Acute malaria has been associated with a decreased antibody response to tetanus and diphtheria toxoids, meningococcal, salmonella, and Hib vaccines. Interest in giving malaria drug therapy and prevention at the time of childhood immunizations has increased greatly following recent trials of intermittent preventive therapy during infancy (IPTi), stimulating this re-analysis of unpublished data. The effect of malaria chemoprophylaxis on vaccine response was studied following administration of measles vaccines and diphtheria-tetanus-whole cell pertussis (DTP) vaccines.In 1975, six villages divided into two groups of children ≤74 months of age from Burkina Faso, were assigned to receive amodiaquine hydrochloride chemoprophylaxis (CH+) every two weeks for seven months or no chemoprophylaxis (CH-). After five months, children in each group received either one dose of measles or two doses of DTP vaccines.For recipients of the measles vaccine, the seroconversion rates in CH+ and CH- children, respectively, were 93% and 96% (P > 0.05). The seroresponse rates in CH+ and CH- children respectively, were 73% and 86% for diphtheria (P > 0.05) and 77% and 91% for tetanus toxoid (P > 0.05). In a subset analysis, in which only children who strictly adhered to chemoprophylaxis criteria were included, there were, likewise, no significant differences in seroconversion or seroresponse for measles, diphtheria, or tetanus vaccines (P > 0.05). While analysis for pertussis showed a 43% (CH+) and 67% (CH-) response (P < 0.05), analyses using logistic regression to control for sex, age, chemoprophylaxis, weight-for-height Z-score, and pre-vaccination geometric mean titer (GMT), demonstrated that chemoprophylaxis was not associated with a significantly different conversion rate following DTP and measles vaccines. Seven months of chemoprophylaxis decreased significantly the malaria IFA and ELISA GMTs in the CH+ group.Malaria chemoprophylaxis prior to vaccination in malaria endemic settings did not improve or impair immunogenicity of DTP and measles vaccines. This is the first human study to look at the association between malaria chemoprophylaxis and the serologic response to whole-cell pertussis vaccine. Malaria accounts for an estimated 1 to 3 million deaths each year, with the majority occurring in children under five years of age in sub-Saharan Africa . The WHOAcute malaria has been associated with a decreased response to tetanus toxoids, and meningococcal polysaccharide, Hib conjugate, and whole cell vaccines for typhoid fever -10. AsymThe study aimed to determine the effect of malaria chemoprophylaxis on vaccine seroconversion or seroresponse to live, attenuated measles vaccine, diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccines.Plasmodium falciparum parasitaemia prevalence was found in 150 children (25 per site) <6 years of age, with no major differences between the sites; during this pre-study investigation, antibodies to P. falciparum were detected by indirect haemagglutination (IHA) in 100 percent of children tested from five of the six villages (25 children per village). Burkinabe clinicians in the nearest dispensaries and hospitals stated that the study area was endemic for measles (cases and deaths occurred during the study), diphtheria, tetanus, and pertussis, but the incidence was unknown; routine data had not been collected from the study villages because the EPI had not yet begun , and the other received no prophylaxis, CH- [N = 508]. Virtually all children within the same village received either measles [N = 482], or DTP vaccine N = 514]  for travel convenience and management by the research team.The populations were of a related Mandinke ethnic group (Bobo in the eastern and Senufo in the western villages) and the communities had similar P. falciparum resistant to chloroquine [CH+ children received a single prophylactic dose of amodiaquine hydrochloride suspension or tablets every 2 weeks for 7 months beginning in May and June, the start of the transmission season; those <12 months of age received 100 mg, those 12 to 47 months received 200 mg, and those 48 to 73 months old received 300 mg. Both amodiaquine and chloroquine are 4-aminoquinolines. Amodiaquine is the prodrug for the active ingredient desethylamodiaquine (DAQ). DAQ has a terminal half life of one to three weeks and is schizonticidal in very low concentrations ,28. Whiloroquine ,30.Seroconversion rates were measured in all CH+ and CH- children for whom paired sera were available. In addition, a CH+ group having strict compliance to drug ingestion was analyzed to examine more carefully the effect of malaria or drug use on serconversion and seroresponse. For this study, criteria for strict compliance included: receipt of ≥75% of the doses, no two consecutive doses missing, no doses missed in the month prior to vaccination(s), and no doses missed between the second vaccination and the last blood draw. At study completion, during the beginning of the low transmission season, families of children in the CH+ group were given a short-term supply of amodiaquine prophylaxis and instructions for home treatment in case of a rebound malaria attack. Follow-up visits occurred every one to two months in all villages for six months after the study.® injector. Following study completion, all children in participating villages received the vaccine that they did not receive during the study. Prior to use, the measles and DTP vaccines were tested for potency and met standard requirements.All children were vaccinated with either measles vaccine or the first dose of DTP at month 5  and the second DTP dose one month later. Two doses of DTP were given during the study  to increase the likelihood that any effect from chemoprophylaxis would be discerned; a third dose was given at the end of the study but bloods were not drawn after this third vaccination. Vaccinations and amodiaquine were administered on the same day. The manufacturer and source of the licensed vaccines used were the Dow, Lirugen (Schwarz strain) measles vaccine, Lot No. 185806 AA and Merrill-National DTP, adsorbed, USP, vaccine, filling number 1036 DM, bulk Lot No. 1832. Measles and DTP vaccines were injected intramuscularly (0.5 ml) via a hydraulic (pressurized), injection device, the Ped-O-JetVenous blood samples were kept refrigerated and within 1 to 3 days serum was separated and kept at -20°C prior to shipment to the CDC, Atlanta, Georgia, USA, in dry ice. Serologic testing for the measles vaccine was performed in 1977 at the then Virology Division, Bureau of Laboratories, CDC. Antibody response to the DTP vaccine was performed in 1977 at the then Division of Bacterial Products, Bureau of Biologics, Food and Drug Administration, in Bethesda, MD.Bordetella pertussis strains 134 and 165 [2 of the reciprocal of the highest final serum dilution resulting in detectable agglutination. When sufficient serum was available, the lowest final serum dilution tested was 1:8; by convention, samples negative at a 1:8 dilution were assigned the titer log2 = 2. If the serum sample volume was low, higher initial dilutions were used. When such sera were negative at the lowest dilution tested, the titer was reported as <lowest dilution tested. Because the actual end-point was not known, titers for these sera were not included in the calculation of geometric mean titer (GMT) or geometric mean fold rise in titer (GMR). For some individuals, it was possible to verify a ≥4-fold rise even if the actual endpoint was not known for both sera. A ≥4-fold rise for DTP antigens was considered positive. For DTP, in cases where the titer decreased from pre- to post-vaccination, a ΔGMT = 0 was used in the calculation of GMR.Measles antibody was assessed by haemagglutination inhibition -33. Sero and 165 . The titP. falciparum IgG antibodies were measured by the Immunofluorescence Assay (IFA) [ay (IFA)  and by tay (IFA)  followinSample size was determined initially by a method comparing two proportions. For measles, 215 subjects were required for each group in order to have 90% assurance of significant results to detect this 10% difference in response rates. Similarly, for DTP vaccines, assuming 70% seroconversion for the test group and 60% for the control group, 387 subjects were needed for each group. SAS software, version 9.00 , was used. Weight-for-height Z-score was calculated using an anthro-system .The primary outcome was rate of seroconversion or seroresponse in CH+ and CH- individuals. As secondary outcomes, geometric mean titers (GMT) and mean fold rise in titer (GMR) were measured for measles, DTP, and malaria antibodies for CH+ and CH- individuals for the strict compliance group.t-test. The Chi-squared test was used for comparison of seroconversion to measles vaccine and seroresponse to DTP vaccinations; the Student's pooled t-test was used for pre- and post-vaccination GMT and GMR. A univariate logistic analysis was performed to assess effects of sex, age (> or < 24 months), prophylaxis, weight-for-height Z-score (> or < median Z-score), and pre-vaccination GMT (> or < median GMT) on seroconversion or seroresponse. Multivariate logistic regression was performed on those factors found to be independently associated with seroresponse. Analyses for seroconversion, GMTs, GMRs, and logistic regression were adjusted for village effect.Study population characteristics at vaccination were compared for the CH+ and CH- children using the Chi-squared test and Student's pooled The study protocol was approved by the Burkina Faso (Upper Volta) Ministry of Health and the Institutional Review Board at the CDC. Verbal permission for the study was obtained from