Defective natural immunity: an early manifestation of human immunodeficiency virus infection.

Cytotoxicity mediated by natural killer (NK) and lymphokine-activated killer (LAK) cells may be of significance in host defense against viral infections. This study included 347 patients infected with human immunodeficiency syndrome virus (HIV) type 1 and 110 controls. The NK cell activity, either unstimulated or stimulated with interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), and the LAK cell activity were suppressed in patients, but the NK/LAK cell activity did not differ between patients with AIDS and patients without AIDS. However, the IFN-alpha-stimulated NK cell activity and LAK cell activity were reduced in patients with symptoms of HIV disease (CDCIV) when compared with asymptomatic patients (CDCII+III). When the data were analyzed by multiple linear regression, the percentage of CD4+ cells had a positive effect on these two parameters in patients without AIDS, whereas the percentage of CD4+ cells had no significant effect on unstimulated and IL-2-stimulated NK cell activity in these patients. In controls and AIDS patients, the percentage of CD4+ cells had no effect on NK/LAK cell activity in multiple linear models. The total number of CD16+ cells was low in patients compared to controls, whereas the percentages of CD16+, CD56+, and CD16+CD56+ were either normal or elevated. Therefore, the decrease in NK cell subpopulations did not contribute to the observed depression in NK/LAK cell activity in vitro. It is concluded that natural immunity is suppressed in HIV-seropositive patients primarily because of a qualitative defect of the NK/LAK cells. This qualitative defect includes a reduced responsiveness to IFN-alpha, which is progressive until the onset of symptoms, and possibly related to the loss of CD4+ cells.

The impact of HIV-1 co-infection on long-term mortality in patients with hepatitis C: a population-based cohort study.

OBJECTIVE: To investigate the impact of HIV co-infection on mortality in patients infected with hepatitis C virus (HCV). METHODS: From a nationwide Danish database of HCV-infected patients, we identified individuals diagnosed with HCV subsequent to an HIV diagnosis. For each co-infected patient, four control HCV patients without HIV were matched on age, gender and year of HCV diagnosis. Data on comorbidity, drug abuse, alcoholism and date of death were extracted from two healthcare databases. We constructed Kaplan-Meier curves and used Cox regression analyses to estimate mortality rate ratios (MRRs), controlling for comorbidity. RESULTS: We identified 483 HCV-HIV co-infected and 1932 HCV mono-infected patients, yielding 2192 and 9894 person-years of observation with 129 and 271 deaths, respectively. The 5-year probability of survival was 0.74 [95% confidence interval (CI) 0.69-0.80] for HCV-HIV co-infected patients and 0.87 (95% CI 0.85-0.89) for HCV mono-infected patients. Co-infection was associated with substantially increased mortality (MRR 2.1, 95% CI 1.7-2.6). However, prior to the first observed decrease in CD4 counts to below 300 cells/muL, HIV infection did not increase mortality in HCV-infected patients (MRR 0.9, 95% CI 0.5-1.50). CONCLUSIONS: HIV infection has a substantial impact on mortality among HCV-infected individuals, mainly because of HIV-induced immunodeficiency.

Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia between 1981 and 2000.

Staphylococcus aureus is a leading cause of bacteraemia. This study analysed temporal trends from 18,702 adult cases of S. aureus bacteraemia in Denmark between 1981 and 2000. After stratification for mode of acquisition, 57% of cases were hospital-acquired (HA), 28% were community-acquired (CA) and 15% were of undetermined acquisition (UA). Incidence rates increased from 18.2 to 30.5 cases/100,000 population. Annual rates increased by 6.4% for CA, by 2.2% for HA and by 3.6% for UA cases, respectively. Case-mortality associated with HA bacteraemia decreased from 36.2% to 20.7% (43% rate reduction, p 0.0001), compared with a decrease from 34.5% to 26.5% (23% rate reduction, p 0.0001) for CA bacteraemia. Following multivariate analysis, age, pneumonia, endocarditis and chronic illness were associated with increased mortality, regardless of the mode of acquisition. Overall, mortality associated with S. aureus bacteraemia declined significantly between 1981 and 2000, but incidence rates doubled, so that the total number of deaths increased. These data emphasise the public health importance of S. aureus bacteraemia and the need for further preventive measures and improved care in order to reduce incidence rates and improve outcomes.

