Clinical Picture and Risk Factors for Poor Outcome in Streptococcus pneumoniae Meningitis of Childhood on Three Continents.

BACKGROUND: Streptococcus pneumoniae meningitis (SpM) remains a major health burden worldwide, particularly in low- and middle-income countries. Identifying the patients at highest risk for mortality and disabling sequelae may reveal potentially avoidable predisposing factors and identify patients most in need of intensive care. We searched for factors that do not require laboratory facilities. METHODS: This study was a secondary analysis of prospectively collected data from 5 clinical trials of childhood bacterial meningitis on 3 continents between 1984 and 2017. SpM cases were analyzed by study site and predictors for poor outcome (death or severe sequelae) were identified from the whole series, Latin America and Angola. RESULTS: Among a total of 1575 children (age range: 2 months to 15 years), 505 cases were due to pneumococci. Compared to other etiologies, SpM doubled the death rate (33% vs. 17%) and tripled poor outcome (15% vs. 6%). In SpM, Glasgow Coma Score <13 [odds ratio (OR): 4.73] and previous antibiotics in Angola (OR: 1.70) were independent predictors for death. Predictors for poor outcome were age <1 year (OR: 2.41) and Glasgow Coma Score <13 (OR: 6.39) in the whole series, seizures in Latin America (OR: 3.98) and previous antibiotics in Angola (OR: 1.91). Angolan children had a 17-fold increased risk for poor outcome when compared with Finnish children ( P = 0.011). CONCLUSIONS: Our study proved the severity of SpM when compared with other etiologies. The outcome was especially poor in Angola. Most patients at risk for poor outcome are easily identified by clinical factors on admission.

Pneumonia in childhood bacterial meningitis-Experience from three continents.

INTRODUCTION: Although concomitant pneumonia is sometimes diagnosed in childhood bacterial meningitis, its role in the illness course and prognosis is not known. We examined these associations using prospectively collected data from Finland, Latin America and Angola. METHODS: This was a secondary descriptive analysis of prospectively collected data (clinical and laboratory findings at admission, during hospitalisation and outcome) from five clinical bacterial meningitis trials. We included children aged 2 months to 15 years from sites with confirmed bacterial meningitis and potential concomitant pneumonia (diagnosed clinically with or without a chest radiograph). RESULTS: Pneumonia was not observed in the 341 children included in Finland. Pneumonia was observed in 8% (51/606) of children in Latin America and in 46% (377/819) in Angola (p < 0.0001). In multivariate analyses, predisposing factors for pneumonia in Latin America were age <1 year, seizures and severe anaemia; the corresponding factors for Angola were preadmission duration of illness >3 days and non-meningococcal meningitis. Concomitant pneumonia increased the severity of the disease and disabling sequelae. CONCLUSION: Bacterial meningitis with pneumonia is a major, previously undescribed entity of severe bacterial meningitis, especially in Angola.

Clinical blindness in conjunction with childhood bacterial meningitis.

Although rarely reported, bilateral loss of vision is a severe complication of childhood bacterial meningitis. We assessed its frequency in five prospective treatment trials performed in Europe, Latin America, and Angola in 1984-2017. Course of illness, follow-up findings, and child's sight were recorded. Sight was examined at discharge, and conditions permitting, also at 1-3 months post-hospitalization and in Angola on hospital day 7. Experienced pediatricians diagnosed clinical blindness if the child did not make eye contact, did not blink or move the eyes, or remained unresponsive to bright light or movement of large objects before their eyes. Of 1515 patients, 351, 654, and 510 were from Finland, Latin America, and Angola, respectively. At discharge, blindness was observed in 0 (0%), 8 (1.2%), and 51 (10%) children, respectively. In Angola, 64 children appeared to be blind on day 7; 16 of these children died. Blindness found at discharge in Angola was not invariably irreversible; approximately 40% had restored the sight at follow-up visit. Clinical blindness rarely occurred in isolation and was usually associated with young age and poor general condition at hospital arrival. Various other serious sequelae were common among the survivors with clinical blindness.

Importance of underweight in childhood bacterial meningitis in Finland, Latin America and Angola.

