Impairment of short-term memory and Korsakoff syndrome are common in AIDS patients with cytomegalovirus encephalitis.

BACKGROUND AND PURPOSE: The diagnosis of cytomegalovirus encephalitis (CMV-E) in AIDS patients is challenging as other illnesses may obscure the symptoms. Here, we characterize the clinical symptoms of CMV-E and link them to post-mortem findings. Patients and methods In 254 homosexual men with AIDS, followed from HIV diagnosis to death before the antiretroviral combination therapy era, CMV-E was suspected in 93 cases. All were CMV-positive in blood. Neurological examination, including cognitive testing was performed in 34 of them within 6 months before death. CMV-E was diagnosed by CMV-PCR in cerebrospinal fluid (n = 24) or by post-mortem (n = 24). RESULTS: The majority complained of forgetfulness (91%), balance difficulties (85%) and impotence (85%). Impaired short-term memory was present in 29 patients. It was extreme in 17, justifying the diagnosis of Korsakoff's syndrome. This was often associated with infectious CMV in blood (P = 0.01). Brainstem symptoms were found in 19 patients. Post-mortem examination often revealed ventriculoencephalitis. CMV was found primarily around the ventricles and in other structures, described in Korsakoff's syndrome. CONCLUSION: The location of CMV in the brain corresponded well to the clinical findings, demonstrating the close relationship between the neurological symptoms and the neuroanatomical lesions.

The X4 phenotype of HIV type 1 evolves from R5 in two children of mothers, carrying X4, and is not linked to transmission.

Previously, we found that emergence of the X4 viral phenotype in HIV-1-infected children was related to the presence of X4 in their mothers (C.H. Casper et al., J Infect Dis 2002; 186:914-921). Here, we investigated the origin of the X4 phenotype in the child, analyzing two mother-child pairs (Ma-Ca, Mb-Cb) where the mothers carried X4 and their children developed X4 after an initial presence of R5. We used nested polymerase chain reaction of the env V3 region to generate 203 HIV-1 clones for sequencing (Ma, n = 44; Ca, n = 73; Mb, n = 61; Cb, n = 25) from DNA of peripheral blood mononuclear cell (PBMC) lysates, altogether 167 clones, or from cDNA of plasma RNA, 36 clones. PBMC and plasma isolate sequences from each time point enabled us to assign the probable phenotype to clone sequences in a phylogenetic tree. The transmission and evolution were reconstructed using the maximum likelihood method. In mother-child pair Ma-Ca, one maternal R5 isolate clustered with the child's R5 sequences, at the earliest time when R5 was isolated in the child, confirming this as a likely source of the transmitted R5 phenotype. At age 3, an X4 population was present in the child that had evolved from the child's own R5-associated population, clearly distinct from the maternal X4 sequences. The second mother-child pair (Mb-Cb) displayed a similar pattern. Amino acid substitution patterns corroborated the conclusions from the phylogenetic tree. Thus, in both children, the X4 virus developed from their own R5 population, and was not caused by transmission of X4.

Vertical transmission of HIV-1 infection and dilemma of infant feeding.

UNLABELLED: The problem of giving proper recommendations on early feeding of infants of HIV-1-positive mothers in countries with deficient hygienic conditions is discussed. Even in exclusive breastfeeding, which is associated with a lower risk of HIV transmission than when supplements are given, the risk that the infant will acquire HIV-1 has to be balanced against the risk of formula feeding. Furthermore, it also has to be stressed that exclusive breastfeeding is a rarity in many poor countries. CONCLUSION: The dilemma of recommending appropriate early feeding to HIV-1-positive mothers will persist until further studies of the type performed by the Coutsoudis group in South Africa have been performed.

Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes.