A curriculum for training healthcare workers in the management of highly infectious diseases.

The SARS epidemic, the threat of bioterrorism, and recent examples of imported highly infectious diseases (HID) in Europe have all highlighted the importance of competent clinical and public health management of infectious disease emergencies. Although the European Union of Medical Specialists in Europe and the Infectious Diseases Society of America have developed curricula for training in infectious disease medicine, neither of those mentions training in the management of HIDs. The European Network for Infectious Diseases (EUNID, http://www.eunid.com) is a European Commission co-funded network of experts in HID management, created to help improve the preparedness for HID emergencies within Europe. One of EUNID's agreed tasks is the development of a curriculum for such a training. Between April 2005 and September 2006, EUNID developed a curriculum and accompanying training course on the basis of a questionnaire that was sent to all country representatives and discussion, followed by amendment of drafts shared through the project website, and a final consensus meeting. The resulting curriculum consists of a two-module course covering the core knowledge and skills that healthcare workers need to safely treat a patient who has, or who may have, an HID. The first module introduces theoretical aspects of HID management, including disease-specific knowledge, infection control, and the public health response, through didactic teaching and class-based discussion. The second module involves a "skill station" and a clinical scenario, and equips trainees with relevant practical skills, including the use of specialised equipment and teamwork practice in patient management. Together, the curriculum and course contribute to the creation of a common framework for training healthcare professionals in Europe, and although they are designed primarily for clinicians that are directly involved in patient care, they are relevant also to public health professionals and others who may be involved in HID management and emergency response.

Virus-associated cancers in Greenland: frequent hepatitis B virus infection but low primary hepatocellular carcinoma incidence.

The incidence of primary hepatocellular carcinoma (PHC) in Greenland between 1960 and 1981 was determined and compared with the rate of this disease in Denmark. The annual age and sex rate (per 100,000) was not significantly different (overall, 1.9 vs. 2.2) despite a large difference in the prevalence of hepatitis B surface antigen (HBsAg) and anti-HBs markers of hepatitis. On the basis of a recent report of a very strong risk of PHC among male HBsAg carriers, 4.0 cases of PHC per year were expected in male Eskimos, but only 0.2 cases per year were observed. The incidence rates of other cancers suggested to be virally associated, including nasopharyngeal carcinoma, salivary gland cancer, and carcinoma of the cervix, were all high in Greenland compared to rates for the Danish population, and these high incidence rates are in accord with the markedly higher prevalences in Greenland Eskimos of viruses with which these other cancers have been associated. Thus Greenland Eskimos do not have a high incidence of PHC despite a high prevalence of HBsAg carriers, which suggests that other carcinogenic factors in this environment may be absent or that protective factors are present.

Invasive group A, B, C and G streptococcal infections in Denmark 1999-2002: epidemiological and clinical aspects.

Group A streptococci (GAS) have been described frequently as an emerging cause of severe invasive infections in population-based surveillance studies, whereas the descriptions of group B, C and G streptococci (GBS, GCS and GGS) have been less frequent. Enhanced surveillance for invasive GAS, GBS, GCS and GGS was performed in Denmark in 1999-2002. A detailed questionnaire was completed for 1237 (98%) of 1260 invasive infections. GAS infections dominated (40%), followed by GGS (32%), GBS (23%) and GCS (6%). Most (74%) patients had predisposing factors, and there were no significant differences between the four serogroups when comparing the prevalence of cancer, diabetes mellitus, chronic heart or lung diseases, immunodeficiency or alcohol abuse. The overall case fatality rate at day 30 was 21%, increasing significantly to 59% for patients with streptococcal toxic shock syndrome (STSS). STSS was significantly more frequent in GAS patients (10%) than in GCS (4%), GBS (2%) and GGS (2%) patients. Regression analyses showed that, despite a younger median age among GAS patients, the probability of developing septic shock and mortality was significantly higher among GAS patients than among GBS and GGS patients. These analyses showed no significant differences between GAS and GCS infections. Invasive infections caused by GAS, GBS, GCS and GGS are still a major challenge for clinicians. Continued epidemiological and microbiological surveillance is important to assess the development of these infections and to improve preventative strategies.

Bacteremic Staphylococcus aureus spondylitis.

