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Objectives To describe the prevalence, aetiology and prognostic implications of coexisting invasive bacterial disease in children admitted with severe malaria in a rural Mozambican Hospital.
Methods Retrospective study of data systematically collected from June 2003 to May 2007 in a rural Mozambican hospital, from all children younger than 5 years admitted with severe malaria.
Results Seven thousand and forty-three children were admitted with a diagnosis of malaria. 25.2% fulfilled the criteria for severe malaria. 5.4% of the children with severe malaria and valid blood culture results had a concomitant bacteraemia. Case fatality rates of severe malaria cases rose steeply when bacteraemia was also present (from 4.0% to 22.0%, P < 0.0001), and bacteraemia was an independent risk factor for death among severe malaria patients (adjusted OR 6.2, 95% CI 2.8–13.7, P = 0.0001). Streptococcus pneumoniae, Gram-negative bacteria, Staphilococcus aureus and non-typhoid Salmonella (NTS) were the most frequently isolated microorganisms among severe malaria cases. Their frequency and associated case fatality rates (CFR) varied according to age and to syndromic presentation. Streptococcus pneumoniae had a relatively low CFR, but was consistently associated with severe malaria syndromes, or anaemia severity groups. No clear-cut relationship between malarial anaemia and NTS bacteraemia was found.
Conclusions The coexistence of malaria and invasive bacterial infections is a frequent and life-threatening condition in many endemic African settings. In Mozambique, S. pneumoniae is the leading pathogen in this interaction, possibly as a consequence of the high HIV prevalence in the area. Measures directed at reducing the burden of both those infections are urgently needed to reduce child mortality in Africa.
Malaria sévère et bactériémie concomitante chez les enfants admis dans un hôpital rural mozambicain
Objectifs: Décrire la prévalence, l’étiologie et les implications pronostiques de la coexistence de maladies bactériennes invasives chez les enfants admis avec une malaria sévère dans un hôpital rural mozambicain.
Méthodes: Etude rétrospective de données collectées systématiquement de juin 2003 à mai 2007 dans un hôpital rural mozambicain, sur tous les enfants de moins de 5 ans admis avec une malaria sévère.
Résultats: 7043 enfants ont été admis avec un diagnostic de malaria. 25,2% répondaient aux critères de malaria sévère. 5,4% des enfants avec une malaria sévère et des résultats valides de culture de sang avaient une bactériémie concomitante. Les taux de létalité des cas de malaria sévère augmentaient fortement lorsqu’une bactériémie était également présente (de 4,0%à 22,0%; p < 0,0001) et la bactériémie était un facteur de risque indépendant de mortalité chez les patients atteints de malaria sévère (OR ajusté = 6,2; IC95%: 2,8-13,7; p = 0,0001). Streptococcus pneumoniae, bactéries à Gram négatif, Staphylococcus aureus et Salmonella non-typhoïdien (NTS) étaient les micro-organismes les plus fréquemment isolés chez les cas de malaria sévère. Leur fréquence et les taux de létalité associée variaient en fonction de l’âge et de la présentation syndromique. S. pneumoniae avait un taux de létalité relativement faible, mais était associé de façon consistante à des syndromes de malaria sévère ou à des groupes d’anémie sévère. Une relation claire entre l’anémie malarique et la bactériémie NTS n’a pas été trouvée.
Conclusions: La coexistence de malaria et des infections bactériennes invasives est une condition fréquente et de danger la vie dans de nombreuses régions endémiques africaines. Au Mozambique, S. pneumoniae est le principal agent pathogène dans cette interaction, peut-être comme une conséquence de la forte prévalence du VIH dans la région. Mesures visant à réduire la charge de ces deux infections sont urgemment nécessaires pour réduire la mortalité infantile en Afrique.
Malaria severa y bacteremia concomitantes en niños ingresados en un hospital rural en Mozambique
Objetivos: Describir la prevalencia, la etiología y las implicaciones del pronóstico de una enfermedad bacteriana invasiva coexistiendo en niños admitidos con malaria severa en un hospital rural de Mozambique.
Métodos: Estudio retrospectivo de datos recolectados sistemáticamente entre el 2003 y Mayo del 2007, en un hospital rural Mozambicano, provenientes de niños menores de 5 años admitidos con malaria severa.
