- Email: [email protected]
What's new in infectious diseases
New Developments
What’s New in Infectious Diseases Stanford T. Shulman,
MD
This is a series of brief reviews covering several areas of the field of infectious diseases in which significant advances have taken place recently.
Hepatitis
C Virus
The term non-A, non-6 (NANB) hepatitis has been used for the past decade or so to include those acute hepatitic illnesses that clearly are not related to infection with hepatitis A virus, hepatitis B virus, cytomegalovirus, or Epstein-Barr virus. NANB hepatitis accounts for an estimated 150,000 cases yearly in the United States, of which 5% to 10% are transfusion-related; 40% are associated with intravenous drug abuse; 5%, with occupational (health care) exposure; and lo%, with heterosexual activity with multiple partners, or household and/or sexual contact with an individual with hepatitis. Forty percent are without an identifiable source of infection. It has been clearly established that a prolonged NANB hepatitis carrier state develops frequently and, more importantly, that chronic hepatitis may develop in about half of patients with NANB hepatitis. Twenty percent of the latter group progress to cirrhosis. In addition, NANB hepatitis may be causally related to hepatocellular carcinoma and to sporadic community-acquired hepatitis. Until recently, attempts to identify a specific viral agent that could be associated with significant numbers of cases of NANB hepatitis had been frustrating and unsuccessful. Choo and associates, using techniques of modern molecular biology and working with sera capable of transmitting NANB hepatitis to primates, isolated a cDNA clone derived from the genome of a blood-borne NANB hepatitis agent.’ This agent, the hepatitis C virus (HCV), is thought to be an RNA virus, probably related to the togaviruses or flaviviruses. An assay for measuring antibodies to this agent was quickly developed,2 and there has been a veritable explosion of related knowledge. It has already been established that HCV is the major cause of posttransfusion NANB hepatitis. Screening of blood donors for antibody to HCV should prevent the majority of such cases and has recently been instituted. In addition, HCV appears to be the etiologic agent of up to 90% of sporadic, community-acquired NANB hepatitis that occurs in patients without a history of parenteral exposure. Studies of sera from patients in Italy and Japan, as well as from those in the United States, have confirmed HCV as a major cause of NANB hepatitis worldwide. Development of anti-HCV antibody is delayed, being first detected an average of 22 weeks after transfusion, or some 15 weeks after onset of clinical hepatitis. It is important to note that some patients do not become seropositive for anti-HCV until as long as 1 year after infection. 3 In patients with chronic liver disease, antiHCV has persisted, but in patients with acute resolving hepatitis, anti-HCV disappeared after approximately 4 years. Treatment trials that utilized interferon alfa for patients with chronic hepatitis C have shown promising results.4 We can expect much additional data to be generated in the next few years to elucidate more fully the impact of HCV. A readily available diagnostic test for anti-HCV has been developed and is now widely available. Stanford T. Shulman, MD is Professor of Pediatrics, Northwestern and Head, Division of infectious Diseases, and Associate Dean for Hospital Memorial Hospital, Chicago.
