F, Kamya MR, Dorsey G, et al. Effectiveness of quinine versus artemetherelumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. BMJ 2009;339:283. 10. Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, et al. Amodiaquine alone, amodiaquine and sulfadoxineepyrimethamine, amodiaquine and artesunate, and artermetherelumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 2005;365(9469):1474e80. 11. Zurovac D, Tibenderana JK, Nankabirwa J, Ssekitooleko J, Njogu JN, Rwakimari JB, et al. Malaria case management under
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17. 18. 19.
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artemetherelumefantrine treatment policy in Uganda. Malar J 2008;7:181. Zurovac D, Njogu J, Akhwale W, Hemer DH, Snow RW. Translation of artemetherelumefantrine treatment policy into paediatric practice: an early experience from Kenya. Trop Med Int Health 2008;13(1):99e107. Abuya TO, Mutemi W, Karisa B, Ochola SA, Fegan G, Marsh V. Use of over the counter malarial medicines in children and adults in three districts of Kenya: implication for private medicine retailer interventions. Malar J 2007;6:57. Goodman C, Kachur SP, Abdulla S, Bloland P, Mills A. Concentration and drug prices in the retail market for malaria treatment in rural Tanzania. Health Econ 2009;18(6): 727e42. Reyburn H, Mbakilwa H, Mwangi R, Mwerinde O, Olomi R, Drakeley C, et al. Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ 2007;334:403. Mwanziva C, Shekalaghe S, Ndaro A, Mengerink B, Megiroo S, Mosha F, et al. Overuse of artemisinin-combination therapy in Mto wa Mbu (river of mosquitoes), an area misinterpreted as high endemic for malaria. Malar J 2008;7:232. StataCorp. Release 10. Statistical software: release 7.0. College Station, TX: Stata Corporation. World Health Organisation, www.who.int/malaria/docs/ TreatmentGuidelines2006.pdf; 2006. Jennings RM, de Souza JB, Todd JE, Armstrong M, Flanagan KL, Riley EM, et al. Imported Plasmodium falciparum. Am J Trop Med Hyg 2006;75:1195e9. Phillips A, Bassett P, Zeki S, Newman S, Pasvol G. Risk factors for severe disease in adults with falciparum malaria. Clin Infect Dis 2009;48:871e8. TropNetEurop. www.tropnet.net/index_2.html.
www.elsevierhealth.com/journals/jinf
The case for outpatient treatment of Plasmodium falciparum malaria in a selected UK immigrant population Mark Melzer a,*, Sandra Lacey a, Greta Rait b a
King George and Queen’s Hospitals, Barking, Havering and Redbridge Trust, Barley Lane, Goodmayes, Essex IG3 8YB, UK Medical Research Council General Practice Research Framework, Stephenson House, 158-160 North Gower St., London NW1 2ND, UK b
Accepted 19 August 2009 Available online 23 August 2009
KEYWORDS Outpatient; Out of hospital; Plasmodium falciparum; Treatment
Summary UK guidance recommends that all patients with falciparum malaria be admitted to hospital, although a number of cohort studies in the developed world demonstrate that outpatient treatment of falciparum malaria is feasible and safe in selected patients. We review the literature on outpatient treatment in developed countries and present local data from East London where a selected immigrant population were successfully treated as outpatients. Although it is premature to claim that outpatient treatment of falciparum malaria is safe in all selected patients, we conclude it is time for a large UK-based safety study or randomised trial to dispel the belief that all patients with uncomplicated Plasmodium falciparum must be admitted to hospital. ª 2009 Published by Elsevier Ltd on behalf of The British Infection Society.
Introduction Plasmodium falciparum malaria, in its severest form, is a lifethreatening illness. Within the UK, approximately 2000 cases of malaria are notified per annum and 15 deaths reported annually.1 Selecting patients with potentially life-threatening infections for outpatient treatment is accepted practice for diseases such as community-acquired pneumonia and neutropenic sepsis but remains controversial for falciparum malaria. Despite recent UK guidance2 that recommends all * Corresponding author. Tel.: þ44 20 8970 4032; fax: þ44 20 8970 5784. E-mail address: [email protected] (M. Melzer).
patients be admitted to hospital, outpatient treatment of selected patients with falciparum malaria is practiced in most developing countries and some parts of the developed world.3e7 We review the literature of outpatient treatment of uncomplicated falciparum malaria in the developed world and then describe our experience of treating a selected immigrant population in an area bordering East London.