the village chiefs, their "council of elders," and each participating family, as was the custom for working in Burkinabe villages.The groups were similar at baseline with regard to age, sex, and nutritional status, except for a slight excess of males in the CH- group for DTP Table . Twenty Table For measles, pre-vaccination measles titers for all children were <1:10 (lowest detectable titer) Figure ; GMR was2 of GMT = 6.19, N = 37) compared to non-compliant CH+ children , this difference was not significantly different (P = 0.80). Chemoprophylaxis was not associated with seroresponse for any of the vaccines. Thus, especially for pertussis, the lower vaccine response rate observed in the CH+ group appears to be due, in part, to the greater proportion of subjects with high pre-immunization titers.Multivariate logistic regression analysis indicated that for tetanus, a lower pre-vaccination GMT was positively associated with seroresponse (P = 0.02); for pertussis, a lower pre-vaccination GMT (P < 0.01) and younger age (P = 0.04) were positively associated with seroresponse. There was no significant difference in pre-vaccination pertussis titres between the CH+ and CH- group (P 0.22) when looking at all children regardless of compliance; however, when excluding non-compliant children, pre-vaccination pertussis titres were higher in CH+ children (P <0.01). While pre-vaccination pertussis titres were higher in compliant CH+ children  vs. CH-, 1089 (N = 219) (P < 0.01) using IFA and CH+, 285 (N = 60) vs CH-, 1990 (N = 64) using ELISA (P < 0.01) and for children receiving DTP vaccine: CH+, 109 (N = 132) vs CH-, 178 (N = 178) (P < 0.01) using IFA and CH+, 86 (N = 63) vs CH-,153 (N = 30) (P = 0.01) using ELISA. Only 13 percent of all CH+ children with detectable malaria titers prior to chemoprophylaxis had undetectable titers post-chemoprophylaxis (N = 159). This indicates that chemoprophylaxis given to young children for five to seven months after previous exposure to malaria was not adequate to eliminate malaria antibodies.No adverse events were recorded after chemoprophylaxis, blood sample collection, or vaccination other than a few children with 1–3 mm nodules on their arms after receiving the vaccine by injector and one child who developed a cellulitis where the venopuncture occurred: this child recovered with systemic antibiotic treatment.Proposed mechanisms for malaria-associated immunodepression include impaired macrophage function -41, alteIn contrast to asymptomatic parasitaemia, acute malaria impairs vaccine response,17,18,20The absence of association between malaria chemoprophylaxis and vaccine response in this study is consistent with findings from other chemoprophylaxis studies in malarious areas involving children with asymptomatic parasitaemia ,16-18,58The agglutination test remains the test of choice for whole-cell pertussis vaccines. Although the antigen-specific ELISA tests can amplify the information provided by the agglutination test, the agglutination test is the only one that has been shown clinically to correlate with vaccine efficacy of whole-cell pertussis vaccines and has been used in relatively recent trials ,60. AlthResults of this study indicated that for the pertussis component, children <24 months of age had a better seroresponse. Vaccinating children <24 months of age will more effectively target the population in greatest need. Pertussis is most serious for very young infants and because complications leading to hospitalization, pneumonias, and death occur most often in those <24 months of age, the recommended age for initiation of pertussis immunization is generally two to three months.Three doses of DTP vaccine comprise the usual primary series;thus, it would have been useful to assess seroconversion after a third DTP dose in addition to the response following the second dose. Technical and logistical considerations precluded this; additionally, there was concern regarding the possibility of decreased compliance with a longer study, as well as the potential to minimize any differences in the effect of chemoprophylaxis on seroconversion.Malaria serologies demonstrated a significant difference in GMTs between the two treatment groups at the time of vaccination, adding some assurance that chemoprophylaxis decreased asymptomatic parasitaemia. Despite assumed effective chemoprophylaxis for five to seven months, virtually all compliant children had malaria antibodies; this probably reflected a durable antibody response to infections acquired before the study began. While not the primary study objective, fever prevalence data and blood smear records would have provided valuable insight on malaria prevention in the chemoprophylaxis group. Given efforts to administer intermittent preventive therapy of infants (IPTi) in conjunction with the vaccines included in the EPI, additional prospective studies are needed to establish more firmly the effect of antimalarials on response to childhood vaccinations . [Malaria chemoprophylaxis does not appear to enhance nor impair the antibody response to DTP and measles vaccines. There have been several changes over the 30 years since the study completion, including development of falciparum malaria resistance to 4-aminoquinolones throughout Africa, and establishment of the EPI 1977) and the Roll Back Malaria Partnership (1998). The continuing development and deployment of new antimalarial drugs and childhood vaccines mandates that the possible immunologic and protective interrelationships of these new products be investigated. Studies are in progress by the IPTi Consortium to address these issues 7 and theDr. Breman was responsible for writing the protocol, carrying out the study in the field, data analysis and writing; Dr. Rosen for synthesis, data analysis and writing; Dr. Manclark for coordinating DTP serologies and doing the pertussis antibody tests; Dr. Meade for editing, assisting with analysis and interpretation of serologic data; Dr. Collins for supervising the malaria antibody testing; Dr. Lobel for assisting with the protocol, field work and expedition of the serologic analyses; Dr. Saliou for participating in field work and manuscript analysis; Ms. Roberts for data registration and preliminary analysis; Dr. Campaoré for serving as the responsible health officer in Burkina Faso; and Dr. Miller for analysis and interpretation of results.The study was supported partly by a grant from the Malaria Unit at the World Health Organization. Amodiaquine was contributed by Warner Lambert Pharmaceuticals.


Early recognition of symptoms and signs perceived as malaria are important for effective case management, as few laboratories are available at peripheral health facilities. The validity and reliability of clinical signs and symptoms used by health workers to diagnose malaria were assessed in an area of low transmission in south-western Uganda.The study had two components: 1) passive case detection where all patients attending the out patient clininc with a febrile illness were included and 2) a longitudinal active malaria case detection survey was conducted in selected villages. A malaria case was defined as any slide-confirmed parasitaemia in a person with an axillary temperature ≥ 37.5°C or a history of fever within the last 24 hrs and no signs suggestive of other diseases.Cases of malaria were significantly more likely to report joint pains, headache, vomiting and abdominal pains. However, due to the low prevalence of malaria, the predictive values of these individual signs alone, or in combination, were poor. Only 24.8% of 1627 patients had malaria according to case definition and > 75% of patients were unnecessarily treated for malaria and few slide negative cases received alternative treatment.In low-transmission areas, more attention needs to be paid to differential diagnosis of febrile illnesses In view of suggested changes in anti-malarial drug policy, introducing costly artemisinin combination therapy accurate, rapid diagnostic tools are necessary to target treatment to people in need. Effective case management (ECM) remains a cornerstone for reduction of malaria morbidity and mortality in sub-Saharan Africa . HoweverReliance on presumptive clinical diagnosis, in the absence of laboratory diagnosis, results in diagnostic inaccuracy, and over-diagnosis of malaria is common ,7. Highe2. According to the 2002 census, the population of Kabale was 461,785 people with a population density of 290 persons per Km2. The average air temperature is 17.5°C, and occasionally drops to 10°C at night. The average rainfall is between 1,000 and 1,480 mm per annum with two peaks, March to June and September to December. Malaria transmission is low and unstable and people of all ages are at risk of malaria. The district is epidemic-prone, and occasional epidemic outbreaks occur shortly after peaks of rainfall [Plasmodium falciparumThe study was conducted in Kamwezi sub-county in Kabale district, situated in south-western Uganda with a catchment population of about 9,300 people. The district lies at an altitude between 1,219 and 2,347 m above see level and covers an area of 1,827 kmrainfall . Lying aThe study had two components: 1) passive case detection where all patients attending the out patient clinic with a febrile illness were included and 2) a longitudinal active malaria case detection survey was conducted in selected villages.in vivo study had shown that malaria parasites in the area were sensitive to this drug combination [®, Ängelholm, Sweden). Hb < 80 g/l was considered as severe anaemia, Hb 80–100 g/l as moderate anaemia and >100 g/l as normal. Hb was not adjusted for altitude. A