Lassa fever in Guinea: I. Epidemiology of human disease and clinical observations

The arenavirus Lassa is found in West Africa, where it sometimes causes a severe illness called Lassa fever. Lassa fever has been seldom investigated outside of a few hyperendemic regions, where the described epidemiology may differ from that in areas of low or moderate incidence of disease. Through a prospective cohort study, we investigated the epidemiology and clinical presentation of Lassa fever in Guinea, where the disease has been infrequently recognized. A surveillance system was established, and suspected cases were enrolled at five Guinean hospitals. Clinical observations were made, and blood was taken for enzyme-linked immunosorbent assay testing and isolation of Lassa virus. Lassa fever was confirmed in 22 (7%) of 311 suspected cases. Another 43 (14%) had Lassa IgG antibodies, indicating past exposure. Both sexes and a wide variety of age and ethnic groups were affected. The disease was more frequently found, and the IgG seroprevalence generally higher, in the southeastern forest region. In some areas, there were significant discrepancies between the incidence of Lassa fever and the prevalence of antibody. Clinical presentations between those with Lassa fever and other febrile illnesses were essentially indistinguishable. Clinical predictors of a poor outcome were noted, but again were not specific for Lassa fever. Case-fatality rates for those with Lassa fever and non-Lassa febrile illnesses were 18% and 15%, respectively. Seasonal fluctuation in the incidence of Lassa fever was noted, but occurred similarly with non-Lassa febrile illnesses. Our results, perhaps typical of the scenario throughout much of West Africa, indicate Lassa virus infection to be widespread in certain areas of Guinea, but difficult to distinguish clinically.     

Seizure disorders among relatives of Kenyan children with severe falciparum malaria

PURPOSE: The cause of seizures in children with falciparum malaria is unclear. In malaria endemic areas, children who develop severe falciparum malaria with seizures may have a genetically higher risk of epilepsy or febrile seizures. We used the history of seizures in relatives of children previously admitted with malaria to determine if there is evidence for a familial predisposition of seizures in children admitted with malaria and seizures or cerebral malaria. METHODS: Family history of seizures were obtained from the parents/guardians of 81 children (35 children previously admitted with severe malaria and 46 children matched for age who had not been admitted with severe malaria). Data were collected on frequency, duration, age of onset, presence of fever and causes of seizures. RESULTS: The prevalence of seizures in the relatives of children not admitted with severe malaria was 4.3%, of whom 2.2% had a history of seizures compatible with febrile seizures, and 1.1% with epilepsy. Overall the odds ratio (OR) for relations of children admitted with malaria, to have a seizure disorder was 1.41 [95% confidence interval (CI) 1.06-1.88]. There was a significant risk of the relatives dying if they had epilepsy [relative risk 1.88 (95% CI 1.11-3.19)], but not for other seizure disorders (i.e. febrile, single or unclassifiable seizures). CONCLUSION: Relatives of children admitted with severe falciparum malaria are more likely to have a seizure disorder compared with controls, but it is unclear if this is because of a genetic propensity or caused by exogenous factors such as malaria.     

Treatable bacterial infections are underrecognized causes of fever in Ethiopian children

Febrile illnesses remain a major cause of morbidity and mortality in resource-poor countries, but too often, tests are not available to determine the causes, leading to misdiagnosis and inappropriate treatment. To determine the cause of febrile illnesses, we recovered the malaria smears from 102 children presenting with fever to Soddo Christian Hospital in Wolaitta Soddo, Ethiopia. DNA was isolated from the smears and evaluated by real-time polymerase chain reaction. We identified pathogen DNA with probes for Plasmodium spp., Streptococcus pneumoniae, Rickettsia spp., Salmonella spp., and Borrelia spp. Overall, we showed that it is possible to isolate high-quality DNA and identify treatable pathogens from malaria blood smears. Furthermore, our data showed that bacterial pathogens (especially Pneumococcus, Rickettsia spp., and Borrelia spp.) are common and frequently unrecognized but treatable causes of febrile illnesses in Ethiopian children.     