Studies outside the UK In developing countries, adults and children with uncomplicated falciparum malaria are routinely managed as outpatients. In Africa, there is one published trial of inpatient versus outpatient treatment.8 Patients, including children,
0163-4453/$36 ª 2009 Published by Elsevier Ltd on behalf of The British Infection Society. doi:10.1016/j.jinf.2009.08.010
260 were randomised to supervised (inpatient) versus outpatient treatment with artemetherelumefantrine and, at 28 days, cure rates were 296/303 (97.7%) and 603/615 (98.0%) respectively. In general, in developing countries, inpatient treatment does not occur due to lack of resources and clinical trials have generally focused on the effectiveness of different anti-malarial regimes.9,10 Where treatment with artemisinin combination therapy has been adopted as national policy, audits of prescribing practice have been published.11,12 Other researchers have described where antimalarials are accessed,13,14 point of care diagnostics in the outpatient setting15 and the consequences of over diagnosis and over prescribing anti-malarials.16 In developing countries, further clinical trials of inpatient versus outpatient treatment are unlikely to occur in the future. In developed countries, inpatient admission and observation of patients with uncomplicated falciparum malaria is the preferred option. Outpatient treatment remains controversial despite clinical trials that suggest it can be performed safely in selected patients. In the largest European cohort study published to date, 214 patients in Belgium with parasitaemia counts <1% were treated predominantly with atovoquoneeproguanil (malarone) as outpatients.5 Ten patients were readmitted, five within three days because of vomiting, four after three days because of persistent fever and parasitaemia and one after 14 days because of recrudescence. No fatalities occurred. In an earlier European study, the Swiss cohort study,3 82/113 (73%) were treated with mefloquine and sulfadoxine/pyrimethamine. Three patients were readmitted to hospital, two with drug intolerance and one with adult respiratory distress syndrome. Two further patients were reviewed with dizziness before their scheduled follow up, probably due to an adverse drug event. Again, no fatalities occurred. Two Australian cohort studies have also recorded successful outcomes. In a 30-month retrospective analysis of West African adult migrants, 52/57 (91.2%) were treated out of hospital, most commonly with atovoquoneeproguanil. Of the 27 (51.9%) patients seen at four weeks all had negative blood films.6 In a paediatric study, 56/90 (62.2%) African refugee children, fulfilling criteria including previous malaria, were treated out of hospital with atovoquoneeproguanil or mefloquine. Of the 88 patients attending for follow up at 28 days, 85 had blood films and one, previously an inpatient, had a positive blood film.7 Despite rare cases of drug intolerance, treatment failure and malaria related complications, the authors conclude that selected outpatient treatment of falciparum malaria is practicable and safe (Table 1).
