Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease

OBJECTIVES: To study the correlation between serum concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in relation to severity of disease in children with meningococcal sepsis. METHODS: Subjects were children with meningococcal sepsis, admitted to the pediatric intensive care unit. Clinical data, laboratory values and blood samples were selected. Arterial cortisol, ACTH, interleukin 6 and tumor necrosis factor alpha concentrations were measured on admission and studied for their relation to severity of disease (sepsis, septic shock/survivors, septic shock/nonsurvivors). RESULTS: Seventy-two patients fulfilled the criteria for meningococcal sepsis. Sixty-two of these children with positive blood cultures of Neisseria meningitidis, who were not treated with corticosteroids before admission, were included. Fifty of the 62 patients had septic shock. Twelve of those children (24%) died. The median age of the subjects was 2.6 years (range, 0.3 to 16.1 years). Cortisol values were significantly lower in non-survivors (median, 654 nmol/l) than in survivors (median, 2184 nmol/l) (P < 0.01). ACTH values were significantly higher in children who died (median, 1271 ng/l) than in survivors (85 ng/l) (P < 0.01). The median cortisol:ACTH ratio decreased significantly depending on the disease severity categories. CONCLUSIONS: Low serum cortisol concentrations in combination with high ACTH concentrations are associated with poor outcome in children with severe meningococcal disease.     

Endothelial cell adhesion molecules in meningococcal disease.

BACKGROUND: Endothelial damage is important in meningococcal disease. Cell adhesion molecules, including P selectin, E selectin, and intercellular cell adhesion molecule 1 (ICAM-1), are expressed by activated endothelium and then subsequently shed. METHODS: ICAM-1, P selectin, and E selectin were measured on admission to hospital in children with meningococcal infections. RESULTS: Concentrations of shed cell adhesion molecules are reported for 78 children. Eleven did not have meningococcal disease. Of the 67 with meningococcal disease, 40 had mild disease (Glasgow meningococcal septicaemia prognostic score (GMSPS) < 8) and 27 had severe disease (GMSPS > or = 8). E selectin and ICAM-1 values were higher in those with meningococcal disease. The E selectin values in those with severe disease were higher than in those with mild disease. P selectin concentrations were not altered in meningococcal disease, but those who died had lower concentrations. CONCLUSIONS: Endothelial activation in meningococcal disease is reflected by shed ICAM-1 and E selectin concentrations.     

Bone mineral density in children with untreated and treated celiac disease

OBJECTIVES: Osteopenia is a common complication in adults with celiac disease. The effect of a gluten-free diet on bone mineral density is a matter of controversy. The aim of this study was to investigate bone mineral density in children with celiac disease at diagnosis and in patients treated for 1 year. METHODS: Bone mineral density and bone mineral content were measured in 34 children with untreated celiac disease at diagnosis and in 28 patients on a gluten-free diet for 1 year. The results were compared with those of 64 gender- and age-matched healthy control subjects. Serum calcium, phosphate, alkaline phosphatase, 25 -hydroxy vitamin D, and intact parathormone levels were determined in treated and untreated patients. RESULTS: The mean values of bone mineral density and bone mineral content of untreated patients with celiac were significantly lower than the control group (P = 0.006 and P = 0.005, respectively) and treated patients (P = 0.015 and P = 0.011 respectively). Treated patients had mean bone mineral density and bone mineral content values not significantly different from those of healthy control subjects. Minor hypocalcemia was detected in 17.6% of the patients with new diagnoses and 3.6% of the treated patients. Of the untreated patients, 29.4% had high intact parathormone concentrations; in untreated patients, the total was 14.3%. Untreated patients had significantly lower serum calcium and significantly higher intact parathormone levels than did treated patients. The other bone metabolism parameters were similar in the two celiac groups. CONCLUSION: Children with celiac disease are at risk for reduced bone mineral density. A strict gluten-free diet improves bone mineralization, even in 1 year. Early diagnosis and treatment of celiac disease during childhood will protect the patient from osteoporosis.     