Change of HIV-1 coreceptor use has been connected to progression of disease in children infected with HIV-1, presumably subtype B. It has not been possible to discern whether the appearance of new viral phenotypes precedes disease development or comes as a consequence of it. We studied the evolution of coreceptor use in HIV-1 isolates from 24 vertically infected children. Their clinical, virological, and immunological status was recorded and the env V3 subtype was determined by DNA sequencing. Coreceptor use was tested on human cell lines, expressing CD4 together with CCR5, CXCR4, and other chemokine receptors. The children carried five different env subtypes (nine A, five B, four C, three D, and one G) and one circulating recombinant form, CRF01_AE (n = 2). Of the 143 isolates, 86 originated from peripheral blood mononuclear cells (PBMCs) and 57 originated from plasma, received at 90 time points. In 52 of 54 paired plasma and PBMC isolates the coreceptor use was concordant. All 74 isolates obtained at 41 time points during the first year of life used CCR5. A change from use of CCR5 to use of CXCR4 occurred in four children infected with subtype A, D, or CRF01_AE after they had reached 1.5 to 5.8 years of age. There was a significant association with decreased CD4+ cell levels and severity of disease but, interestingly, the coreceptor change appeared months or even years after the beginning of the immunological deterioration. Thus CXCR4-using virus may emerge as a possible consequence of immune deficiency. The results provide new insights into AIDS development in children.

Broad spectrum of time of detection, primary symptoms and disease progression in infants with HIV-1 infection.

The relationship between time of HIV-1 detection, appearance of symptoms and disease progression was studied in all 24 HIV-1-infected infants from a cohort of 117 children who were born to HIV-1-infected mothers and monitored from birth. HIV isolation from plasma and mononuclear cells, HIV-1 DNA PCR (polymerase chain reaction) and, retrospectively, a quantitative assay for HIV-1 RNA were used for virus detection. Two infants possibly exhibited a symptomatic primary HIV infection. More children with than without symptoms during the first year of life progressed to immunological class 3 (P=0.013) and to AIDS or death (P=0.003) during follow-up. HIV-1 was detected within 4 days of age in 4 of 16 infants: 3 of them became symptomatic within 1 year, as did 6 of the remaining 12 infants (not statistically significant). All four infants in whom virus was detected within 4 days of age progressed to severe immunosuppression, compared to 6 of 14 in whom the virus detection test was initially negative prior to the first positive result (n.s.). Two children with previous repeatedly negative HIV detection tests were diagnosed with HIV-1 infection at 8 and 9 months, respectively. Repeated blood sampling is needed for the diagnosis of HIV-1 infection in perinatally exposed infants, and virus detection tests for exclusion of HIV-1 infection must be used with caution.

HIV-1 in placentas of untreated HIV-1-infected women in relation to viral transmission, infectious HIV-1 and RNA load in plasma.

The presence of HIV in the placenta was analysed in relation to virological and immunological factors and vertical transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without zidovudine prophylaxis. HIV-1 was detected in 12 of 37 (31%) placentas by immunohistochemistry and in 3 of 18 by PCR. Altogether 14/39 (36%) placentas bore evidence of HIV-1 infection, although there was no relation with the outcome of HIV infection in the child. Neither was there a relation between placental infection and either CD4 cell counts or HIV-1 RNA levels. However, HIV-1 was isolated from plasma in 20 of 39 (50%) pregnancies, which was inversely related to the presence of HIV in the placenta. When HIV-1 was identified in the placenta, HIV-1 was isolated from plasma in 3/14 (21%) pregnancies, vs 17/25 (68%) when it was not (p = 0.01), with a relative risk of having a placenta positive for HIV of 3.9 in pregnancies with a negative plasma HIV isolation. This inverse relation may point to differences in tropism between HIV-1 in placenta and plasma. The results show that the placental barrier prevents HIV transmission, irrespective of whether HIV enters the placenta or not.

[Reduced mother-to-child transmission of HIV-1 infection. Exclusive breast feeding and weaning--a possible model in developing countries?]. / Minskning av HIV-1-smitta från mor till barn. Exklusiv amning och tidig avvänjning--möjlig modell i u-länder?

Antiretroviral therapy with zidovudine during pregnancy, delivery, and to the newborn in combination with Cesarean section has markedly reduced the rate of mother-to-child transmission of HIV-1 in industrialized countries. These strategies are not realistic in the less developed world. Nevertheless, short-term antiretroviral therapy during delivery and shortly after birth has proven feasible as a means of reducing the rate of vertical transmission in less developed countries, in some studies even in combination with exclusive breast-feeding. The risks and benefits of breast-feeding among HIV-1 infected mothers are discussed.

Long-term pattern of HIV-1 RNA load in perinatally infected children.