Our objective was to explore the importance of underweight on the course of childhood bacterial meningitis (BM) at different study sites, because prior studies showed discrepant results. Using directly comparable, prospective data from three continents, weight-for-age z-scores (WAZ) were determined by WHO Anthro programs in children with BM in Finland (N = 318), LatAm (N = 580), and Angola (N = 780) and compared with data describing the admission, course, and outcome of BM. WAZ < -1 indicates underweight; either mild (< -1 to -2), moderate (< -2 to -3), or severe (< -3). The mean WAZ (SD) was 0.17 (1.17), -0.42 (1.53), and -1.36 (1.44), and the prevalence of moderate-severe underweight 2.8%, 12.6%, and 31.3%, in Finland, LatAm, and Angola, respectively. In univariate analysis, LatAm and Angola showed an association between lower WAZ and poorer condition on admission, slower recovery, and more deaths. In Finland, infrequent underweight limited meaningful analysis. In multivariate analysis of different variables for increasing the odds of death, severe underweight had lower odds compared to disease severity in Angola, but highest in LatAm. Thus, the apparent discrepancy in underweights´ importance for increasing deaths varied from primary to more secondary according to locally more prominent risks.

Unusual Gram-negative bacteria cause more severe bacterial meningitis than the three classical agents in children.

AIM: To compare the characteristics, mortality and sequelae at hospital discharge of childhood bacterial meningitis (BM) caused by the three "classical" agents Neisseria meningitidis, Haemophilus influenzae or Streptococcus pneumoniae versus BM due to other aetiology in Finland, Latin America and Angola. METHODS: This observational study is a secondary analysis of data from five prospective treatment trials on non-neonatal BM in Finland, Latin America and Angola in 1984-2017. RESULTS: Of the 1568 cases, 1459 (93%) were caused by the classics, 80 (5%) by other Gram-negative and 29 (2%) by other Gram-positive bacteria. Nonclassical Gram-negative disease was encountered especially in Angola (p < 0.0001). Overall, children in the nonclassical group presented later for treatment and were more often underweight and anaemic (p < 0.001). In multivariate analysis, even if the area was strongest predictor of poor outcome, nonclassical Gram-negative BM increased the odds for death twofold and the odds for death or severe sequelae 2.5-fold. CONCLUSION: BM of a nonclassical aetiology is a particularly severe disease affecting especially Angolan children poorly armoured to fight infections. Since vaccinations are diminishing the role of classical agents, that of nonclassical agents is growing.

Prevalence and significance of anaemia in childhood bacterial meningitis: a secondary analysis of prospectively collected data from clinical trials in Finland, Latin America and Angola.

OBJECTIVES: To describe the prevalence and severity of anaemia and to examine its associations with outcome in children with bacterial meningitis (BM). DESIGN: Secondary analysis of descriptive data from five randomised BM treatment trials. SETTING: Hospitals in Finland, Latin America and Angola. PARTICIPANTS: Consecutive children from 2 months to 15 years of age admitted with BM and who had haemoglobin (Hb) measured on admission. OUTCOME MEASURES: Prevalence and degree of anaemia using the WHO criteria, and their associations with recovery with sequelae or death. RESULTS: The median Hb was 11.8 g/dL in Finland (N=341), 9.2 g/dL in Latin America (N=597) and 7.6 g/dL in Angola (N=1085). Of the children, 79% had anaemia, which was severe in 29%, moderate in 58% and mild in 13% of cases. Besides study area, having anaemia was independently associated with age <1 year, treatment delay >3 days, weight-for-age z-score <-3 and other than meningococcal aetiology. Irrespective of the study area, anaemia correlated with the markers of disease severity. In children with severe to moderate anaemia (vs mild or no anaemia), the risk ratio for death was 3.38 and for death or severe sequelae was 3.07. CONCLUSION: Anaemia, mostly moderate, was common in children with BM, especially in Angola, in underweight children, among those with treatment delay, and in pneumococcal meningitis. Poor outcome was associated with anaemia in all three continents. TRIAL REGISTRATION NUMBER: The registration numbers of Angolan trials were ISRCTN62824827 and NCT01540838.

Outcome of childhood bacterial meningitis on three continents.