Current
Problems
University Academic
Medical School, Affairs, Children’s
in Pediatrics
I January
1991
3
New Developments Steroids and Meningitis Considerable attention over the past several years has been devoted to study of the hypothesis that the outcome of bacterial meningitis in children may be improved by the adjunctive administration of corticosteroids together with antibiotics. This is not a new idea; at least eight published studies (five of which were reported between 1959 and 1969) evaluated the efficacy of such adjunctive therapy. A recent meta-analysis of these studies5 concluded that corticosteroid administration did not reduce the risk of death or the frequency of neurologic abnormality as assessed either at the time of hospital discharge or at follow-up examination. In contrast, the most recent trials from Dallas, carried out by George McCracken and colleagues, suggest that at least for children with Hemophilus influenzae type b meningitis, the risk of bilateral moderate or severe sensorineural hearing loss may be reduced by approximately 9% (with 95% confidence limits of 3% to 15%) by the addition of cor-ticosteroids.6 When cefuroxime at 240 mg/kg/day was utilized for treatment, the addition of dexamethasone at 0.6 mg/kg/day given in four daily dosages for 4 days was associated with significantly less hearing loss. However, in another trial at the same institution in which cefuroxime at 300 mg/kg/day or ceftriaxone was utilized as the antibiotic, no significantly decreased incidence of hearing loss was observed. In the earlier study employing the lower dosage of cefuroxime, an unusually high rate of hearing loss (21%) was observed in the placebo (nondexamethasone) group, suggesting the possibility that both the choice and the dosage of the antibiotic selected might be important determinants of risk for the development of hearing loss. Over the past 1 to 2 years, a growing body of literature, including apumber of studies carried out by Dr. Moshe Arditi and Dr. Ram Yogev in Chicago-and by McCracken and coworkers in Dallas, has led to the concept that antibiotic therapy of bacterial meningitis results in the release of bacterial endotoxin and perhaps other bacterial cell wall materials. These materials, in turn, stimulate the release of host mediators of inflammation, such as tumor necrosis factor, interleukin-1, and platelet-activating factor, which may directly contribute to neuronal injury.7 Thus, the use of an anti-inflammatory agent, such as a corticosteroid, might block these mechanisms that are potentially detrimental to the host and that may be largely responsible for the neurologic consequences of bacterial meningitis. Nevertheless, such anti-inflammatory therapy has a number of potential associated hazards. For example, corticosteroids might reduce the degree of meningeal inflammation so promptly that impaired penetration of antibiotic into the cerebrospinal fluid (CSF) could result, resulting in inadequate antibiotic concentrations in CSF. Several circumstances in which such an event has occurred have been reported. Gastrointestinal hemorrhage has been observed in at least two reported dexamethasone recipients, and we have observed one such patient. In addition, the potential deleterious effects of corticosteroids on those patients who are originally thought to have bacterial meningitis, but who are later proved to have nonbacterial meningitis, are unknown. Additional well-designed and well-controlled studies to evaluate the efficacy of corticosteroids in children with bacterial meningitis and to assess the risk-benefit ratio of such therapy will be essential to clarify its precise value. A large multicenter study has been organized by Dr. Ram Yogev to address these issues. This study involves patients at several major pediatric centers in the United States. In this study, all patients receive antibiotic therapy with ceftriaxone and are randomized to receive placebo or dexamethasone in a double-blind fashion. Careful audiologic
4
Current Problems in Pediatrics I January 1991
New Developments and neurologic follow-up and monitoring of their response to therapy should help to resolve this important therapeutic issue.
Pediatric Human lmmunodeficiency Virus Infection Recently, there have been several important advances related to children who are infected or who are suspected of being infected with the human immunodeficiency virus (HIV). Only about one-third of babies born to HIV-infected women become infected with this retroviral agent. However, essentially all term or nearterm babies of seropositive women are initially seropositive because of transplacental passage of IgG. Because these antibodies may persist for as long as 15 to 18 months, accurate identification of the infected infants and of the two-thirds who escape infection is difficult in the presence of anti-HIV. Attempts to culture HIV from lymphocytes of infants generally has proved impractical by virtue of cost, logistics, and the large amount of blood usually required. Therefore, additional diagnostic measures have been sought. Identification of infected infants is essential for studies that attempt to assess the efficacy of early intervention with antiviral agents and with agents to prevent certain complications such as Pneumocystis carinii pneumonitis. Two new diagnostic procedures may solve this problem of identification of vertically infected infants. The polymerase chain reaction (PCR) is a recently developed tool of molecular biology that repeatedly and cyclically amplifies gene sequences, resulting in logarithmic increase. With this technique, a single gene copy in a biologic specimen can be amplified to the extent that a detectable signal is produced. Several groups have reported on the application of PCR techniques to the diagnosis of HIV-infected infants. 