Variation in serum C-reactive protein across the clinical spectrum of meningococcal disease

In a multicentre prospective study, 124 cases of meningococcal disease were classified into the clinical categories, meningitis alone (n = 15), meningitis and septicaemia (n= 79) and septicaemia alone (n = 30). A further 60 children referred with other illnesses served as controls. Serial measurements of serum C-reactive protein (admission, day 1, day 2, days 5–7) were compared. Children with septicaemia had significantly lower C-reactive protein levels on admission than those with meningitis alone or meningitis and septicaemia which were unexplained by differences in the duration of the presenting illness or severity of the disease. Within each clinical category of meningococcal disease, significant changes in C-reactive protein concentration occurred during the course of the disease. Four control children had other types of septic meningitis: admission C-reactive protein concentrations did not differ from those with meningitis or meningitis and septicaemia, but were significantly higher than those with septicaemia alone. The other 56 patients had a significantly lower admission C-reactive protein concentration compared with all cases of meningococcal disease. For the diagnosis of meningococcal disease, admission C-reactive protein levels of ≥ 40 mg/l had a sensitivity of 79%, specificity of 80% and positive predictive value of 87%. For the prognostic prediction of death in meningococcal disease (or meningococcal disease with shock) CRP < 100 mg/l on admission had a sensitivity of 69% (69%), specificity of 50% (56%) and positive predictive value of 18% (53%). In children with suspected meningococcal disease, serum C-reactive protein, measured on admission, has diagnostic value but not prognostic value. The C-reactive protein concentration on admission varies with the clinical category of meningococcal disease and the day of illness.     

Endothelial cell adhesion molecules in meningococcal disease

BACKGROUND—Endothelial damage is important in meningococcal disease. Cell adhesion molecules, including P selectin, E selectin, and intercellular cell adhesion molecule 1 (ICAM-1), are expressed by activated endothelium and then subsequently shed.METHODS—ICAM-1, P selectin, and E selectin were measured on admission to hospital in children with meningococcal infections.RESULTS—Concentrations of shed cell adhesion molecules are reported for 78 children. Eleven did not have meningococcal disease. Of the 67 with meningococcal disease, 40 had mild disease (Glasgow meningococcal septicaemia prognostic score (GMSPS) < 8) and 27had severe disease (GMSPS ? 8). E selectin and ICAM-1 values were higher in those with meningococcal disease. The E selectin values in those with severe disease were higher than in those with mild disease. P selectin concentrations were not altered in meningococcal disease, but those who died had lower concentrations.CONCLUSIONS—Endothelial activation in meningococcal disease is reflected by shed ICAM-1 and E selectin concentrations.     

甲状旁腺功能减低-感音神经性耳聋-肾发育不良综合征1例及文献复习

目的探讨甲状旁腺功能减低-感音神经性耳聋-肾发育不良(HDR)综合征诊断和治疗措施。方法对1例HDR综合征患儿的临床、实验室资料及诊疗过程进行分析,并复习相关文献。结果患儿以听力减退、手足搐搦为主要表现,查体有面神经征及陶瑟征阳性。多次查血钙均低于正常,甲状旁腺激素(PTH)为正常值低限,ALP正常。电测听显示感音性神经性耳聋。腹部CT示右侧肾脏缺如,肌酐清除率下降。入院后予补充钙剂及维生素D治疗,病情好转。结论应提高对本病的认识,对怀疑甲状旁腺功能降低的患儿及其家庭成员应行肾脏影像学及听力检查,避免漏诊。     

Use of disodium pamidronate in children with hypercalcemia awaiting liver transplantation

We report four children with advanced liver disease awaiting liver transplantation who developed moderately severe hypercalcemia (range: 1.65-2.40 mmol/L) while receiving total parenteral nutrition. Hypercalcemia had been unresponsive to cessation of calcium intake and therapy with loop diuretics and calcitonin. One or two intravenous doses of disodium pamidronate (35-50 mg/m2) resulted in normalization of plasma calcium concentration within 2-4 d in all four children. Pamidronate may be useful for children with hypercalcemia associated with liver disease.     