Complicated malaria and other severe febrile illness in a pediatric ward in Libreville, Gabon

ABSTRACT: BACKGROUND: Although a substantial decline of Plasmodium falciparum infection is observed in Africa following implementation of new control strategies, malaria is still considered as the major cause of febrile illness in hospitalized African children. The present study was designed to assess the management of febrile illness and to determine the proportion of children with febrile illness hospitalized for primary diagnosis of malaria who had confirmed complicated malaria after implementation of new malaria control strategies in Libreville, Gabon. METHODS: Demographic, clinical and biological data from hospitalized children with fever or a history of fever with a primary diagnosis of clinical malaria, aged less than 18 years old, who benefited from hematological measurements and microscopic malaria diagnosis were recorded and analyzed during a prospective and observational study conducted in 2008 in the Centre Hospitalier de Libreville. RESULTS: A total of 418 febrile children were admitted at hospital as malaria cases. Majority of them (79.4%) were aged below five years. After medical examination, 168 were diagnosed and treated as clinical malaria and, among them, only 56.7% (n = 95) had Plasmodium falciparum positive blood smears. Age above five years, pallor, Blantyre Coma Score <=2 and thrombocytopenia were predictive of malaria infection. Respiratory tract infections was the first leading cause of hospitalization (41.1%), followed by malaria (22.7%); co-morbidities were frequent (22%). Less than 5% of suspected bacterial infections were confirmed by culture. Global case fatality rate was 2.1% and 1% for malaria. Almost half (46%) of the children who received antimalarial therapy had negative blood smears. Likewise, antibiotics were frequently prescribed without bacteriological confirmation. CONCLUSIONS: The use of clinical symptoms for the management of children febrile illness is frequent in Gabon. Information, training of health workers and strengthening of diagnosis tools are necessary to improve febrile children care.     

Renal involvement in Gambian children with cerebral or mild malaria

Kidney function was studied in 80 Gambian children with cerebral malaria, 73 children with mild malaria, and in 19 children with other febrile illnesses. Serum creatinine was measured, and the excretion in urine of immunoglobulin G, transferrin, albumin and alpha 1 microglobulin was determined. Twenty-five percent of children with cerebral malaria, and 4% of children with mild malaria had an elevated serum creatinine above 62 mumol/l. Increased urinary protein excretion was frequent: 53% of children with cerebral malaria had a glomerulo-tubular pattern of protein excretion, and 46% a tubular pattern. Median albuminuria was 68 mg/l in children with cerebral malaria, 18 mg/l in children with mild malaria, and 9 mg/l in febrile children with other diseases (P < 0.0001). There was no significant association between the proteinuria and height of fever or the degree of parasitaemia, and there was no significant association between death and signs of renal impairment. Renal involvement is common in children with malaria in The Gambia, with prerenal, glomerular, and tubulo-interstitial factors contributing. It is more pronounced in children with cerebral malaria than in those with mild malaria. However, renal dysfunction is relatively mild and does not indicate a worse prognosis.     

Salicylates, nitric oxide, malaria, and Reye's syndrome

Reye's syndrome virtually disappeared from much of the world after the use of salicylate in febrile children was successfully discouraged. This severe sepsis-like disease was thought to be caused by a hypersensitivity to salicylates in children with mild viral infections, although no mechanism consistent with this proposal was ever established. Salicylate toxicity in African children has been noted to have many clinical features in common with severe falciparum malaria, including acidosis, altered consciousness, convulsions, and hypoglycaemia. Salicylates are widely available in various formulations in many African countries, and are commonly used for initial treatment of the symptoms that malaria shares with other diseases. There is now experimental evidence that salicylate increases and prolongs the activity of key elements along the signalling pathway through which interferon gamma generates inducible nitric oxide synthase (iNOS), and we have shown that iNOS is strongly expressed in fatal malaria and other acute fevers in African children. We further propose that, in areas where salicyaltes are still used to treat the symptoms of febrile illnesses in children, this mechanism could exacerbate potentially serious infectious diseases, including falciparum malaria. In contrast, the absence of salicylate use in children in some Pacific islands could contribute to the milder outcome of falciparum malaria than is observed in Africa. Widespread expression of iNOS has also been seen in the tissues of a patient with fatal clinically defined Reye's syndrome. This finding suggests that Reye's syndrome can be mediated through salicylate enhancement of iNOS expression, the initial trigger in this instance usually being a viral infection.     

Compliance, safety, and effectiveness of fixed-dose artesunate-amodiaquine for presumptive treatment of non-severe malaria in the context of home management of malaria in Madagascar

Home management of malaria is recommended for prompt, effective antimalarial treatment in children less than five years of age. Compliance, safety, and effectiveness of the new fixed-dose artesunate-amodiaquine regimen used to treat suspected malaria were assessed in febrile children enrolled in a 24-month cohort study in two settings in Madagascar. Children with fever were asked to visit community health workers. Presumptive antimalarial treatment was given and further visits were scheduled for follow-up. The primary endpoint was the risk of clinical/parasitologic treatment failure. Secondary outcomes included fever/parasite clearance, change in hemoglobin levels, and frequency of adverse events. The global clinical cure rate was 98.4% by day 28 and 97.9% by day 42. Reported compliance was 83.4%. No severe adverse effects were observed. This study provides comprehensive data concerning the clinical cure rate obtained with artesunate-amodiaquine and evidence supporting the scaling up of home management of malaria.     