8l g Ellen Chadwick and colleagues* (Northwestern University Medical School and Children’s Memorial Hospital) and Martha Rogers and coworkers9 (Centers for Disease Control) each have reported a prospective series of infants born to HIV-infected women who were studied early in life by PCR and then followed to determjne whether they ultimately proved to be HIV-infected. Both groups found PCR to be promising for this purpose and effective in distinguishing infected from noninfected infants. Additional studies utilizing this exciting and potentially revolutionary methodology are in progress. Another promising new technique for diagnosis of infants infected with HIV is the demonstration of the in vitro production of HIV antibody by their peripheral blood lymphocytes in tissue culture. lo After culture of lymphocytes for 10 days in vitro, the culture supernates were harvested and examined by enzyme-linked immunosorbent assay (ELISA) and Western blot, the same assays used for routine serum testing. Lymphocytes from infected children produced IgG anti-HIV in vitro, with 87% concordance between specific IgG anti-HIV production and subsequent diagnosis of HIV infection. This technique will require further refinement, but may prove to be a useful adjunct for HIV diagnosis among offspring of HIV-infected women. The large majority of vertical transmissions of HIV from mothers to their offspring appear to result from infection at the time of parturition. However, in utero transmission occurs in some cases. This distinction is important; it relates to strategies under study to prevent infection of the neonate (see below). In a few cases, HIV has been isolated from the amniotic fluid of a third-trimester pregnancy. This documentation recently was carried an important additional step. Investigators at the National Institutes of Health reported that the CD4 receptor on human cells to which HIV binds can be demonstrated to be present in fetal-derived placental tissue.” Both the CD4 protein and the messenger RNA that directs its synthesis were found in fetal-derived placental tissue as early as 9 to 11 weeks’ gestation.
Current
Problems
in Pediatrics
I January
-
5
1991
5
New Developments Organ cultures of the CD4 + chorionic villus cells were able to be infected by HIV. Thus, direct placental infection by HIV is a potential mode of fetal infection as early as the end of the first trimester. Scott and associates recently reviewed the survival data for the large group of children with acquired immunodeficiency syndrome (AIDS) who have been followed in Miami.12 A total of 172 perinatally HIV-infected children were cared for in Miami from 1981 to 1987. The 148 mothers had acquired HIV infection through heterosexual contact (89%), intravenous drug abuse (30%), or blood transfusion (17%). The median age of the infants with symptomatic HIV disease at presentation was 8 months, with initial symptoms developing in only 21% after the age of 2 years. The earliest manifestations of HIV infection were lymphoid interstitial pneumonia (17%), encephalopathy (12%), recurrent bacterial infection (lo%), P. carinii pneumonitis (9%), and candidal esophagitis (8%). Median survival times varied markedly and were highly dependent on the nature of the initial disease manifestation. For example, those with pneumocystis pneumonitis as their initial disease had a median survival of only 1 month, whereas those who initially presented with lymphocytic interstitial pneumonitis had a median survival time of 72 months. For the entire group of 172 children, the median duration of survival from the time of diagnosis was 38 months, with the highest mortality occurring in the first year of life (17%). After the first year, the mortality rate decreased and remained fairly constant. No significant difference in survival time was observed between boys and girls. Multivariate analysis showed that survival was influenced by the pattern of the initial illness (as outlined above) and by the age at diagnosis: A younger age at diagnosis was highly associated with shorter survival time. It is likely that the latter factor is merely a surrogate marker for the severity and aggressiveness of the HIV-associated disease process. The dreadful prognosis for infants-with early pneumocystis infection highlights the importance of early and accurate diagnosis of HIV infection (during the asymptomatic period) and the value of early institution of prophylaxis against this infection. Additionally, the data of Scott and coworkers serve as benchmark natural history dataj2; these children did not receive any form of antiviral therapy. Now that azidothymidine (AZT) is available for children with HIV infection, the success of current and future interventions will be measured against these landmark data.
