Warren A. Andiman

Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex

Two major pulmonary diseases were defined on the basis of lung biopsies in 15 children with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Pneumocystis carinii pneumonia was observed in eight children, and pulmonary lymphoid hyperplasia in six. One child had nonspecific interstitial pneumonitis. Children with P. carinii pneumonia had more severe hypoxemia, with higher alveolar-arterial oxygen gradients, and higher isomorphic elevations of serum lactate dehydrogenase. Clinically, children with pulmonary lymphoid hyperplasia were older, and had digital clubbing, parotid gland enlargement, and elevated serum IgG levels. Results of serologic assays and lung tissue analysis were suggestive of persistent Epstein-Barr virus infection exclusively in patients with pulmonary lymphoid hyperplasia. Recognition of the clinical and laboratory findings characteristic of each entity may assist in the differential diagnosis without the need of surgical biopsy.

Diffuse Polyclonal B-Cell Lymphoma during Primary Infection with Epstein–Barr Virus

ALTHOUGH most primary infections with Epstein–Barr virus (EBV) in childhood are silent or associated with mild nonspecific illness, a few are recognized as infectious mononucleosis, a lymphoprolife...

We never thought this would happen: transitioning care of adolescents with perinatally acquired HIV infection from pediatrics to internal medicine

Abstract Purpose. Transitioning the medical care of children with perinatally acquired HIV from pediatric care to internal medicine practices has become increasingly important as newer therapies prolong survival. The study aims to describe challenges to caring for these adolescents and the potential barriers to transitioning them to internal medicine-based care. Methods. Qualitative study in which data were gathered from open-ended interviews conducted from November 2005 to April 2006 with 18 adolescents with HIV, 15 of their parents, and 9 pediatric health care providers from the Yale Pediatric AIDS Care Program, New Haven, Connecticut. Results. Issues of stigma played a prominent role in both the challenges to care and barriers to transitioning care. Challenges to care were: (1) poor adherence to medication regimens; (2) adolescent sexuality; and (3) disorganized social environments. Potential barriers to transitioning care were: (1) families’ negative perceptions of and experiences with stigma of HIV disease – which undermined the desire to meet new providers; (2) perceived and actual lack of autonomy – pediatric providers feared that staff in adult clinics would demand a level of independence that adolescents did not have; and (3) difficulty letting go of relationships – adolescents, guardians, and providers described a familial relationship and expressed anxiety about terminating their relationships. Conclusion. Understanding these challenges and barriers can inform both pediatric and adult HIV care providers and enable them to create successful transition programs, with the goal of improving retention and follow-up to care.

Update on successes and challenges regarding mother-to-child transmission of HIV.

Purpose of review There is an unprecedented global commitment to reverse the pediatric HIV epidemic by making prevention of mother-to-child transmission (PMTCT) services accessible in all countries. This review outlines the successes made and the challenges that remain. Recent findings In resource-rich countries, mother-to-child transmission rates of HIV as low as 1% have been achieved. The efficacy of short-course antiretrovirals for PMTCT in Africa is estimated at 50%. Coinfections with herpes simplex virus type 2, other sexually transmitted infections resulting in genital ulcers, and endemic infectious diseases (e.g., malaria) may increase the risk of mother-to-child transmission of HIV. Vertical transmission of drug-resistant viruses has been reported; the prevalence and effect of transmitted resistant virus on treatment outcomes are under investigation. Obstacles facing PMTCT in resource-limited countries include the lack of healthcare infrastructure, limited manpower, and competing public health priorities with the limited healthcare budget. Summary Although the birth of an HIV-infected child in a resource-rich country is now a sentinel health event, in most resource-limited countries the birth of an HIV-infected child continues to be the status quo. Comprehensive PMTCT, including antiretroviral treatment for HIV-infected women and children, should be paramount in resource-limited countries.

Increased Replication of Non-Syncytium-Inducing HIV Type 1 Isolates in Monocyte-Derived Macrophages Is Linked to Advanced Disease in Infected Children

Non-syncytium-inducing (NSI) strains of HIV-1 prevail among most infected children, including pediatric patients who develop advanced disease, severe immune suppression, and die. A study was designed to address the hypothesis that genotypic and/or phenotypic markers can distinguish NSI viruses isolated during early infection from NSI viruses found in advanced disease. Primary HIV-1 isolates, which were obtained from 43 children, adolescents, and adults who displayed a cross-section of clinical disease and immune suppression but were untreated by protease inhibitor antiretroviral therapy, were characterized for replication phenotype in different cell types. Most individuals (81%) harbored NSI viruses and almost half had progressed to advanced disease or severe immune deficiency. About 51% of NSI isolates produced low levels of p24 antigen (median, 142 pg/ml) in monocyte-derived macrophages (MDMs), 31% produced medium levels (median, 1584 pg/ml), and 17% produced high levels (median, 81,548 pg/ml) (p < 0.001). Seven of eight syncytium-inducing isolates also replicated in MDMs and displayed a dual-tropic phenotype that was associated with advanced disease. Replication of NSI viruses in MDMs varied as much as 100- to 1000-fold and was independent of replication in peripheral blood mononuclear cells. Replication in MDMs provided a clear biological feature to distinguish among viruses that were otherwise identical by NSI phenotype, V3 genotype, and CCR5 coreceptor usage. Low-level MDM replication was characteristic of viruses isolated from asymptomatic individuals, including long-term survivors. Enhanced MDM replication was related to morbidity and mortality among patients. Replication levels in MDMs provide a novel prognostic indicator of pathogenic potential by NSI viruses.