The objective of this study was to describe the natural history of HIV-1 RNA load in vertically HIV-1-infected children. HIV-1 RNA in 156 plasma or serum samples (1-14, median 4 from each child) from 32 vertically HIV-1-infected children was detected with the NASBA technique (Organon Teknika, The Netherlands). Twenty-one children were prospectively followed from birth, and 11 were identified and included at the age of 7-89 (median 61) months. The highest numbers of HIV-1 RNA copies were seen at 1.5-3 months of age. A quadratic curve model showed a reduction of HIV-1 RNA with increasing age up to approximately 8 years, and thereafter increasing numbers, p(age) = 0.002, p(age2) = 0.008. This pattern was not typical for individual children in whom a great variation in HIV-1 RNA numbers was seen over time. The interval from birth to the first HIV-1 RNA peak ranged from 1.5 months to more than 2 years. The HIV-1 RNA levels remained relatively high and fluctuating over the years in symptomatic as well as in long-term asymptomatic children. This makes HIV-1 RNA determination in children more difficult to use than in adults, as the only tool for prediction of disease progression and for initiation of therapy.

The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia.

BACKGROUND: In addition to earlier reports on the association between viral infections and intrahepatic neonatal cholestasis, in recent studies, investigators have suggested a similar link to extrahepatic biliary atresia. METHODS: Fifty-nine cholestatic infants (mean age 8 weeks) were investigated for signs of infection with a large spectrum of viruses. Twenty-one infants had extrahepatic biliary atresia, 38 had intrahepatic cholestasis. The virologic methods included serologic investigation in 59 infants and 54 mothers, virus isolation from stools (49 infants), urine (58 infants) and liver biopsies (40 infants). Polymerase chain reaction was used to detect cytomegalovirus DNA in 25 of the liver biopsy specimens. Two control groups, one with 35 noncholestatic infants and one with 111 healthy, pregnant women were checked for serologic signs of cytomegalovirus. RESULTS: Nineteen of 59 (32%) cholestatic infants, including 8 of 21 (38%) with extrahepatic biliary atresia, compared with 2 of 35 (6%) control infants had cytomegalovirus-immunoglobulin (Ig) M detected in serum (p < 0.01). Fifty-one of 54 (94%) tested mothers of cholestatic infants were seropositive for cytomegalovirus, compared with 83 of 111 (75%) control mothers (p < 0.01). Cytomegalovirus DNA in liver specimens was detected by polymerase chain reaction in 9 of 18 (50%) analyzed patients with biliary atresia and in specimens from 3 of 7 patients with intrahepatic cholestasis. CONCLUSIONS: Cytomegalovirus infection may play a role, not only in intrahepatic neonatal cholestasis, as was suggested earlier, but also in extrahepatic biliary atresia. The pathogenetic mechanism for this link remains to be established.

Mother-to-infant transmission of human immunodeficiency virus type 1 involving five envelope sequence subtypes.

Genetic analysis of human immunodeficiency virus type 1 (HIV-1) from cases of mother-to-infant transmission were analyzed in an effort to provide insights into the viral selection that may occur during transmission, as well as the timing and source of transmitted viruses. HIV-1 env genes obtained from seven mothers and their perinatally infected infants in Sweden were studied. Five envelope sequence clades (A to E) were found to be represented. We used a heteroduplex tracking assay (HTA) to assess the genetic relatedness between early viral isolates from the infants and serial maternal virus populations taken during pregnancy and at delivery. HTA findings were used to select for DNA sequence analysis maternal virus populations that were either closely or more distantly related to the infant virus. In each case, nucleotide sequence analysis confirmed the genetic relationships inferred by the HTA. Only maternal peripheral blood was sampled, and large sets of maternal specimens throughout pregnancy were generally not available. However, no consistent correlation was found to support the hypothesis that infant viruses should match blood-derived maternal virus genotypes found early in pregnancy if infants were found to be infected at birth or, conversely, that infant viruses should match blood-derived maternal virus genotypes found at delivery if infants were found to be infected only some time later.

Guillain-Barré syndrome in Stockholm County, 1973-1991.

