Comparison of acute-phase reactants in pediatric patients with fever.

We compared WBC count greater than or equal to 15,000/cu mm (high WBC count). Wintrobe ESR greater than or equal to 30 mm/hr (high ESR), temperature greater than or equal to 40 degrees C, and positive slide tests for C-reactive protein (CRP) at a serum dilution of 1:50 in febrile, ambulatory children. The CRP test was performed with and without heat inactivation of serum. An excellent correlation was found between noninactivated and inactivated CRP test results. Since the noninactivated CRP test can be done quickly, its results would be readily available in an outpatient setting. High ESR demonstrated the best balance of specificity and sensitivity for bacteremia, pneumonia, and other possible or proved bacterial illnesses. A positive CRP test was highly specific for these diagnoses but less sensitive than an ERS greater than or equal to 30 mm/hr. Three combinations of acute-phase reactants, high WBC count and/or high ESR, high ESR and/or positive CRP test, and high WBC count and/or high ESR and/or positive CRP test performed as well as high ESR alone. Each was less specific but more sensitive than high ESR for possible or proved bacterial illnesses. The evaluation of an ambulatory, febrile child with acute-phase reactants should include at least determination of ESR.

Temperature greater than or equal to 40 C in children less than 24 months of age: a prospective study.

In a prospective study, 330 consecutive children less than 24 months old coming to the emergency room of Yale-New Haven Hospital with a temperature greater than or equal to 40 C were evaluated. Nearly all patients had a white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) (Wintrobe), blood culture, and chest roentgenogram. Eighty-eight percent were evaluated 24 to 48 hours later. The mean WBC count and ESR were significantly elevated in children with positive blood cultures or pneumonia. The risk of bacteremia was increased threefold and the risk of pneumonia was increased twofold in children with a WBC count greater than or equal to 15,000/cu mm or an ESR greater than or equal to 30 mm/hr compared to children without leukocytosis or elevated ESR. Sixty-one percent of children with bacteremia or pneumonia. 63% of children in whom these diagnoses were not apparent on physical examination, and 86% of children with otitis media complicated by pneumonia or bacteremia had either a WBC count greater than or equal to 15,000/cu mm or an ESR greater than or equal to 30 mm/hr. A WBC count greater than or equal to 15,000/cu mm and an ESR greater than or equal to 30 mm/hr were more effective than a polymorphonuclear leukocyte count greater than or equal to 10,000/cu mm and/or a band count greater than or equal to 500/cu mm in screening young children with high fever for bacteremia, pneumonia, or complicated otitis media.

Bacteremia in children: an outpatient clinical review.

In a 20-month period, 1,783 children seen in the pediatric outpatient department had blood cultures performed and 117 (6.5%) of these children had bacteremia. Two thirds of the isolates were Diplococcus pneumoniae and Hemophilus influenzae b. Ninety-three percent of children with H. influenzae b bacteremia and 20% of children with pneumococcal bacteremia had soft tissue involvement at the initial visit. Most children with positive blood cultures (102) were previously well and beyond the newborn period and many (46) had seemingly trivial illnesses initially: upper respiratory tract infection, fever of unknown origin, otitis media, and diarrhea. In the absence of soft tissue infection, the latter three diagnoses correlated best with bloodstream invasion. Nineteen children had persistent bacteremia and five developed soft tissue complications not noted initially. Two factors, age between 7 and 24 months and temperature between 39.4 and 40.6 C, showed increased specificity for bacteremia but were sensitive only for pneumococcal disease. A temperature larger than or equal to 40.5 C showed more specificity for bacteremia than lesser fevers. A white blood cell count greater than 20,000/cu mm was poorly sensitive, and pulmonary infiltrates were neither specific nor sensitive for positive blood cultures. Five bacteremic children had aseptic lymphocytosis in the cerebrospinal fluid. Two days of intravenous antibiotic therapy and eight days of oral therapy were adequate for pneumococcal bacteremia without soft tissue involvement. This therapy may not be without soft tissue involvement. This therapy may not be ideal, however, since other routes and duration of therapy were not evaluated.

History and observation variables in assessing febrile children.