Our objective was to quantify the differences in the outcomes from childhood bacterial meningitis (BM) and to describe the factors associated with them in different parts of the world. This study is a secondary analysis of prospectively collected data from five clinical BM trials conducted in Finland, Latin America (LatAm), and Angola between 1984 and 2017. As all data were collected uniformly, direct comparison of the series was possible. Associations between patient characteristics and death or dismal outcome-the triad of death, severe neurological sequelae, or deafness-were explored. In all, data on 2123 children with BM were analyzed. Etiology was confirmed in 95%, 83%, and 64%, in Finland, LatAm and Angola, respectively. The leading agents were Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Dismal outcome was the end result for 54%, 31%, and 5% of children in Angola, LatAm, and Finland, respectively. Although underweight, anemia, and tardy arrival worsened prognoses in Angola and LatAm, it was the presenting condition that was central in terms of outcome. In multivariate analysis, the factors independently associated with dismal outcome were the study site (Angola vs. Finland, OR 11.91, 95% CI 5.54-25.63, p < 0.0001 or LatAm vs. Finland, OR 9.46, 95% CI 4.35-20.61, p < 0.0001), Glasgow Coma Score < 13 (OR 4.58, 95% CI 3.31-6.32, p < 0.0001), seizures (OR 1.96, 95% CI 1.43-2.69), age < 1 year (OR 1.55, 95% CI 1.13-2.14, p = 0.007), and pneumococcal etiology (OR 1.49, 95% CI 1.08-2.06, p = 0.015). Greatly dissimilar outcomes from BM reflected the findings on admission on all three continents. Optimizing growth, preventing anemia, and prompt treatment may improve outcomes in resource poor areas.

Antibiotic Treatment and Surgery for Acute Hematogenous Calcaneal Osteomyelitis of Childhood.

Acute hematogenous calcaneal osteomyelitis characteristically affects children. A recent trend has emerged toward shorter courses of antibiotics. In our randomized, prospective treatment trial of children aged 3 months to 15 years, the intravenous antibiotic (clindamycin or a first-generation cephalosporin) was given only for the first 2 to 4 days and the remainder of the 20- to 30-day course was completed orally. A bone sample for culture was to be taken routinely, but all additional surgery was performed on special demand. We performed a retrospective subanalysis of cases affecting the calcaneus. The follow-up period was 1 year. Of the 14 participants enrolled, 11 completed the 1-year follow-up period, and their data were analyzed. Staphylococcus aureus was the cause of 10 cases; all strains were methicillin sensitive. The median intravenous treatment duration was 3 days. Four patients required open incisional trepanation (trephination). All participants attending the 1-year follow-up examination had fully recovered. The outcome of calcaneal osteomyelitis caused by methicillin-sensitive S. aureus in a child will be good, if the patient seeks treatment early and antibiotic therapy is started promptly. A bone biopsy is needed to obtain a representative sample for bacteriology.

Allergen skin prick testing in early childhood: reproducibility and prediction of allergic symptoms into early adulthood.

OBJECTIVE: To assess the predictive value of skin prick testing in early childhood on subsequent allergic symptoms up to adult age. STUDY DESIGN: A cohort of 200 unselected healthy newborns was prospectively followed from birth to 20 years of age. Of them, 163 (82%) were reassessed at age 5 years, 150 (76%) at age 11 years, and 164 (83%) at age 20 years with a skin prick test that included 11 common allergens. On the basis of clinical examination and structured interview, the occurrence of atopic dermatitis, allergic rhinoconjunctivitis, recurrent wheezing, and symptoms of food hypersensitivity were recorded at each of the follow-up visits. RESULTS: The reproducibility of skin prick test positivity at age 5 years was 100% at ages 11 and 20 years, ie, none of the skin prick-positive subjects turned negative during the follow-up. Gaining of new sensitizations to aeroallergens was common. Skin prick test positivity at age 5 years predicted allergic symptoms at ages 11 (sensitivity 28%, specificity 94%) and 20 years (sensitivity 23%, specificity 91%) but not atopic dermatitis. CONCLUSIONS: Skin prick test positivity at age 5 years strongly predicts later skin prick test positivity and is associated with respiratory symptoms, ie, allergic rhinoconjunctivitis and recurrent wheezing, at ages 11 and 20 years. However, skin prick test negativity at age 5 years does not exclude sensitization and allergic symptoms at a later age.

Preceding trauma in childhood hematogenous bone and joint infections.

Preceding trauma may play a role in the etiology and pathogenesis of hematogenous bone and joint infections. Among 345 children with an acute hematogenous bone and/or joint infection, 20% reported trauma during a 2-week period leading to infection. Blunt impact, bruises, or excoriations were commonly reported. The rate was similar to that in the general pediatric population obtained from the literature. In the study group, patients with and without trauma were similar in age, serum C-reactive protein and erythrocyte sedimentation rate, length of hospitalization, and late sequelae. Preceding minor trauma did not prove to be significant as an etiological or as a prognostic factor.