Prevalence of malaria parasitemia among clients seeking treatment for fever or malaria at drug stores in rural Tanzania 2004

OBJECTIVE: To determine the prevalence of malaria parasitemia and other common illnesses among drug store clients in one rural community, with a view to the potential role of specialist drug stores in expanding coverage of effective malaria treatment to households in highly endemic areas. METHOD: Follow-back study of 2466 client visits selected from all 10 drug stores operating in the town of Ikwiriri between May 30 and August 31 2004. Of these, 521 (21.2%) were made by or on behalf of persons ill with fever or malaria. Two hundred and ninety three were eligible as residents of the surrounding nine villages and all agreed to participate in the study. Each patient was evaluated by a clinical officer and provided a blood sample for malaria on the day of the shop visit, either at the shop or at home. RESULTS: Only 50 (17.1%) visits by or on behalf of febrile patients resulted in the purchase of an antimalarial drug, while an antipyretic medication was obtained at 226 visits (77.1%). Clinicians diagnosed malaria in 63.8% of patients. Malaria parasites were identified in blood film samples from 24.2% (95% CI: 19.6, 29.5). This is double the parasite prevalence rate of 10.7% (95% CI: 8.6, 13.1) obtained from a household survey of 1004 healthy individuals selected from these villages at the same time. It is not significantly lower than the prevalence observed among 880 clients presenting with fever at health facilities in the district: 29.7% (95% CI: 23.0, 37.3). The prevalence of malaria parasitemia among children younger than 5 years whose families sought fever treatment from drug stores (42.1%; 95% CI: 31.4, 53.5) was equal to that of children presenting with fever at health facilities (42.5%; 95% CI: 25.0, 62.2). CONCLUSIONS: Currently, drug store clients do not obtain malaria-specific treatment in the majority of cases where it might be warranted. Parasitological findings indicate that drug store clients, especially children, are as likely to be infected with malaria as patients seeking care for similar illnesses at health facilities. Drug stores may be attractive partners for policy makers eager to engage the private retail sector in expanding coverage of malaria treatment.     

Validity of clinical case definitions for influenza surveillance among hospitalized patients: results from a rural community in North India

Objective: Clinical case definitions used for influenza surveillance among hospitalized patients vary and need systematic evaluation. Design, setting and sample: During July 2009–August 2011, we collected clinical data and specimens (nasal and throat swabs) from rural patients hospitalized for acute medical illnesses. Specimens were tested by rRT‐PCR for influenza viruses. Main outcome measures: Case definitions evaluated the following: influenza‐like illness (ILI: measured fever plus cough or sore throat); severe acute respiratory illness (SARI: ILI with difficulty breathing in ≥5 years, Integrated Management of Childhood Illness–defined pneumonia or severe pneumonia, or physician diagnosed lower respiratory infection in <5 years); acute respiratory infection (ARI: ≥1 of cough, nasal discharge, difficulty breathing or sore throat); febrile acute respiratory illness (FARI: fever plus either cough, sore throat, runny nose, difficulty breathing, or earache). Variants that included “reported fever” and additional sign–symptom combinations were also evaluated. Results: We enrolled 1043 hospitalized patients, including 257 children <5 years of age (range 1 day–86 years). Seventy‐four patients tested influenza virus positive (including 28 A(H1N1)pdm09). Sensitivity(95% CI) and specificity (95% CI) for influenza infection were 78% (67–87) and 60% (57–63) for ILI (measured/reported fever); 37% (26–49) and 78% (75–80) for SARI (measured/reported fever); 82% (72–90) and 57% (54–60) for FARI (measured/reported fever); 88% (78–94) and 45% (42–49) for ARI; and 74% (63–84) and 61% (58–64) for measured/reported fever plus cough. Case definitions including only measured fever had lower sensitivity. Conclusion: ILI and FARI with measured/reported fever provided good balance between sensitivity and specificity among hospitalized patients. The simpler case definition of measured/reported fever plus cough is suited for field surveillance.     

