David S. Hodes

Cytomegalovirus Infection and HIV-1 Disease Progression in Infants Born to HIV-1–Infected Women

Background and Methods Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1–infected and 365 of whom were not) whose CMV status was known, who were born to HIV-1–infected women, and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age.

Quantitative blood cultures in the evaluation of septicemia in children with Broviac catheters

We applied quantitative methods of analysis to all blood cultures drawn during the course of treatment in 28 children with Broviac catheters in a central vein. Thirty febrile episodes in 14 of these patients were evaluated. Samples of blood obtained from a peripheral vein and through the central catheter were cultured quantitatively on agar plates and nonquantitatively in standard broth media. Catheters were judged to be a source of septicemia nine times in seven children. In all nine positive catheter samples, the concentration of pathogens was 10 times as great as that observed in the peripheral venous sample. The blood drawn through the Broviac catheter contained greater than or equal to 2000 colony-forming units per milliliter in six cases. Quantitative cultures in two patients with septicemia not attributable to the catheter yielded low colony counts in the catheter sample. Cultures of blood samples drawn through the catheter when a child was well were not helpful in predicting subsequent septicemia. The technique of inoculating blood directly onto agar plates is easily performed and superior to standard broth cultures, because it detected pathogens within 16 hours and identified infections with multiple organisms.

Attenuated Respiratory Syncytial Virus Vaccines in Asthmatic Children

Extract: Two live “attenuated” respiratory syncytial virus (RSV) vaccines were administered intranasally and by aerosol in placebo-controlled trials among asthmatic children hospitalized at National Jewish Hospital and Research Center (NJH). The first vaccine, a 26° -adapted RSV vaccine, was given to 28 children, and a placebo control was given to 25. Twenty-one of 28 vaccinees (75%) had “takes,” as judged by virus shedding and/or rises in serum antibody and/or rises in nasal secretion neutralizing activity. No excess in wheezing was attributable to the vaccine administration, although there was a high background level of acute respiratory symptoms in both vaccinees and control subjects. In an outbreak of natural RSV infection which occurred some months after the vaccine was given, there was some evidence that those who received the vaccine less than 4 months before exposure to wild virus were protected against reinfection. Protection was not evident when this interval was greater than 4 months.The second vaccine, a temperature-sensitive mutant strain (ts-1), was administered to 22 children, and placebo to 21. Thirteen children (59%) had “takes.” In vaccinees under 6 years of age, 7 of 7 had “takes.” Again, no excess wheezing was seen in vaccinees as compared with control subjects, although there was some evidence that upper respiratory symptoms were more frequent in younger vaccinees. Four of 10 vaccinees shed virus with temperature-sensitive characteristics somewhat different from those of the vaccine strain. Vaccine virus was demonstrated to spread to uninoculated or placebo control children. Natural RSV challenge did not occur during the period of study.Speculation: One of two live “attenuated” RSV vaccines may have produced a brief period of protection against natural infection. This finding offers hope that such live vaccines might prevent disease in selected children over a critical time period, such as infants for the 1st year of life, or allergic or asthmatic children during periods of epidemic prevalence.Asthmatic children did not appear to develop symptoms of wheezing after attenuated RSV infection. This finding suggests that the mechanism of wheezing in asthmatic children with RSV infection may be dependent on, among other factors, the virulence of the virus strain (perhaps its capacity to replicate in and, possibly, invade the lower respiratory tract), rather than on an allergic response to antigens introduced into, and limited to, the upper airway.In view of the spread of the ts-1 vaccine and its apparent loss of temperature sensitivity in some vaccinees, the vaccine may have had the potential for reversion to virulence and hence initiation of epidemic disease. These characteristics are undesirable in live respiratory virus vaccines and should, if possible, be avoided in the development of future such vaccines.

Maternal and perinatal factors related to maternal-infant transmission of HIV-1 in the P2C2 HIV study : The role of EBV shedding

The association of maternal and perinatal factors with mother-infant transmission of HIV-1 was examined in a prospective multicenter cohort of singleton live births to 508 HIV-1-infected women with children of known HIV-1 infection status (91 [18%] HIV-1-infected, 417 [82%] uninfected). From multivariate logistic regression, independent predictors of HIV-1 transmission included maternal CD4 percentage (CD4%) (odds ratio [OR] per 10% increase in CD4% = 0.70; p = .003), ruptured membranes <24 hours (OR = 3.15; p = .02), and maternal bleeding (OR = 2.90; p = .03), whereas maternal zidovudine (ZDV) use was marginally associated (OR = 0.60; p = .08). The associations of maternal urinary cytomegalovirus (CMV) shedding, oropharyngeal Epstein-Barr virus (EBV) shedding, and serology profiles during pregnancy with HIV-1 transmission were examined in the subset of mothers in whom the CMV and EBV measurements were available. Maternal EBV seropositivity, CMV shedding, and CMV seropositivity were 100% (279 of 279), 7% (16 of 229), and 92% (270 of 274), respectively. These rates did not differ between transmitting and nontransmitting mothers. In univariate analyses, maternal EBV shedding was higher among transmitting than nontransmitting mothers (40 of 49 [82%] compared with 154 of 226 [68%]; p = .06) and was independently associated with transmission in multivariate logistic analyses adjusting for CD4%, ruptured membranes, and ZDV use, with an OR of 2.45 (95% confidence interval (CI), 1.03-5.84; p = .04). This permits the conclusion that EBV shedding is associated with maternal-infant HIV-1 transmission, independent of CD4%.