Resultados: Se admitieron 7043 niños con un diagnóstico de malaria. 25.2% cumplían con los criterios de malaria severa. 5.4% de los niños con malaria severa y un resultado válido en el hemocultivo, tenían una bacteremia concomitante. La tasa de letalidad (TL) de la malaria severa aumentaba considerablemente cuando la bacteremia estaba también presente (del 4.0% al 22.0%, p < 0.0001), y la bacteremia era un factor de riesgo independiente para muerte entre pacientes con malaria severa (OR ajustado 6.2, 95% IC 2.8-13.7, p = 0.0001). Streptococcus pneumoniae, bacterias Gram negativas, Staphilococcus Aureus y Salmonella no tifoidea (NTS) eran los microorganismos más frecuentemente aislados entre los casos de malaria severa. Su frecuencia y las TL asociadas variaban de acuerdo con la edad y la presentación del síndrome. S. pneumoniae tenía una TL relativamente baja, pero estaba consistentemente asociada con grupos de síndrome de malaria severa, o anemia severa. No se halló una relación clara entre la anemia por malaria y bacteremia por NTS.
Conclusiones: La coexistencia de la malaria con infecciones bacterianas invasivas es una condición frecuente y potencialmente mortal en muchos lugares endémicos de África. En Mozambique, S.pneumoniae es el principal patógeno en esta interacción, posiblemente como una consecuencia de la alta prevalencia de VIH en el área. Se requieren urgentemente medidas dirigidas a reducir la carga de estas dos infecciones para reducir la mortalidad infantil en África.
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During the 4-year study period, 14 337 children younger than 5 years were admitted to MDH. 7043 (49.1%) children had malaria, and a quarter of these (n = 1780) fulfilled the severe malaria definition. A flow chart (Figure 1) summarises the number of study children according to diagnosis, age group (<2 years and >2 years), availability and validity of blood culture results. 12.8% (207/1616) of severe malaria patients with a blood culture performed grew contaminant microorganisms, and 0.3% (5/1616) grew S. viridans. 5.4% (76/1404) of severe malaria patients with a valid culture result (excluding contaminations or S. viridans), had bacteraemia.
Figure 1. Flow chart summarizing the number of study children according to diagnosis age group (<2 years and ≥2 years) availability and validity of blood culture results.
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Among severe malaria patients with bacteraemia, S. pneumoniae was the most frequent isolate (26.3%, n = 20), followed by Gram negative bacteria (21.1%, n = 16), S. aureus (17.1%, n = 13) and NTS (15.8%, n = 12).
Figure 2 shows the aetiology of bacteraemia in patients with severe malaria, as compared to the aetiology of bacteraemia for all other non-malaria admissions. Distribution of microorganisms varied according to admission diagnosis, but in both cases S. pneumoniae was the most frequent isolate, although differences were non-significant. Figure 3 shows the prevalence of bacteraemia according to the different severe malaria syndromes. While the prevalence in the severe malaria cases with hypoglycaemia was very high (12.5%), it decreased substantially in the severe malaria cases with convulsions (1.7%). Figure 4 shows the relative contribution of the main bacteria within each syndromic group. S. pneumoniae was consistently the most important isolate in each of these groups, except for patients with convulsions or prostration.
Figure 2. Relative contribution (in %) of the main 4 bacterial isolates as causes of bacteraemia among severe malaria cases compared to all other non-malaria diagnoses.
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Figure 3. Prevalence of bacteraemia among different severe malaria syndromes in children with valid blood culture results.
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Figure 4. Relative contribution (in %) of different bacterial isolates according to different severe malaria syndromes/symptoms.
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Table 1 shows clinical and laboratory parameters of children with severe malaria according to blood culture result, and Table 2 refers them to different bacterial isolates. Bacteraemic children with severe malaria had a higher CFR, were more severely malnourished and had lower mean parasitaemias than severe malaria patients with a negative blood culture.
Table 1. Clinical and laboratory parameters of children with severe malaria according to blood culture result
| ||Negative (N = 1328)||Positive (N = 76)|| P (+ vs.−)|
|Age (mean (SD)) (months)||22.0 (14.7)||19.1 (13.9)||0.09|
|Case fatality rate† (% (n))||4.0 (50)||22.0 (13)||<0.0001|
|Respiratory distress (% (n))||40.8 (542)||48.7 (37)||0.175|
|Haematocrit‡ (mean (SD))||23.4 (8.4)||22.7 (8.4)||0.440|
|Mean parasitaemia (parasite/μl) (geometric mean (95% CI))||16 639 (14 914–18 562)||6537 (3718–11 494)||0.002|
|Weight for age Z-score§ (median (IQR))||−1.6 (−2.7/−0.6)||−2.2 (−3.5/−1.2)||0.001|
Table 2. Clinical and laboratory parameters of children with severe malaria and bacteraemia according to blood culture isolate
| || S. pneumoniae (n = 20)||Non-typhoid Salmonella NTS (n = 12)|| Gram negative bacteria (n = 16)|| S. aureus (n = 13)|
|Age (mean (SD)) (months)||17.2 (10.8)||16.4 (6.1)||23.3 (19.9)||22.0 (14.8)|
|Case fatality rate (% (n/N))||13.3 (2/15)||25.0 (2/8)||25.0 (3/12)||30.0 (3/10)|
|Respiratory distress (% (n))||60.0 (12)||33 (4)||37.5 (6)||30.8 (4)|
|Haematocrit† (mean (SD))||20.8 (6.9)||22.1 (9.3)||22.3 (8.8)||23.2 (7.6)|
|Mean parasitaemia (parasite/μl) (geometric mean (95% CI))||1753 (564–5449)||9687 (3233–29 030)||13 338 (3079–57 778)||11 883 (2326–60 717)|
|Weight for age Z-score (median (IQR))||−2.7 (−3.4/−1.6)||−2.6 (−3.3/−2.1)||−2.2 (−4.1/−1.1)||−2.0 (−3.1/−0.4)|
The prevalence of NTS bacteraemia was not significantly different between severe malaria and non-malaria cases (data not shown). Respiratory bacteria (S. pneumoniae and Hib) were isolated more frequently from patients with severe malaria who had respiratory distress (43.2%) than from patients without it (20.5%; P = 0.03).