In order to describe the incidence of Guillain-Barré syndrome (GBS) in Stockholm County (SC) and hospital use by GBS patients, we conducted a retrospective epidemiological study on GBS covering 1973-1991, using the Hospital Inpatient Register in SC. There were 556 patients, bona fide residents in the county during the study period, discharged from hospitals with GBS diagnosis. The mean annual incidence, age-adjusted to the European population, was 1.84 (2.15 for males and 1.57 for females) per 100,000 population. The incidence increased with age and showed a bimodal distribution with peaks in the 10-29 and 70-79 age-groups. Annual incidence rates were highest in 1978 and 1983. Neither heterogeneity of annual or monthly rates nor linear trends during the period were found to be significant, except in 1978 for patients below 40 years of age, RR 1.72 (95% CI 1.08-2.71) and in 1983 for patients at ages 40 years and over, RR 1.48 (95% CI 1.02-2.16), when compared with GBS incidences in the same age-groups during the remaining study period. The mean +/- SD duration of hospital stay, including long-term care or rehabilitation institutions, for GBS patients, was 86 +/- 210 days, with considerably longer duration for the elderly. The rate of hospital use by GBS patients was 162 days per 100,000 inhabitants per year. In accordance with results of prior studies in South-West Stockholm and described GBS epidemics in Sweden, this study supports that an etiologically different subgroup of GBS exists at ages below 40 years, and that relevant but small time-space variations, such as the reported zimeldine epidemic in 1983, resist detection by hospital data analysis of pooled GBS cases. Efficient epidemiological surveillance of GBS may require targeted development of clinico-epidemiological tools.

Lymphotropic herpesviruses in allogeneic bone marrow transplantation.

Human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), Epstein-Barr virus (EBV), and human cytomegalovirus (CMV) DNA were repeatedly assayed in peripheral blood leukocytes from 37 allogeneic bone marrow transplant (BMT) patients by polymerase chain reaction. Before BMT, HHV-6 DNA was detected in 8 (22%) patients. HHV-7, EBV, and CMV DNA were detected in 21 (57%), 10 (27%), and 1 (3%) patient, respectively. After BMT, HHV-6 DNA was detected in 26 (70%), HHV-7 in 21 (57%), EBV in 28 (76%), and CMV in 21 (57%) patients. Thirty-two (87%) patients were positive with more than one virus. HHV-6, HHV-7, and EBV DNA were found earlier than CMV DNA in most patients after BMT. The proportions of HHV-6-positive samples during the first 3 months after BMT were higher in the patients with either delayed granulocyte engraftment (P = .04, Fisher's exact test) or delayed platelet engraftment (P = .001, Fisher's exact test). The HHV-6 DNA in samples from the patients with delayed engraftment was confirmed to be variant B. The detection of any lymphotropic herpesvirus was not related to the development of acute graft-versus-host disease (aGVHD). High-dose acyclovir (ACV) prophylaxis significantly (P < .01) reduced the proportion of HHV-6-positive samples and tended to lower HHV-6 DNA levels (P = .06). Our data indicate that HHV-6 variant B can inhibit marrow engraftment and that high-dose ACV may be beneficial to engraftment after BMT by preventing HHV-6 reactivation. No relation between the proportions of HHV-7-, EBV-, and CMV-positive samples in the first 3 months and engraftment or aGVHD was found.

Antiviral treatment with WIN 54 954 reduces mortality in murine coxsackievirus B3 myocarditis.

BACKGROUND: Coxsackieviruses B (CBVs) are dominant causative agents in myocarditis and are associated with pathogenesis is some cases of dilated cardiomyopathy, a clinical entity with a poor survival without heart transplantation. METHODS AND RESULTS: In vitro, the antiviral agent WIN 54 954 was shown to inhibit replication of CBV3 at a minimal inhibitory concentration value of 0.02 mg/L. Administration of WIN 54 954, 100 mg/kg BID PO, beginning on the day of infection resulted in complete protection from enteroviral mortality (P < .01). WIN 54 954 treatment did not abrogate the inflammatory reaction in the myocardium. No difference was found in the expression of surface lymphocyte subset markers. At 3 weeks, macrophages seemed to dominate the inflammatory reaction, regardless of treatment. There was no difference in CBV3 antibody titers, indicating that WIN 54 954 does not interfere with the development of protective immunity. Complement factors C3 and B were synthesized at a higher level during infection and correlated well with the degree of inflammatory reaction. CONCLUSIONS: The results show that WIN 54 954 is a potent antiviral agent with a highly significant effect on survival in CBV-induced myocarditis in the A/J mouse if treatment is started early. It is suggested that the reduction in mortality seen with WIN 54 954 administration is due to an inhibitory effect on virus replication in affected organs that does not interfere with cellular or humoral immunity.

