An effective and safe protocol involving zidovudine and caesarean section to reduce vertical transmission of HIV-1 infection.

OBJECTIVE: To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. INTERVENTIONS: Elective caesarean section before labour, usually at 36-38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen). RESULTS: Of 179 mother-infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0-4.7] and 12.6% (6.4-19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6-8 weeks. CONCLUSION: A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.

Addison-disease - an unusual clinical manifestation of CMV-end organ disease in pediatric AIDS.

CMV infection is common in pediatric HIV-1 infected patients. We present a case report, to our knowledge the first pediatric patient, in which Addison-disease due to CMV was suspected during lifetime. We want to point out the importance of routine clinical and laboratory follow up once a HIV-1 infected child is shown to be infected with CMV.

Primäre Kaiserschnittentbindung mit und ohne antiretrovirale Prophylaxe und Prävention der materno-fetalen Transmission von HIV-1.

BACKGROUND: Studies of caesarean section and the rate of perinatal transmission of HIV-1 (RPT) have reported conflicting results if AZT was not administered simultaneously. METHODS: To investigate the probable sources of error, 387 singleton pregnancies of HIV-1-infected mothers were enrolled in a prospective, observational study. To avoid contamination of the fetal mouth with maternal blood at caesarean section, the uterus was opened under careful preparation of the fetal membranes, maintaining their integrity as long as possible. To 105 pregnant women AZT was administered at various gestational ages (median 29th week), depending on the stage of the disease of the mother or obstetrical complications. The majority of newborns received AZT for 10 days I.V. RESULTS: Group 1: For those, for whom vaginal delivery was intended (n=163, RPT=20.2%), this could be realized in 82% of the cases only. There was no significant difference in the RPT (23%-19,5%) between emergency caesarean section and vaginal delivery (odds ratio [OR]=1,25; 95% CI 0,41-3,44). Risk factors of fetal HIV infection (p≤0.05) were delivery <37th week, rupture of membranes (ROM) ≥4 h, labor ≥5 h before delivery, CD4 ≤400 cells/µl, p24 antigenemia, and viral load. Group 2: If an elective caesarean section (n=119) was intended, the RPT (4,2%) was reduced compared to group 1 (OR=0.17; 95% CI 0.04-0,52; p=0.0002); however, in 16% emergency sections had to be performed because labor or ROM occurred before the planned date of elective caesarean section without difference in the RPT (4-5%) (OR 1,35; 95% CI 0,03-14,51). Significant risks (p≤0.05) of fetal infection were preterm labor and viral load. Group 3: If an elec- tive caesarean section under AZT (n=105) was intended, the RPT (1,3%) was significantly different to group 1 (OR=0,08; 95% CI 0.1-0.31; p=0.00003), but not to group 2 (OR=0.44; 95% CI 0.04-2.79). However, an elective caesarean section was feasible only in 74% without significant differences in the RPT (1,3-4%) (OR=2,96; 95% CI 0,04- 235,42). Except for the viral load (p=0.04), no risk factor was associated with fetal infection. CONCLUSIONS: Elective and emergency caesarean section, performed early in parturition under surgical care to avoid contamination, significantly decreases the risk of fetal transmission, irrespec-tive of low CD4 cell counts, p24 antigenemia, viral load and ROM, but not preterm labor. Simultaneous administration of AZT in gestation and to the newborn further reduces the risk of peripartal infections and obviously provides additional safety at caesarean sections.

[HIV infection in childhood]. / HIV-Infektion im Kindesalter.

As a result of preventive measures during pregnancy and improved antiretroviral combination treatment, the problem area of HIV infection in childhood has undergone a change in recent years. Thanks to intensive cooperation between obstetricians and pediatricians, mother-to-child transmission of HIV in Germany has been decreased to less than 2%. Improvements in the diagnosis of HIV infection in childhood, infected children have been identified very early, and started on antiretroviral treatment, and prophylactic measures initiated. In the case of life-long anti-HIV treatment beginning in childhood, the same problems as those seen in adults must be expected (development of resistance, adherence, adverse effects).

[HIV diagnostics in the child--methodology, rational use and value]. / HIV-Diagnostik beim Kind--Methodik, rationeller Einsatz und Aussagefähigkeit.