C-reactive protein versus erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase in diagnosing bacteraemia in bone and joint infections.

AIM: Bacteraemia is common in childhood acute bone and joint infections and demands urgent treatment. Blood C-reactive protein (CRP), erythrocyte sedimentation rate and white blood cell count (WBC) are well known and established markers in these infections. Instead, no information is available on serum alkaline phosphatase whose concentration is known to increase in septic conditions. METHODS: In our large prospective treatment trial comprising of 265 children with acute culture-positive bone or joint infection, all these laboratory indices were monitored on admission to hospital. The predictive value to detect bacteraemia was assessed for each of these four indices. RESULTS: In all, 59% of the patients showed bacteraemia. CRP was significantly (P < 0.05) higher among bacteraemic patients, whereas erythrocyte sedimentation rate, white blood cell count and alkaline phosphatase were not. The area under receiver operator characteristic curve for CRP was 0.588 (CI95% 0.524-0.649) and the significance level P (Area = 0.5) was <0.05. CONCLUSION: None of the markers could reliably diagnose bacteraemia. CRP alone was significantly higher among bacteraemic patients.

Significance of Negative Cultures in the Treatment of Acute Hematogenous Bone and Joint Infections in Children.

BACKGROUND: Synovial fluid and blood cultures often remain negative in acute bone and joint infections of childhood even when characteristic symptoms, signs, and/or radiologic proof are present. METHODS: We analyzed 345 prospectively documented osteoarticular infections in children at age 3 months to 15 years. In 23% of the cases (N = 80), synovial, bone, and/or blood cultures remained negative. The characteristics of these cases were compared with patients with culture-positive bone and joint infections. RESULTS: The 2 groups did not differ in age or gender distribution, surgical procedures performed, or outcome. In the culture-negative cases, the initial serum C-reactive protein level was lower (58 vs 87 mg/L, P < .0001) and the hospital stay was shorter (8 vs 11 days, P < .0001). CONCLUSIONS: Bone and joint infections in which cultures fail to identify the causative agent can be treated similarly as culture-positive cases.

Shortened hospital stay for childhood bone and joint infections: analysis of 265 prospectively collected culture-positive cases in 1983-2005.

BACKGROUND: In recent decades the treatment of childhood acute bone and joint infections has shifted towards shorter antibiotic courses and rapid transition to oral therapy. METHODS: We prospectively collected 265 culture-positive cases of non-neonatal bone and joint infections in Finnish children during 1983-2005. The duration of antimicrobial treatment and the extent of surgery were defined in the study protocol, but for ethical reasons, the liaison clinician determined the time of discharge using normalization of the serum C-reactive protein (CRP) level as a yardstick. We examined changes during the study in the distribution of causative organisms, severity of disease, and length of hospital stay. RESULTS: Staphylococcus aureus was overwhelmingly the most common causative agent throughout the study, whereas Haemophilus influenzae type b was eliminated soon after the introduction of vaccination. The mean time from initial symptoms to presentation remained the same at 4 days, and no significant change was observed in the severity of disease, CRP, or the rate of sequelae. The mean duration of intravenous antibiotic administration was only 4 days. The average hospital stay shortened significantly from 13 days to 9 days (p = 0.0001). CONCLUSIONS: The shortened hospital stay was not due to a change in the anatomical site of these infections, but to simplified treatment. Considerable savings in hospital stay, and thus costs, are feasible in osteoarticular infections of childhood by using CRP in monitoring the disease and shortening intravenous treatment by a swift move to per oral administration.

Management of osteoarticular infections caused by Staphylococcus aureus is similar to that of other etiologies: analysis of 199 staphylococcal bone and joint infections.

BACKGROUND: Acute hematogenous osteomyelitis, septic arthritis, and their combination are considered to warrant especially aggressive treatment if caused by Staphylococcus aureus. METHODS: Our prospective treatment trial of children aged 3 months to 15 years included 199 cases of S. aureus osteomyelitis, septic arthritis, or their combination. These cases were compared with 66 cases caused by other agents, mainly Haemophilus influenzae type b, Streptococcus pneumoniae, or Streptococcus pyogenes. According to protocol, the treatment was initiated intravenously only for 2 to 4 days and completed orally. Nonstaphylococcal and staphylococcal infections were treated similarly. Primary antibiotics were clindamycin or a first-generation cephalosporin. Follow-up lasted ≥ 12 months posthospitalization. RESULTS: Staphylococcal infections did not significantly differ in the duration of medication, hospital stay, surgery performed, or the number of sequelae when compared with the other etiologic groups. One child with S. aureus arthritis developed 2 late infections by other agents in the same anatomic site. Except 3 mild sequelae (2 caused by S. aureus and 1 by S. pyogenes) 12 months posthospitalization, all patients recovered completely. CONCLUSIONS: Osteoarticular infections of childhood caused by methicillin-susceptible S. aureus can be treated according to the same protocol as those used for infections caused by other agents.