thick blood film was also prepared for the detection of malaria parasites from all patients suspected of having malaria.All patients attending the outpatient clinic of a Health Centre IV in Kamwezi sub-county  from December 2001 to March 2003 complaining of a febrile illness were included in the study. The history of illness, the presenting symptoms, their duration and axillary body temperature were recorded on a case record form developed for the study. Patients were asked about what diseases they perceived themselves to be suffering from based on the presenting symptoms. A full clinical examination of patients was undertaken by the health facility workers and was more comprehensive than routine examination, including examination for clinical anaemia and respiratory tract infection, and a presumptive diagnosis was made based on presenting signs and symptoms. Those patients suspected to be having malaria were treated according to national guidelines with a combination of chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), which was by then the approved first line treatment and an bination . PatientA longitudinal active malaria case detection was conducted in four villages randomly selected by balloting from the list of the Health Centre catchment villages. The villages were categorized as far (at a distance >5 km) or near (within a distance < 5 km) from the health centre. Two villages were randomly selected in each category and they had a total population of about 800 people. The health workers examined all household members with fever or a history of fever within 24 hrs. The history of illness, presenting symptoms, and axillary body temperature were recorded on a case record form developed for the study. A sample of blood was collected from a finger prick using a dipstick capillary tube for antigen detection using the Uni-Gold™ Malaria (p.f) test  based on detection of histidine-rich protein II (PfHRP-II). Health workers were trained to interpret the test results in the field and administer treatment. A thick blood film was also prepared for the detection of malaria parasites from all patients suspected of having malaria in the villages.All blood slides were stained and kept at the Health Centre and collected monthly by the principal investigator and examined by a senior laboratory technician at the Vector Control Division, Ministry of Health, Kampala. Another laboratory technician read at least a random 10% of the slides to ensure quality control. There were few discrepancies in the slide readings by the two technicians. In cases where there were discrepancies, the two technicians came together and re-examined the slides and made a collective decision on the reading. There were few patients who had only gametocytes but were not classified as malaria cases unless they had fever or a history of fever within the last 24 hrs and no symptoms suggestive of other febrile illness. Parasites were counted against 200 leukocytes and expressed as number of parasites/μl of blood assuming a standard leukocyte count of 8,000/μl. A malaria case was defined as any slide-confirmed parasitaemia in a person with an axillary temperature ≥ 37.5°C or a history of fever within the last 24 hrs and no signs suggestive of other diseases.Ethical approval for the study was obtained from the Uganda National Council for Science and Technology and the Danish National Committee on Biomedical Research Ethics. Permission to conduct the study was obtained from the district authorities. Participation in the study was voluntary after informed consent.Data were entered and analyzed using SPSS version 10.0. In order to obtain the best subset of symptoms for prediction of parasitaemia or a malaria episode, symptoms were evaluated using a nominal regression method based on the probability of likelihood ratios.A total of 1627 patients, attending the Health Centre between December 2001 to March 2003 and given a presumptive clinical diagnosis of malaria, were interviewed (caretakers of children < 5 years responded for their child) about their presenting symptoms and what diseases they perceived themselves to be suffering from. Between 52 and 160 presumptive diagnoses of malaria were made each month based on history of fever, headache, joint pains, rigors and raised axillary body temperature (> 37.5°C). Mean age was 27 years (range 1–85 years) and 804 (49.4%) of patients were female. The majority of patients were adults  with 101 children less than five years and 344 patients aged 5–15 years. Most patients  perceived themselves to be suffering from malaria, whilst 32 (2.0%) thought that they had malaria with a respiratory tract infection, and 215 (13.4%) were not sure what diseases they were suffering from, and for 13 (0.8%) no records were available.P = 0.001). Not all parasitaemic cases were febrile. Parasitaemia in the absence of demonstrable fever was found in 25.6% of patients overall, and was more common in older children and adults with 14.1%, 27.8% and 25.8% in the age groups < 5, 5–15 and 16 years respectively, (P = 0.03). Parasite density was generally low with only 25 % of the patients having parasite density ≥ 1,000/μl of blood.A blood slide was prepared for 1577 (96.9%) of the patients suspected to be having malaria and 794 (50.3%) were found to be parasitaemic. Overall, 391 (24.8%) were classified as malaria cases according to the case definition (axillary temperature ≥ 37.5°C with positive blood slide confirmation): with 29.4%, 23.6% and 24.8% in the age groups < 5, 5–15 and ≥ 16 years respectively , whilst dizziness and cough had negative association with parasitaemia . The overall sensitivity, specificity and positive predictive values of individual symptoms for predicting Plasmodium falciparum parasitaemia are also summarized in Table The symptoms most frequently reported by suspected malaria patients presenting to the health facility were headache (84%), fever (79%), joint pain (73%), loss of appetite (64%), vomiting (55%), and general weakness (55%). Parasitaemia status by reported symptoms among patients visiting the health facility is summarized in Table P = 0.009, P = 0.03 and P = 0.03 respectively), while patients reporting joint pains (P = 0.009) were less likely to be a malaria case. For diagnosis of a malaria case, headache had the highest sensitivity (84.7%), followed by joint pains (73.2%), fever (74.7%), loss of appetite (61%) and vomiting (59.2 %). However the specificity of each symptom was low 19.0%, 20.2%, 21.1 %, 37% and 47.9%, for headache, joint pains, fever, loss of appetite and vomiting, respectively. Further analysis was done to identify a combination of symptoms with a high sensitivity and specificity predictive of a malaria episode. However, no clinical algorithm could be identified.Reported symptoms among health facility patients fulfilling the case definition of malaria, and non-malaria cases are summarized in table P < 0.001). Severe anaemia was found in 16%, 3% and 1% of patients in the age groups < 5, 5–15 and >16 years, respectively (P < 0.001). Hb level was not associated with parasitaemia or being a malaria case.A total of 1,516 patients had their Hb measured . Moderate anaemia and severe anaemia was found in 6.7% and 2.4% of patients, respectively. Anaemia was found in 57.0%, 88% and 94% of patients in the age groups < 5, 5–15 and ≥ 16 years, respectively (During active case detection 669 patients had a blood slide prepared and RDT done. Of these 371 55.5%) were smear-positive and 391 58.4%) were RDT positive. Of the RDT positive samples, 243 (65.5%) were also smear-positive, and 148 (49.7%) were smear-negative  of the patients, 3.4% were diagnosed as malaria plus anaemia, 20% as malaria with respiratory tract infection and 1.4% as malaria and a chronic disease. Of the 1627 patients suspected to be having malaria, 54.3% were treated with a combination of SP and CQ (47.8% with CQ +SP and 6.8% with CQ + SP + an antibiotic) in accordance with National policy. However, about 34% of the patients were treated with CQ without SP  and 8.7% with SP only in combination with haematinics or antibiotics. All cases were treated with at least one antimalarial and 22% were also treated with an antibiotic. Among the 783 cases who were slide negative only 215 (27.5%) received antibiotic treatment (mainly co-trimoxazole and penicillin V tablets)P. falciparum infections in endemic areas do not present with elevated temperature [P. falciparum infection may be synonymous with a malaria episode due to lack of acquired immunity ["Omushwija"  is a broad term meaning any febrile illness, which could include acute respiratory tract infections that were also common and the reason why more than 27.6 % of the patients had elevated temperature without parasitaemia. Similarly, other symptoms such as headache, rigors and joint pains may occur in other febrile illness making them non-specific for malaria. Severe anaemia was most frequently seen in children less than five years as previously observed [In malaria holoendemic areas with no laboratory facilities, anti-malarial treatment is recommended for all patients with fever or a history of fever . Howeverperature . Studiesperature . Slide cperature ,18 and tperature . Howeverimmunity ,20 and timmunity . Howeverimmunity . In the observed . Howeverobserved .A presumptive diagnosis of malaria was made on 1627 patients but only 24.8% had a malaria episode according to the case definition, resulting in more than 75% of the patients receiving anti-malarial drugs unnecessarily. Only about 18% of the patients received antibiotics. Over diagnosis of malaria in sub-Saharan Africa is common . Lack ofThe