The determination of an HIV infection in children of infected mothers has been a problem for years. Despite the development of new diagnostic methods, this problem has not been simplified. On the contrary, contradictions between the clinical courses and the laboratory results become ever more obvious and complicate the assessment of HIV exposed child's infection status. It is therefore necessary to monitor all HIV-exposed children through longitudinal examinations in order to verify or exclude HIV infection.

[Screening for HIV antibodies in pregnancy]. / Zur Frage eines Screenings auf HIV-Antikörper in der Schwangerschaft.

The results of the first screening in pregnant women for HIV antibodies published in the literature were obtained at the Charlottenburg Gynecological Clinic of the Free University of Berlin, and are communicated here. They indicate that in future it will be questionable whether AIDS should be looked for only among risk groups, as is currently the case in many obstetric centers. Tests for HIV were positive in 0.5% of 1295 pregnant women who did not belong to a risk group (heroin addicts, prostitutes, transfusion recipients); the findings were confirmed with the more specific Western Blot. Consequently, therefore, it is recommended that HIV screening should be included among the basic antenatal care examinations, the patient having been thoroughly informed. In order that the patient be aware of the reality of the risk, she should, if possible, be informed in early pregnancy: the family physician therefore has a special obligation to fulfil. The fact that increasing numbers of infected women do not belong to risk groups is a further argument in favor of HIV screening. Moreover, AIDS has become the most common infection with serious consequences for mother and child. Patients in whom the test for HIV antibodies is positive also require appropriate counseling and care. Finally, the need to protect both patients and staff against infection during birth must not be neglected.

[Molecular epidemiology of Candida infections in HIV-infected mothers and their offspring]. / Molekulare Epidemiologie von Candida-Infektionen bei HIV-infizierten Müttern und ihren Kindern.

In a prospective study 15 consecutive children and 12 HIV-infected mothers were examined according to their colonization with Candida species in the oral cavity and on the hands. From 39 samples a total of 49 Candida isolates could be recovered (26 C. albicans, 4 C. glabrata, 9 Rhodotorula rubra, 4 C. dubliniensis, 3 C. tropicalis, 2 C. famata, 1 S. cerevisiae). Antifungal susceptibility testing revealed fluconazole MICs from 0.09 microgram/ml to 100 micrograms/ml. Genotyping was done with an AP-PCR technique using the primer "M13" and "(GACA)4". From the mycologic culture identical yeast isolates were found in 10 families. However, with PCR typing identical findings were seen only in 5 families. A C. albicans isolate resistant to fluconazole in vitro was found in a child and the mother of the same family. It could be summarized that yeast strains are transmitted between HIV infected mothers and their children. With PCR typing diversity among yeast isolates could be demonstrated even between members of the same family.

[Chemotherapy of brain-tumors in children (author's transl)]. / Chemotherapie der Hirntumoren.

The poor permeability of the blood/brain barrier for most cytostatic agents makes it difficult to achieve an adaequate drug concentration in brain-tumors. This is the main problem in developing a chemotherapy of brain tumours. On the other hand the therapeutic effect is difficult to evaluate not only because of clinically and hitherto also technically poor accessability of the brain but also because of differences in tumour classification systems, and consequently limited comparability. There is however definite knowledge on the effectiveness of several single drugs as well as strong evidence on the effectiveness of some polychemotherapeutic programs. The measure of success presently is rather prolongation of survival time for months than a change in cure rate. A general recommendation for the cytostatic treatment of brain tumors may not be given in that situation, but within a clinical study the use of cytostatic agents seems promising anyway.

[Cerebral symptoms in pre- or perinatally HIV-infected children]. / Zerebrale Symptome bei prä- oder perinatal mit HIV 1 infizierten Kindern.

Eight of 13 children pre- or perinatally infected with the HIV virus subsequently developed neurological symptoms. Three children also had other nonspecific symptoms (fever, lymphadenopathy, diarrhoea, hepatosplenomegaly, failure to thrive and mucocutaneous thrush). Five children developed illnesses associated with AIDS (opportunistic infections, cachexia and lymphocytic interstitial pneumonia). The neurological abnormalities predominantly affected motor functions, only later also involving sensory ones. Motor, cognitive and language development was impaired in all eight children. A loss of developmental milestones occurred in three children with HIV encephalopathy: they have since died. In all the children the HIV infection caused symptoms within the first year, progressing more quickly in the three with encephalopathy. There were no discernible risk factors to account for the difference in the course of the disease.