Attending pediatricians listed five history and eight observation variables on which they base their "instinctive" judgment (prior to performing a physical examination) of overall degree of illness of febrile children. Attending pediatricians and house staff observer pairs independently scored these variables in an overall assessment on 219 young, febrile children. The observation variable playfulness had the strongest correlation with overall assessment. Observer agreement in scoring the variables and overall assessment, while statistically significant, was only fair. When an attending pediatrician judged a child as moderately or severely ill on overall assessment, serious illnesses were four times as likely as when such a judgment was not made. When a house officer judged a child as moderately or severely ill, serious illnesses were less than twice as likely as when such a judgment was not made. However, only 57% of children with serious illnesses were judged by the attending pediatrician as moderately or severely ill on overall assessment. These data demonstrate the importance and limitations of "instinctive" clinical judgments about young, febrile children; the association between observation of complex behavioral patterns, especially playfulness, and overall assessment; and the need for further study of these complex behavioral patterns in order to define a reliable clinical approach to febrile children.

Further definition of history and observation variables in assessing febrile children.

The experienced clinician makes a judgment (hereafter called overall assessment [OA]) about the degree of illness of a febrile child prior to physical examination. In order to define the history and observation variables on which OA is based, 262 febrile children less than or equal to 24 months of age were evaluated simultaneously by multiple observers including attending pediatricians, practicing pediatricians, pediatric house officers, and nurses. The observer listed history and observation variables he/she thought most important in making an OA on a blank, lined form and then scored those variables and OA as normal, or mildly, moderately, or severely impaired. Scoring for observation rather than history variables was better correlated with scoring for OA and serious illness. The observation variables most frequently mentioned by all observers were the child's "looking at the observer" and "looking around the room." There were 20 observation variables frequently mentioned, the scoring of which significantly correlated with scoring for OA; four of these 20 variables related to eye function. The child's response to a stimulus was noted in 105/186 different observation variables listed; both the attending pediatrician and the house officer scored these stimulus-response variables significantly different in children with, vs those without, serious illnesses. For attending pediatricians, house officers, and nurses, serious illness was five to seven times as likely if an OA of moderate or severe impairment was made than if it were not made. OA is a key skill in evaluating febrile children; these data identify variables on which OA is based, document the importance of assessing eye function in young, febrile children, and demonstrate that eye function is one key type of stimulus-response behavior on which the pediatrician as clinician and developmentalist relies to make judgments about febrile children.

Olfactory and taste sensitivity in children with cystic fibrosis.

Psychophysical experiments measured both olfactory sensitivity to 1-butanol and sodium chloride and taste sensitivity to sodium chloride in normal children and in children with cystic fibrosis. The sensitivity of the children with cystic fibrosis fell within the normal range. These results stand in contrast to those of Henkin and Powell, who found children with cystic fibrosis to be hypersensitive to both olfactory and taste stimuli. Apparent hypersensitivity to taste stimuli could have resulted from the adapting effects of the relatively high level of sodium in the saliva of children with cystic fibrosis. If the contaminating effects of saliva are removed, children with cystic fibrosis yield, on the average, a taste threshold identical to that of normal children. There appears to be no simple explanation for why Henkin and Powell found hypersensitivity to odorants. The present results indicate that, in fact, children with cystic fibrosis display a slight hyposensitivity to odorants.

Non-ionic surfactant vesicles, niosomes, as a delivery system for the anti-leishmanial drug, sodium stibogluconate.

Liver and serum concentrations of antimony in the mouse have been determined after administration of sodium stibogluconate in the free, liposomal and niosomal form. High liver and low serum values were attained by the use of both vesicular formulations. Niosomal sodium stibogluconate was shown to be more active than free drug against experimental murine visceral leishmaniasis, an effect apparently dependent on maintaining high drug levels in the infected reticuloendothelial system.

The therapeutic effect of sodium stibogluconate in BALB/c mice infected with Leishmania donovani is organ-dependent.

A study of the antileishmanial efficacy of sodium stibogluconate was carried out in BALB/c mice. The drug was administered to Leishmania donovani-infected animals on days 7 and 8 post-infection in one of three forms; free (40-50 mg Sbv Kg-1), liposomal, or niosomal (6.4-8.0 mg Sbv Kg-1) drug. On day 14 post-infection counts of the number of parasites present in the liver, spleen and bone marrow of treated and control animals showed that although all three drug preparations significantly reduced parasite numbers in the liver (approximately equal to 99% suppression) they had little effect on those residing in the spleen or bone marrow. The carrier forms of the drug were therefore significantly more effective than free drug in reducing liver parasite burdens. Increasing the concentration and the number of doses of free drug (maximum of 500 mg Sbv Kg-1), and reducing the size of the vesicles used to deliver the drug had a minimal effect on parasite numbers in the spleen and bone marrow. It is proposed that because of the resistance of spleen and bone marrow parasites to drug therapy, the BALB/c mouse infected with L. donovani provides an excellent model system for the study of drug delivery to these deeper tissue sites.