Hypercalcitoninemia and hypocalcemia in acutely ill children: studies in serum calcium, blood ionized calcium, and calcium-regulating hormones

We studied the hypotheses that serum calcium and blood ionized calcium would be low in acutely ill children and would rise with clinical improvement. In 15 children admitted to the pediatric intensive care unit, the blood ionized calcium level was 4.45 +/- 0.06 mg/dl (1.11 +/- 0.015 mmol/L) on entry versus 5.17 +/- 0.03 mg/dl (1.29 +/- 0.01 mmol/L) in control subjects (p less than 0.005), rose significantly on days 2 and 3, and was 5.12 +/- 0.04 mg/dl (1.28 +/- 0.01 mmol/L) at discharge (p less than 0.005). Changes in serum calcium level were similar, whereas serum magnesium and phosphorus levels were normal and did not change. Basal serum parathyroid hormone concentrations were elevated, rose further during the study, and were normal at discharge. Serum parathyroid hormone levels correlated inversely with blood ionized calcium levels, indicating that compensatory hyperparathyroidism occurs with low blood ionized calcium concentrations. Basal serum calcitonin values were evaluated on entry and decreased with clinical improvement. Serum calcitonin levels correlated significantly with low blood ionized calcium levels, indicating that hypercalcitoninemia may play a role in the pathogenesis of hypocalcemia in these children. Urine calcium excretion was not increased in the four children studied. We speculate that with clinical improvement, a rise in serum parathyroid hormone levels and a decline in serum calcitonin levels may help restore normocalcemia in these acutely ill children.     

Diagnostic significance of calcitonin analysis in children with rickets and rickets-like diseases administered calcium test

The secretory activity of C-cells of the thyroid was investigated in 25 children with rickets and rickets-like diseases. There were 13 children with grades II and III rickets, 6 with vitamin D-dependent rickets, and 6 with Debre-de Toni-Fanconi disease. Five normal children constituted a control group. The basal concentration of calcitonin did not differ from the control parameter in all patients' groups. An increased release of the hormone to the blood was noticed in response to calcium stimulation. The rise of blood calcitonin was determined by the disease pattern, which made it possible to use the test with a one-minute intravenous calcium injection for differential diagnosis purposes. The maximal changes were discovered in children suffering from vitamin D-dependent rickets.     

Calcium, phosphorus, magnesium, and calcitonin concentrations in the serum and cerebrospinal fluid of children

Mineral metabolism in the cerebrospinal fluid (CSF) of children is poorly understood. Recent reports have suggested a neuroregulatory role for calcitonin. We examined the hypotheses that in children (1) CSF levels of calcium and phosphorus might be low, (2) CSF levels of magnesium might be higher than serum levels of magnesium, and (3) immunoreactive calcitonin might be present in the CSF. We examined serum and CSF samples of 45 children, aged 8 days to 16 years, undergoing spinal taps for suspected meningitis or as part of leukemia therapy. Both serum and CSF levels of calcium correlated with those of magnesium. There was no correlation for CSF levels vs serum levels of calcium, magnesium, or phosphorus. The CSF levels of calcium and phosphorus were lower than the serum levels of these elements, but the CSF levels of magnesium were higher than the serum levels of magnesium. Calcitonin was detected in the CSF of 8% of samples assayed (range, 14 to 175 ng/L [14 to 175 pg/mL]). Two of these five samples had bacteriologically proven meningitis, and two samples were from patients less than 2 months of age. The CSF levels of calcitonin did not correlate with the serum levels of calcitonin. Thus, in children CSF levels of calcium and phosphorus are low, CSF levels of magnesium are higher than the serum levels, and the level of immunoreactive calcitonin is usually not present in the CSF but possibly is elevated in meningitis and early infancy.     