[Immunologic findings in HIV infected children with bacterial infections]. / Immunologische Befunde bei HIV-infizierten Kindern mit bakteriellen Infektionen.

BACKGROUND: Bacterial infections are a major cause of illness in HIV-infected children. HIV-infected children with severe dysfunction of cellular and humoral immunity are particularly vulnerable. METHODS AND PATIENTS: We conducted a retrospective study to analyse the incidence and spectrum of bacterial infections in HIV-infected children compared to HIV-exposed but not infected controls related to their immunological status. Data collected during 1985 to May 1993 were evaluated considering 333 HIV-infected and 81 controls. RESULTS: During observation time 359 episodes (29% of the visits) of purulent rhinitis were diagnosed in HIV-infected children compared to the controls (53 episodes/8%); p = 0.0001. Comparable results were seen in otitis media. 178 episodes/14% were found in HIV-infected children and 66 episodes/10% in the controls (p = 0.001). 53 episodes/5% of bacterial pneumonia were represented in HIV-infected versus 11 episodes/2% in controls (p = 0.001). The increase of lymphocyte immune defect correlated to an increase of bacterial infections. This alterations were particularly observed in HIV-infected children with bacterial pneumonia. Severe dysfunction of cellular immunity was found in children with recurrent pneumonia compared to children with only one episode of bacterial pneumonia. The proliferate response of peripheral blood lymphocyte to pokeweed mitogen (13,351 cpm versus 3080 cpm); p = 0.009 and Concanavalin A (12,607 cpm versus 2470 cpm); p = 0.01 was significantly reduced in both groups, although the defect was much more pronounced in the group with the recurrent pneumonia. CONCLUSIONS: Our observations results showed that bacterial respiratory tract infections occurred significantly more frequently in HIV-infected children compared to an age related control group. Not only the occurrence of opportunity infections but also severe bacterial infections especially recurrent pneumonia are associated with a defect in cell-mediated immunity.

[Successful chemotherapy in a primary cerebral centroblastic non-Hodgkin's lymphoma in childhood]. / Erfolgreiche Chemotherapie bei einem primär zerebralen zentroblastischen Non-Hodgkin-Lymphom im Kindesalter.

Primary lymphomas of the central nervous system (CNS) are rare diseases. Often these tumors are surrounded by glia cells and may, therefore, be misdiagnosed as 'astrocytomas' with accompanying reactive lymphocytosis. A 15-year old patient was irradiated to the posterior cranial fossa and the brain stem because of a supposed astrocytoma. Five months after completion of radiotherapy he presented two lesions each in the right and left cerebral hemisphere. Repeated biopsy led to a revision of the primary diagnosis in favor of a B-cell Non-Hodgkin lymphoma (centroblastic type). After cyclic polychemotherapy including high-dose methotrexate and cytosine-arabinoside he entered a complete remission. No further radiotherapy was given. So far, 18 months after discontinuating therapy, the patient has been in complete remission and is in an excellent physical condition.

IgG2 deficiency in children with human immunodeficiency virus infection.

Infection with the human immunodeficiency virus (HIV) induces a polyclonal B-cell activation. Despite elevated serum immunoglobulin levels, a significant deterioration of the antigen specific humoral immune response exists in most cases. We studied the influence of HIV infection on the serum levels of IgG subclasses in children. We investigated 76 children (aged 15 months to 18 years) with HIV-1-infection. Most children (88%) showed elevated serum immunoglobulin levels. IgA (87%) and IgM (74%) were more often above normal levels for age than IgG (60%). IgG subclass serum levels were significantly altered. The increase in total IgG was mainly due to a marked augmentation of the IgG1 fraction. In most cases IgG3 was simultaneously elevated. Ten children (13%) had very low IgG4 levels (less than 0.03 g/l). Out of 61 patients older than 2 years 8 (13%) had a profound IgG2 deficiency with normal or elevated total IgG. Four of them also had low IgG4 levels (less than 0.03 g/l). A correlation between IgG2 deficiency and HIV infection according to the Centres for Disease Control classification for acquired immunodeficiency syndrome could not be demonstrated (three patients with symptomatic and five with asymptomatic infection).

[Lymphocyte function in children with iron deficiency]. / Lymphozytenfunktionen bei Kindern mit Eisenmangel.