Local UK experience From June 2003 to December 2006, at King George Hospital, part of Barking, Havering and Redbridge University (BHRU) Hospitals, we encouraged physicians to treat selected patients with P. falciparum as outpatients. Patients were eligible for outpatient treatment if they were aged 16 years and over, non-pregnant, non-UK born, alert and orientated, able to tolerate their first dose of oral treatment, normotensive, had normal renal function and a parasitaemia
M. Melzer et al. count of 2% or less. Patients were advised to return to A&E or their GP if vomiting occurred or their symptoms worsened within 48 h. All cases were laboratory confirmed. An antigen detection assay, Malaria-ICT-now, Binax (Portland, USA) was used as a screening assay and thin blood films used for speciation and parasitaemia counts. Two clinical microbiologists collected demographic, clinical and laboratory data on all patients within 72 h of admission. Attending physicians were advised to treat patients with atovoquoneeproguanil, four tablets once daily for three days or quinine 600 mg every 8 h for five to seven days followed by doxycycline (200 mg once daily for seven days), in accordance with UK guidance.2 Some outpatients were switched from oral quinine to atovoquoneeproguanil to aid compliance. At least seven days after treatment, patients were reviewed in an outpatient setting or contacted by telephone to ensure successful completion of treatment. Blood films were repeated if patients were symptomatic. Twentyeight days post-treatment, the hospital’s patient administration computer system was checked to ensure there were no hospital readmissions. Data was analysed using Stata 10.17 Univariate associations were tested using two-tailed Chisquare tests. Where the smallest expected value was less than five, Fisher’s exact test was used. The study was registered as a clinical audit at Barking, Havering and Redbridge Trust and the standards used were a modified version of a Swiss cohort study (2002)3 and the World Health Organisation’s severity criteria for P. falciparum.18 Advice was taken from the NE London ethics committee. It was noted that as this study was registered as an audit, ethical approval was not required. 142 cases of falciparum malaria were diagnosed between June 2003 and December 2006. Parasitaemia counts ranged from <0.1 to 26% (median value 1%; IQR: <0.1e2.0%). Threequarters of cases had a parasitaemia of 2% or less, 106/142 (74.6%). Among these patients, 28/142 (19.7%) patients were not eligible for outpatient treatment as 24 were aged <16 years, two were pregnant and two UK born (Fig. 1). Seventy-eight (54.9%) patients were eligible for out of hospital treatment. Almost two-thirds, 47/78 (60.3%), were male and most had travelled to Nigeria or Ghana, 65/78 (83.3%), their country or origin. Over half the patients, 47/78 (60.3%) had a previous history of malaria. Few had taken prophylaxis, 11/78 (14.1%), and only three had taken appropriate prophylaxis. Most patients were treated with atovoquoneeproguanil, 53/78 (68.0%), and the others quinine/doxycycline, 10/78 (12.8%), quinine/atovoquonee proguanil, 8/78 (10.3%) and quinine alone, 7/78 (9.0%). At presentation, median haemoglobin was 12.7 g/dl (IQR: 11.7e14.0), white cell count 5.2 109/l (IQR: 4.3e6.6) and platelet count 106 109/l (IQR: 79e134). Fifty-two (66.7%) out of 78 patients were treated out of hospital. More than three-quarters of the patients, 41/52 (78.8%) were diagnosed in A&E, commenced on treatment and sent home. The remaining were treated by their GP’s, following advice from the microbiologists, 11/52 (21.2%). In those treated as outpatients, 37 out of 52 (71.2%, 95% CI 58.8e83.5%) were contactable at least 7 days posttreatment and all had successfully completed treatment. The remaining 15 patients were not contactable. Twentyeight days post-treatment, no patients were readmitted to the Trust.
0
0
25 (43.9%)
2 (2.2%)
Discussion
Two patients had drug intolerance, one developed ARDS. Two further patients were assessed as outpatients before scheduled follow up. a
56 (62.2%) 90 Children Ref7
Australia
52 (91.2%) 57 Adults Ref6
Australia
82 (72.6%) 214 (55.3%) 113 387 Adults Adults Ref3 Ref5
Switzerland Belgium
One third of patients, 26/78 (33.3%) eligible for outpatient treatment, were admitted to hospital and treated as inpatients. Five (6.4%) were intolerant of oral treatment and 21 (26.9%) were admitted for reasons not stated. Their median length of stay was 3-days (IQR: 2e4). There was no significant difference in age, gender, country of birth, parasitaemia, haemoglobulin content and platelet count between those treated as inpatients and outpatients.
28 days
28 days 28 days
28 days
3a 10
0 15 (10.6%) 7 days
Atovoquoneeproguanil Quinine/atovoquoneeproguanil Quinine/doxycycline Quinine Mefloquine/fansidar Atovoquoneeproguanil Halofantrine Quinine Mefloquine Atovoquoneeproguanil Quinine/doxycycline Atovoquoneeproguanil Mefloquine 52 (36.6%) 142 Adults Present study
UK
Drug treatment No. treated as outpatients No. of patients with falciparum malaria Age group
Country
261
Study
Table 1
Treatment of falciparum malaria in patients eligible for outpatient treatment in the developed world.