interpretation of the RDT by health workers during case detection could not have been influenced by haemoglobin level since it was not measured at community level or by blood slide readings which was done at later stage in Kampala. The health workers used presumptive diagnosis to treat all patients suspected to be having malaria with the recommended anti-malarial drugs in the national guidelines. The sensitivity of RDT could have been higher than what is observed in this study if more sensitive diagnostic tests such as polymerase chain reaction (PCR) had been used as the gold standard.In the absence of more reliable malaria diagnosis, the current practice of treating all febrile infections with antimalarial drugs remains unavoidable in low transmission areas, despite increasing drug costs. Although RDTs are easy to use, require minimal expertise and no special equipment, the variability in sensitivity both within and between products calls for an urgent development of high quality, accurate, rapid and affordable diagnostic tools for malaria so that new anti-malarial drugs which are costly and associated with increased toxicity are targeted to people with definite malaria illness.The author(s) declare that they have no competing interests.The authors, roles in the research process and in the preparation of the manuscript were as follows:RN, PM & SC participated in the conception and design of the study. RN implemented the study and collected data. RN performed the data and statistical analysis and wrote the manuscript. PM and SC supervised field work. All authors read and approved the final manuscript:


Malaria rapid diagnostic tests (RDTs) are relatively simple to perform and provide results quickly for making treatment decisions. However, the accuracy and application of RDT results depends on several factors such as quality of the RDT, storage, transport and end user performance. A cross sectional survey to explore factors that affect the performance and use of RDTs was conducted in the primary care facilities in South Africa.This study was conducted in three malaria risk sub-districts of the Limpopo Province, in South Africa. Twenty nurses were randomly selected from 17 primary health care facilities, three nurses from hospitals serving the study area and 10 other key informants, representing the managers of the malaria control programmes, routine and research laboratories, were interviewed, using semi-structured questionnaires.There was a high degree of efficiency in ordering and distribution of RDTs, however only 13/20 (65%) of the health facilities had appropriate air-conditioning and monitoring of room temperatures. Sixty percent (12/20) of the nurses did not receive any external training on conducting and interpreting RDT. Fifty percent of nurses (10/20) reported RDT stock-outs. Only 3/20 nurses mentioned that they periodically checked quality of RDT. Fifteen percent of nurses reported giving antimalarial drugs even if the RDT was negative.Storage, quality assurance, end user training and use of RDT results for clinical decision making in primary care facilities in South Africa need to be improved. Further studies of the factors influencing the quality control of RDTs, their performance of RDTs and the ways to improve their use of RDTs are needed. The South African National Malaria treatment guidelines stipulate that malaria treatment (using artemesinin-based combination therapy) should be based on definitive diagnosis using microscopy or malaria rapid diagnostic tests (RDTs) . South AThe Limpopo Province, is one of three malaria endemic provinces in South Africa and has the highest malaria incidence . Figure Purposefully selected key informants and randomly selected nurses at the primary health facility level were interviewed using a semi-structured questionnaire. Key informants included three hospital pharmacy staff, one regional pharmacy manager, three district malaria managers, one provincial malaria control manager and two researchers. Among the nurses interviewed, 17 were from primary health care (PHC) clinics and three were from hospitals.A two-stage sampling procedure was used to select PHC clinic staff . All cliThe University of Limpopo Research Ethics Committee, the Limpopo Department of Health and Social Development and the London School of Hygiene and Tropical Medicine granted ethical permission for this study. Informed consent was acquired from all interviewees.In all health facilities, there was evidence that stocks and expiry dates were monitored regularly. Stock monitoring methods ranged from stock cards (paper based) to electronic systems. Nursing staff were aware of the seasonal increase in malaria cases and stated that they ordered more RDT stock before and during the season; however, only 20% of the nurses interviewed were able to accurately give the limits of the malaria season (September-May). More than half (55%) of the nurses indicated that stock-outs of RDTs occurred. However, they reported that this was rare (one or two times in a season) and contingency plans existed to replace stock from either the nearest clinic or hospital pharmacies. Replacement of stock took place within 24 hours. District malaria managers reported RDT stock-outs in clinics in the 2005/2006-malaria season. They responded by alerting the necessary authorities  or transporting malaria kits to facilities.Pharmacy staff reported deploying pharmacy assistants to some health facilities to assist with ordering of pharmaceuticals including RDTs. One hospital had a bar code system for ordering pharmaceutical supplies. At the regional pharmacy level an electronic system is in place to increase stock as demand increased, and in most cases this is proportional to the seasonal increase in malaria cases.Sixty five percent (13/20) of the nurses reported that RDTs were stored correctly i.e. in an air-conditioned room with regular temperature monitoring. Among the nurses from the seven facilities that did not implement correct storage, three (42%) were very concerned with temperature fluctuation as thermometers were unavailable for temperature monitoring. The remaining 4/7 (53%) indicated that although their clinics lacked air conditioning, room temperature was monitored, and that it rarely rose above 30°C. This however was not corroborated with any recorded data.the kits did not stay in the clinics for too long", due to their frequent use.Malaria managers  accepted that some clinics did not keep RDTs in a cool environment; however they were not concerned about this, commenting that "Pharmacy managers in hospitals and regional depots stored RDTs in an air-conditioned environment (temperature range 15–25°C). Monitoring charts were produced when requested by the interviewer.Only 4/20 nursing staff said that they checked the quality of RDTs, this they reported to have been done, by comparing the agreement between a diagnosis based on clinical signs and symptoms and the RDT result. Two of 20 nurses reported that they used blood smear results to confirm the RDT results occasionally. Three (15%) nurses reported that they gave antimalarial drugs to RDT negative patients if the clinical presentation was suggestive of malaria.Figure RDT quality control, both at the manufacturing side and at the testing stage, was lacking. The key is the end user's ability to distinguish between positive and negative results."In summary, managers were very concerned that RDTs quality were not being monitored at health facility level. One informant stated, "Nursing staff had huge praise for the use of the RDTs, Figure More than half the nurses (12/20) however reported that they did not receive external training on RDT use; however, 10 nurses reported receiving in-house training. Almost all (19/20) nurses said that they were confident in using the RDT.The accuracy of RDT result was the key concern for 35% of the respondents, false positive and negatives were stated as major challenges.the fault could have been due to the clinic staff not reading the test in time." One laboratory technologist said that the nurses were not doing the test properly – "When we receive the test back we see that they are putting too much blood."Malaria managers commented that RDT readings were problematic – "adhoc basis leading to nurses sometimes offering antimalarials to RDT-negative cases on the basis of their clinical judgment; (4) there is a possibility that RDTs under-diagnose malaria in the current context and (5) there is very limited training on the use of RDT at the PHC level.Although this study involved a small representative sample of users of RDT at the primary care facilities in South Africa, it has revealed that (1) there are sporadic problems of stock-out of RDT during peak transmission seasons; (2) the storage facilities and monitoring is inadequate in many primary care facilities; (3) the accuracy of the RDT was tested on an According to the WHO, temperatures above 30°C are considered inappropriate for storing RDTs . As tempThe quality of the RDT can be established at three levels: post-manufacture level, end user level and through the use of positive control wells ,12. Due This study in South Africa may not be applicable to other countries in Africa. However, the lessons on storage, quality assurance and training observed in this study would be applicable to most settings where RDTs are introduced. Further studies of the factors influencing the appropriate use of RDTs and the ways to improve the use of RDTs are needed in the study setting.All the authors conceptualized the study, participated in the analysis, drafting of the manuscript and writing the final version of the paper.