In 23 children with mild iron-deficiency anemia, 22 children with latent iron-deficiency, and in 46 healthy controls the 3H-thymidine incorporation in blood lymphocytes after stimulation with phytohemagglutinin, concanavalin A, pokeweed mitogen, and serum against thymocyte cells was measured. In 11 of the children with iron-deficiency anemia, in 13 of the children with latent iron-deficiency, and in 20 controls the lymphotoxin secretion after phytohemagglutinin stimulation was also performed. All patients studied were without intercurrent infections and were well nourished. No alteration of the lymphocyte function in the patients was found. The concentrations of immunoglobulins and the components C3 and C4 of complement system were also found to be normal. It is suggested that lymphocyte functions are eventually only altered in more severe states of iron-deficiency anemia.

[Labor, method of delivery and maternofetal transmission of HIV]. / Wehen, Geburtsmodus und maternofetale Transmission von HIV.

Within a prospective study of the course of HIV-infection in women, 80 HIV-infected women without AIDS were delivered of 80 children between 1985 and September 1992. The median of the age of gestation was 38 weeks. Until 1988 Caesarean section was chosen as mode of delivery (45 women). Later when the mode of delivery appeared to have no influence on the frequency of maternofetal HIV transmission, vaginal delivery was preferred (35 women). None of the infants was breastfed. Three infants --delivered vaginally--died within the first 6 months of life before their infection status could be determined. Seventy-seven children could be observed for 18 months or longer regularly every three months. 10 of the 77 children were found to be HIV- infected by serological, virological and clinical criteria. Taking into account the mode of delivery, of 32 children who were delivered vaginally or by emergency Caesarean section 8 were found to be HIV-infected. None of 26 children delivered by elective Caesarean section after an uneventful pregnancy is infected. In 19 women Caesarean section was performed within 2 hours after onset of labour or after episodes of preterm labour which required hospital admission for treatment. Two children of these women are infected. No differences of CD4+ cell counts and p24 antigenaemia could be determined between the mothers of the three groups. The risk of fetal HIV infection was increased by preterm labour (p < 0.01) and the mode of delivery (p < 0.01). A correlation between loss of CD4 cells in the mother and increased risk of infection for the child is seen in children born spontaneously or delivered by emergency Caesarean section (p < 0.001). No correlation was found between the length of labour at delivery, the time of the rupture of membranes before birth as well as of the parity and the risk of fetal infection in that group. These findings point to labour as an important factor which increases the risk of maternofetal transmission of HIV. The onset of labour is accompanied by dramatic immunological alterations as a sudden increase of chemotactics and inflammatory cytokines at the maternofetal interface. The accumulation and stimulation of maternal immune cells will--if these cells are carriers of HIV--result in production and release of infectious HIV. This virus may accumulate in the maternofetal interface or gain access to the amniotic cavity. Since amniotic fluid is swallowed by the fetus, the largest potential port of entry for HIV in the fetus are the fetal lungs and the gastrointestinal tract. For the prevention of maternofetal transmission of HIV delivery before onset of labour or alternatively the protection of the fetus during parturition by means of potent antiviral compounds can be considered.

[Therapy of childhood acute lymphoblastic leukemia. Treatment results 1971-75 in 78 patients (author's transl)]. / Zur Behandlung der akuten lymphoblastischen Leukämie im Kindesalter - Erfahrungsbericht

From December 1971 until July 1973 44 children with ALL have been treated according to branch A of the randomised DAL study series of June 3rd 1972 (1/71), which is a slight modification of study VII of Memphis. Afterwards until July 1975 34 patients received a somewhat intensified initial therapy (11/73). The results of 1/71 with a 3-year-remission rate of 39% and an expected 5-year-remission rate of 32% are comparable to those of study VII. The results of 11/73 with an expected 3-year-remission rate of 54% seems clearly superior and unterline the importance of an intensive initial therapy, like it is introduced now in a still more aggressive manner in our running protocol III/75. Therapy mortality was found to be about 5% and seemed to be dependant on the staff's experience. Cytosin-arabinoside orally proved effective as a prophylactic measure during incubation as well as a therapeutic agent in manifest varicalla/zoster infections.

[Chemotherapy of osteosarcoma (author's transl)]. / Die Chemotherapie des Osteosarkoms.