Vesicular systems (niosomes and liposomes) for delivery of sodium stibogluconate in experimental murine visceral leishmaniasis.

Suppression of Leishmania donovani liver amastigotes by sodium stibogluconate has been determined in a murine model of experimental visceral leishmaniasis. Niosomal and liposomal drug formulations were equiactive and both increased drug efficacy by an order of magnitude compared with that of free drug. Niosomes containing 30 mol % cholesterol were prepared from three different non-ionic surfactants and no significant difference in activity was detected among the different drug-loaded niosomes. Both negatively charged and neutral vesicles were found to be equally effective. However, vesicle cholesterol content had a slight influence on the antiparasitic activity of the drug-loaded niosomes. Empty vesicles produced a dose-dependent parasite suppression for all vesicles studied. Studies of antimony distribution in the mouse using neutron activation analysis showed high liver levels after i.v. administration of the carrier forms of the drug.

Visceral leishmaniasis: drug carrier system characteristics and the ability to clear parasites from the liver, spleen and bone marrow in Leishmania donovani infected BALB/c mice.

The efficacy of various sodium stibogluconate formulations against Leishmania donovani has been investigated using a BALB/c mouse model of visceral leishmaniasis. Only one therapy, multiple dosing with drug loaded sonicated vesicles, liposomes or niosomes, was found to be effective against parasites in the liver, spleen and bone marrow. Other treatments significantly reduced parasite liver burdens but either failed to effect spleen and bone marrow parasites, or were effective but toxic. Prophylactic treatment with sodium stibogluconate preparations, six days before infection, reduced parasite multiplication in the liver (free, niosomal and liposomal drug) and the spleen (sonicated, drug loaded niosomes only), but had no suppressive effect on bone marrow parasite burdens compared with controls. These results indicate that in-vivo sodium stibogluconate persists in some compartments at parasiticidal concentrations and that failure to reach this concentration at some sites of infection such as bone marrow, is the cause of treatment failure and relapse.

Biodegradable microspheres: polyacryl starch microparticles as a delivery system for the antileishmanial drug, sodium stibogluconate.

Liver parasite burdens of Leishmania donovani in the mouse have been determined after treatment with intravenous administration of sodium stibogluconate in the free or carrier form. The carrier form, in which the drug was covalently bound to polyacryl starch microparticles, was up to 100x more effective than the free form in this murine model of visceral leishmaniasis. Empty microparticles had no effect on liver parasite burdens and the enhanced in-vivo antileishmanial activity of the carrier form of the drug was apparently due to passive drug delivery to the infected liver.

Hemolytic anemia and edema as the initial signs in infants with cystic fibrosis. Consider this diagnosis even in absence of pulmonary symptoms.

This is a report of five infants eventually proven to have cystic fibrosis of the pancreas, who presented with hemolytic anemia and edema. Since the sweat test is often unreliable in edematous states, the possibility of cystic fibrosis should be considered. Use of either a protein hydrolysate or addition of pancreatic enzymes will improve nutritional status, and when edema disappears, a definite sweat test can be performed. Evidence of vitamin E deficiency in some of the cases is presented, and the possibility of this as a cause of anemia is raised.

Abnormal sweat chloride in auto-immune hypothyroidism.

A case of an 11-year-old girl with autoimmune hypothyroidism and a positive sweat test is presented. When the hypothyroidism was corrected the sweat test reverted to normal.

Mild cystic fibrosis presenting as an asymptomatic distended appendiceal mass: A case report.

A case of cystic fibrosis presenting as a right lower quadrant mass in a five-year-old white female is presented. At laparotomy, a mucoid, impacted appendix was found which microscopically suggested the diagnosis of cystic fibrosis. Cystic fibrosis must be added to conditions presenting with abdominal masses.

Predicting fever response of children with pneumonia treated with antibiotics.