BACKGROUND: The incidence of hematogenous Staphylococcus aureus osteomyelitis of the vertebral column is rapidly increasing and few studies dealing with the diagnosis, treatment, and outcome of this severe disease are available. METHODS: Based on a nationwide registration, the clinical and bacteriological data were reviewed from 133 cases with a positive blood culture for S aureus and symptoms of vertebral osteomyelitis in Denmark for the period 1980 to 1990. RESULTS: The 133 cases of vertebral S aureus osteomyelitis reviewed were mainly community-acquired infections (82%) in older patients (median age, 65 years) and often occurred with underlying diseases. Both symptoms and laboratory values were relatively unspecific. Bone scan methods proved to be more optimal for diagnosis of vertebral S aureus osteomyelitis in the early stages compared with conventional radiography that proved a lack of consistency in the formative stages. The infection was mostly (70%) localized in the lower part of the column. The recurrence rate and rate of therapeutic failure depended on the duration and dosage of penicillinase-stable penicillins, respectively. Patients treated with fusidic acid in addition to penicillinase-stable penicillins had a significantly lower recurrence rate. Based on these findings, we recommend treatment with penicillinase-stable penicillins and fusidic acid for a total of 8 weeks, with a daily dosage of penicillinase-stable penicillins higher than 4 g. CONCLUSIONS: The diagnosis of vertebral S aureus osteomyelitis based on clinical findings is difficult to ascertain. Bone scans are necessary because radiographic methods do not detect disease as early. Treatment with penicillinase-stable penicillins, at least 4 g/d for at least 8 weeks, is recommended.

Staphylococcus aureus meningitis. A review of 104 nationwide, consecutive cases.

METHODS: Based on a nationwide registration, the clinical and bacteriologic data from 61 postoperative and 43 hematogenous cases of Staphylococcus aureus meningitis in Denmark from 1986 through 1989 were reviewed. RESULTS: Postoperative meningitis was a foreign body infection in 89% of the cases and had a lower mortality (18% [11/61]) compared with hematogenous meningitis (56% [24/43]). Hematogenous S aureus meningitis seems to be part of an overwhelming, disseminated infection as indicated by the following: 81% of the patients had bacteremia, 21% had endocarditis, and 12% had osteomyelitis. Most patients were older, often with underlying diseases, community-acquired infections, and a clinical picture of severe meningitis. The major findings were mental status changes and a high rate (34%) of focal neurological changes. The initial leukocyte count in the cerebrospinal fluid sample was low, and the bacteria were seen in Gram's stain smears in 40% of cases only. The prognosis was related to the age of the patients and the initial antibiotic treatment. Patients treated with penicillinase-stable penicillins in combination with fusidic acid may have a better prognosis. Three (12%) of 25 surviving patients had severe sequelae. CONCLUSIONS: Hematogenous S aureus meningitis is a severe disease with a high mortality related to age, presence of shock, and infection with strains of phage type 95.

Clinical features of Staphylococcus aureus endocarditis: a 10-year experience in Denmark.

BACKGROUND: Both morbidity and mortality resulting from Staphylococcus aureus endocarditis are known to be high, and the incidence of this disease seems to increase. The Statens Serum Institut, Copenhagen, Denmark, made it possible for us to analyze the clinical features of S aureus endocarditis in a nation-wide population of non-drug addicts. METHODS: Almost all Danish cases of bacteremia due to S aureus are reported to the Staphylococcus laboratory, Statens Serum Institut. The medical records were reviewed in cases reported from 1982 to 1991 in which the diagnosis of endocarditis was reported or suspected. RESULTS: A total of 260 patients, 145 males and 115 females, fulfilled the diagnostic criteria. The median age was 67.5 years. In 83 patients, the diagnosis of endocarditis was not suspected clinically. The overall mortality rate among those patients whose disease was diagnosed clinically was 46%. Among the subset of patients who received medical therapy only and appropriate antistaphylococcal treatment, mortality was significantly associated with late congestive heart failure, age, and involvement of the central nervous system. CONCLUSIONS: A raised awareness of the paucity of clinical findings and a more frequent use of echocardiography as a screening method seem essential to improve the prognosis of patients with S aureus endocarditis. Involvement of the central nervous system constitutes a relative indication of early valve replacement.