Rotavirus Viral gastroenteritis is a major cause of childhood morbidity and mortality worldwide. A recent estimate of its magnitude yielded 3 to 5 billion cases and 5 to 10 million deaths annually, the latter particularly in developing countries. Rotaviruses are the leading known agents of viral gastroenteritis. In some tropical areas of Latin America, mortality in the first 5 years of life exceeds 14%, with diarrhea accounting for one-third to one-half of these deaths, 15% of which are related to rotavirus infection. A recent study from Ecuador examined the prevalence of serum antibodies to the four most common human rotavirus serotypes.13 Evidence of primary rotaviral infection was observed in 6 to 12-month-old children, and those with serum antibody were more than three times as likely to have had a significant diarrhea1 illness than were seronegative infants. Younger children were likely to have antibody to a single rotaviral serotype, usually type 4. Several other recent studies examined rotavirus infection in children in the United States. The Centers for Disease Control investigators have estimated that more than 200,000 U.S. children under 5 years of age are hospitalized yearly for
Current Problems in Pediatrics I January 1991
New Developments diarrhea, a large portion of which is due to rotaviral infection. Investigators at the Texas Children’s Hospital in Houston, the largest pediatric hospital in the southwest region of the United States, attempted to determine the impact of rotavirus enteritis at their institution over the period 1979 to 1989 and to extrapolate their data to the entire U.S. population. I4 It was found that 67% of rotavirus-positive samples represented children with community-acquired acute gastroenteritis, with most of the remainder representing hospital-acquired nosocomial infections, emphasizing the substantial risk of nosocomial infection in hospitalized children. It was estimated that 473 children on average were hospitalized yearly at Texas Children’s Hospital, accounting for 3% of total hospital days. Extrapolation to the U.S. population as a whole yielded a national total of 110,000 cases and 583,000 hospital days at a cost of $352 million. The highest hospitalization rate, 11.1/l ,000 children/year, was encountered in children in the first year of life, falling to half that level in the second year of life. The same group of investigators studied the relative frequencies of group A rotavirus serotypes 1,2,3, and 4 in Houston and in the northcentral region of the United States. The predominant serotype varied from year to year in Houston, with types 1, 3, and 4 each predominant in more than 1 year. A different pattern was seen in the isolates from the northcentral region of the United States, in which serotype 1 dominated each year. Clearly, the implication of these data on the development and implementation of rotaviral vaccines will need to be carefully considered.
References 1. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-382. 2. Kuo G, Choo Q-L, Alter HJ, et al: An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244:362-364. 3. Alter HJ, Purcell RH, Shih JW, et al: Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989; 321:1494-1500. 4. DiBisceglie AM, Martin P, Kassianides C, et al: Recombinant interferon alfa therapy for chronic hepatitis C. A randomized doubleblind, placebc-controlled trial. N EnglJ Med 1989; 321:1506-1510. 5. Havens PL, Wendelberger KJ, Hoffman GM, et al: Corticosteroids as adjunctive therapy in bacterial meningitis. Am J Dis Child 1989; 143:1051-1055. 6. Lebel MH, Freij BJ, Syrogiannopoulous GA, et al: Dexamethasone therapy for bacterial meningitis. N Engl J Med 1988; 319:964-967. 7. Arditi M, Manogue KR, Caplan M, Yogev R: Cerebrospinal fluid cachectin/TNF and plateletactivating factor concentrations and severity of bacterial meningitis in children. J infect Dis 1990; 162:139-147. 8. Chadwick EG, Yogev, Kwok S, et al: Enzymatic amplification of HIV in peripheral blood mononuclear cells from pediatric patients. J Infect Dis 1989; 160:954-959. 9. Rogers MF, Ou C-Y, Rayfield M, et al. Use of the polymerase chain reaction for early detection of the proviral sequences of HIV in infants born to seropositive mothers. N Engl J Med 1989; 320: 1649-l 854. 10. Amadori A, Giaquinto C, Zacchello F, et al: In vitro production of HIV-specific antibody in children at risk of AIDS. Lancet 1988; 1:852-854. 11. Maury W, Potts BJ, Rabson AB: HIV-l infection of first-trimester and term human placental tissue. J Infect Dis 1989; 160:583-588. 12. Scott GB, Hutto C, Makuch RW, et al: Survival in children with perinatally acquired HIV-1 infection. N Engl J Med 1989; 321:1791-1796. 13. Brussow H, Sidoti J, Barclay D, et al: Prevalence and serotype specificity of rotavirus antibodies in different age groups of Ecuadorian infants. J Infect Dis 1990; 162:615-620. 14. Matson DO, Estes MK: Impact of rotavirus infection at a large pediatric hospital. Jlnfect Dis 1990; 162:598-604.
