Expansion of neopterin and beta 2-microglobulin in cerebrospinal fluid reaches maximum levels early and late in the course of human immunodeficiency virus infection.

Elevated cerebrospinal fluid (CSF) levels of neopterin and beta 2-microglobulin (beta 2MG) reflect activation of the cellular immune response in the central nervous system (CNS). In 118 consecutive subjects [15 controls and 103 patients with human immunodeficiency virus (HIV) infection classified according to the Walter Reed staging system (WR)], neopterin and beta 2MG were determined in paired samples of CSF and serum. The permeability of the blood-CSF barrier and local release of neopterin and beta 2MG were taken into account: The molecular weight and diameter were used to determine filtration at the blood-CSF barrier. CSF neopterin levels were increased in all stages of HIV infection. beta 2MG levels were elevated in WR2 and later stages. Neopterin, beta 2MG, and cell counts similarly showed peaks in WR2, as did neopterin and beta 2MG also in the later stages WR5 and WR6. Neurologically asymptomatic patients exhibited higher neopterin CSF levels than did controls (12.67 +/- 11.6 vs. 2.34 +/- 1.05 nmol/l, P less than 0.001) and higher CSF beta 2MG (2.12 +/- 1.25 vs. 1.3 +/- 0.37 mg/l, P = 0.001). Patients with HIV encephalopathy had higher levels of beta 2MG (3.75 +/- 1.83 mg/l) than asymptomatic patients (P less than 0.01). CSF levels of neopterin were markedly different in patients with HIV encephalopathy and toxoplasmosis (P less than 0.01). A high quantity of local release of the markers neopterin and beta 2MG may reflect HIV infection of the CNS in early and late stages and additional release upon opportunistic infections.

[Survival in HIV infection and AIDS]. / Uberlebenszeit bei HIV-Infektion und AIDS.

Duration of the AIDS-free period after HIV-infection and survival time vary to a wide extent. About 50 percent of the patients develop AIDS within 10 years. The most important prognostic factor is the CD4-lymphocyte count. The risk of AIDS increases significantly after CD4-lymphocyte counts drop below 400/microliters. Another prognostic factor is age. In older patients disease progresses more rapidly. AIDS often is preceded by an AIDS-Related-Complex characterized for example by Oral Candidiasis, Hairy Leukoplakia or Zoster of more than one dermatome. AIDS mostly develops 1/2 to 1 year after AIDS-Related-Complex. After AIDS is diagnosed the median survival time is not longer than 1 1/2 years. Single patients live much longer. Prognosis is influenced by the disease defining AIDS. Kaposi's Sarcoma often occurs early in the course of immunodeficiency and median survival is longer than after other opportunistic diseases. Survival also is longer after Pneumocystis Carinii Pneumonia since it is well treatable. A very short survival has been noticed after Non-Hodgkin-Lymphoma. During the last few years survival after HIV-infection and AIDS has been prolonged a little by sufficient prophylaxis of Pneumocystis Carinii Pneumonia which is the most frequent opportunistic disease, by antiretroviral treatment with Zidovudine and by increase of knowledge which makes early diagnosis and treatment of opportunistic diseases possible.

2.5 years survival with sequential ganciclovir/foscarnet treatment in a patient with acquired immune deficiency syndrome and cytomegalovirus retinitis.

The case with the longest survival time (30 months) after the diagnosis of cytomegalovirus retinitis in a group of 53 patients with the acquired immune deficiency syndrome and cytomegalovirus retinitis (median survival time 8.4 months) is described. The patient developed cytomegalovirus retinitis in his left eye and received intravenous virustatic treatment for 29.5 months. Treatment was started with ganciclovir. After withdrawal from maintenance treatment, a relapse of cytomegalovirus retinitis occurred, which was again successfully treated with ganciclovir. A secondary cataract developed, and cataract extraction was performed. After 12.5 months on treatment with ganciclovir, a change to foscarnet was necessary because of neutropenia. Maintenance treatment with foscarnet was well tolerated for 17 months. The cytomegalovirus retinitis showed no signs of reactivation during this period. Vision in the right eye was preserved until death, and no sign of cytomegalovirus retinitis developed in the right eye. This case report demonstrates that an unusual long survival time is possible in a patient sequentially treated with ganciclovir and foscarnet.