When assessing specific signs and symptoms among severe malaria patients with valid blood culture results, bacteraemia was significantly more frequent in patients who presented with hypoglycaemia on admission (12.5%vs. 5.1% in those that did not, P = 0.01), hepatomegaly (16.1%vs. 5.0%, P < 0.0001) or oral candidiasis (30.8%vs. 5.2%, P < 0.0001), and significantly less frequent among those with convulsions (1.7%vs. 6.0%, P = 0.02). No significant differences were observed between children presenting and not presenting other signs or symptoms.
Anaemia and bacteraemia in severe malaria patients
The prevalence of anaemia (PCV < 33%) among severe malaria patients was high (83.0%). The frequency of bacteraemia seemed to be independent of the presence of anaemia and this remained true for the different degrees of anaemia severity, being 6.3% (26/416) among children with mild anaemia, 4.6% (22/474) among those with moderate anaemia and 7.0% (18/256) among severe anaemia cases (p = 0.4). Figure 5 illustrates the aetiology of bacteraemia cases among severe malaria patients according to admission haematocrit. S. pneumoniae was the most frequent bacterial isolate among all malarial anaemia groups (mild, moderate and severe).
Figure 5. Aetiology (% (n)) of bacteraemia cases in severe malaria patients according to haematocrit on admission. PCV, packed cell volume.
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Case fatality rates
Severe malaria accounted for 12% (81/669) of all in-hospital deaths in children <5 years of age. Thirteen children with bacteraemia and severe malaria died. CFR for severe malaria was overall 4.9% (81/1648), rising significantly to 22.0% (13/59) when associated with concomitant bacteraemia.
The impact of having a concomitant bacteraemia was important in some but not all severe malaria syndromic presentations. Among patients with severe malaria and severe anaemia which also had bacteraemia, CFR rose when compared to those without bacteraemia [31.3% (5/16) vs. 5.2% (11/211), P = 0.002]. Similarly, severe malaria patients with respiratory distress and superimposed bacteraemia had a much higher CFR than those without bacteraemia [32.1% (9/28) vs. 5.2% (26/498), P < 0.0001]. This increased CFR related to the concomitant bacteraemia could not be confirmed in those severe malaria cases with deep coma, although numbers were very small.
CFRs of the different bacterial isolates among severe malaria patients ranged from 12.5% for Streptococci to 33.3% for H. influenzae. Among severe malaria bacteraemic patients, CFRs did not significantly vary according to antibiotic use (25.0% for children who received antibiotics vs. 17.4% among those who did not; P = 0.49).
Risk factors for death
Independent risk factors for death among severe malaria patients are shown in Table 3. Importantly, a positive blood culture independently increased the odds of death by 6.2 (95% CI 2.8–13.7).