Current
Problems
in Pediatrics
I January
1991
7
What’s New in Infectious Diseases Stanford T. Shulman,
MD
This is a series of brief reviews covering several areas of the field of infectious diseases in which significant advances have taken place recently.
Hepatitis
C Virus
The term non-A, non-6 (NANB) hepatitis has been used for the past decade or so to include those acute hepatitic illnesses that clearly are not related to infection with hepatitis A virus, hepatitis B virus, cytomegalovirus, or Epstein-Barr virus. NANB hepatitis accounts for an estimated 150,000 cases yearly in the United States, of which 5% to 10% are transfusion-related; 40% are associated with intravenous drug abuse; 5%, with occupational (health care) exposure; and lo%, with heterosexual activity with multiple partners, or household and/or sexual contact with an individual with hepatitis. Forty percent are without an identifiable source of infection. It has been clearly established that a prolonged NANB hepatitis carrier state develops frequently and, more importantly, that chronic hepatitis may develop in about half of patients with NANB hepatitis. Twenty percent of the latter group progress to cirrhosis. In addition, NANB hepatitis may be causally related to hepatocellular carcinoma and to sporadic community-acquired hepatitis. Until recently, attempts to identify a specific viral agent that could be associated with significant numbers of cases of NANB hepatitis had been frustrating and unsuccessful. Choo and associates, using techniques of modern molecular biology and working with sera capable of transmitting NANB hepatitis to primates, isolated a cDNA clone derived from the genome of a blood-borne NANB hepatitis agent.’ This agent, the hepatitis C virus (HCV), is thought to be an RNA virus, probably related to the togaviruses or flaviviruses. An assay for measuring antibodies to this agent was quickly developed,2 and there has been a veritable explosion of related knowledge. It has already been established that HCV is the major cause of posttransfusion NANB hepatitis. Screening of blood donors for antibody to HCV should prevent the majority of such cases and has recently been instituted. In addition, HCV appears to be the etiologic agent of up to 90% of sporadic, community-acquired NANB hepatitis that occurs in patients without a history of parenteral exposure. Studies of sera from patients in Italy and Japan, as well as from those in the United States, have confirmed HCV as a major cause of NANB hepatitis worldwide. Development of anti-HCV antibody is delayed, being first detected an average of 22 weeks after transfusion, or some 15 weeks after onset of clinical hepatitis. It is important to note that some patients do not become seropositive for anti-HCV until as long as 1 year after infection. 3 In patients with chronic liver disease, antiHCV has persisted, but in patients with acute resolving hepatitis, anti-HCV disappeared after approximately 4 years. Treatment trials that utilized interferon alfa for patients with chronic hepatitis C have shown promising results.4 We can expect much additional data to be generated in the next few years to elucidate more fully the impact of HCV. A readily available diagnostic test for anti-HCV has been developed and is now widely available. Stanford T. Shulman, MD is Professor of Pediatrics, Northwestern and Head, Division of infectious Diseases, and Associate Dean for Hospital Memorial Hospital, Chicago.