A prospective evaluation of a clinical algorithm for the diagnosis of malaria in Gambian children

Diagnosis of clinical malaria remains difficult, especially in areas where a high proportion of the asymptomatic population have parasitaemia, for the symptoms and signs of malaria overlap with those of other common childhood diseases, such as acute lower respiratory tract infections. However, a study of symptoms and signs in a group of children who presented to Farafenni Health Centre, The Gambia with a history of recent fever identified a group of signs and symptoms which were strong predictors of malaria as opposed to other febrile illnesses. Using these predictors, an algorithm was developed which could be used by fieldworkers and which had a similar sensitivity and specificity for the diagnosis of malaria as that of an experienced paediatrician working without laboratory support. This algorithm has been validated prospectively on 518 children who presented to the Medical Research Council clinic at Basse, The Gambia with fever or a history of recent fever during a 10-month period. A fieldworker obtained a detailed history from the parent or guardian of each child and performed a clinical examination which included measurement of axillary temperature and respiratory rate. Packed cell volume was measured and a thick smear was examined for malaria parasites. A malaria score, based on the presence or absence of malaria-related signs and symptoms, was determined for 382 children who were seen at the clinic during the high transmission season. Using the cut-off score which was optimal during the previous retrospective study, a sensitivity of 70% and a specificity of 77% for a diagnosis of malaria was obtained. The optimal cut-off score for the Basse population was a score of 7; this gave a sensitivity of 88% and a specificity of 62%, figures comparable to those obtained by an experienced paediatrician without laboratory support.     

Concurrent bacteraemia and malaria in febrile Nigerian infants

In the tropics, febrile illnesses are often presumed to be due to malaria, because of its endemicity, and treatment can lead to delay in diagnosis or failure to detect severe infections such as bacteraemia.This study sought to determine the prevalence of bacteraemia and malaria parasitaemia in febrile post-neonatal infants (age 1-12 months) at the University College Hospital, Ibadan, Nigeria, and the bacterial aetiological agents of bacteraemia in the infants. Therefore, 102 infants aged 1-12 months who presented with fever with a negative history of antimicrobial use in the week prior to presentation were evaluated and had blood cultures done for the detection of aerobic organisms by standard methods and blood films for malaria parasites. Bacteraemia was found in 38.2% of the infants, malaria parasitaemia was found in 46.1%.The most common organisms isolated were Escherichia coli (35.9%), Staphylococcus aureus (33.3%) and Klebsiella spp. (10.3%). Febrile children should be investigated for the presence of bacterial infection even if the blood film for malaria parasites is positive. Where laboratory facilities are not available, consideration should be given to the use of both anti-malarial therapy and empiric antibiotic therapy in the management of febrile infants, depending on the clinician's judgement.     

Causes of fever in adults on the Thai-Myanmar border

A hospital-based study was conducted along the Thai-Myanmar border to provide greater knowledge of the causes of febrile illness and to determine what zoonotic and vector-borne emerging infectious diseases might be present. A total of 613 adults were enrolled from June 1999 to March 2002. Cases were classified based on clinical findings and laboratory results. An etiologic diagnosis was made for 48% of subjects. Malaria was the most common diagnosis, accounting for 25% of subjects, with two-thirds Plasmodium falciparum. Serologic evidence for leptospirosis was found in 17% of subjects. Other etiologic diagnoses included rickettsial infections, dengue fever, and typhoid. The most frequent clinical diagnoses were nonspecific febrile illness, respiratory infections, and gastroenteritis. Clinical associations were generally not predictive of etiologic diagnosis. Apparent dual diagnoses were common, particularly for malaria and leptospirosis. Findings have been used to modify treatment of unspecified febrile illness in the area.     

Malaria and its treatment in rural villages of Aboh Mbaise, Imo State, Nigeria

We examined the malaria situation among 489 children under 5 years of age in the rural villages of Aboh Mbaise, Nigeria, using a combination of a standard questionnaire technique and laboratory diagnosis to confirm clinical observations. The results show a high prevalence rate of 52.8% for Plasmodium falciparum in this area. The geometric mean parasite density (GMPD) was 19,361.4/mm3. The proportion of children with fever and/or parasitaemia was not related to age, although the numbers in the febrile group appeared to increase with age. Using 37.5 degrees C as the threshold for fever, 48.7% of the heavily infected group (more than 1000/mm3) were afebrile while 51.3% were febrile. High grade temperatures above 38 degrees C were associated with high parasitaemia above 10,000 parasites/mm3. Of the 911 children who died in the area within the last five years, 22.4% died of fever of unknown origin, 39.7% from malaria, 22.5% from convulsion, 10.5% from diarrhoea and 4.6% from cough. Chloroquine is the drug of choice for the treatment of malaria and there were many cases of drug abuse, and use of sub-curative doses prescribed by non-medically qualified staff.     

Case management of childhood pneumonia in developing countries: recent relevant research and current initiatives.

