Karina M. Butler

Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.

Abstract Background. 2′,3′-Dideoxyinosine (ddI) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddI showed evidence of antiretroviral activity with little hematologic toxicity. Methods. We conducted a phase I–II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddI was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddI: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. Results. After oral administration, ddI was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddI at each of the two highest doses. The median CD...

Candida: An Increasingly Important Pathogen in the Nursery

Advances in neonatal care now permit the survival of very immature infants. Although candidiasis is not a new disease, the spectrum of clinical disease has greatly widened and the rate of invasive disease has increased significantly. This article reviews the history, microbiology, and epidemiology of candidal infections, both superficial and invasive. Particular attention is paid to the pathogenesis of and risk factors associated with the development of invasive disease, as well as its clinical manifestations, diagnosis, and treatment.

Growth and neuroendocrine dysfunction in children with acquired immunodeficiency syndrome

To assess whether neuroendocrine dysfunction is present in children with acquired immunodeficiency syndrome (AIDS) and growth failure, we evaluated the thyroid, adrenal, and growth hormone-insulin-like growth factor I (IGF-1) axes in nine children with AIDS and failure to thrive. Basal thyroid-stimulating hormone, free thyroxine, and triiodothyronine levels were normal in eight of the nine children and indicated primary hypothyroidism in one child; thyroxine levels were elevated in four and normal in five children. Thyroxine-binding globulin levels were elevated in all children. Serial measurements of thyroid-stimulating hormone, made hourly from 2 to 6 pm and from 10 pm to 2 am, revealed a flat diurnal rhythm of thyroid-stimulating hormone in six children, which may indicate early central hypothyroidism, and a normal nocturnal rise in the remaining three children. Basal plasma corticotropin and aldosterone levels were normal in all children, plasma renin levels were normal in three and elevated in six children, and cortisol levels were normal or elevated in all children. Corticotropin-stimulated cortisol levels exceeded 500 nmol/L (18 micrograms/dl) in all children except one, who was receiving treatment with ketoconazole. Thus adrenocortical function appeared to be grossly intact. The peak growth hormone responses to provocative testing was normal (greater than 7 ng/ml) in eight children and low in one child. The plasma level of insulin-like growth factor I was normal in eight of the nine children and low in one child. We conclude that growth failure in children with AIDS does not usually result from a recognized endocrine cause and that adrenal function is usually normal. However, endocrine deficiency may contribute to morbidity in some children with AIDS.

Cerebral artery aneurysms in children infected with human immunodeficiency virus

More than 250 children treated at our institution on antiretroviral treatment protocols have been monitored with brain imaging studies. We documented the occurrence and progression of aneurysms of major cerebral arteries in two children with advanced human immunodeficiency virus infection. In both cases these lesions remained clinically silent initially, despite progression to marked dilation.

Defining the population of human immunodeficiency virus-infected children at risk for Mycobacterium avium-intracellulare infection

We reviewed the 22 cases of Mycobacterium avium-intracellulare (MAI) infection that occurred among 196 human immunodeficiency virus-infected children seen at the National Cancer Institute Pediatric Branch from December 1986 through April 1991, and an additional 65 charts from children with cultures negative for MAI. All patients with proven MAI were receiving antiretroviral therapy with zidovudine, dideoxyinosine, or a combination of zidovudine and dideoxycytidine. All patients had disseminated MAI infection, except one adolescent who had only evidence of localized lymphadenitis. All cases of MAI but one were diagnosed before death. The overall incidence of MAI was 11% in our patients but increased to 24% in patients whose absolute CD4 cell counts were < 100 cells/mm3. Symptoms most commonly associated with MAI infection included recurrent fever (86% of patients), weight loss or failure to thrive (64%), neutropenia (55%), night sweats (32%), and abdominal pain (27%). Children infected with MAI had a mean CD4 percentage of 2% (range, 0% to 7%) and a mean absolute CD4 count of 12 cells/mm3 (range, 0 to 48 cells/mm3), significantly lower than in the remainder of the clinic population or the group of children with cultures negative for MAI. Of 20 patients with MAI infection who were tested, 10 had measurable p24 antigen with a mean value 939 pg/ml (range, 77 to 3270 pg/ml) compared with 19 of 59 patients without MAI infection in whom the mean positive value was 413 pg/ml. There was no difference in survival time between those children with documented MAI infection (median survival time, 45.5 weeks) and those with similarly low CD4 counts and cultures negative for MAI (median survival time, 50.4 weeks). Future improvements in therapeutic options may make screening of pediatric human immunodeficiency virus-infected patients with low CD4 counts a reasonable plan.