Current
Problems
University Academic
Medical School, Affairs, Children’s
in Pediatrics
I January
1991
3
New Developments Steroids and Meningitis Considerable attention over the past several years has been devoted to study of the hypothesis that the outcome of bacterial meningitis in children may be improved by the adjunctive administration of corticosteroids together with antibiotics. This is not a new idea; at least eight published studies (five of which were reported between 1959 and 1969) evaluated the efficacy of such adjunctive therapy. A recent meta-analysis of these studies5 concluded that corticosteroid administration did not reduce the risk of death or the frequency of neurologic abnormality as assessed either at the time of hospital discharge or at follow-up examination. In contrast, the most recent trials from Dallas, carried out by George McCracken and colleagues, suggest that at least for children with Hemophilus influenzae type b meningitis, the risk of bilateral moderate or severe sensorineural hearing loss may be reduced by approximately 9% (with 95% confidence limits of 3% to 15%) by the addition of cor-ticosteroids.6 When cefuroxime at 240 mg/kg/day was utilized for treatment, the addition of dexamethasone at 0.6 mg/kg/day given in four daily dosages for 4 days was associated with significantly less hearing loss. However, in another trial at the same institution in which cefuroxime at 300 mg/kg/day or ceftriaxone was utilized as the antibiotic, no significantly decreased incidence of hearing loss was observed. In the earlier study employing the lower dosage of cefuroxime, an unusually high rate of hearing loss (21%) was observed in the placebo (nondexamethasone) group, suggesting the possibility that both the choice and the dosage of the antibiotic selected might be important determinants of risk for the development of hearing loss. Over the past 1 to 2 years, a growing body of literature, including apumber of studies carried out by Dr. Moshe Arditi and Dr. Ram Yogev in Chicago-and by McCracken and coworkers in Dallas, has led to the concept that antibiotic therapy of bacterial meningitis results in the release of bacterial endotoxin and perhaps other bacterial cell wall materials. These materials, in turn, stimulate the release of host mediators of inflammation, such as tumor necrosis factor, interleukin-1, and platelet-activating factor, which may directly contribute to neuronal injury.7 Thus, the use of an anti-inflammatory agent, such as a corticosteroid, might block these mechanisms that are potentially detrimental to the host and that may be largely responsible for the neurologic consequences of bacterial meningitis. Nevertheless, such anti-inflammatory therapy has a number of potential associated hazards. For example, corticosteroids might reduce the degree of meningeal inflammation so promptly that impaired penetration of antibiotic into the cerebrospinal fluid (CSF) could result, resulting in inadequate antibiotic concentrations in CSF. Several circumstances in which such an event has occurred have been reported. Gastrointestinal hemorrhage has been observed in at least two reported dexamethasone recipients, and we have observed one such patient. In addition, the potential deleterious effects of corticosteroids on those patients who are originally thought to have bacterial meningitis, but who are later proved to have nonbacterial meningitis, are unknown. Additional well-designed and well-controlled studies to evaluate the efficacy of corticosteroids in children with bacterial meningitis and to assess the risk-benefit ratio of such therapy will be essential to clarify its precise value. A large multicenter study has been organized by Dr. Ram Yogev to address these issues. This study involves patients at several major pediatric centers in the United States. In this study, all patients receive antibiotic therapy with ceftriaxone and are randomized to receive placebo or dexamethasone in a double-blind fashion. Careful audiologic
4
Current Problems in Pediatrics I January 1991
New Developments and neurologic follow-up and monitoring of their response to therapy should help to resolve this important therapeutic issue.
Pediatric Human lmmunodeficiency Virus Infection Recently, there have been several important advances related to children who are infected or who are suspected of being infected with the human immunodeficiency virus (HIV). Only about one-third of babies born to HIV-infected women become infected with this retroviral agent. However, essentially all term or nearterm babies of seropositive women are initially seropositive because of transplacental passage of IgG. Because these antibodies may persist for as long as 15 to 18 months, accurate identification of the infected infants and of the two-thirds who escape infection is difficult in the presence of anti-HIV. Attempts to culture HIV from lymphocytes of infants generally has proved impractical by virtue of cost, logistics, and the large amount of blood usually required. Therefore, additional diagnostic measures have been sought. Identification of infected infants is essential for studies that attempt to assess the efficacy of early intervention with antiviral agents and with agents to prevent certain complications such as Pneumocystis carinii pneumonitis. Two new diagnostic procedures may solve this problem of identification of vertically infected infants. The polymerase chain reaction (PCR) is a recently developed tool of molecular biology that repeatedly and cyclically amplifies gene sequences, resulting in logarithmic increase. With this technique, a single gene copy in a biologic specimen can be amplified to the extent that a detectable signal is produced. Several groups have reported on the application of PCR techniques to the diagnosis of HIV-infected infants. 