End point
Loss to follow up
Hospital readmissions
Outpatient treatment of P. falciparum
Within the UK, there remains opposition to outpatient treatment of falciparum malaria due to a perceived risk of complications occurring despite country of origin, ethnicity and parasitaemia <2%. In a recent prospective study from London,19 25 (25.2%) out of 99 consecutive patients with falciparum malaria were classified as having severe disease, in accordance with WHO criteria.18 When compared to the other 74 patients with mild disease, there were no significant differences in ethnicity, residential history and previous malaria, factors associated with immunity to disease. Admission to ITU was high, 6%, and mortality 1%, probably a consequence of selection bias due to referrals to this tertiary centre. If our selection criteria were applied to these 25 severe cases, only three (two Africans and one Southern Asian) had parasitaemia counts of 2% or less and, of these, two had elevated creatinine levels. In accordance with our criteria, one patient, potentially suitable for outpatient treatment, may have developed out of hospital malaria-associated complications and required readmission. If, as the authors conclude, it is unsafe to assume that patients from a malaria endemic area have clinical immunity, one might infer from this paper that all patients with falciparum malaria should be admitted to hospital. In contrast, Phillips et al.,20 recently demonstrated in a West London cohort that patients of ‘black ethnicity’, presenting with a parasitaemia of <2%, are significantly less likely to develop ‘severe malaria’ compared to ‘non-blacks’. Unlike Jennings et al., where ethnicity was not considered to protect against severe disease, Phillip et al.’s paper adds weight to the argument that, in a selected immigrant population, patients with uncomplicated falciparum malaria might be safely treated out of hospital. There were limitations to our study. The numbers treated as outpatients were small but comparable to other published work (Table 1). Approximately a quarter were lost to follow up seven days after starting treatment. Patients, however, had been advised to return to A&E or their GP’s if symptoms persisted and cross-referencing of trust patient administration system at 28 days failed to demonstrate any hospital readmissions. We did not perform end of treatment blood films at 28 days, which would have provided laboratory evidence of cure. Despite the fore-mentioned studies and our own clinical observations, we do not claim that the case for outpatient treatment of falciparum malaria in selected patients has been proven beyond doubt. Measures to further reduce risk might include a safety leaflet outlining the necessity to return if symptoms worsened or vomiting occurred, emergency hotlines and the necessity of being accompanied
262
M. Melzer et al.
172 cases of malaria
142 patients with falciparum malaria
36 patients with a parasitaemia count >2%
30 patients with non-falciparum malaria
106 patients with a parasitaemia count <2%
28 patients failed to fulfil criteria for outpatient treatment
78 patients fulfilled criteria for outpatient treatment
52 patients treated out of hospital
39 patients treated in A&E and discharged same day
Figure 1
26 patients treated as in hospital
13 patients treated by GP’s
In or out of hospital environment where patients with falciparum malaria were treated.
home by a friend or family member. Other laboratory criteria, used as markers of severity, included anaemia, (Hb < 8 g/dl) and hyperbilirubinaemia, as outlined by WHO.18 Consideration of the likelihood of ‘malarial immunity’ might also reduce risk. For this reason we excluded all UK born patients but additional inclusion criteria such as residence in a malaria endemic area or a past history of malaria may improve safety. The majority of our patients, although resident in the UK, frequently returned to their country of origin and re-exposure to malaria may have boosted their pre-existing immunity. Another concern is a rapidly rising parasitaemia. This was observed in one of our inpatients, eligible for outpatient treatment, but no complications occurred and a 3-day course of oral atovoquoneeproguanil was completed without changing treatment. The successful treatment of our cohort, in and around East London, may have been due to patients born in Ghana and Nigeria, returning to their country of origin, 60% of whom had a past history of malaria. This contrasts with 42% of patients with falciparum malaria, seen in travel clinics throughout Europe, who are either European born travellers or Western expatriates.21 We, therefore, cannot say that our findings are applicable to all ethnic groups or populations, living in other countries.
Conclusion Our findings and results from other cohort studies in developed countries challenge UK national guidance and add weight to those advocating a review of national policy. We do not claim to have proven that outpatient treatment of selected patients is safe in every circumstance. It is, however, time for an appropriately powered UK-based safety study or a randomised trial to dispel the belief that all patients with P. falciparum malaria must be admitted to hospital.
Conflicts of interest The authors declare there were no conflicts of interest.
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