Endotoxin levels in immunocompromised children with fever

Febrile episodes for which no cause can be found are common in immunocompromised children. We postulated that circulating endotoxin, a known pyrogen, might be responsible for some of these episodes in the absence of documented infection. Plasma endotoxin levels were assayed using a recently developed Limulus amebocyte lysate assay enhanced in sensitivity and objectivity by the addition of a chromogenic substrate. Eighty-seven plasma endotoxin determinations were made in 36 immunocompromised children with fever. Convalescent endotoxin levels and levels in normal children were also obtained. It was concluded that a plasma endotoxin level of 35 pg (0.10 EU)/ml constitutes the upper limit of normal in children. Five children (14%) had elevated endotoxin levels in the course of the febrile episodes, in the absence of bacteremia or clinically diagnosed infection. In each case, the levels returned to normal during convalescence. It is concluded that endotoxemia is a possible cause or contributing cause of unexplained fever in immunocompromised children.

Acute hemiplegia associated with HIV infection

An acute hemiplegia secondary to a large cerebral infarct is described in a 16-month-old infant with congenitally-acquired human immunodeficiency virus infection. Serial imaging studies during the next year documented improvement in his hemiplegia and a static underlying human immunodeficiency virus encephalopathy. Acquired immunodeficiency syndrome should be included in the differential diagnosis of children with acute hemiplegia.

HIV Vertical Transmission Rate Determinations Are Subject to Differing Definitions and Therefore Different Rates

The HIV infection status of a cohort of 600 prospectively followed children born to HIV infected mothers was determined using HIV peripheral blood culture tests at 0, 3, and 6 months of age, HIV serology at > or = 15 months, and CDC AIDS criteria. We estimated transmission rates using five methods which differed in how HIV indeterminates are handled. These methods were applied at two points in time to illustrate effects of length of follow-up of the cohort on results. In January 1997, 30 months after the last birth, transmission rate estimates ranged from 15.5% (known positives/known positives x known negatives) to 18.1% (known positives x those with one positive culture x deaths/entire cohort minus those lacking negative cultures at age > or = 5 months). Estimates ranged from 14.8% to 20.7% using the subcohort of 284 children followed > or = 12 months as of May 1993. These results indicate that methods for assigning HIV infection status and for handling HIV indeterminates should be carefully defined when estimating transmission rates.

Cutaneous Herpes Simplex Virus Infection in a Child With Acquired Immunodeficiency Syndrome

Infections with herpes simplex virus (HSV) are common in children with human immunodeficiency virus (HIV) infection and can be severe and atypical.1 Herein, we report a case of a progressive wound of the hand associated with HSV type 1 in a child with the acquired immunodeficiency syndrome (AIDS).

ACTIVATION BY CANDIDAL B-GLUCANS OF THE AMEBOCYTE LYSATE CLOTTING CASCADE OF THE JAPANESE HORSESHOE CRAB TACHYPLEUS TRIDEHTATUS

We have previously reported that cultures of C. albicans activated the amebocyte lysate clotting cascade of the Japanese horseshoe crab Tachypleus tridentatus. In order to isolate the active agent in these cultures, hydrophilic molecules were solubilized by autoclaving the cells in distilled water and testing the resulting aqueous extract. Strongly positive results were obtained. Because previous work showed that the cascade could be activated by synthetic β-glucans, we isolated naturally occurring β-glucans from the fungi, using the alkaline Fehlings solution tehnique of Peat and of Grimmecke. β-glucans isolated in this fashion activated the cascade. By contrast, commercially prepared α-glucans (glycogen, starch) had no effect.In contrast with these findings, commercial amebocyte lysates of the American horseshoe crab Limulus polyphemus gave equivocal and inconsistent results.The possibility that our results were due to contaminating endotoxin was excluded in two ways. First, when quantities of endotoxin were deliberately added to our preparations in reconstruction experiments they were undetectable after our washing procedures. Second, our preparations did not react appreciably with a Tachypleus preparation (Seikagaku Kogyo, Tokyo) made specific for endotoxin by the removal of an alternate activation pathway. It is postulated that it is this pathway that is activated by fungal β-glucans. Clinical applications based on this differential activation of the cascade by fungal and bacterial products are currently being explored.

1109 BLOOD ENDOTOXIN DETERMINATIONS IN THE EVALUATION OF FEBRILE NEUTROPENIC PATIENTS

An increasing number of febrile episodes in neutropenic patients are never explained etiologically. As a result many such episodes are managed by purely empiric therapy. We wished to explore the hypothesis that some of these episodes might be explained by endotoxemia in the absence of bacteremia. To test this possibility we employed a highly sensitive endo toxin assay which is based on the chromogenic release of p-nitroaniline from a peptide-linked form in the presence of endotoxin (ET) and limulus lysate. This assay, as developed by Seikagaku Kogyo Co, Tokyo, is capable of detecting circulating ET in pg/ml concentrations.We found that circulating ET was not detectable in normal patients. By contrast circulating ET in concentrations ranging from 20–200 pg/ml was found in neutropenic patients suffering febrile episodes. Endotoxemia was found in the absence of bacteremia and, on occasion, the detection of endotoxemia preceeded the onset of demonstrable gram negative septicemia by several days.We believe that the sensitive detection of circulating ET can be a valuable adjunct in the assessment of the febrile neutropenic patient, and we are currently extending our studies.