No longer a historical ailment: two cases of childhood scurvy with recommendations for bone health providers.

PURPOSE: Scurvy, due to vitamin C deficiency, is commonly referenced as a "forgotten" or "historical" disease. A growing number of case reports challenge this notion. Bone health providers are often consulted early in the presentation of scurvy to evaluate musculoskeletal complaints resulting from impaired collagen production and disrupted endochondral bone formation. In this report, we describe two cases of childhood scurvy. Our objective is to summarize the key features of scurvy for bone health providers, with the goal of raising awareness and facilitating diagnosis in future cases. CASE DESCRIPTIONS: Case one occurred in a 12-year-old non-verbal, non-ambulatory female on a ketogenic diet for refractory epilepsy. Clinical findings included hemarthrosis, transfusion dependent anemia, elevated inflammatory markers, and epiphysiolysis. Magnetic resonance imaging (MRI) revealed multi-focal bone marrow signal abnormalities and physeal irregularities. Case two occurred in a typically developing 5-year-old male presenting with limp and knee pain. Symptoms progressed despite casting and immobilization. Mild anemia, elevated inflammatory markers, and multi-focal marrow and physeal MRI abnormalities were identified. Subsequent dietary history revealed total absence of fruit or vegetable consumption. The diagnosis of scurvy was confirmed in both cases by undetectable plasma vitamin C concentrations. Treatment with vitamin C led to rapid clinical improvement. CONCLUSION: Scurvy can no longer be considered a historical diagnosis and should not be forgotten when evaluating children with musculoskeletal ailments. Early recognition of the signs, symptoms, and imaging findings of scurvy can reduce the clinical burden of this disease with the timely initiation of vitamin C therapy.

Estimating the undetected burden of influenza hospitalizations in children.

During the 2004-2005 influenza season two independent influenza surveillance systems operated simultaneously in three United States counties. The New Vaccine Surveillance Network (NVSN) prospectively enrolled children hospitalized for respiratory symptoms/fever and tested them using culture and RT-PCR. The Emerging Infections Program (EIP) and a similar clinical-laboratory surveillance system identified hospitalized children who had positive influenza tests obtained as part of their usual medical care. Using data from these systems, we applied capture-recapture analyses to estimate the burden of influenza related-hospitalizations in children aged<5 years. During the 2004-2005 influenza season the influenza-related hospitalization rate estimated by capture-recapture analysis was 8.6/10,000 children aged<5 years. When compared to this estimate, the sensitivity of the prospective surveillance system was 69% and the sensitivity of the clinical-laboratory based system was 39%. In the face of limited resources and an increasing need for influenza surveillance, capture-recapture analysis provides better estimates than either system alone.

Erythromycin for the prevention of chronic lung disease in intubated preterm infants at risk for, or colonized or infected with Ureaplasma urealyticum.

BACKGROUND: Controversy exists over whether or not Ureaplasma urealyticum colonization or infection of the respiratory tract contributes to the severity of chronic lung disease (CLD), a major cause of morbidity and mortality in preterm infants. OBJECTIVES: To evaluate the efficacy and safety of prophylactic or therapeutic erythromycin in preventing chronic lung disease in intubated preterm infants with unknown U. urealyticum status or proven positivity. SEARCH STRATEGY: Searches were done of MEDLINE (1966-June 9, 2003), EMBASE (1980-May 5, 2003), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2002), previous reviews including cross-references, and abstracts of conference proceedings (Pediatric Academic Societies 2000-2003, American Thoracic Society 2001-2003). There were no language restrictions. Expert informants were contacted. SELECTION CRITERIA: Randomized or quasi-randomized studies comparing either prophylactic or therapeutic administration of oral or intravenous erythromycin (regardless of dose and duration) versus no treatment or placebo among intubated preterm infants <37 weeks and <2500 grams with either unknown U. urealyticum status or proven positivity by culture or polymerase chain reaction. DATA COLLECTION AND ANALYSIS: Data were extracted by all of the authors independently and differences were resolved by consensus. Treatment effects for categorical outcomes were expressed as relative risk, with 95% confidence intervals. MAIN RESULTS: Two small controlled studies, both involving intubated babies <30 weeks gestation, were eligible for inclusion. Lyon 1998 tested prophylactic erythromycin in babies whose U. urealyticum status was unknown at the time of initiation of treatment. Jonsson 1998 tested erythromycin in babies known to be culture positive for U. urealyticum. Neither trial showed a statistically significant effect of erythromycin on CLD, death or the combined outcome CLD or death. Because the two studies differed importantly in their design, the results were not combined in meta-analyses. No adverse effects of a 7-10 day course of erythromycin were reported in either study. REVIEWER'S CONCLUSIONS: Current evidence does not demonstrate a reduction in CLD/death when intubated preterm infants are treated with erythromycin prophylactically before U. urealyticum culture/PCR results are known or when Ureaplasma colonized, intubated preterm infants are treated with erythromycin. However, a true benefit could easily have been missed with the small sample sizes in the two eligible studies. The studies were greatly underpowered to detect uncommon adverse effects such as pyloric stenosis. Additional controlled trials are required to determine whether antibiotic therapy of Ureaplasma reduces CLD and/or death in intubated preterm infants.

Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children.

OBJECTIVE: To assess the safety of live, attenuated influenza vaccine (LAIV) administered to relatively asymptomatic or mildly symptomatic HIV-infected children and non-HIV-infected children. METHODS: Twenty-five non-HIV and 24 HIV-infected children (CDC Class N or A1,2) were enrolled into this double blind, placebo-controlled study. Children were randomized within each HIV status group to one of two dosing regimens: Regimen 1, Dose 1 = LAIV, Dose 2 = placebo, Dose 3 = LAIV; or Regimen 2, Dose 1 = placebo, Dose 2 = LAIV, Dose 3 = LAIV. Study doses were separated by 28 to 35 days. Reactogenicity events within 10 days and adverse events within 28 to 35 days after each study dose were recorded. Blood HIV RNA concentrations, CD4 counts and CD4% were measured throughout the study on HIV-infected children. Quantitative influenza cultures were performed on nasal aspirates collected periodically from all children up to 28 to 35 days after each study dose. Influenza isolates were assessed for retention of the temperature-sensitive phenotype. Serum influenza HAI antibodies were measured before and after each LAIV vaccination. RESULTS: No significant differences were found in rates of reactogenicity events and vaccine-related adverse events after placebo or the first dose of LAIV within each HIV status group, nor were differences found between HIV-infected and HIV-uninfected children after each dose of LAIV. Overall none of the HIV-infected children experienced a significant LAIV-related serious adverse event or influenza-like illness, making the one sided 95% CI of such a serious event occurring after LAIV 0 to 12%. No significant changes in geometric mean HIV RNA concentrations, CD4 counts or CD4% or prolonged or increased quantity of LAIV virus shedding occurred in HIV-infected children after receiving either dose of LAIV. All recovered influenza isolates retained the temperature-sensitive phenotype. After two doses of LAIV, 83% of the non-HIV-infected and 77% of the HIV-infected children had a > or = 4-fold rise in influenza antibody to at least one of the three LAIV strains. CONCLUSION: If relatively healthy HIV-infected children become exposed to LAIV inadvertently, then serious adverse outcomes would not be expected to occur frequently.

Short course directly observed therapy to monitor compliance with antiretroviral therapy in human immunodeficiency virus-infected children.

We report our experience with short course directly observed therapy (DOT) in six human immunodeficiency virus-infected children who had a poor response to their prescribed therapy. Four to 8 days of DOT resulted in a significant drop in the viral load of all six children, demonstrating that short course DOT is an effective way to document poor compliance with antiretroviral therapy.

Delayed tooth eruption: association with severity of HIV infection.

PURPOSE: HIV status is monitored by expression of clinical symptoms as well as CD4 lymphocyte counts. The purpose of this study is to assess the relationship between delayed dental eruption (DDE) and the progression of pediatric HIV infection to AIDS. METHODS: A population of 70 perinatally HIV-infected children, aged 5 months to 13 years at their time of entry into the study, received dental examinations. Regression analysis between dental age and chronological age was performed. Subject CDC classification, adjusted for age, was used to determine an association between eruptive delay and severity of disease progression. RESULTS: Data revealed no significant difference in timing of eruption based on severity of CD4 depletion alone (P = 0.09). However, clinical symptom status was strongly associated with DDE (P = 0.003). The relationship between symptoms and DDE persisted after controlling for CD4 depletion. CONCLUSIONS: Our study indicates that there is a correlation between the progression from HIV infection to Pediatric AIDS and DDE and that this delay is most closely linked to severity of symptoms and not CD4 depletion.

The effect of protease inhibitor therapy on growth and body composition in human immunodeficiency virus type 1-infected children.