The cyclic chemotherapy scheme OS I/75 was tried in 6 patients with newly diagnosed osteosarcoma and in 3 patients with secondary metastases. The treatment consists of high dose methotrexate, followed by citrovorum-factor rescue, doxorubicine (Adriblastin) and cyclophosphamide (Endoxan). All 6 primary patients are in a continuous remission of 6+ to 21+ months (median 12+ months). The length of remission in the patients with metastases is 5.5+ and 8+ months. The haematological side effects led to an average prolongation of the cycle by 11 days in a planned cycle duration of 42 days. However, they were readily manageable. Among the other side effects two cases of Adriblastin myocardiopathy are remarkable which became apparent after methotrexate and ifosfamide. In order to improve possibilities for treatment regional centralisation of patient care and interdisciplinary and supraregional cooperation of treatment centres are necessary. A prospective treatment programme has been developed for the Federal Republic of Germany and Austria.

[Presentation of the cooperative study COALL-80 on treatment of childhood ALL (author's transl)]. / Vorstellung der kooperativen Studie COALL-80 zur Behandlung der akuten lymphoblastischen Leukämie (ALL) im Kindesalter.

The cooperative study COALL-80 is derived from the BFM-78-study. The aim of the study is a reduction of the initial therapy-morbidity and -mortality without loss of efficacy by omitting asparaginase from the four drug-induction regimen and interposing it between induction- and CNS-therapy phase. The expected two years disease free survival rate of a pilot study will be 82%. This finding is hitherto comparable with the BFM-study results.

Infants born to mothers seropositive for human immunodeficiency virus. Preliminary findings from a multicentre European study.

As part of a project within the European Community research activities on acquired immunodeficiency syndrome (AIDS), infants born to human-immunodeficiency-virus-seropositive mothers are being followed up from birth. By October, 1986, 71 infants from Padua, Berlin, and Edinburgh had been followed up to a median age of 6 months (range 1-15 months). Symptoms of AIDS or AIDS-related complex (ARC) had developed in 5, 3 of whom had died. The median age at antibody loss was during the 10th month. An estimated 75% will have lost maternal antibody by 12 months, but loss of antibody did not exclude infection confirmed by virus culture. Numbers were too small to draw conclusions about the risk of AIDS/ARC and mode of delivery or breast-feeding. The study suggested that the risk of AIDS/ARC is higher in infants born to mothers who have AIDS symptoms during pregnancy.

Vertical human immunodeficiency virus transmission: a study of placental pathology in relation to maternal risk factors.

We examined 48 placentas of human immunodeficiency virus (HIV)-exposed pregnancies morphologically for HIV-specific changes and immunohistologically for the presence of HIV antigen and RNA. Findings were correlated to infectious states of the children and maternal risk factors. Few HIV antigen-positive Hofbauer cells and HIV RNA positive syncytiotrophoblast and Hofbauer cells were detected. HIV-positive cells in the placenta did not correlate with intrauterine infection and maternal immunologic parameters. Light microscopically, we found two changes: immaturity of the terminal villi and allantois vasculopathy. These changes, however, are not HIV specific. Our results show that vertical HIV transmission cannot be diagnosed by morphological examination of the placenta.

Genotypic relatedness of yeast isolates from women infected with human immunodeficiency virus and their children.

The objective of this study was to compare polymerase chain reaction (PCR) fingerprinting with other molecular typing methods as an epidemiologic tool to investigate the transmission of Candida strains between HIV-positive mothers and their children. Forty-nine yeast strains (including Candida albicans, Candida glabrata, Rhodotorula rubra, Candida tropicalis, Candida famata, Candida dubliniensis, Saccharomyces cerevisiae) from 30 individuals (15 children and 15 HIV-infected mothers or accompanying person) were isolated. Colonization/infection with yeast was observed in 80% of all individuals in the oral cavity, and in 33% from hand cultures, respectively. Thirteen out of 15 children (86%) and 12 out of 15 adults (80%) were colonized/infected with yeasts. Candida dubliniensis strains were found in four HIV-infected women but not in children. The results with an arbitrarily primed (AP)-PCR mediated genotyping assay using phage M13 core sequence were compared with the hybridization patterns using the species-specific DNA probe CARE-2 for the C. albicans isolates. Typing of non-C. albicans strains was done using AP-PCR in comparison with pulsed-field gel electrophoresis (PFGE). Twenty-six C. albicans strains gave two different genotypes by AP-PCR but 16 genotypes by CARE-2 hybridization. The CARE-2 probe appeared to have a higher discriminatory power compared with the primer 'M13'-mediated AP-PCR in typing C. albicans isolates.