Risk factors for hospital-acquired Staphylococcus aureus bacteremia.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) acquired in hospitals continues to be a frequent and serious complication to hospitalization, and no previous case-control studies dealing with risk factors of this severe disease are available. METHODS: Based on a 1-year prospective analysis, the data from all patients with hospital-acquired SAB admitted to 4 hospitals in Copenhagen County, Denmark, from May 1, 1994, through April 30, 1995, were evaluated. Eighty-five patients with hospital-acquired SAB were matched to 85 control patients with a similar primary diagnosis at admission (matched controls). Of these, 62 patients with hospital-acquired SAB were compared with 118 other patients with a similar time of admission, who were randomly selected with no clinical evidence of SAB (unmatched controls). RESULTS: The incidence of hospital-acquired SAB was 0.71 per 1000 hospital admissions. The presence of a central venous catheter (odds ratio, 6.9; 95% confidence interval [CI], 2.8-17.0), anemia (odds ratio, 3.3; 95% CI, 1.4-7.6), and hyponatremia (odds ratio, 3.3; 95% CI, 1.5-7.0) was significantly associated with hospital-acquired SAB in a conditional and a usual logistic regression analysis. Nasal carriage was not an independent risk factor, but nasal carriers among patients in surgery (odds ratio, 4.0; 95% CI, 1.3-13.0) had a significantly higher risk for hospital-acquired SAB compared with matched and unmatched controls. The presence of hospital-acquired SAB increased the mortality rate 2.4-fold (95% CI, 1.1-5.2). CONCLUSIONS: The presence of a central venous catheter is an important risk factor, and hyponatremia and anemia are associated with the development of hospital-acquired SAB. Furthermore, hospital-acquired SAB in itself increases mortality.

Cellular profiles in bronchoalveolar lavage fluid of HIV-infected patients with pulmonary symptoms: relation to diagnosis and prognosis.

Bronchoalveolar lavage (BAL) cell differentials and T-lymphocyte subpopulations were analysed in 95 HIV-infected patients with pulmonary symptoms to determine whether the type of cellular inflammatory response could be useful in diagnosis or as a prognostic marker. Patients with Pneumocystis carinii pneumonia (PCP) had more BAL fluid lymphocytes, mainly comprising CD8+ cells, and patients with bacterial infection had more neutrophils than other patients. Neither of these changes were mirrored in peripheral blood. Seven patients who died after their acute episode of PCP had significantly higher BAL fluid neutrophils than 53 patients with PCP who survived (P = 0.002). There seems to be correlation between BAL fluid neutrophilia, PCP and concomitant bacterial infection since four out of seven patients with a fatal outcome had coinfection with bacteria, whereas only one patient with PCP and bacterial coinfection survived (P = 0.0007).

Increased losses of CD4+CD45RA+ cells in late stages of HIV infection is related to increased risk of death: evidence from a cohort of 347 HIV-infected individuals.

OBJECTIVE: To examine changes in the distribution of CD4+CD45RA+ (naive) and CD4+CD45RO+ (memory) lymphocytes in various stages of HIV infection and the effect of these changes on disease progression. DESIGN AND METHODS: Expression of CD45RA+ and CD45RO+ on CD4+ lymphocytes was analysed by flow cytometry in a prospectively followed cohort of 300 HIV-infected individuals (median follow-up time, 2.90 years; range, 0.02-4.54 years) and in a group of 102 age- and sex-matched uninfected controls. Survival analysis was performed considering AIDS development and death as endpoints. RESULTS: The median CD4+CD45RA+/CD45RO+ ratio was 1.3 (25-75% quartiles, 0.9-2.4) in controls; it was increased to 1.8 (1.1-2.5) in 40 HIV-infected individuals with CD4+ cell counts > 500 x 10(6)/l (P < 0.05); it was similar at 1.4 (0.8-2.0) in 106 HIV-infected individuals with CD4+ cell counts of 200-500 x 10(6)/l; and it was decreased to 0.9 (0.5-1.4) in 154 HIV-infected individuals with CD4+ cell counts < 200 x 10(6)/l (P < 10[-6]). When fitted in a Cox model adjusting for the total number of CD4+ cells and age a lower concentration of CD4+CD45RA+ cells was associated with an increased risk of dying. The concentration of CD4+CD45RO+ cells was not significantly associated with AIDS or death in age- and CD4+ cell count-adjusted Cox models. CONCLUSIONS: This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.

Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test.

OBJECTIVE: Cytomegalovirus (CMV) is a frequent opportunistic viral pathogen in patients with AIDS leading to retinitis and other serious manifestations. CMV disease may be successfully treated. Prophylactic antiviral therapy has been shown to reduce the risk of CMV disease if initiated early. We evaluated PCR and the antigenemia tests as methods for early detection of CMV disease. METHODS: Two-hundred HIV-seropositive subjects with CD4 T-cell counts below 100 x 10(6)/l were monitored with CMV polymerase chain reaction (PCR), the antigenemia test, blood cultures and CMV immunoglobulin (Ig) G and IgM titres every second month for 1 year. RESULTS: Thirty-eight patients (19%) developed CMV disease. The PCR test detected CMV DNA a median of 46 days before onset of disease. This was earlier than the median of 34 for the antigenemia test and a median of 1 day for CMV blood cultures. Univariate analysis showed that the CMV PCR, the antigenemia test and blood cultures all had significant predictive values for subsequent development of CMV disease with odds ratios (OR) of 30, 22 and 20. CMV serology had no predictive value. Multivariate analysis showed that the PCR method was superior to the other tests; OR: CMV PCR 10.0, antigenemia test 4.4 and CMV cultures 4.3. No clinical parameters had any significant predictive value in the stepwise multivariate model. CONCLUSIONS: The CMV PCR and the CMV antigenemia tests are both sensitive methods that may predict development of CMV disease up to several months prior to clinical disease. These methods make it possible to select patients at high risk for CMV disease and suitable for prophylactic therapy against CMV.

The effect of treatment with zidovudine with or without acyclovir on HIV p24 antigenaemia in patients with AIDS or AIDS-related complex.

OBJECTIVE: To evaluate changes in serum HIV p24-antigen levels in a subset of patients who participated in a European/Australian double-blind, placebo-controlled trial evaluating the efficacy of zidovudine (250 mg every 6 h) alone or in combination with acyclovir (800 mg every 6 h) in patients with AIDS, AIDS-related complex (ARC) or Kaposi's sarcoma (KS). DESIGN: Double-blind, placebo-controlled randomized clinical trial of less than or equal to 6 months' therapy. SETTING: Samples were obtained from patients attending teaching hospital outpatient clinics in seven European countries and Australia. SUBJECTS: One hundred and ninety-seven HIV-infected patients (60 with AIDS and 137 with ARC or KS). MAIN OUTCOME MEASURES: Serum HIV p24-antigen levels measured using the Abbott HIV solid-phase enzyme immunoassay. RESULTS: Of 76 ARC/KS patients who were initially HIV p24-antigen-positive, one out of 25 randomized to placebo, eight out of 23 to zidovudine and 11 out of 28 to the zidovudine/acyclovir combination became antigen-negative. The proportion of patients who became antigen-negative was significantly higher in both the zidovudine group (P = 0.016) and the zidovudine/acyclovir group (P = 0.004), compared with the placebo group. There were no statistical differences between the zidovudine and the zidovudine/acyclovir groups. During the trial p24-antigen levels in the zidovudine-treated patients reached their minimum after 4-8 weeks of therapy, and tended to increase gradually thereafter. Disease progression occurred irrespective of whether p24-antigen levels declined during therapy. No association between p24-antigen responses to therapy and baseline disease stage, Karnofsky score or baseline CD4 cell count was detectable. CONCLUSION: Acyclovir does not potentiate the effect of zidovudine on p24-antigen levels. Change in antigen level in response to antiviral therapy needs further investigation before it is used as a surrogate marker for clinical efficacy of antiviral therapy.

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection.

OBJECTIVE: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. DESIGN: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54). SETTING: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. MAIN OUTCOME MEASURE: Survival time. RESULTS: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). CONCLUSIONS: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

Natural immunity and HIV disease progression.