IN THE VERTICAL TRANSMISSION OF HIV, TIMING MAY BE EVERYTHING

The significance of understanding the vertical transmission of HIV lies in the 78% of womens AIDS cases (1991) of sexually active women who may transmit the infection to their offspring. 2% of children in the US and 5-25% of children in developing countries are HIV infected. The current rates of maternal-fetal transmission average 25-30%. Interrupting this mode of passage would provide protection for children. The Van de Perre study on postnatal transmission by breast feeding is discussed in order to the timing of HIV infection and the relationship to infant risk of infection. Postnatal infection of infants suggests that the risk is enhanced during the primary infection of the mother. It is pointed out that transient but large elevations in plasma virus titers have been observed during primary infection of homosexual men, before anti-p24 and anti-gp160 antibodies appear. These plasma titers may increase the efficiency of vertical transmission. It is also possible that the absence of neutralizing or nonneutralizing antibodies may enhance transmission. The frequency of new infections is estimated by Van de Perre in the rate of seroconversion in Rwandan women as 4.7-7.3%/year. The US rate is .6-.8/1000/year for all adults and adolescents. Pregnancy can occur after primary HIV infection or at the onset when plasma titers are high and antibody levels are low. It is reported that the rate of transmission may be highest when mothers are in a more advanced disease state. Another factor affecting transmission is the presence or absence of maternal antibodies. Lower HIV transmission may be related to the presence of epitopes on the hypervariable V3 loop of HIV gp120 or the principal neutralizing domain. Although HIV virus has been identified in fetal tissues after 8-15 weeks gestation, there is reason to believe that the greatest transmission is intrapartum because maternal blood may be ingested or there is maternal-fetal transfusion during labor and delivery. New York studies have suggested that 50% of infected infants of known seropositive women will be positive by the polymerase chain reaction by 3 months of age and 50% by 3-6 months of age. It is likely that the delay is due to infection late in gestation.

Phase I study of continuous-infusion soluble CD4 as a single agent and in combination with oral dideoxyinosine therapy in children with symptomatic human immunodeficiency virus infection

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

Group F Streptococcus: an unusual cause of arthritis

Bacterial arthritis is a serious infection in children occurring either as the result of direct inoculation of organisms into the joint space, of spreading from a contiguous focus of infection, or of hematogenous seeding of the synovium. Although the etiologic agent can be identified in 60% to 70% of cases, joint fluid cultures may remain negative in a substantial number of patients. The most likely etiologic agent depends both on the route of infection and the age of the child. Overall Staphylococcus aureus, Hemophilus influenzae type b and streptococci are the leading causes of bacterial arthritis. Lancefield groups A, B, C, D, and G have all been implicated. However, septic arthritis due to hematogenous seeding with Group F Streptococcus has not been previously reported. A normal 10-month-old boy presented with acute monoarticular arthritis of the knee and had Group F Streptococcus isolated from the blood. Antimicrobial therapy resulted in complete resolution of the arthritis.

The Febrile Neutropenic Patient: Newer Options for Empirical Therapy

It has become well accepted that the onset of fever in a neutropenic patient requires the prompt initiation of empirical antimicrobial therapy. The main goal of empirical antibiotics is to protect against the early morbidity and mortality associated with untreated bacterial infections in the neutropenic population.