In order to study predictors of fever response in children with radiologic pulmonary infiltrates treated with antibiotics, 156 children with pneumonia were evaluated with slide test C-reactive protein (CRP), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), blood cultures, acute and convalescent viral and mycoplasma titers, and then followed clinically. Both CRP (+) at a serum dilution of 1:50 and WBC greater than or equal to 15,000 were better predictors of rapid resolution of fever while the patient was receiving antibiotics than were ESR greater than or equal to 30 or temperature greater than or equal to 40 C. WBC greater than or equal to 15,000 was nearly as specific but more sensitive than CRP (+) 1:50 for resolution of fever in either 8, 12 or 24 hours. Positive blood or lung bacterial cultures, but not four-fold or greater viral or mycoplasma titer increases, were also associated with rapid resolution of fever. WBC greater than or equal to 15,000 is useful in predicting rapid fever response in children with pneumonia treated with antibiotics.

Evaluation of arthritis and arthralgia in the pediatric patient.

The records of 250 consecutive children presenting to a university pediatric service with joint complaints of unknown cause were reviewed to determine the frequency of diagnoses and the utility of laboratory data and physical examination findings. Eighteen per cent of children had orthopedic disorders (Group I), 17.6 per cent had autoimmune disorders (Group II), 19.6 per cent had joint complaints related to a bacterial infection (Group III), and 44 per cent had miscellaneous problems (Group IV). Autoimmune or infectious disd/or erythrocyte sedimentation rate was greater than or equal to 30 mm/h was present than if absent (65% vs. 8% respectively); the sensitivity of fever and/or elevated erythrocyte sedimentation rate was 93 per cent for Group II and III patients. The presence of rash was predictive of an autoimmune disorder in 67 per cent of the instances; a positive joint examination was seen disproportionately in Group I patients. A negative joint examination all but ruled out an infectious etiology. Other test results, such as diagnostic radiograms, WBC greater than or equal to 15,000 per cu mm; or a positive ANA or rheumatoid factor were predictive but not sensitive indicators of selected groups. If the tiology of a child's joint complaints is unknown, the likelihood of an orthopedic, autoimmune or infectious disorder may be suggested by reviewing temperature and ESR data and skin and joint findings.

Diagnostic styles of attending pediatricians, residents, and nurses in evaluating febrile children.

In order to compare the diagnostic styles of attending pediatricians (A), residents (R), and nurses (N) in judging the degree of illness of a febrile child prior to physical examination, we studied the frequency with which they used 139 different history variables and 186 observation variables in evaluating 162 consecutive children less than or equal to 24 months of age with temperature greater than or equal to 38.3 C. Because individual history and observation variables were not used with sufficient frequency, comparison of diagnostic styles based on the individual variables was not possible. The individual history and observation variables were then combined into 25 history and 30 observation categories respectively. One observation category, "Eyes," was used with sufficient frequency to allow comparison of A, R, and N diagnostic styles. In the Eyes category, there were 11 variables describing visual response to stimuli (e.g., looking at the observer) and 10 variables describing appearance of the eyes (e.g., glassy, shiny). Attendings used variables describing visual response to stimuli significantly more frequently than R or N, which may indicate a greater facility in evaluating age-appropriate behavior and/or may be a technique to increase the sensitivity of clinical judgments. These data demonstrate the variety of diagnostic styles of A, R, and N. There is a need to define valid and reliable observation data to identify serious illness in febrile children.

Radiographic findings and etiologic diagnosis in ambulatory childhood pneumonias.

The chest roentgenograms of 128 consecutive ambulatory children with radiologic pneumonia were read independently and without clinical information by a faculty general pediatrician (Ped), a pediatric radiologist (R-P) and a general radiologist (R-G). The films were classified as normal, indicative of a viral or bacterial process, or indeterminate. Readings were compared with results of viral titers and bacterial cultures. Agreement between any two observers in classifying films, measured by unweighted Kappa, while statistically significant (p less than 0.001) for any pair, was low. There was no significant difference between the agreement scores of Ped/R-P, Ped/R-G, and R-P/R-G. Twenty-one patients had fourfold viral titer increases (N = 16) or positive bacterial cultures of blood or pulmonary aspirate (N = 5). The sensitivity of viral readings for titers increases varied from 19% to 68% depending on observer type; the sensitivity of bacterial readings for positive bacterial cultures varied from 60% to 80%. The three observers agreed on a correct reading in only three children with viral and three with bacterial pneumonia. Because of poor observer agreement and appreciable false-negative errors when viral and bacterial readings were compared to titer increases and positive bacterial cultures, respectively, we conclude that radiographic findings are poor indicators of etiology diagnosis in ambulatory childhood pneumonias and, of themselves, are an insufficient data base for making therapeutic decisions.