OBJECTIVE: To investigate the clinical implications of impaired levels of the natural immunity mediated by natural killer (NK) cells and lymphokine activated killer (LAK) cells during infection with HIV-1. DESIGN: Data used were from 172 individuals with an estimated measure of NK cell activity and 146 with an estimated measure of LAK cell activity. Patients had active HIV infection at the time of enrolment in the study and have been followed-up prospectively for a median of 3.0 years. METHODS: The lytic activity of NK cells and LAK cells, the CD4 T lymphocyte count, and the concentration of CD16/CD56 NK cells were measured at enrolment. HIV RNA in plasma was measured retrospectively. Survival analysis was performed considering three main endpoints: CD4 cell counts below 100 x 10(6) cells/l, clinical AIDS, and death. RESULTS: In unadjusted analysis and after adjustment for age, CD4 T lymphocyte count and plasma HIV RNA at enrolment, low LAK cell activity was significantly associated with higher risk of progression to a CD4 T lymphocyte count < 100 x 10(6) cells/l (crude P = 0.001; adjusted P = 0.04) and to death (crude P = 0.0002; adjusted P = 0.02). Patients with low NK cell responsiveness to interferon-alpha tended to be at higher risk of death (crude P = 0.04; adjusted P = 0.13) whereas unstimulated NK cell activity and the concentration of NK cells were of no prognostic value for patients in this cohort. CONCLUSIONS: The present study suggests that low LAK cell activity and low NK cell responsiveness to interferon-alpha may be important in the pathogenesis of HIV infection.

PASSHIV-1 treatment of patients with HIV-1 infection. A preliminary report of a phase I trial of hyperimmune porcine immunoglobulin to HIV-1.

OBJECTIVE: To study the safety of intravenously administered porcine-derived hyperimmune immunoglobulin to HIV-1, PASSHIV-1, in humans. METHODS: Fourteen HIV-1-infected individuals were treated for 5-7 days with intravenous infusions of highly purified PASSHIV-1 (> 95% pure). Two of the 14 patients were retreated 3 months later with PASSHIV-1 for an additional 5 days to evaluate side-effects from retreatment with porcine immunoglobulins. RESULTS: Ten of the patients had no side-effects from PASSHIV-1 therapy. Three patients experienced transient urticarial eruptions, which responded to antihistamine administration and did not require discontinuation of therapy. One patient, who received concomitant administration of human gammaglobulin, experienced serum sickness (type 3 hypersensitivity reaction). All patients demonstrated a significant improvement in fatigue (100% response), weight (all those with previous weight loss gained weight), fever (100% response), polyneuropathy (100% response), bronchitis (100% response), candidiasis (100% response), diarrhea (100% response), and dermatitis (100% response). One out of the five patients with Kaposi's sarcoma demonstrated > 50% improvement. Mean CD4+ cell counts in the group rose from 143 +/- 263 to 234 +/- 323 x 10(6)/l 4-6 months following completion of therapy (P = 0.013, paired Student's t-test); CD4+ counts rose > twofold in six individuals. p24 antigen, present in four patients, was negative following therapy in all patients. Other laboratory parameters that responded to therapy included: platelet counts (71% response), leukopenia (57% response), elevated lactic dehydrogenase (100% response), and elevated alkaline phosphatase (100% response). PASSHIV-1 was well tolerated by HIV-1-infected individuals. CONCLUSION: This therapy appears to be efficacious in ameliorating some of the clinical aspects and symptoms of HIV-1 infection.

Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals.

OBJECTIVE: Recently, it has been shown that a homozygous 32 base-pair deletion in the gene encoding CKR-5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1. We have investigated whether HIV-seropositive individuals who were heterozygous for the CKR-5 deletion had a different course of the disease. DESIGN: Thirty-five high-risk HIV-seronegative and 99 HIV-seropositive Danish homosexual men followed form 1985 to 1996 and 37 blood donors were analysed for their CKR-5 genotype by polymerase chain reaction. RESULTS: Two (6%) of the 35 HIV-seropositive subjects at high-risk of infection were homozygous and seven (20%) were heterozygous for the CKR-5 deletion. This was not significantly different from the distribution in normal donors. Twenty-two (22%) of the 99 HIV-seropositive subjects were heterozygous and none was homozygous. Two subgroups of patients who had an opposite course of the HIV disease were identified. Of nine long-term non-progressors, six (66%) were heterozygous for the deletion. This frequency is significantly higher than in nine rapid progressors of whom non was heterozygous. The frequency of heterozygotes in long-term non-progressors was also significantly higher than in the cohort as a whole. A Kaplan-Meier plot of the HIV-seropositive subjects, of whom 57 developed AIDS, showed a significantly better prognosis within the first 7 years of follow-up for those who were heterozygous for the deletion. Heterozygous individuals also had a significantly slower decrease in CD4 T-cell count per year. CONCLUSION: Individuals who are heterozygous for the 32-base-pair deletion in the CKR-5 gene have a slower decrease in their CD4 T-cell count and a longer AIDS-free survival than individuals with the wild-type gene for up to 11 years of follow-up.