8l g Ellen Chadwick and colleagues* (Northwestern University Medical School and Children’s Memorial Hospital) and Martha Rogers and coworkers9 (Centers for Disease Control) each have reported a prospective series of infants born to HIV-infected women who were studied early in life by PCR and then followed to determjne whether they ultimately proved to be HIV-infected. Both groups found PCR to be promising for this purpose and effective in distinguishing infected from noninfected infants. Additional studies utilizing this exciting and potentially revolutionary methodology are in progress. Another promising new technique for diagnosis of infants infected with HIV is the demonstration of the in vitro production of HIV antibody by their peripheral blood lymphocytes in tissue culture. lo After culture of lymphocytes for 10 days in vitro, the culture supernates were harvested and examined by enzyme-linked immunosorbent assay (ELISA) and Western blot, the same assays used for routine serum testing. Lymphocytes from infected children produced IgG anti-HIV in vitro, with 87% concordance between specific IgG anti-HIV production and subsequent diagnosis of HIV infection. This technique will require further refinement, but may prove to be a useful adjunct for HIV diagnosis among offspring of HIV-infected women. The large majority of vertical transmissions of HIV from mothers to their offspring appear to result from infection at the time of parturition. However, in utero transmission occurs in some cases. This distinction is important; it relates to strategies under study to prevent infection of the neonate (see below). In a few cases, HIV has been isolated from the amniotic fluid of a third-trimester pregnancy. This documentation recently was carried an important additional step. Investigators at the National Institutes of Health reported that the CD4 receptor on human cells to which HIV binds can be demonstrated to be present in fetal-derived placental tissue.” Both the CD4 protein and the messenger RNA that directs its synthesis were found in fetal-derived placental tissue as early as 9 to 11 weeks’ gestation.
Current
Problems
in Pediatrics
I January
-
5
1991
5
New Developments Organ cultures of the CD4 + chorionic villus cells were able to be infected by HIV. Thus, direct placental infection by HIV is a potential mode of fetal infection as early as the end of the first trimester. Scott and associates recently reviewed the survival data for the large group of children with acquired immunodeficiency syndrome (AIDS) who have been followed in Miami.12 A total of 172 perinatally HIV-infected children were cared for in Miami from 1981 to 1987. The 148 mothers had acquired HIV infection through heterosexual contact (89%), intravenous drug abuse (30%), or blood transfusion (17%). The median age of the infants with symptomatic HIV disease at presentation was 8 months, with initial symptoms developing in only 21% after the age of 2 years. The earliest manifestations of HIV infection were lymphoid interstitial pneumonia (17%), encephalopathy (12%), recurrent bacterial infection (lo%), P. carinii pneumonitis (9%), and candidal esophagitis (8%). Median survival times varied markedly and were highly dependent on the nature of the initial disease manifestation. For example, those with pneumocystis pneumonitis as their initial disease had a median survival of only 1 month, whereas those who initially presented with lymphocytic interstitial pneumonitis had a median survival time of 72 months. For the entire group of 172 children, the median duration of survival from the time of diagnosis was 38 months, with the highest mortality occurring in the first year of life (17%). After the first year, the mortality rate decreased and remained fairly constant. No significant difference in survival time was observed between boys and girls. Multivariate analysis showed that survival was influenced by the pattern of the initial illness (as outlined above) and by the age at diagnosis: A younger age at diagnosis was highly associated with shorter survival time. It is likely that the latter factor is merely a surrogate marker for the severity and aggressiveness of the HIV-associated disease process. The dreadful prognosis for infants-with early pneumocystis infection highlights the importance of early and accurate diagnosis of HIV infection (during the asymptomatic period) and the value of early institution of prophylaxis against this infection. Additionally, the data of Scott and coworkers serve as benchmark natural history dataj2; these children did not receive any form of antiviral therapy. Now that azidothymidine (AZT) is available for children with HIV infection, the success of current and future interventions will be measured against these landmark data.