Evaluation of saliva as a specimen for monitoring zidovudine therapy in HIV-infected patients.

To facilitate studies of the pharmacokinetic properties of zidovudine, the relationship between plasma and salivary concentrations of the drug was studied, after oral dosage, in 10 HIV-infected patients. Zidovudine concentrations were determined in plasma, unstimulated mixed saliva and citric-acid-stimulated mixed saliva over a period of 3 1/2 hours by high-performance liquid chromatography. Correlation coefficients were r = 0.97 (P less than 0.0001) for stimulated saliva compared with plasma and r = 0.89 (P less than 0.0001) for unstimulated saliva, with average values in unstimulated saliva being 113.8 +/- 44.6% in plasma and 67.8 +/- 25.4% in stimulated saliva. Stimulated saliva values found to be 70% of the total reflected the concentration of the unbound drug in plasma. Except for a shorter half-life time (t1/2) in saliva, pharmacokinetic parameters showed a good correlation in the three types of specimen. These findings and the convenience of sample collection suggest that citric-acid-stimulated saliva might be an appropriate specimen for monitoring zidovudine therapy.

Serological markers as prognostic criteria for the course of HIV infection.

576 serum samples from 139 HIV infected patients were analyzed for the presence of HIV antigens, as well as anti-core, anti-env and neutralizing antibodies. The results were correlated with the clinical and immunological stages of the patients. While almost all sera were positive for anti-env antibodies, only two thirds of the same sera had antibodies to core proteins. The average antibody titres, particularly of anti-core antibodies, decreased with the onset of clinical symptoms. The presence of p24 antigen could be demonstrated in only 16% of the sera. A positive reaction for core antigen seemed to be correlated with the absence of anti-core antibodies. Env specific neutralizing antibodies were found to be present in all of the sera analyzed in the LC5-test with a maximum neutralizing capacity observed in sera from WR 4 patients. A useful serological marker must fulfil two criteria, namely positive reactivity in the majority of sera examined and a broad range of antibody titres. None of the above described parameters meet these demands. Here we describe the search for new antibody markers, for example antibodies directed against HIV regulatory proteins.

[Electro-ophthalmologic studies in HIV patients]. / Elektroophthalmologische Untersuchungen bei HIV-Patienten.

We examined 44 HIV-positive patients in different disease stages with electroretinogram (ERG), pattern-electroretinogram (PERG), and visually evoked cortical potentials (VECP). Sixty-eight of the 88 eyes examined had a normal fundus and full central vision. Twelve eyes showed cotton-wool ecudates and 8 eyes CMV retinitis. Fifty-four eyes with normal fundus were examined by ERG. Of these 28 (52%) showed marked reduction of the amplitude. In the PERG, 20 eyes out of 50 examined (40%) showed an amplitude reduction. In the VECP, 12 out of 65 eyes (19%) had a reduced amplitude. In the ERG, 7 of 11 eyes (64%) with cotton-wool exudates showed marked pathological findings, as opposed to 4 of 10 cases (40%) in the PERG and 3 of 12 (12%) in the VECP. Seventy-five percent of the eyes with CMV retinitis (6 of 8 cases) showed pathological findings in the ERG and VECP and 100% (all 7 cases examined) in the PERG. These electrophysiological findings suggest that there are diffuse disorders in the retina of HIV-positive patients. It is possible that these findings are based on direct infection of the retina with HIV, or that they represent a vascular disorder, subclinical infection or are related to side effects of the drugs used for the HIV infection.

Reduced cerebral blood flow in early stages of human immunodeficiency virus infection.