Bone mineral density of the lumbar spine in children and adolescents with celiac disease on a gluten-free diet in São Paulo, Brazil

BACKGROUND: To compare bone mineral density (BMD) in children and adolescents with celiac disease (CD) and control subjects and to evaluate diet adequacy and calcium metabolism in patients with CD. METHODS: Thirty patients with asymptomatic CD (17 children, 13 adolescents), on a gluten-free diet, and 23 healthy subjects were studied. BMD of the lumbar spine (dual energy x-ray absorptiometry) was performed on all patients and control subjects. In patients, food diaries for nine nonconsecutive days were obtained and analyzed. In patients, laboratory tests pertaining to calcium balance were obtained. RESULTS: The mean weight and height of the adolescents with CD were lower than those of control subjects (weight: 45.8 +/- 10.5 kg v 55.3 +/- 10.5 kg, P = 0.037; height: 153.0 +/- 11.0 cm v 167 +/- 12.0 cm, P = 0.007). The mean BMD in adolescents with CD was significantly lower than that of the control subjects (0.917 +/- 0.116 g/cm2 v 1.060 +/- 0.158 g/cm2, P = 0.015), whereas no significant difference was found between children with CD and control subjects (P = 0.595). A multiple-regression model shows that increases in BMD relative to height were lower in adolescents with CD than in control subjects. The proportion of adolescents who had started a gluten-free diet after 2 years of age was higher than that of children with CD (P < 0.001). High percentages of magnesium, calcium, and phosphorous deficiencies were present in CD patients' diets. The serum levels of ionized and total calcium and parathormone were normal. CONCLUSIONS: The BMD of adolescents with CD was lower than that of the control subjects, whereas no difference was found between the BMD of children with CD and that of control subjects.     

The child with a non-blanching rash: how likely is meningococcal disease?

AIMS: To examine a number of simple clinical features and investigations in children with a non-blanching rash to see which predict meningococcal infection. METHODS: A total of 233 infants and children up to 15 years of age presenting with a non-blanching rash were studied over a period of 12 months. Clinical features and laboratory investigations were recorded at presentation. The ability of each to predict meningococcal infection was examined. RESULTS: Eleven per cent had proven meningococcal infection. Children with meningococcal infection were more likely to be ill, pyrexial (>38.5 degrees C), have purpura, and a capillary refill time of more than two seconds than non-meningococcal children. Five children with meningococcal disease had an axillary temperature below 37.5 degrees C. No child with a rash confined to the distribution of the superior vena cava had meningococcal infection. Investigations were less helpful, although children with meningococcal infection were more likely to have an abnormal neutrophil count and a prolonged international normalised ratio. No child with a C reactive protein of less than 6 mg/l had meningococcal infection. CONCLUSIONS: Most children with meningococcal infection are ill, have a purpuric rash, a fever, and delayed capillary refill. They should be admitted to hospital and treated without delay. Children with a non-blanching rash confined to the distribution of the superior vena cava are very unlikely to have meningococcal infection. Measurement of C reactive protein may be helpful-no child with a normal value had meningococcal infection. Lack of fever at the time of assessment does not exclude meningococcal disease.     

Mortality in severe meningococcal disease.

AIM: To evaluate mortality of critically ill children admitted with meningococcal disease. METHODS: Prospective study of all children admitted to a regional paediatric intensive care unit (PICU) between January 1995 and March 1998 with meningococcal disease. Outcome measures were actual overall mortality, predicted mortality (by PRISM), and standardised mortality ratio. RESULTS: A total of 123 children were admitted with meningococcal disease. There was an overall PICU mortality of 11 children (8.9%). The total mortality predicted by PRISM was 24.9. The standardised mortality ratio (SMR) was 0.44. Results were compared with those from four previously published meningococcal PICU studies (USA, Australia, UK, Netherlands) in which PRISM scores were calculated. The overall PICU mortality and SMR were lower than those in the previously published studies. CONCLUSION: Compared with older studies and calibrating for disease severity, this study found a decrease in the mortality of critically ill children with meningococcal disease.     