Co-morbidity with conditions such as fever, diarrhoea and pneumonia is a common phenomenon in tropical Africa. However, little is known about geographical overlaps in these illnesses. Spatial modelling may improve our understanding of the epidemiology of the diseases for efficient and cost-effective control.This study assessed subdistrict-specific spatial associations of the three conditions  in relation to malaria endemicity. We used data from the 2000 Malawi demographic and health survey which captured the history of childhood morbidities 2 weeks prior to the survey date. The disease status of each child in each area was the outcome of interest and was modelled using a trivariate logistic regression model, and incorporated random effects to measure spatial correlation.r = 0.29); while weak associations were estimated between fever and pneumonia (r = 0.01); and between diarrhoea and pneumonia (r = 0.05). The proportion of structured spatial variation compared to unstructured variation was 0.67 : 0.31–0.91) for fever, 0.67 (95 % CI: 0.27–0.93) for diarrhoea, and 0.87 (95% CI: 0.62–0.96) for pneumonia.The risk of fever was positively associated with high and medium malaria endemicity levels relative to low endemicity level, while for diarrhoea and pneumonia we observed marginal positive association at high endemicity level relative to low endemicity level, controlling for confounding covariates and heterogeneity. A positive spatial correlation was found between fever and diarrhoea (The analysis suggests some similarities in subdistrict-specific spatial variation of childhood morbidities of fever, diarrhoea and pneumonia, and might be a result of shared and overlapping risk factors, one of which is malaria endemicity. Children in sub-Saharan Africa experience a disproportionately large burden of morbidity and mortality. About 180 deaths per 1000 live births occur in the region . Often tOne of the common childhood co-morbidities is of diarrhoea, malaria, HIV and acute respiratory illnesses such as pneumonia ,5. Each The HIV epidemic in sub-Saharan Africa exacerbates the risk of morbidity and mortality to which children are exposed. The HIV prevalence among adults aged 15–49 years in Malawi is estimated at 14.1% (range: 6.9–21.4%), 91,000 children  are living with HIV . HIV infet al [This study applied a spatial model to investigate the effect of malaria endemicity on childhood co-morbidity of fever, diarrhoea and pneumonia. This relationship was investigated using the 2000 Malawi Demographic and Health Survey (DHS) databases and data from the Mapping Malaria Risk in Africa (MARA). The DHS survey contains data on childhood health, and included questions on childhood fever, diarrhoea and pneumonia. Malaria risk was based on prevalence predicted at precise DHS survey sampling locations, by applying a geostatistical model developed and described in Kazembe et al .Since high malaria risk is likely to affect other diseases, it was important to examine its effect on the spatial patterns of childhood fever, diarrhoea and pneumonia. Moreover, as fever, diarrhoea and pneumonia share risk factors ,11, spatSpatial models have been applied in previous studies ,14, in wThe analysis used self-reported data from the 2000 Malawi Demographic and Health Survey (MDHS) . The MDHThe self-reported sickness status (0/1) of each child for each disease was the outcome of interest. The data set contained 4,778 cases where responses to all three illnesses were available. The following individual covariates were included in the analysis: (1) age of the child; (2) ownership of bednets ; (3) received vitamin A within 6 months prior to the survey date ; (4) weight-for-age as a general indicator of nutritional status, measured as Z-scores; (5) type of place of residence ; (6) crowding indicator based on whether household size exceeded 6 members .At community level , malaria endemicity  was included, assuming that each child at each site was equally exposed to the underlying risk. Malaria prevalence was predicted for MDHS precise sampling locations using a geostatistical model developed and described elsewhere . The malyijk is the status (0/1) of disease k, k = 1 (fever), 2 (diarrhoea), 3 (pneumonia) for child j in subdistrict i, i = 1, . . .,364. Suppose that the observed outcomes arise from a trivariate Bernoulli distribution, with pijk as the probability of disease k occurring in child j in area i, then the outcome is modelled using a logistic regression model with predictor given by,Assume αk is the intercept for disease k, the terms β = T are vectors of regression parameters corresponding to the set of covariates (Xijk)  ∝ 1, while for the other fixed effects, β, highly dispersed normal distribution priors were chosen, that is, p(β) ~ N. The unstructured spatial effects uik were assumed to follow a multivariate normal distribution, i.e., T ~ MVN, with covariance matrix Ω. The spatial structured effects sik were assigned a multivariate conditional autoregressive (MCAR) prior, i.e.,T ~ MCAR, again Σ is a covariance matrix [Model estimation was carried out using the Bayesian approach and the following prior distributions were specified for all parameters of the model (1). Without empirical evidence about the magnitude and direction of covariate effects, non-informative priors were assigned to the regression coefficients. For the intercept, diffuse priors were assumed, that is, e matrix .11, Σ22, Σ33 are variance components corresponding to fever, diarrhoea and pneumonia respectively, while Σ12, Σ13, Σ23 are correlation components between fever and diarrhoea, fever and pneumonia and diarrhoea and pneumonia respectively. Correspondingly, r12 = IW , Σ ~ IW  where q,r are scalars, while Q, R are symmetric and positive definitive matrices. The hyperpriors were assigned q = r = 3, Q = R = 0.01I where I is an identity matrix.The covariance matrices of the spatiall effects have their diagonal elements equal to the variances and the off-diagonals are correlation components between the diseases. Thus, for example ΣModel fitting used Markov Chain Monte Carlo simulation techniques to draw samples from the posterior distribution and was implemented in WinBugs 1.4 . Three ps et al. . After 5Q = R = 0.005, 0.01,0.05 with q = r = 3, were carried out and the MCMC simulations were re-run for each choice. Using these priors gave satisfactory results, and although the prior can give problems on convergence, we did not have any problem on convergence or mixing of the chains in this application. The estimates of fixed and random effects, obtained from the posterior distributions, were similar indicating that the results were not sensitive to changes in prior distributions.Because of the known concerns about the Wishart prior's possible informativity, a sensitivity analysis was carried out. Three specifications, i.e., n = 4,778 children. The corresponding proportions were 50% (range: 0–100), 21% (range: 0–75) and 53% (range: 0–100) for fever, diarrhoea and pneumonia respectively. Very young infants (age 0 to 5 months) and older children (36 to 59 months) were less likely to be sick compared to the other age groups across all the three diseases. The proportions sick were more at higher malaria endemicity levels for all illnesses. Diarrhoea occurred mostly in underweight children. Rural children were disproportionately more sick than their urban counterparts. Those with bednets were less sick than those without.Table Table The risk of childhood fever increased with rural residence relative to urban residence . Children aged 0–5, 6–11, 12–23, 24–35 months relative to 36–59 months were at higher risk of fever (Table 11 = 0.62 (95% CI: 0.41–1.01) for fever, Σ22 = 0.27 (95% CI: 0.16–0.51) for diarrhoea, and Σ33 = 0.88 (95% CI: 0.59–1.31) for pneumonia. For the unstructured heterogeneity, we estimated Ω11 = 0.43 (95% CI: 0.25–0.94) for fever, Ω22 = 0.19 (95% CI: 0.10–0.36) for diarrhoea, and Σ33 = 0.34 (95% CI: 0.21–0.59) for pneumonia. The proportion of variation due to the spatially structured variation was estimated as p11 = 0.67 (95% CI: 0.29–0.91) for fever, p22 = 0.67 (95% CI: 0.28–0.93) for diarrhoea, and p33 = 0.87 (95% CI: 0.63–0.96) for pneumonia.The degree of spatial heterogeneity is given by Σ and Ω in Table r12 = 0.18 (95% CI: -0.48–0.72) for fever and diarrhoea; r13 = 0.02 (95% CI: -0.56–0.56) for fever and pneumonia; and q23 = 0.04 (95% CI: -0.56–0.63) for diarrhoea and pneumonia. For the unstructured heterogeneity, the correlations were q12 = 0.47 (95% CI: -0.32–0.87) for fever and diarrhoea, q13 = -0.01 (95% CI: -0.64–0.68) for fever and pneumonia, while q23 = 0.09 (95% CI: -0.62–0.73) for diarrhoea and pneumonia. The total spatial correlations (q + r) were 0.29 (95% CI: -0.26–0.69), 0.01 , and 0.05 (95% CI: -0.43–0.51) for fever and diarrhoea, fever and pneumonia; and diarrhoea and pneumonia respectively.The correlations between diseases at subdistrict level are also presented in Table Figures Recent studies have shown significant district-specific spatial variation in childhood fever and diarrhoea in Malawi ,14, and We observed that the risk of the three illnesses varied with different risk factors, including age of the child, underweight, use of bednet, Vitamin A, and place of residence . The effect of age on the three illnesses is interesting. Generally, all children under the age of 5 years were at increased risk, however, those of an age where they were likely to be weaned (6–23 months) appeared to be at the greatest risk. Very young infants (0–5 months) may have been breastfed, and therefore protected by maternal immunity, and children older than 3 years were less at risk of disease, probably because of acquired immunity. Children who were underweight were at greater risk of diarrhoea. The prevalence of diarrhoea appears to have increased amongst children reported to have had a Vitamin A supplement. This has not been confirmed by other studies and a decrease in morbidity and mortality is the rationale for the provision of Vitamin A supplement. This finding may be a question of reverse causality , i.e., cIn this analysis, the risk of all three illnesses, i.e., fever, diarrhoea and pneumonia was found to be associated with malaria endemicity, although this relationship was stronger with fever. It is also evident that malaria endemicity acts as a shared risk factor that increases the risk of other diseases, such as diarrhoea and pneumonia ,3. This The relationship between fever and malaria endemicity is particularly interesting. In malaria-endemic countries, fever is often equated to malarial morbidity for prompt treatment due to non-availability of definitive diagnosis in most places. Although fever as an indicator of malaria infection generates many false positives , our finAs shown in other studies , moderatet al. [Excluding malaria endemicity as a risk factor, childhood morbidities are a combined result of several determinants, including the socio-demographic covariates as observed in Table et al.  argued tet al. . Undernuet al. . The reset al. . Furtheret al. .Use of DHS data has limitations. Concerns have been raised about potential bias of relying on the ability of mothers to identify and separate symptoms of fever, pneumonia or diarrhoea .Nevertheless, ethnographic studies generally agree that mothers consistently distinguish symptoms of various diseases- the easiest to diagnose being diarrhoea and pneumonia . SecondlHIV is an important confounder in this study and the lack of HIV data in the 2000 survey is a major limitation, thus our results need to be interpreted bearing in mind the co-existence of malaria and HIV. The relationship observed between fever, diarrhoea and pneumonia may be due to the fact that symptoms of HIV include fever, diarrhoea and pneumonia . This isThe use of modelled values of malaria prevalence might be prone to errors in the malaria endemicity covariate, resulting in a possible overestimation of standard errors. The use of predicted prevalence values is justified by highly endemic malaria risk in Malawi which has changed little over the years due to lack of sustainable malaria control programmes in the country. As such, modelled estimates provide a realistic pattern of malaria risk, which also agrees with expert opinion . This apIn conclusion, the results have depicted similarities in the spatial pattern of fever, diarrhoea and pneumonia. The co-occurrence of fever and diarrhoea was the strongest mainly due to shared risk factor such as malaria endemicity. Although overlaps between fever and pneumonia or between diarrhoea and pneumonia were weak, malaria still played an important role. The magnitude of overlap in symptoms strongly suggest the need to strengthen strategies for the integrated management of childhood illnesses through home and community case management innovations that jointly address such illnesses. Since malaria home and community management are widely accepted in the country, it is possible to include treatments for diarrhoea and pneumonia in the existing malaria dispensing strategies.The author(s) declare that they have no competing interests.LNK conceptualised, collected data, analysed and drafted the manuscript. ASM, CCA and IK participated in the conception and critical review of the manuscript. The authors read and approved the final manuscript.