Acute respiratory infections (ARI), mostly pneumonia, are one of the leading causes of death in young children in developing countries, accounting for 28% of childhood mortality. This paper provides a summary of the research and technical development efforts made in the last 15 years which contributed to improving the effectiveness of the case management strategy to reduce mortality from pneumonia in children in developing countries. Community intervention studies provided strong evidence that the strategy was feasible and effective in producing a substantial impact on pneumonia mortality. Clinical studies provided the rationale for improving the sensitivity and specificity of key signs of pneumonia, and for enhancing the therapeutic efficacy of standard home treatment. Research also provided data to deal with the problem of the clinical overlap of pneumonia and malaria in children. Technological initiatives succeeded in making appropriate diagnostic and therapeutic devices available. An important body of socio-cultural knowledge about family practices regarding pneumonia and ARI in children was built up and provided orientation on effective communication between health workers and families about home care of children with ARI. Health systems research focused on methods for surveillance of bacterial drug resistance and methodologies for evaluating the control programmes. Despite advances in the development of vaccines against respiratory bacteria and in the prevention of risk factors for pneumonia in children, case management will continue to be a central strategy for preventing mortality. Current international research initiatives are looking into measures that can improve the referral of severe pneumonia and effective management of severe pneumonia at first level hospitals.     

Deconstructing “malaria”: West Africa as the next front for dengue fever surveillance and control

Presumptive treatment of febrile illness patients for malaria remains the norm in endemic areas of West Africa, and “malaria” remains the top source of health facility outpatient visits in many West African nations. Many other febrile illnesses, including bacterial, viral, and fungal infections, share a similar symptomatology as malaria and are routinely misdiagnosed as such; yet growing evidence suggests that much of the burden of febrile illness is often not attributable to malaria. Dengue fever is one of several viral diseases with symptoms similar to malaria, and the combination of rapid globalization, the long-standing presence of Aedes mosquitoes, case reports from travelers, and recent seroprevalence surveys all implicate West Africa as an emerging front for dengue surveillance and control. This paper integrates recent vector ecology, public health, and clinical medicine literature about dengue in West Africa across community, regional, and global geographic scales. We present a holistic argument for greater attention to dengue fever surveillance in West Africa and renew the call for improving differential diagnosis of febrile illness patients in the region.     

Clinical algorithms for malaria diagnosis lack utility among people of different age groups

We conducted a study to determine whether clinical algorithms would be useful in malaria diagnosis among people living in an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of all age groups participated. We took smears and recorded clinical signs and symptoms (prompted or spontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was defined as a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinical signs and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria case was selected for the age groups /=15 years. These age-optimized derived algorithms were able to identify about 66% of the cases among those <15 years of age but only 23% of cases among adults. Were these algorithms to be used as a basis for a decision on treatment among those presenting to the clinic, 16% of children /=5000 parasites/microl of blood would be sent home without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis, performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials would make more drugs available to the really needy population of children under 5 years of age.     

Etiology of Pediatric Fever in Western Kenya: A Case–Control Study of Falciparum Malaria,Respiratory Viruses,and Streptococcal Pharyngitis

In Kenya, more than 10 million episodes of acute febrile illness are treated annually among children under 5 years. Most are clinically managed as malaria without parasitological confirmation. There is an unmet need to describe pathogen-specific etiologies of fever. We enrolled 370 febrile children and 184 healthy controls. We report demographic and clinical characteristics of patients with Plasmodium falciparum, group A streptococcal (GAS) pharyngitis, and respiratory viruses (influenza A and B, respiratory syncytial virus [RSV], parainfluenza [PIV] types 1–3, adenovirus, human metapneumovirus [hMPV]), as well as those with undifferentiated fever. Of febrile children, 79.7% were treated for malaria. However, P. falciparum was detected infrequently in both cases and controls (14/268 [5.2%] versus 3/133 [2.3%], P = 0.165), whereas 41% (117/282) of febrile children had a respiratory viral infection, compared with 24.8% (29/117) of controls (P = 0.002). Only 9/515 (1.7%) children had streptococcal infection. Of febrile children, 22/269 (8.2%) were infected with > 1 pathogen, and 102/275 (37.1%) had fevers of unknown etiology. Respiratory viruses were common in both groups, but only influenza or parainfluenza was more likely to be associated with symptomatic disease (attributable fraction [AF] 67.5% and 59%, respectively). Malaria was overdiagnosed and overtreated. Few children presented to the hospital with GAS pharyngitis. An enhanced understanding of carriage of common pathogens, improved diagnostic capacity, and better-informed clinical algorithms for febrile illness are needed.