Bone mineral density in patients with classic galactosaemia.

BACKGROUND: Diminished bone mineral density (BMD) is a well known complication in women with classic galactosaemia caused by premature ovarian failure. Diminished BMD in prepubertal patients of either sex has, however, only been reported once. Aim: To assess BMD in children with classic galactosaemia. METHODS: Eleven treated patients (five males, six females, aged 2-18 years) had BMD determined by dual energy x ray absorptiometry. Two measurements were performed, an areal measurement of the total body and a volumetric measurement of the femoral neck. Results were expressed as Z scores. Dietary calcium intake, blood calcium, phosphate, vitamin D, parathormone, and markers of bone formation (bone alkaline phosphatase, osteocalcin) and bone resorption (NTX) were determined. RESULTS: All patients had a significantly diminished BMD. Mean Z score of the volumetric BMD was -1.76 (range -0.7 to -3.3), and of the areal BMD -0.99 (range -0.5 to -1.4). Dietary calcium intake and calcium, phosphate, parathormone, bone alkaline phosphatase, vitamin D metabolites, and osteocalcin (free and carboxylated) were normal in all patients. NTX levels in blood were significantly lower (p < 0.001) than in control subjects. CONCLUSION: BMD in this group of children of both sexes with classic galactosaemia under dietary treatment was decreased. Lower NTX levels in galactosaemics point to an apparent decreased bone resorption.     

Disturbed calcium and phosphate homeostasis during treatment with ACTH of infantile spasms.

Kidney histology of five infants who died during or immediately after treatment with adrenocorticotrophic hormone (ACTH) showed severe tubular and interstitial calcinosis. We therefore studied serum concentrations of calcium, inorganic phosphate, and parathormone, serum activities of alkaline phosphatase, and urinary excretion of calcium, inorganic phosphate, and cyclic adenosine monophosphate (cAMP) in 16 other children with infantile spasms before, during, and after 6 weeks of treatment with ACTH. During the treatment the following observations were made: hypocalcaemia developed in three infants; the mean daily urinary excretion of calcium in the group increased threefold and seven infants had hypercalciuria; the excretion of phosphate increased but its tubular reabsorption remained stable; and in most infants serum parathormone and urinary cAMP excretion increased, and in four infants they increased to supranormal concentrations. These biochemical changes were reversible in most infants. Radiographs suggested loss of bone mass by 3-4 weeks of treatment, with rapid recovery after treatment. We conclude that infants treated with ACTH for infantile spasms are at risk of suffering disturbance in calcium and phosphate homeostasis, which leads to nephrocalcinosis.     

Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease

Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001), concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.     

Hearing in children after meningococcal meningitis

OBJECTIVE: To review the outcome of sensorineural hearing loss in children who have had confirmed meningococcal meningitis. METHODS: A retrospective audit of children admitted to the Starship Children's Hospital with a confirmed diagnosis of meningococcal meningitis during a 4-year period. RESULTS: Sixty-five children had confirmed meningococcal meningitis. Dexamethasone was administered according to recommended guidelines in 46 children (72%) while 12 children (19%) did not receive steroids at any stage. All children were appropriately referred for hearing assessment. Forty-nine children (75%) had their hearing tested and reliable sensorineural evaluation was obtained in all but one case. Thirty-four children (70%) were seen up to 6 weeks from discharge, 86% by 12 weeks. Sixteen cases (25%) did not attend for audiological assessment. Sensorineural hearing impairment was found in two children (4.2%). CONCLUSIONS: Children with meningococcal meningitis were reliably referred for audiological assessment but 39% either failed to attend for an outpatient hearing evaluation (25%) or had an unacceptable delay between discharge and testing (14%). Of those reliably tested, two children (4.2%) had significant sensorineural hearing loss.     