OBJECTIVE: To determine the effect of protease inhibitors (PIs) on growth and body composition in children with human immunodeficiency virus type 1 (HIV-1) infection. BACKGROUND: HIV-1-infected children have chronic problems with both linear growth and weight gain. Viral load may directly influence growth and nutritional status of HIV-1-infected children with reduction of viral load improving the nutritional condition. DESIGN/METHODS: Data from 67 patients who initiated PI therapy between 1996 and 1999 and who were enrolled in a prospective, longitudinal study of growth and nutrition in HIV-1-infected children were analyzed. Outcomes included pre-PI versus post-PI measures of height, weight, weight-for-height, triceps skinfold thickness, and arm muscle circumference. Predictor covariates included age, race, gender, Tanner stage, CD4 z score, Centers for Disease Control and Prevention stage, route of infection, plasma HIV-1 RNA, other antiretroviral therapy, recommended daily allowances for calories, treatment with megestrol acetate, and PI therapy. RESULTS: Sixty-seven children were followed for a median of 2.4 years with a total of 362 visits (median: 5 visits; range: 1-12). During follow-up, they received PIs for a median of 5 months. Fifty-one percent were girls, 54% black, 15% Hispanic, and 25% white. The mean age at first visit was 6.8 years. In a univariate analysis, weight z score (-0.67 to -0.35) and weight/height z score (0.25-0.76) improved on PI therapy. Using repeated-measures regression analysis, controlling for the above named covariates, PI treatment showed a significant effect on weight z score (increase in z score by 0.46), weight/height z score (increase in z score by 0.49), and arm muscle circumference (increase in percentile by 11.5). A borderline effect was found for height z score (increase in z score by 0.17) and no effect was found for triceps skinfold thickness. In a separate analysis, PI therapy increased CD4 counts twofold and reduced plasma HIV-1 RNA copies by 79%. CONCLUSION: In addition to a significant reduction in viral load, PI therapy in children has a positive effect on several growth parameters, including weight, weight/height, and muscle mass.

Laboratory diagnosis of ehrlichiosis and babesiosis.

Over the past 15-20 years, four notable tick-borne infections have emerged in the US, Lyme disease, human monocytic ehrlichiosis (HME), human granulocytic ehrlichiosis (HGE) and babesiosis (Table). In contrast to the laboratory diagnostic procedures established for Lyme disease, RMSF and tularemia, the laboratory diagnostic procedures for the diagnosis of HME, HGE and babesiosis are not yet standardized and continue to be revised.

Characterization of the gene encoding a histidine and aspartic acid-rich protein from Pneumocystis carinii.

A cDNA clone derived from Pneumocystis carinii contained an unusual sequence (GTGATG)2(ATGGTG)4(ATG)4 and many GAT repeats. It was found to encode a histidine and aspartic acid-rich protein (HARP). The complete cDNA contained an 888-bp open reading frame encoding a putative protein of 32.6 kDa. The deduced HARP protein contained 39 aspartic acid and 22 histidine residues. The genomic copy of the HARP gene (1203 bp in length) was found to contain 3 small introns of 46, 44, and 38 bp, respectively. HARP was predicted by computer programs to be a plasma membrane protein with nickel-binding activity.

Molecular characterization of KEX1, a kexin-like protease in mouse Pneumocystis carinii.

Expression screening of a Pneumocystis carinii-infected mouse lung cDNA library with specific monoclonal antibodies (mAbs) led to the identification of a P. carinii cDNA with extensive homology to subtilisin-like proteases, particularly fungal kexins and mammalian prohormone convertases. The 3.1 kb cDNA contains a single open reading frame encoding 1011 amino acids. Structural similarities to fungal kexins in the deduced primary amino acid sequence include a putative proenzyme domain delineated by a consensus autocatalytic cleavage site (Arg-Glu-Lys-Arg), conserved Asp, His, Asn and Ser residues in the putative catalytic domain, a hydrophobic transmembrane spanning domain, and a carboxy-terminal cytoplasmic domain with a conserved tyrosine motif thought to be important for localization of the protease in the endoplasmic reticulum and/or Golgi apparatus. Based on these structural similarities and the classification of P. carinii as a fungus, the protease was named KEX1. Southern blotting of mouse P. carinii chromosomes localized kex1 to a single chromosome of approximately 610 kb. Southern blotting of restriction enzyme digests of genomic DNA from P. carinii-infected mouse lung demonstrated that kex1 is a single copy gene. The function of kexins in other fungi suggests that KEX1 may be involved in the post-translational processing and maturation of other P. carinii proteins.

The dilemma of postnatal mother-to-child transmission of HIV: to breastfeed or not?

The promotion of nearly universal breastfeeding has played an important role in improving child health by providing optimum nutrition and protection against common childhood infections, and by promoting child spacing. Unfortunately, it has become clear that breastfeeding is responsible also for much of the increasing burden of worldwide pediatric human immunodeficiency virus (HIV) infection, especially in the developing nations (12-14% additional risk of HIV infection transmitted by breastfeeding; 35% total proportion of all HIV-infected children in an area infected through breastfeeding). Several factors influence the transmission of HIV by breastfeeding, including whether a woman acquires her infection during breastfeeding (29% risk of transmission) or before pregnancy (7-10% risk of breastfeeding transmission),the degree of maternal plasma and breastmilk viral load, and the presence of mastitis. In areas of the world where adequate sanitary replacement feeding is not available, the decision to withhold breastfeeding so as to decrease HIV transmission may lead to increased rates of child morbidity and mortality from diarrheal and respiratory diseases, and malnutrition. This review summarizes current data on the pathophysiology of breastfeeding transmission of HIV infection, the risk factors for and incidence rates of transmission, and the feasibility of possible alternatives to exclusive breastfeeding in the setting of maternal HIV infection. Clearly, women must be fully informed about the risks of breastfeeding transmission of HIV, the risks of morbidity and mortality among nonbreastfed infants, and the expense and availability of procuring adequate replacement formula. If an uninterrupted access to a nutritionally adequate breastmilk substitute that can be safely prepared is ensured (as is possible in industrialized countries), HIV-infected women should be counseled not to breastfeed their infants.