In order to determine if brain perfusion abnormalities, which are known in patients with acquiredimmunodeficiency syndrome dementia, occur in early stages of human immunodeficiency virus infection, technetium 99m hexamethyl-propyleneamine oxime-single-photon emission computed tomography studies were performed in 20 patients infected with human immunodeficiency virus who belonged to Walter Reed stages I through IV. None of these patients demonstrated signs of dementia or severe neurological dysfunction. Pathological patterns of hexamethyl-propyleneamine oxime uptake were seen in 14 patients, seven of whom had normal results during neurological examination. Only four patients had signs of cerebral atrophy on cranial computed tomographic scan. These data suggest that subtle changes in cerebral perfusion seem to arise early in the course of human immunodeficiency virus infection and may indicate human immunodeficiency virus encephalopathy before neurological symptoms or noticeable structural damage occurs.

Erythrocyte antibodies in AIDS are associated with mycobacteriosis and hypergammaglobulinemia.

Positive direct antiglobulin results prior to transfusion in some of our AIDS patients, as well as some reports in the literature on red cell antibodies in AIDS patients, prompted us to investigate the prevalence of erythrocyte antibodies in AIDS patients with transfusion requiring anemia. In addition we studied the question of relevant correlations with clinical diagnosis and with hematological and immunological laboratory parameters. Of 145 consecutive hospitalized AIDS patients (CDC criteria), 34 (23%) presented with anemia requiring transfusion. With each cross-match a routine antibody screening was performed. In cases of positive reaction additional antibody differentiation was done. Diagnoses, hematologic parameters, and therapy were studied retrospectively. Agglutination was positive in at least one test for 41% (14/34) (group 1). C3d, anti I, cold agglutinins, and IgG occurred most frequently (n = 9/8/7/6 out of 14). Seventy-five per cent (12/14) had leukopenia (less than 4000/microliters), 57% (8/14) had thrombocytopenia (less than 150,000/microliters), and 43% (6/14) showed both. Average values for leukocytes, thrombocytes, and CD4-positive lymphocytes did not differ significantly in patients with (group 1) and without (group 2) erythrocyte antibodies. Average gamma globulin levels were significantly increased in group 1 (23.2 g/l versus 16.9 g/l; p less than 0.001). In group 1, 64% (9/14) had proven mycobacteriosis (6 atypical), in contrast to only 15% (3/20) in group 2 (p less than 0.05). There were no significant differences between the two groups in prevalence of other opportunistic infections, malignant lymphoma, and Kaposi's sarcoma. Autoimmune versus infectious pathogenesis of pathologic erythrocyte antibodies in AIDS has been discussed in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

67Ga-scintigraphy for evaluation of AIDS-related intestinal infections.

This study was designed to evaluate the role of 67Ga-scintigraphy in AIDS-related intestinal infections. Seventeen out of twenty-five HIV-positive patients (68%) primarily investigated with 67Ga-scans to screen for opportunistic pneumonia presented pathologic abdominal 67Ga-uptake which was, in most cases, due to proven opportunistic intestinal infection (cytomegalovirus, atypical mycobacteria, cryptosporidiosis etc.). The correlation of abdominal with pulmonary findings has shown that AIDS-related intestinal infections and opportunistic pneumonia may occur concomitantly in the majority cases (11/17). In 6/17 patients positive abdominal findings were observed without opportunistic pneumonia at the same time. Gallium imaging of the abdomen has shown to identify successfully the most common extrapulmonary sites of HIV-related infections. Thus, abdominal imaging or whole body scintigraphy should be a mandatory part of each 67Ga-scan in patients with HIV infection, even if it was primarily performed to screen for opportunistic pneumonia only. Knowledge of multilocular opportunistic infections, usually caused by different pathogens, is clinically important for further diagnostic and therapeutic management.

Expansion of activated T lymphocytes (CD3 + HLA/DR +) detectable in early stages of HIV-1 infection.

The phenotypic characterization of lymphocyte subsets in relation to different clinical stages of HIV infection has mainly focussed on CD4 and CD8 cells. Some reports focus on expansion of activated T lymphocytes in AIDS patients. Yet there is no detailed knowledge whether such changes occur also in earlier stages of HIV infection. In order to describe the kinetics and possible pathogenetic meaning of this subset when related to all distinct chronologic stages, we performed two-color flow cytometric lymphocyte differentiation in 173 HIV-infected patients and 30 healthy controls. All subjects were classified according to the Walter Reed (WR) system. Our results show that a significant increase of activated T lymphocytes (CD3 + HLA/DR +) occurs early, in WR1 and WR2, thus preceding the clinically relevant CD4 depletion. This increase is paralleled by an expansion of CD8 + Leu7 + cytotoxic cells. We conclude, that early changes of lymphocyte subsets are detectable in addition to inversion of the CD4/CD8 ratio. The possible pathogenetic meaning including the question of possible autoimmune mechanisms is discussed.