HIV-associated lymphoma: histopathology and association with Epstein-Barr virus genome related to clinical, immunological and prognostic features.

All 51 cases of HIV-related malignant lymphoma in Denmark diagnosed from 1983 to 1989 were reviewed. There were 12 Burkitt-type lymphomas, 30 immunoblast-rich lymphomas and 9 other lymphomas. Patients with immunoblast-rich lymphomas had significantly lower CD4 cell counts (median 60 vs. 188 x 10(6)/l, P less than 0.05), and more often a history of previous AIDS-defining illnesses (50% vs. 0%, P less than 0.005), compared with patients with Burkitt-type lymphomas. Epstein-Barr virus (EBV) DNA was demonstrated in 14 of 19 immunoblast-rich tumours, and in 2 of 7 Burkitt-type lymphomas (P = 0.10). Compared with EBV DNA-negative tumours EBV DNA-positive tumours were associated with lower CD4 cell counts (median 39 vs. 188 x 10(6)/l, P = 0.01). It is concluded that two main types of HIV-related malignant lymphoma exist. One is associated with severe immunosuppression, is often of immunoblast-rich morphology, and may be linked to EBV, whereas the other may occur in the absence of immunosuppression, is often of Burkitt-type morphology, and is probably not linked to EBV. In addition to these two main types, other non-Hodgkin lymphomas and Hodgkin's disease do occur.

Neurologic manifestations in Staphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts.

PURPOSE: To investigate the neurologic manifestations of infective endocarditis caused by Staphylococcus aureus in a population of nondrug addicts with special emphasis on the clinical presentation, epidemiology, and mortality. PATIENTS AND METHODS: During the period from 1982 to 1991 a total of 8,514 cases of bacteremia with S aureus were reported to the Staphylococcus Laboratory, Copenhagen, Denmark. The medical records of cases of suspected infective endocarditis were retrospectively reviewed and classified according to the new diagnostic criteria for endocarditis proposed by Durack. RESULTS: A total of 260 cases from 63 hospitals fulfilled the diagnostic criteria. Overall, 91 patients (35%) experienced neurologic manifestations. Sixty-one presented with neurologic symptoms, whereas 30 patients developed neurologic complications at various intervals (median: 10 days) after the debut of the disease. The most frequent neurologic manifestation was unilateral hemiparesis, which occurred in 41 patients (45%). Forty-two percent of the females had neurologic manifestations compared to only 30% of the males (P = 0.06). Cases with native mitral valve infection had a significantly higher frequency of neurologic manifestations compared with all other valvular involvement (44% versus 29%, P = 0.02) but the frequency of neurologic complications was only nonsignificantly higher in those patients with native mitral valve infection than in those patients with native aortic valve infection (44% versus 31%, P = 0.10). Only two of the patients with tricuspid valve infection and none of those with congenital heart disorder experienced neurologic manifestations. A neurologic manifestation occurred in 22 (35%) of the 63 episodes in which vegetations were detected on the echocardiograms, compared with 17 (26%) of the 65 episodes without vegetations (P = 0.38). The mortality was 74% in patients with major neurologic manifestations and 56% in patients without neurologic manifestations (P = 0.008). In patients with neurologic complications the mortality was significantly higher among those treated with antibiotics alone as compared with those treated surgically (65 of 81, 80% versus 2 of 10, 20%; P = 0.0003). CONCLUSIONS: In a population of nondrug addicts with infective endocarditis caused by S aureus the following main conclusions can be drawn: neurologic manifestations occur with a higher frequency in patients with native mitral valve infection. The presence of vegetations on echocardiograms is not a risk factor for developing neurologic complications but this conclusion is based on the results of transthoracic echocardiograms performed in only one half of the patients. The majority of the neurologic manifestations occur on presentation or shortly thereafter and the risk of recurrent embolism is low. Mortality is increased in patients with neurologic manifestations. A neurologic event per se may constitute an indication for surgical treatment.