Invasive bacterial infections in children born to women infected with human immunodeficiency virus type 1

To determine the rates and characteristics of invasive bacterial infections in children infected with the human immunodeficiency virus type 1 (HIV-1), we conducted a prospective, longitudinal, observational cohort study of infants born to HIV-1-infected mothers between Dec. 1, 1985, and Sept. 30, 1989. Of 104 subjects whose HIV-1 infection status could be definitively determined, 21 were infected with HIV-1 and 83 were not. In all, 11 (48%) of 23 invasive infections occurred among 10 HIV-1-infected patients and 12 (52%) of 23 occurred among 11 uninfected subjects. Infections with Streptococcus pneumoniae (n = 8), all of which were community acquired, accounted for the greatest proportion (35%) of the organisms isolated from either the blood or the cerebrospinal fluid. Five episodes of pneumococcal bacteremia occurred in the HIV-infected patients; all resolved promptly after treatment was begun, and no serious focal infections developed. Of 13 instances of bacteremia with an organism other than S. pneumoniae, seven were nosocomial. The rate of community-acquired invasive bacterial infections among the HIV-infected children was nearly three times higher than the rate in the non-HIV-infected children (overall, 1.02 infections per 100 person-months vs 0.37 infection per 100 person-months; rate ratio, 2.8; p = 0.05). Most of the increased risk occurred in children > 1 year of age. In contrast, the difference in the rates of infection between those patients in the two groups who were less than 12 months of age was not significant (1.3 infections per 100 person-months vs 0.81 infection per 100 person-months; rate ratio, 1.6; p = 0.47). We conclude that the rate of invasive bacterial infection is higher in HIV-infected children than in their peers, especially after 1 year of age.

Inhibition of Human Immunodeficiency Virus Type 1 (HIV-1) Replication by a Two-Amino-Acid Insertion in HIV-1 Vif from a Nonprogressing Mother and Child

ABSTRACT We studied a 15-year-old girl, patient X, who has maintained consistently low plasma loads of human immunodeficiency virus type 1 (HIV-1) RNA, as well as normal and stable CD4+ T-cell concentrations. She has presented no clinical manifestations of AIDS, despite having only received zidovudine monotherapy for a part of her life. Patient Xs HIV-positive mother (patient Y) has also not progressed to AIDS and has never been treated with antiretroviral agents. HIV-1 isolated from patient X replicated poorly in human peripheral blood mononuclear cells (PBMC). In order to map the determinant of the poor growth of patient Xs isolate, viral sequences from patient X were determined and examined for insertion or deletion mutations. These sequences contained a two-amino-acid insertion mutation in the Vif gene, which was also observed in uncultured PBMC acquired at different times. Furthermore, Vif sequences harbored by patient Y contained the identical mutation. These observations suggest that polymorphic HIV-1 was transmitted to patient X perinatally 15 years previously and has been maintained since that time. Recombinant HIV-1, engineered with Vif sequences from patient X, replicated in PBMC to levels approximately 20-fold lower than that of wild type. Removal of the insertion mutation from this recombinant restored replication efficiency to wild-type levels, while introduction of the insertion mutation into wild-type Vif sequences resulted in greatly decreased replication. Furthermore, Vif protein from patient Xs HIV-1 was aberrantly cleaved, suggesting a mechanism for loss of Vif function. Since HIV-1 containing these sequences replicates poorly, the implication is that the two-amino-acid insertion mutation in Vif contributes significantly to the nonprogressor status of this mother and child. Further studies of these sequences might provide information regarding contributions of Vif structure and/or function to HIV-1 virulence.

Complex determinants in human immunodeficiency virus Type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages

ABSTRACT Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-R5 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4+-T-cell attrition and commingled with M-R5 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.

The Epstein-Barr virus and EB virus infections in childhood

A DECADE has passed since the Epstein-Barr virus was shown to be the etiologic agent of heterophile-positive infectious mononucleosis. In the intervening ten years much attention has been focused on the pathogenesis of the disease, the unique biologic characteristics of the virus, the epidemiology of EBV infection in various parts of the world, and the possible oncogenic potential of the virus in specific human populations as well as in subhuman primates. The purpose of this review is to summarize some of the important discoveries that have been made in these areas. In addition, attention is directed to current knowledge of the differences that distinguish primary EBV infection in young children from the more clinically obvious infectious mononucleosis syndrome, which principally affects adolescents and young adults. Information is provided concerning the serologic and virologic tools that are currently available for confirming the suspicion of primary infection in different age groups. We also review those fatal infections which have occurred in a number of kindreds: these cases provide clues to understanding the normal host defenses which keep the infection in check, Finally we present some of the evidence

Development of a prognosis-based clinical staging system for infants infected with human immunodeficiency virus

PURPOSE To develop a prognosis-based clinical staging system for infants infected with human immunodeficiency virus. METHODS Abstraction of data from medical records of 75 infected children. For each clinical finding present in infancy, the magnitude of the relative risk (RR) for early death was used to assign subjects to different clinical stages. RESULTS Stage IV (RR > 3) included subjects with Pneumocystis carinii pneumonia, other opportunistic infections, or encephalopathy. Stage III (RR, 2 to 3) included those with anemia, thrombocytopenia, hepatitis, fever, oral candidiasis, or one or more serious bacterial infections. Stage II included those with hepatomegaly, splenomegaly, failure to thrive, or persistent diarrhea, and stage I included those who had lymphadenopathy or were free of symptoms. When clinical staging was applied to the study population at ages as early as 6 months, survival curves were significantly different (IV vs III: p < 0.0005; III vs II + I: p < 0.005). CONCLUSIONS Clinical staging should be beneficial in advising parents about an infants prognosis, therapeutic decision making, and stratification for clinical trials.