Malaria is a leading cause of hospitalization and in-hospital mortality among children in Africa, yet, few studies have described the spatial distribution of the two outcomes. Here spatial regression models were applied, aimed at quantifying spatial variation and risk factors associated with malaria hospitalization and in-hospital mortality.Paediatric ward register data from Zomba district, Malawi, between 2002 and 2003 were used, as a case study. Two spatial models were developed. The first was a Poisson model applied to analyse hospitalization and minimum mortality rates, with age and sex as covariates. The second was a logistic model applied to individual level data to analyse case-fatality rate, adjusting for individual covariates.Rates of malaria hospitalization and in-hospital mortality decreased with age. Case fatality rate was associated with distance, age, wet season and increased if the patient was referred to the hospital. Furthermore, death rate was high on first day, followed by relatively low rate as length of hospital stay increased. Both outcomes showed substantial spatial heterogeneity, which may be attributed to the varying determinants of malaria risk, health services availability and accessibility, and health seeking behaviour. The increased risk of mortality of children referred from primary health facilities may imply inadequate care being available at the referring facility, or the referring facility are referring the more severe cases which are expected to have a higher case fatality rate. Improved prognosis as the length of hospital stay increased suggest that appropriate care when available can save lives. Reducing malaria burden may require integrated strategies encompassing availability of adequate care at primary facilities, introducing home or community case management as well as encouraging early referral, and reinforcing interventions to interrupt malaria transmission. Measuring malaria burden in a population is a challenge in most developing countries ,2. RoutiUse of spatial analysis is increasingly being applied in epidemiological research in recent years , and exaBecause malaria transmission intensity varies geographically, the distribution of hospital cases and subsequent mortality rates may exhibit systematic spatial variation . Thus spZomba, one of the 28 districts located in southern Malawi, is generally classified as malaria endemic, although the highland zones in the central parts of the district are of low transmission and may be prone to epidemic malaria -17. In 2Data used in this study were obtained from discharge records of all paediatric hospital admissions at Zomba district hospital, Malawi, between 1 January 2002 to 31 December 2003. Zomba district hospital, with over 500 beds is the largest facility in the district which serves both as the first consultation point for patients within its catchment, and as a referral centre for other 25 primary health centres. These facilities are managed by the Ministry of Health and the Christian association of Malawi.For this study, cases with primary diagnosis as malaria, from the hospital wards, were used. Each cases was clinically assessed and definitively confirmed as malaria on admission. The registers included patients' age, sex, date of admission and discharge, outcome , village or location of residence, and treatment given. Based on the name of the village, each case was matched to one of 21 residential wards in the district. Approximately 86% of cases were successfully linked to wards, the other 14% having either missing or insufficient residential information. Only geo-referenced cases were included in the spatial analysis, using ward as the spatial unit. Population at risk data for the age  – sex – residential ward strata, projected from the 1998 census, were obtained from the Malawi National Statistics Office [day when admitted ; season of the year when admitted ; treatment given ; distance to the hospital . The distance of 5 km was chosen to reflect travel time of 1 hour [referral was defined, with children who used the hospital as a first point of consultation given a code 0 and those referred to the district hospital from peripheral health facilities in the district given the code 1.From the data, the following the variable were derived: f 1 hour ,21. Lengyijk be the total number of cases observed in age group k , sex j  and residential ward i , and Nijk the corresponding population at risk. The yijk are Poisson distributed with expectation μijk, given all the random effects. The Poisson regression model for hospitalization and minimum mortality rates has the form,Based on the number of hospital admissions or mortality and the population at risk in each age-sex-residential ward stratum we fitted a Poisson model. More specifically, let μijk) = log (Nijk) + β0 + β1 Agek + β2 Sexj + si + ui,     (1)log (Nijk) is an offset, β0 is an intercept, β1 and β2 are regression coefficients corresponding to age and sex covariates respectively. The terms si and ui are random effects that allow for spatially structured variation and unstructured heterogeneity respectively.where log . The CFR is modelled using the logistic regression model, i.e.,Defining pij) = ηij = β + si + ui + f (t)     (2)logit , and si and ui are the random effects for the i-th ward of residence as defined above. The calendar effect, at month t, is included through f (t). Bivariate logistic models were fitted for each covariate , a Bayesian approach was used for inference. The following prior distributions were specified for the parameters in Equations 1 and 2. A conditional autoregressive (CAR) prior , was chosi and sl are adjacent areas, and the number of adjacent areas is mi, where β) were assigned diffuse priors. The calendar effect was assigned a second-order random walk priors for flexible smoothing, i.e, f (t) ~N (2f (t -1) – f (t - 2), The fixed effects . Figure χ2 = 24.61, p < 0.05).A total of 302 deaths were registered among 3,969 children hospitalised for malaria, between January 2002 to December 2003, resulting in an overall case fatality rate of 7.6%. Figure χ2 = 0.13, p = 0.94). The hospital received relatively more patients from a distance of more than 5 kms (52%), with distant patient likely to die in hospital .Table The same table gives unadjusted odds ratios (OR) and 95% CI of OR from the bivariate logistic models. Children aged 1–4 years were at reduced risk of dying in hospital relative to children aged 5–14 years . Children referred to the district hospital from networking health facilities were at increased risk of dying in hospital relative to non-referred children . Children hospitalised during the wet season were at reduced risk of dying in hospital relative to those hospitalised during the dry season . Those coming from a distance of within < 5 km were at reduced risk of dying in hospital relative to those coming from a distance of more than 5 km . Length of hospital stay was also associated with the risk of hospital death. Day 1 showed a raised risk relative to 7 or more days in hospital . Day 2, day 3 and day 4–6 recorded reduced risk relative to day 7 or more. No treatment differences were observed between those given quinine as treatment relative to those who received other drugs: OR = 0.98, 95% CI: 0.60, 1.61  are relatively far from the general hospital, since the hospital is located at the centre of the district. Areas of lower risk of dying (negative) were closer to the district hospital or within the district centre.The multiple spatial logistic regression model included age, season, distance, referral and length of stay as fixed effects. Results were similar to those obtained in the bivariate model . Distant areas with low hospitalisation rates suggest problems of access, which does translate into high mortality rate Figure . HoweverThe residual spatial heterogeneity Figures  and 5, sAnother possible explanation of varied clinical outcomes may be the socio-economic discrepancies in the district. For instance, people from remote or rural areas are relatively poor compared to those at the centre of the district, and these are at increased risk of malaria infection and death because they are not able to pay for effective malaria drugs nor afford transport to a health facility that can treat malaria ,26. RuraHealth seeking behaviour plays a critical role in accessing prompt and effective care. Because this was not directly observed, we suggest that this may also explain some of the spatial variation in hospitalisation rates Figure . Home baIn the 2-year review, the overall case fatality rate of 7.6% was lower than the national rate of 18% . This maThe results indicated that risk of malaria hospitalization decreased with increasing age, with those under the age of 1 years at highest risk than subsequent ages Figure , 3. CFR The study showed that patients within 5 km of hospital were less likely to die in hospital than those beyond 5 km, and does reflect the fact that nearness to the hospital improved early access to care ,34, thusWith regard to the length of hospital stay, it was found that the pattern of hospital deaths was significantly associated with the length of hospital stay. The findings indicated that the sickest patients had a short length of stay terminating in death, with highest risk of dying in hospital the same day of admission. The high CFR on day 1 can be attributed to severe or complicated cases. Indeed in some settings, biomedical care is sought when the condition is near fatal ,29. HoweMalaria transmission is more intense in the wet season, yet the results showed that the risk was lower in the wet than the dry season. The likely reason for this is that there were more cases in the wet season Figure , hence tThese analyses depended on data collected from routine hospital registers. One major shortcoming of using such data is that they only represent those patients who visited the clinics or hospital. As demonstrated in other studies ,28, and This study provides evidence that hospital admissions and mortality rates for malaria among Malawian children are high, and that they vary in space. This analysis, accordingly, is the first of its kind and its advantage over other methods is that the impact of location on the two health outcomes was accounted for. These geographical disparities in malaria risk may largely be explained by determinants of malaria transmission, health services availability and accessibility, and health seeking behaviour. Although treatment was not significantly associated with CFR, improved prognosis increased with length of hospital stay indicating that appropriate care when available can save lives. The increased mortality risk for those referred from primary facilities signifies lack of adequate care provided by the primary health care system, but may also be a factor of referring facilities were referring more severe cases, which are expected to have a higher case fatality rate or that patients present later to the hospital if they have been referred. Improved case management at primary facilities by ensuring adequate stocks of effective drugs, combined with home or community interventions, for example, educating the community in management of malaria including training of shopkeepers in the appropriate choice and dose of antimalarial drugs for the treatment of childhood fevers is therefore a high priority , and strLNK conceptualized, analysed and drafted the manuscript. IK and BLS participated in the conception, and critical review of the manuscript.