Lack of relation of granulocyte antibodies (antineutrophil antibodies) to neutropenia in children with human immunodeficiency virus infection.

BACKGROUND: Neutropenia in children and adults with HIV infection is frequently observed, perhaps as a result of impaired myelopoiesis, drug myelotoxicity, immune destruction or opportunistic infection. The presence of antineutrophil antibodies (granulocyte antibodies) has been associated with severe neutropenia in some reports but not in others, and such antibody assays can be confounded by the presence of immune complexes and HLA antibodies. METHODS: To determine both the prevalence of granulocyte antibodies in children with HIV infection and whether such antibodies were related to neutropenia, we screened the sera of 30 HIV-infected children by performing granulocyte immunofluorescence, granulocyte agglutination and lymphocytotoxic anti-HLA antibody assays. Reactivity was graded by a standard numeric score calculated per number of reactive cells. RESULTS: Of 26 evaluable sera, 16 (62%) had granulocyte antibodies, 6 (23%) had HLA antibodies and 4 (15%) had neither. There was no correlation between presence of granulocyte antibodies and degree of neutropenia. CONCLUSIONS: We conclude that granulocyte antibodies are highly prevalent in children with HIV infection but do not correlate with the degree of neutropenia. Antineutrophil antibody determination as currently performed does not appear to be useful in the evaluation of the HIV-infected neutropenic child.

IMP dehydrogenase from Pneumocystis carinii as a potential drug target.

Mycophenolic acid, a specific inhibitor of IMP dehydrogenase (IMPDH; EC 1.1.1.205), is a potent inhibitor of Pneumocystis carinii growth in culture, suggesting that IMPDH may be a sensitive target for chemotherapy in this organism. The IMPDH gene was cloned as a first step to characterizing the enzyme and developing selective inhibitors. A 1.3-kb fragment containing a portion of the P. carinii IMPDH gene was amplified by PCR with two degenerate oligonucleotides based on conserved sequences in IMPDH from humans and four different microorganisms. Northern hybridization analysis showed the P. carinii IMPDH mRNA to be approximately 1.6 kb. The entire cDNA encoding P. carinii IMPDH was isolated and cloned. The deduced amino acid sequence of P. carinii IMPDH shared homology with bacterial (31 to 38%), protozoal (48 to 59%), mammalian (60 to 62%), and fungal (62%) IMPDH enzymes. The IMPDH cDNA was expressed by using a T7 expression system in an IMPDH-deficient strain of Escherichia coli (strain S phi 1101). E. coli S phi 1101 cells containing the P. carinii IMPDH gene were able to grow on medium lacking guanine, implying that the protein expressed in vivo was functional. Extracts of these E. coli cells contained IMPDH activity that had an apparent Km for IMP of 21.7 +/- 0.3 microM and an apparent Km for NAD of 314 +/- 84 microM (mean +/- standard error of the mean; n = 3), and the activity was inhibited by mycophenolic acid (50% inhibitory concentration, 24 microM; n = 2).

Altered iron metabolism in HIV infection: mechanisms, possible consequences, and proposals for management.

The progression of human immunodeficiency virus (HIV) infection toward its more advanced stages is accompanied by increasing body iron stores. Iron accumulates in macrophages, microglia, endothelial cells, and myocytes. The iron burden is especially heavy in bone marrow, brain white matter, muscle, and liver. Excess iron potentially enhances oxidative stress, impairs several already compromised immune defense mechanisms, and directly promotes the growth of microbial cells. Thus, we hypothesize that the prevention (or at least, reduction) of iron loading might slow the progression of the infectious complications of HIV infection, and perhaps indirectly, the HIV infection itself. A twofold strategy is proposed, consisting of (a) limitation of iron intake through the alimentary, parenteral, and respiratory routes, and (b) possibly the use of iron chelator drugs that could decrease the iron burden, redistribute the metal to the erythroblasts, and suppress the growth of microorganisms. This approach is still to be considered as hypothetical. However, the available data suggest that there is an urgent need for careful clinical studies to clarify the role of iron status on the course of HIV infection.