Foscarnet for pre-emptive therapy of CMV infection detected by a leukocyte-based nested PCR in allogeneic bone marrow transplant patients.

Fifteen allogeneic BMT patients in a phase II study were given foscarnet 60 mg/kg twice daily for 14 days as pre-emptive therapy against CMV disease. CMV infection was diagnosed by a leukocyte-based nested PCR. All 15 patients were evaluable for toxicity. One patient did not fulfill the inclusion criteria of two consecutively positive CMV PCR tests and therefore was not evaluable for efficacy. Thus, 14 of 15 patients were evaluable for development of CMV disease. None of the patients developed CMV disease and all 14 assessable patients had a negative CMV isolation at the end of therapy. None of the 15 patients had to discontinue therapy due to toxicity. Six patients reported mild gastrointestinal disturbances, three patients headaches, and three patients mild urethritis or hemorrhagic cystitis. Serum-electrolyte disturbances were common including abnormal magnesium, potassium and calcium levels. Two patients developed mild serum-creatinine increases requiring adjustment of the foscarnet dosage according to protocol. We conclude that a dosage of foscarnet of 60 mg/kg given twice daily seems to be safe and effective in preventing CMV disease in allogeneic BMT recipients. A study comparing foscarnet and ganciclovir is indicated.

A three-center European external quality control study of PCR for detection of cytomegalovirus DNA in blood.

The presence of cytomegalovirus (CMV) in the blood has important consequences for patient management, and an external quality control study of its detection by the PCR was conducted by the Infectious Disease Working Party of the European Group for Blood and Marrow Transplantation. Forty-eight coded peripheral blood samples from bone marrow transplant recipients were processed in parallel in three European centers by using the routine in-house PCR assay. Protocols varied in choice of primers, specificity and amplificability controls, and sample processing. Results for 38 of 47 samples agreed, 35 being negative and 3 positive. Of the 12 samples reported as positive by a least one center, only 3 were found to be positive by all three centers, 1 was found to be positive by two centers, and the remaining 8 were found to be positive by one center only. The nine discrepant samples appeared to contain around 1,000-fold less viral DNA than the three concordant positive samples. CMV detection was affected both by the number of leukocytes from which DNA was extracted and by the number of cell equivalents added per PCR. External quality control schemes for CMV PCR are clearly necessary in order to compare data from different centers, and recommendation for standardizing the PCR detection of CMV in blood leukocytes are made.

Use of a semi-quantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients.

The aim of this study was to evaluate the efficacy of pre-emptive antiviral therapy, based on a semi-quantitative nested PCR for cytomegalovirus (CMV) DNA in leukocytes, for the prevention of CMV disease after allogeneic BMT. Fifty-eight patients were prospectively followed with PCR for CMV DNA and antiviral therapy with ganciclovir was initiated after two consecutive positive tests. The levels of CMV DNA were determined by serial dilutions of the positive samples. The probability of detection of CMV DNA was 48.3% and the probability of CMV disease 6% at 100 days after BMT. Patients with CMV disease had higher CMV DNA levels compared with patients without CMV disease (P = 0.001). In comparison to 58 matched historical controls detection of CMV DNA was 5 days earlier (NS) and antiviral therapy could be initiated 10 days earlier in patients followed by PCR (P = 0.05). Pre-emptive antiviral therapy was given to 28 patients in a total of 36 courses. Patients became negative in PCR after 28 of 36 courses (77%). We conclude that PCR for CMV DNA can be used for early detection of CMV infection and as the basis of initiation of pre-emptive antiviral therapy in BMT patients.

Respiratory infection and iatrogenic diarrhea in Honduras and El Salvador during the 1991-1992 season.