Effect of the Factor V Leiden mutation on the severity of meningococcal disease.

BACKGROUND: One of the most serious complications of meningococcal disease is the syndrome of purpura fulminans, which is characterized by intravascular thrombosis and hemorrhagic infarction of skin, limbs and digits. The reasons why some patients with meningococcal disease develop purpura fulminans while others have minimal thrombotic and skin involvement despite having profound septic shock are not yet understood. The Factor V Leiden mutation (FV(L)) is associated with thrombotic events, and we hypothesized that children carrying FV(L) who develop meningococcal disease may be at increased risk of purpura fulminans. METHODS: We determined the FV(L) genotype by PCR and restriction enzyme digestion (Mnl1) in 259 children with meningococcal disease and 80 healthy controls. In addition 79 parents of children with fatal meningococcal disease were studied. RESULTS: There was no significant increase in the frequency of FV(L) in patients with meningococcal disease (10%) as compared with healthy controls (9%) or with the parents of children who died of meningococcal disease (12%). Although the mortality was not increased in patients heterozygous for FV(L), they had increased complications of purpura fulminans, as assessed by requirement for skin grafting, referral to plastic surgeon and/or amputation. Among survivors 5 of 24 (21%) of those heterozygous for FV(L) had complications, compared with 14 of 233 (7%) who were wild type [P < 0.03; relative risk, 3.1 (95% confidence intervals, 1.2 to 7.9)]. CONCLUSIONS: FV(L) exacerbates purpura fulminans in meningococcal disease but does not have a significant effect on mortality.     

Effect of calcitonin replacement therapy in idiopathic juvenile osteoporosis

An 8-year-old boy with idiopathic juvenile osteoporosis and multiple fractures had three abnormalities of bone mineral metabolism: calcitonin deficiency, elevated serum calcitriol concentrations, and hypercalciuria. Calcitonin deficiency was documented by two attempts to stimulate calcitonin secretion with intravenous calcium and pentagastrin. Treatment for 11 months with daily subcutaneous injections of human calcitonin and oral administration of calcitriol failed to reduce the excessive bone resorption observed on bone biopsy, and the fracture rate did not decrease. Treatment was discontinued for two months, then resumed with calcitonin injections and oral calcium supplementation. The fracture rate decreased but bone biopsy continued to show excessive resorption. Therapy was discontinued. After the onset of puberty, endogenous calcitonin was detectable. Exogenous calcitonin therapy may have failed to control bone resorption for several reasons: insufficient dose, reduction of bone receptors from long-term calcitonin exposure, secondary hyperparathyroidism, or lack of association between calcitonin deficiency and the bone disease.     

Case-control study of breast milk calcium in mothers of children with and without nutritional rickets

Aim: Despite similarly low calcium intakes and normal vitamin D status, only some Nigerian children develop nutritional rickets. We hypothesized that mothers with children who had developed rickets might have lower breast-milk calcium concentration than mothers with normal children and compared the breast-milk calcium concentration of mothers who had had children with rickets with those who had not (controls). Methods: We collected breast milk from 35 Nigerian mothers who had previously had children with nutritional rickets. For each case mother, we collected breast milk from three matched control mothers at the same stage of lactation (±4 weeks) who had had no children with rickets. Data were collected about parity, stage of lactation, and the infant's intake. The mother's bone density was measured. Results: The mean breast milk calcium concentration of mothers of children with rickets (4.30±1.24 mmol/L) was less than that of control mothers (4.65±1.03 mmol/L; P=0.034 in multivariate regression controlling for duration of lactation and resumption of menses). Forearm bone mineral content was significantly related to breast milk calcium concentration (r = 0.20) after adjusting for height, weight, and bone area (P=0.028). Conclusion: : Reduced breast-milk calcium concentration may contribute to a reduced calcium intake in infancy and predispose children to nutritional rickets.