Table 3. Risk factors independently associated with mortality in children <5 years (n = 1165) with severe malaria according to a multivariate logistic regression model
|Risk factor||Adjusted OR|| 95% CI|| P (LR χ2-test 1 d.f.)|
|Positive blood culture†||6.2||2.8–13.7||<0.0001|
|Weight for age Z-score (per unit increase)||0.74||0.62–0.88||0.0005|
|Having been previously visited‡||2.2||1.2–4.0||0.01|
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Severe malaria is the predominant cause of hospital admission among children younger than 5 years of age attending Manhiça hospital (Bassat et al. 2008). This study portrays the frequent coexistence of bacteraemia among severe malaria patients, and its detrimental prognostic implications. Despite a substantial degree of overlap between the two diseases, it seems difficult to establish whether one infection predisposes to the other or whether they are both coincidental. Indeed, 5.4% of all admitted patients with severe malaria and valid blood culture results had concurrent bacteraemia, and conversely, 7.3% of bacteraemic patients had also severe malaria. Bacteraemia substantially increased, as anticipated (Berkley et al. 1999; Bronzan et al. 2007), the risk of death. Bacteraemia should therefore be considered in future revisions as one of the defining criteria for severe malaria. The remaining independent risk factors for death among malaria cases are concordant with those previously described for the area (Bassat et al. 2008), disparities being attributable to differences in sample size. CFRs of patients with both diseases were much higher than CFRs of any of the infections alone. Parasite densities among severe malaria patients with bacteraemia were significantly lower than those among non-bacteraemic, suggesting that some of those low-grade malarial infections could be incidental. This finding contrasts with previous studies (Berkley et al. 1999; Bronzan et al. 2007) in which parasitaemias in severe malaria patients with or without bacteraemia did not differ significantly, but such studies did not look at all consecutive admissions, and were only based on selected series of severe malaria cases predominantly presenting with cerebral malaria, severe anaemia or respiratory distress. It is important to note, however, that due to the age-related differences in the criteria for taking blood cultures, an important proportion of children older than two years of age may lack a blood culture in admission, as compared to younger children. The fact that only 117 severe malaria patients (15.7%) older than two years of age did not have a blood culture performed reassures us that most severe malaria patients did indeed fulfil severity criteria despite their age for blood to be cultured. The lack of microbiological data on these admitted children may, however, bias our estimates on the magnitude of the coexistence of both diseases in any direction, but should not represent, in any case, a major deviation from reality.
As all blood cultures were performed on admission in this study, both diseases, when coexisting, were simultaneously present on arrival. It is however not possible to ascertain the causal pathway leading to such co-infection, as it is problematic to distinguish whether one patient dies with bacteria or parasites in their blood or as a result of such parasites or bacteria.
A consistent relationship between malaria and NTS bacteraemia has been documented (Graham et al. 2000; Walsh et al. 2002; Bronzan et al. 2007), and several studies have suggested that malaria parasites or malarial anaemia may predispose to NTS bacteraemia (Mabey et al. 1987). Other African series (Prada et al. 1993; Bahwere et al. 2001; Evans et al. 2004; Norton et al. 2004) confirmed this and also underlined the importance of other GRAM negative bacteria among malaria cases. In contrast to these findings, our data highlight the importance of S. pneumoniae as the principal isolate related with severe malaria cases in Manhiça. Difficulties inherent to the isolation of S. pneumoniae (such as its slow growth rate and subsequent potential for contamination of the truly infected samples by other faster-growing contaminant bacteria) could partially explain why such infection was rare in previous African studies (Evans et al. 2004). The HIV infection, highly prevalent in Manhiça [23.6% positivity among pregnant women attending the antenatal clinic in 2001–2006 (Menendez et al. 2008)], has traditionally been considered a risk factor for pneumococcal invasive disease (Greenwood 1999). Unfortunately, no HIV data were available for these patients, and its relevance cannot be confirmed, potentially bringing an important bias to these results. However, the importance of HIV infection may be inferred indirectly by the high prevalence of oral candidiasis among children in the study, an unusual finding in severe malaria patients, but a good marker of immunosuppression. Similarly, the absence of sickle cell disease in Manhiça (Menéndez, personal communication), a genetic trait traditionally associated with an increase in NTS and other GRAM negative bacterial infections, may also contribute to enhance the burden of pneumococcal disease in detriment of NTS.
These data also challenge a clear-cut relation between severe malaria cases with any degree of anaemia and NTS. Indeed, S. pneumoniae was again the most frequent isolate in any of the different anaemia groups, and also showed the lowest associated mean admission haematocrit. NTS bacteraemias were associated with higher geometric mean parasitaemias than S. pneumoniae bacteraemias, contrary to previous reports (Mabey et al. 1987; Brent et al. 2006a) which linked NTS infections to low-level parasite loads or recently cured malaria episodes. This study did not replicate the previously described relationship between malarial anaemia and NTS bacteraemia, although an association between them may still exist, and might not have been detected due to the relatively small number of severe malaria cases with bacteraemia. The contribution of other factors to the development of anaemia in this setting may partially explain why such an association was not clearly confirmed.
This retrospective analysis of all under-five admissions over four years has given insight on the way malaria and bacteraemia intertwine. Importantly, these data may however underestimate what really occurs in the community (Brent et al. 2006b), where an important proportion of the burden of these two diseases remains undetected. Individually, these two diseases have an enormous impact on the health of African children, and this study has shown that the coexistence of bacteraemia drastically worsens the clinical prognosis in malaria. The deployment of existing, already registered and effective antibacterial tools, such as the pneumococcus conjugate vaccine, necessary to decrease the silent but constant burden of bacteraemia, may also have an impact in reducing malaria mortality.