Little is known about children undergoing critical care for malaria. The purpose of this survey was to evaluate the outcome in African children requiring endotracheal intubation for life-threatening malaria.All children with a primary diagnosis of severe malaria (2000 WHO definition) requiring endotracheal intubation, hospitalised over a five-year period, within a tertiary-care hospital in Dakar, Senegal, were enrolled in a retrospective cohort study.24 score: 14; IQR: 10–19, multiple organ dysfunctions: 91.5%). The median duration of ventilation was 36 hrs (IQR: 4–72). Indications for intubation were deep coma , overt cortical or diencephalic injury, i.e, status epilepticus/decorticate posturing (n = 20), severe brainstem involvement, i.e., decerebrate posturing/opisthotonus (n = 15), shock (n = 15), cardiac arrest (n = 13) or acute lung injury (ALI) . Death occurred in 50 cases , 60%) and was associated with multiple organ dysfunctions . Median PRISMh24 score was significantly lower when testing deep coma against other indications , ditto for PELODh24 score . Multivariate analysis identified deep coma as having a better outcome than other indications . Decerebrate posturing/opisthotonus  10.7, 95% CI 2.3–49.5) were associated with a far worse prognosis than status epilepticus/decorticate posturing . Thrombocytopaenia  was associated with death  and second-line anticonvulsant use  with survival . Complications, mostly nosocomial infections (n = 20), ALI/ARDS (n = 9) or sub-glottic stenosis (n = 3), had no significant prognostic value.83 consecutive patients were included (median PRISM hper se. In sub-Saharan Africa, mechanical ventilation for life-threatening childhood malaria is feasible, but seems unlikely to dramatically improve the prognosis.In this study, the outcome of children requiring intubation for malaria depends more on clinical presentation and progression towards organ failures than on critical care complications  Malaria remains one of the most serious infections on a global basis. In Africa it accounts for about 20% of mortality in children under five . Severe Diffuse or focal brain ischaemia, ring haemorrhages and transtentorial herniation are common patterns of the central nervous system involvement (CNS) in fatal CM. However, cerebral oedema was thought to be a non-specific agonic event . In receIn sub-Saharan Africa, most hospitals face the curse of malaria without access to paediatric intensive cares. Severe forms of malaria are rare among expatriate children, and critical care for childhood malaria is not well-documented in developed countries. Thus, outcomes in children intubated for life-threatening malaria have not been assessed. In non-immune adults mechanically-ventilated for severe malaria, high cases fatality rates (25 to 75%) were observed both for residents of endemic countries ,15 and tThe aim of the current study was to investigate the outcome and complications in African children requiring endotracheal intubation during resuscitation for life-threatening malaria.This retrospective observational cohort study took place in the Hôpital Principal, a tertiary-care hospital in Dakar, Senegal. All children who required endotracheal intubation for life-threatening falciparum malaria between January 1, 1996 and December 31, 2000, either in the 15-bed Intensive Care Unit (ICU), or in one of the two emergency rooms on the paediatric ward were evaluated. Whatever the ward, the mean ratios nurses: patients were 1:5 on day or 1:10 on night.h24) score ; (5) shock, defined as systolic blood pressure <50 (under 5 years) or <80 (beyond 5) mmHg; (6) cardiac arrest.Indications for intubation included: (1) normal; (2) mild disability; (3) moderate disability; (4) severe disability; (5) coma or vegetative state; (6) brain death ).Intra-cranial hypertension (protracted episodes of decorticate or decerebrate rigidity in addition to dilated sluggish pupils) was treated with 10–20 ml/kg of 20% mannitol and short-time induced hypocapnia . A p value < 0.05 was considered statistically significant.Kaplan-Meier curves were drawn to compare survival relative to the indications for intubation. A Cox proportional hazards regression model was performed to determine independent predictors of outcome. The cumulative incidence of nosocomial infections was graphically presented according to the duration of ventilation. All these analyses were computed in Statah24 score was 14 (IQR: 10–19) and multiple organ dysfunctions (MOD) were present in 91.5% (n = 76). During stay, the case fatality rate was 60.2% (n = 50). The population characteristics according to the status at discharge are presented in Table During the study period, 502 children were hospitalized with a primary diagnosis of severe malaria. 83 of whom required mechanical ventilation . The median age was 8.6 years IQR: 7–11), the sex ratio  1.6. At admission, median PRISM1, the seh24 score was statistically lower when testing deep coma against other indications , ditto for PELODh24 score . Among CM indications, PELODh24 scores correlated with the degree of severity in CNS involvement .Indications for mechanical ventilation were deep coma , clinically evident status epilepticus or decorticate posturing (n = 20), decerebrate posturing (n = 15), shock (n = 15), cardiac arrest (n = 13), and severe respiratory distress with a PaO2/Fio2 < 300 Torr [40.1 kPa] (n = 4). Median PRISMvs 70.2%, crude relative risk 0.5, 95% CI 0.3–0.8, p < 0.01).All the children intubated for a cardiac arrest deceased within 24 hours of ventilation Figure  and werevs 40 to 100%, p < 0.0001) and sedation remained significantly associated with survival. Thrombocytopaenia was an independent predictor for death. Conversely, in children with MODs, platelet counts correlated to the amount of ODs  and platelet counts under 50,000/mm3 were only observed in children with MOD syndrome.The Cox model showed deep coma was the indication of better outcome than other situations . Only three severe disabilities  persisted after a 2-month follow-up, occurred in two children intubated for opisthotonus, and in another one intubated for an acute lung injury.Of the survivors, neurological status on discharge was normal in 30% (n = 10) or impaired in 70% (n = 23), and median PCPC score was 2 (IQR: 1–3). Compared to deep coma, PCPC score was significantly higher in other motives for intubation (6 Of 18 21.7%) patients with community-acquired infections, no significant difference was noted between survivors and non-survivors. Among the 61 children surviving more than two days, 20 (32.8%) experienced 23 episodes of hospital-acquired infections. Cumulative incidence, as correlated with duration of ventilation, was as follows: 2.3% after 48 hrs, 15.3% after 72 hrs, 26.6% after 92 hrs, 63.4% after 120 hrs . However, the survival and functional outcome with these complications were not affected after controlling for the indications for intubation.i.e., non-ventilated group, since the Hôpital Principal had ventilation capability for years. Benchmarking of other CM series was not possible, since CM cases were not ventilated and had different epidemiological  or clinical characteristics . This could lead to misleading interpretations of severity and fatality rates [h24: 14, IQR: 10–19) twice as high as in our hospital's overall SM cases at the same period , of which fatality rate was 12% [This article is the first to report a series of African children living in an hypoendemic area, treated with mechanical ventilation for life-threatening falciparum malaria. For ethical reasons, the study involved no control group, ty rates ,23-26,28 was 12% ,30. Howe was 12% ,31.Acidosis, a major contributor for death, both in adults and in children ,13,16,17CM was the principal condition accounting for more than 80% of our critically-ill SM cases. This is consistent with hospital-based studies highlighting CM as the most frequently fatal clinical form in hypoendemic settings ,9. Amongstatus epilepticus, which would have deprived these patients of the benefit of second line anticonvlusivants, as recently described in African children [e.g., clonazepam or thiopenthal, than in absence of treatment or when phenobarbital was the sole anticonvulsivant. Non-ventilated children with CM receiving prophylactic phenobarbital have increased mortality rates, possibly caused by drug-induced respiratory depression [Surprisingly, children with multiple convulsions had lower case fatality rates than patients with one or no convulsion. Given the lack of EEG facilities in our center, this might be explained by the failure to diagnose subtle children . This hypression . Mechanie.g., decerebrate/opisthotonic posturing, could be explained by the progression of MOD syndrome and CNS failure.All children intubated for shock displayed a hyperkinetic profile  prior to intubation. This pathophysiological profile has already been shown to predict multiple organ failure (MOF) and poor outcome in non-immune adults with SM ,17,36. I3 was associated with a higher risk for death. All the patients were living in and round Dakar, an hypoendemic area where the prognostic value of thrombocytopaenia in paediatric falciparum malaria had been previously reported [A platelet count under 100,000/mmreported . More rereported . In adulreported . In paedreported . In lighreported , the relOn discharge, neurological disorders were observed in 70% of children requiring ventilation for life-threatening falciparum malaria. Nevertheless, except for three cases, these disabilities were mild to moderate and disappeared or regressed at follow-up, as previously reported -9,26. Hoe.g., impossibility of isolating children in the two paediatric emergency rooms, and a lack of nurses. In our setting, interventions such as efforts to increase hygiene and nurse ratios might reduce the occurrence of hospital-acquired infections. Another important issue was the higher rate of ALI/ARDS in mechanically-ventilated children than in other African paediatric series [Another noteworthy feature was that the incidence of nosocomial infections rose from 2.3% to 63.4% after 48 hrs and 120 hrs of ventilation, respectively. Its prevalence (24.2%) was twice those reported in an Indian ICU , but wasc series . This dic series ,41,42. LThere are several potential benefits of endotracheal intubation and mechanical ventilation in children with life-threatening malaria: (i) airways protection in comatose children; (ii) prevention or treatment of hypoventilation in comatose children, especially for those requiring anticonvulsive drugs; (iii) optimizing oxygenation in case of pulmonary malaria, ALI or ARDS ,43. Thise.g., as soon as GCS falls to 7 , and before progression towards MOF or brainstem involvement, two intimately tied complications difficult to cure in low-standard-care countries.Finally, mechanical ventilation for resuscitation of life-threatening childhood malaria was required for a short time and its outcome depended more on clinical presentation than on critical care complications. Despite the retrospective uncontrolled design of this study, it is thought that in the absence of such technical support, more patients would have died. Then, the better outcome in deep comas would support early intubation for airways protection in CM, Effective paediatric intensive care for severe childhood malaria exists in a sub-Saharan African country. Further investigations are warranted to ascertain whether endotracheal intubation is effective and if so, whether the capability for it should be more widely developed in malaria endemic areas.The author(s) declare that they have no competing interests.P.G., A.S.K., P.J., B.D. and P.I. took part in the clinical management of cases and did the data collection. P.I and P.G designed the study, reviewed the data for inconsistencies and entry errors prior to computerization into the database. C.R and P.G. performed the statistical analysis. P.G., P.I. and C.R. wrote the manuscript which was critically reviewed by all authors. This study was not supported by funding research.


Malaria prevention in Africa merits particular attention as the world strives toward a better life for the poorest. Insecticide-treated nets (ITNs) represent a practical means to prevent malaria in Africa, so scaling up coverage to at least 80% of young children and pregnant women by 2010 is integral to the Millennium Development Goals (MDG). Targeting individual protection to vulnerable groups is an accepted priority, but community-level impacts of broader population coverage are largely ignored even though they may be just as important. We therefore estimated coverage thresholds for entire populations at which individual- and community-level protection are equivalent, representing rational targets for ITN coverage beyond vulnerable groups.Using field-parameterized malaria transmission models, we show that high (80% use) but exclusively targeted coverage of young children and pregnant women (representing <20% of the population) will deliver limited protection and equity for these vulnerable groups. In contrast, relatively modest coverage  of all adults and children, rather than just vulnerable groups, can achieve equitable community-wide benefits equivalent to or greater than personal protection.Coverage of entire populations will be required to accomplish large reductions of the malaria burden in Africa. While coverage of vulnerable groups should still be prioritized, the equitable and communal benefits of wide-scale ITN use by older children and adults should be explicitly promoted and evaluated by national malaria control programmes. ITN use by the majority of entire populations could protect all children in such communities, even those not actually covered by achieving existing personal protection targets of the MDG, Roll Back Malaria Partnership, or the US President's Malaria Initiative. Based on malaria transmission models, Gerry Killeen and colleagues suggest that, while coverage of pregnant women and children should still be prioritized, wide-scale communal use of insecticide-treated bed nets would provide considerable benefit to vulnerable groups and should be promoted and evaluated in the field. Plasmodium falciparum. Like all malaria parasites, it has a complex life cycle, part of which takes place inside mosquitoes. When a malaria-carrying mosquito bites a person , parasites enter the human blood stream and travel to the liver where they reproduce before invading red blood cells. Here, they multiply again before bursting out and infecting more red blood cells as well as causing a high fever and sometimes damaging the nervous system, liver, and kidneys. When a mosquito bites someone who is infected, it often picks up parasites in its blood meal , thus completing the malarial transmission cycle.Malaria—a parasitic disease common in tropical and subtropical countries—causes about a million deaths every year, mainly among young children and pregnant women living in sub-Saharan Africa. The parasite responsible for most of these deaths is One way to break this cycle and reduce malarial transmission is to decrease the number of contacts between people and mosquitoes by encouraging people to sleep under insecticide-treated nets (ITNs). Field studies have shown that ITN use reduces deaths from malaria, so the Roll Back Malaria Partnership, the United Nations Millennium Development Goals, and the US President's Malaria Initiative have set a target of at least 80% use of ITNs by young children and pregnant women  by 2010. But would broader population coverage with ITNs interrupt the malarial transmission cycle more effectively? Might the wider use of ITNs (which both directly kill mosquitoes and repel them so that mosquitoes have to travel farther to get the blood they need to reproduce) be a more effective way to reduce local mosquito numbers and, consequently, human–mosquito contacts and malarial transmission? In this study, the researchers used mathematical modeling to ask how much community-wide coverage with ITNs is needed to protect vulnerable individuals against malaria without them personally using an ITN.The researchers developed a model for the transmission of the malaria parasite using data collected in Tanzanian villages where malaria is common, and used it to investigate how different patterns of ITN use might affect the individual protection of ITN users and the communal protection of nonusers. High (80%) coverage targeted at young children and pregnant women (less than 20% of the population) provided limited but valuable protection to these vulnerable individuals. However, the model predicted that a similar degree of community-wide protection would result if 35% of the whole population slept under ITNs provided there was no nonhuman blood supply for the mosquitoes. In other words, the vulnerable individuals in the population received the same degree of protection from this intervention as they would have got from personally using an ITN. If an alternative blood supply for the mosquitoes  was included in the model, just over half of the population needed to sleep under ITNs to provide the same degree of community-wide protection as targeted ITN use.Although the use of ITNs by vulnerable groups should remain a priority, these findings suggest that the wide-scale ITN use by the entire population should also be promoted. The use of ITNs by about half the population, predict the researchers, could protect all the young children in that population, even those who did not sleep under a net. As with all mathematical models, the accuracy of this prediction depends on the assumptions and data incorporated into the model. So before recommending community-wide use of ITNs, the actual level of communal protection provided by increased ITN coverage must be measured by rigorously evaluating ongoing national programmes. If such surveillance data confirm this model's predictions, wide coverage with ITNs might do more for public health in Africa than previously thought, suggest the researchers, provided the financial and logistical challenges associated with achieving high ITN coverage in this poor region of the world can be solved.http://dx.doi.org/10.1371/journal.pmed.0040229.Please access these Web sites via the online version of this summary at malaria and on insecticide-treated nets (in English and Spanish)The US Centers for Disease Control and Prevention provide information on MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)The malaria  and from the Roll Back Malaria Partnership on the use of insecticide-treated netsInformation is available from the World Health Organization on President's Malaria Initiative is available, including a fact sheet on the use of ITNsInformation about the US  Anopheles mosquitoes that act as vectors for human Plasmodium parasites must access sugar, blood, and aquatic oviposition sites to complete their life cycle and maintain parasite transmission. The availability of such ecological resources to mosquitoes has long been recognized as a crucial determinant of malaria transmission  = 0.64), as measured in a typical experimental hut trial  = 0.96). The proportion of normal biting exposure that occurs while nets are actually in use i)Click here for additional data file.