[Pediatric septic shoulder arthritis. Is routine arthrotomy still necessary?]. / Onko rutiinileikkaus tarpeen lasten septisen olka-artriitin hoidossa?

BACKGROUND: Arthrotomy is recommended as a routine treatment for childhood septic arthritis of the shoulder, although scientific evidence is lacking. Suggested alternatives are arthroscopic lavage, serial aspirations and a mere diagnostic aspiration. MATERIAL AND METHODS: 9 patients with septic arthritis of the shoulder aged 3 months to 12 years underwent a diagnostic aspiration after which large dose antimicrobials were given qid (clindamycin or 1st generation cephalosporin). RESULTS: One child underwent arthrotomy, otherwise all patients recovered normally. There were no sequelae. CONCLUSIONS: Routine arthrotomy for all patients is of questionable value in the emergency treatment of septic shoulder arthritis in children.

Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases.

BACKGROUND: Considerable uncertainty exists on the optimal duration of antimicrobials for acute hematogenous osteomyelitis (AHOM) in children. Often they are administered for 1 to 2 months, the first 1 to 2 weeks intravenously, and decompressive surgery is usually added. No prospective, randomized, sufficiently powered comparative trial has been available. METHODS: Children aged 3 months to 15 years with culture-positive AHOM were randomly assigned to receive clindamycin or a first-generation cephalosporin for 20 or 30 days, including an intravenous phase for the first 2 to 4 days. Surgery was kept at minimum. Illness was monitored with preset criteria. Antimicrobial was discontinued once most signs had subsided and serum C-reactive protein decreased ≤20 mg/L. The primary end point was full recovery without need for further antimicrobial therapy because of an osteoarticular indication during the 12 months after the primary therapy. RESULTS: Of the 131 cases, 18% also involved the adjacent joint. Staphylococcus aureus caused 89% of cases, and all strains were methicillin susceptible. The median duration of treatment was 20 days for 67 children, and 30 days for 64 children. Most children underwent only the diagnostic percutaneous aspiration or drilling, and 24% had no surgery. Except for 1 mild sequela in both treatment groups, all patients recovered entirely. CONCLUSIONS: Most cases of childhood AHOM can be treated for 20 days, including a short period intravenously, with large doses of a well-absorbed antimicrobial such as clindamycin or a first-generation cephalosporin, provided the clinical response is good and C-reactive protein normalizes within 7 to 10 days. Extensive surgery is rarely needed.

Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition.

BACKGROUND: Small intestine essentially regulates cholesterol homeostasis. AIMS: To evaluate cholesterol metabolism in short bowel syndrome (SBS). METHODS: Cholesterol precursors (e.g., cholestenol, desmosterol and lathosterol) and plant sterols (campesterol and sitosterol), respective markers of cholesterol synthesis and absorption, were determined in SBS patients (n=12) an average of 31 months after weaning off parenteral nutrition and in age-matched controls (n=80). RESULTS: Among patients, serum cholesterol precursor sterol to cholesterol ratios were 2-10 times higher (P<0.0001 for each). Those without any remaining ileum had 1.2-2.8 times higher precursor sterol to cholesterol ratios than those with an ileal remnant (P<0.05 for each). Serum cholesterol concentration, campesterol/cholesterol and campesterol/sitosterol were 34-39% lower (P<0.05 for each) in relation to controls. Bile acid absorption was markedly impaired (2.4 (0.2-3.2)%). Plant sterol ratios reflected the absolute length of remaining jejunum (r=0.625-0.663), and precursor sterol ratios inversely that of ileum (r=-0.589 to 0.750, P<0.05 for all). CONCLUSION: After weaning off parenteral nutrition, patients with pediatric onset SBS continue to have marked intestinal malabsorption of bile acids and moderate cholesterol malabsorption resulting in decreased serum cholesterol despite a marked compensatory increase in cholesterol synthesis.