Rotavirus Viral gastroenteritis is a major cause of childhood morbidity and mortality worldwide. A recent estimate of its magnitude yielded 3 to 5 billion cases and 5 to 10 million deaths annually, the latter particularly in developing countries. Rotaviruses are the leading known agents of viral gastroenteritis. In some tropical areas of Latin America, mortality in the first 5 years of life exceeds 14%, with diarrhea accounting for one-third to one-half of these deaths, 15% of which are related to rotavirus infection. A recent study from Ecuador examined the prevalence of serum antibodies to the four most common human rotavirus serotypes.13 Evidence of primary rotaviral infection was observed in 6 to 12-month-old children, and those with serum antibody were more than three times as likely to have had a significant diarrhea1 illness than were seronegative infants. Younger children were likely to have antibody to a single rotaviral serotype, usually type 4. Several other recent studies examined rotavirus infection in children in the United States. The Centers for Disease Control investigators have estimated that more than 200,000 U.S. children under 5 years of age are hospitalized yearly for
Current Problems in Pediatrics I January 1991
New Developments diarrhea, a large portion of which is due to rotaviral infection. Investigators at the Texas Children’s Hospital in Houston, the largest pediatric hospital in the southwest region of the United States, attempted to determine the impact of rotavirus enteritis at their institution over the period 1979 to 1989 and to extrapolate their data to the entire U.S. population. I4 It was found that 67% of rotavirus-positive samples represented children with community-acquired acute gastroenteritis, with most of the remainder representing hospital-acquired nosocomial infections, emphasizing the substantial risk of nosocomial infection in hospitalized children. It was estimated that 473 children on average were hospitalized yearly at Texas Children’s Hospital, accounting for 3% of total hospital days. Extrapolation to the U.S. population as a whole yielded a national total of 110,000 cases and 583,000 hospital days at a cost of $352 million. The highest hospitalization rate, 11.1/l ,000 children/year, was encountered in children in the first year of life, falling to half that level in the second year of life. The same group of investigators studied the relative frequencies of group A rotavirus serotypes 1,2,3, and 4 in Houston and in the northcentral region of the United States. The predominant serotype varied from year to year in Houston, with types 1, 3, and 4 each predominant in more than 1 year. A different pattern was seen in the isolates from the northcentral region of the United States, in which serotype 1 dominated each year. Clearly, the implication of these data on the development and implementation of rotaviral vaccines will need to be carefully considered.
References 1. Choo Q-L, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-382. 2. Kuo G, Choo Q-L, Alter HJ, et al: An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244:362-364. 3. Alter HJ, Purcell RH, Shih JW, et al: Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989; 321:1494-1500. 4. DiBisceglie AM, Martin P, Kassianides C, et al: Recombinant interferon alfa therapy for chronic hepatitis C. A randomized doubleblind, placebc-controlled trial. N EnglJ Med 1989; 321:1506-1510. 5. Havens PL, Wendelberger KJ, Hoffman GM, et al: Corticosteroids as adjunctive therapy in bacterial meningitis. Am J Dis Child 1989; 143:1051-1055. 6. Lebel MH, Freij BJ, Syrogiannopoulous GA, et al: Dexamethasone therapy for bacterial meningitis. N Engl J Med 1988; 319:964-967. 7. Arditi M, Manogue KR, Caplan M, Yogev R: Cerebrospinal fluid cachectin/TNF and plateletactivating factor concentrations and severity of bacterial meningitis in children. J infect Dis 1990; 162:139-147. 8. Chadwick EG, Yogev, Kwok S, et al: Enzymatic amplification of HIV in peripheral blood mononuclear cells from pediatric patients. J Infect Dis 1989; 160:954-959. 9. Rogers MF, Ou C-Y, Rayfield M, et al. Use of the polymerase chain reaction for early detection of the proviral sequences of HIV in infants born to seropositive mothers. N Engl J Med 1989; 320: 1649-l 854. 10. Amadori A, Giaquinto C, Zacchello F, et al: In vitro production of HIV-specific antibody in children at risk of AIDS. Lancet 1988; 1:852-854. 11. Maury W, Potts BJ, Rabson AB: HIV-l infection of first-trimester and term human placental tissue. J Infect Dis 1989; 160:583-588. 12. Scott GB, Hutto C, Makuch RW, et al: Survival in children with perinatally acquired HIV-1 infection. N Engl J Med 1989; 321:1791-1796. 13. Brussow H, Sidoti J, Barclay D, et al: Prevalence and serotype specificity of rotavirus antibodies in different age groups of Ecuadorian infants. J Infect Dis 1990; 162:615-620. 14. Matson DO, Estes MK: Impact of rotavirus infection at a large pediatric hospital. Jlnfect Dis 1990; 162:598-604.
Current
Problems
in Pediatrics
I January
1991
7