The etiology of acute respiratory tract infection and its association with diarrhea was analyzed in 135 hospitalized children less than three years of age with mainly respiratory symptoms in two pediatric hospitals in Honduras and El Salvador. Etiologic diagnoses were performed on nasopharyngeal samples by tissue culture and immunofluorescence, including a search for the presence of respiratory virus-specific immunoglobulin A antibodies. Fecal samples were subjected to electron microscopy and tissue culture. The majority (83%) of the children (65% boys and 35% girls) were less than 12 months old and 45% were less than four months old. In 63 (47%) patients, at least one viral infection of the respiratory tract was identified. Respiratory syncytial virus (RSV) or the respective IgA antibodies were found in 43 (32%) patients., influenza A and B viruses in 29 (21%) patients, adenovirus in four patients, and enterovirus in two patients. Twenty (15%) patients had two or more viral agents. An association between RSV cases and environmental temperature was established. In 124 fecal samples, we identified four cases with astrovirus, seven with nonpolio enterovirus, and eight with adenovirus, but only three cases with rotavirus. Diarrhea was present in 55 (45%) of the patients. There was a statistically significant association between diarrhea and cases with RSV. This was shown to be associated with antibiotic treatment.

Wheezing bronchitis in children. Incidence, viral infections, and other risk factors in a defined population.

Risk factors for severe wheezing bronchitis were studied in children aged 4 months to 4 years in need of hospitalization. The children included in the study consisted of all cases generated from a geographically defined population, the catchment area of St Göran's hospital in Stockholm. The incidence was 3/1000 children and year, during the two years of observation, with the highest rate in boys under the age of 18 months (4.7/1000). Symptoms of a preceding upper respiratory tract infection were reported in 90% of the cases, but a viral etiology could only be demonstrated with virus isolation in 26%. Respiratory syncytial virus was the most common finding in younger children. Rhinovirus was primarily seen in older children with a history of previous wheezing. Regardless of whether the cases had a positive or negative virus isolation they showed the same seasonal distribution. Furthermore, there was no difference in risk factors between children with a positive and negative virus isolation. Children older than 18 months with negative virus isolation had higher IgE levels than those with positive isolation, suggesting that atopy is of greater importance in this group.

Detection of virus in vertically exposed HIV-antibody-negative children.

BACKGROUND: HIV-infected mothers can transmit their infection to their children in utero or at delivery (vertical transmission). There have been cases of children who were reported as acquiring infection vertically and later clearing the infection. We report the frequency of this phenomenon in a European cohort study. METHODS: In four centres of the European Collaborative Study of children born to HIV-infected mothers, 299 children became HIV-antibody-negative and 264 of these had been followed up with virus culture and PCR for viral DNA at least once. FINDINGS: Nine of the 264 children were positive by virus culture or PCR, and subsequently seroreverted. Two of the nine tested virus-positive after they became antibody-negative. Six cases were virus-positive early in life and became negative thereafter, which is consistent with clearance of infection. The pattern was less clear in the other three. The nine cases had had their last virus test at age 16-101 months. All nine children had been bottlefed only. Eight had been delivered vaginally. The children had no HIV-related symptoms and received no anti-HIV treatments. Based on only those children who had two or more positive virological tests, we estimate that 2.7% (6/219) cleared or "tolerated" the virus. INTERPRETATION: The detection of virus or viral DNA in "uninfected" children born to HIV-infected mothers was rare and was not associated with clinical disease or immunological abnormalities. The timing of samples will affect the documentation of clearance since, in uninfected children of HIV-positive mothers who cleared the virus, viraemia was intermittent. Current paediatric opinion is to inform parents of children who serorevert that the child is not HIV-infected.

Echovirus type 23 observed as a nosocomial infection in infants.

Echovirus type 23 was isolated from 5 children, aged 1-13 months, during a 7-month period, covering a study period of several decades. The children were hospitalized for long periods because of chronic conditions. In 4 cases the virus was isolated from faecal samples, collected because of diarrhoea and/or vomiting. In one case echovirus type 23 was collected from nasopharyngeal secretions from a child with respiratory symptoms. The features of echovirus type 23 infection were similar to those of echovirus type 22, but it is striking that infections with echovirus type 23 were less common during the same decades covered by the study.