Myelin basic protein in the cerebrospinal fluid of patients infected with HIV.

The major pathological abnormalities of HIV encephalopathy are infiltrates of macrophages, multinucleated giant cells, microglial nodules and demyelination. Elevated myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) provide a marker for central nervous system demyelination. The purpose of this study was to investigate the possible role of CSF MBP as a useful and early marker for HIV encephalopathy. The CSF of 40 consecutive patients with HIV infection of various clinical stages was investigated, including 13 patients with clinical signs of HIV encephalopathy. CSF MBP was elevated in 2 patients (5.0 and 5.3 ng/ml), both of whom had moderate to severe HIV encephalopathy. The course of the disease was rapid in both patients. In the remaining 38 patients, CSF MBP levels were marginally elevated (n = 12) or normal (n = 26). Our results suggest that CSF MBP is not a sensitive marker for the diagnosis and evaluation of HIV encephalopathy, but may be an indicator of prognosis for the course of the disease. There were only few findings of elevated CSF MBP levels in patients with HIV encephalopathy in the current study, and this may be because the disorder progressed slowly in most patients. It is possible that CSF MBP levels in HIV encephalopathy may only be elevated with acute clinical deterioration but are normal in slowly progressive forms of demyelination, as seen in multiple sclerosis.

[False-positive test of autonomic neuropathy in HIV infection and AIDS? Case control study of heart rate variability in 62 HIV positive patients]. / Falsch-positiver Test einer autonomen Neuropathie bei HIV-Infektion und AIDS? Fallkontrollstudie der Herzfrequenzvariabilität bei 62 HIV-positiven Patienten.

False positive tests for autonomic neuropathy in HIV-infection and AIDS? Case-control-study of heart rate variation in 62 cases Autonomic neuropathy is said to be common in AIDS. In a cross section study we tested heart rate variability, a simple and sensitive test, in relation to disease severity. The expiratory-inspiratory RR-interval-ratio (RRR) was normal in HIV-infected clinically healthy persons (mean 1.45; n = 10), but progressively lowered in LAS (1.24; n = 12), ARC (1.20; n = 7), AIDS (1.13; n = 20), AIDS with pneumocystis carinii pneumonia (1.07; n = 7) and patients who died within the four month study (1.06; n = 6). The progressive decrease of heart rate variability (from 45% to 6% for group means) is in accord with previous reports. - In a simultaneous case-control study we compared RRR of these 62 patients with those of 62 not HIV infected patients matched for age, sex, resting heart rate and presence of pneumonia. Neither in the six subgroups nor in the total group we found a difference between HIV infected patients and their controls (1.20 +/- 0.18 SD and 1.22 +/- 0.17, respectively; 62 pairs). The decrease of RRR with increasing disease severity in HIV-infected patients was mainly dependent upon increasing heart rate and to a lesser degree upon increasing age. Therefore, a decreased heart rate variability in AIDS is not a specific sign of autonomic neuropathy and likely to be a false positive test result.

Treatment of secretory diarrhea in AIDS with the somatostatin analogue SMS 201-995.

We have observed two patients with AIDS suffering from severe watery diarrhea refractory to conventional medical treatment. In the first patient the reason for the diarrhea could not be revealed in spite of extensive investigations; however, the clinical picture suggested cryptosporidia infection. In the second patient cytomegalovirus could be shown in colonic biopsy specimens. After failure of several attempts of symptomatic, antibiotic, and antiviral therapy, the long-acting somatostatin analogue SMS 201-995 was administered to the patients subcutaneously in a dose between 2 x 50 micrograms and 3 x 100 micrograms/day. This treatment resulted in a prompt reduction of stool volume and bowel motions. Somatostatin may be a useful addition to the symptomatic treatment of refractory diarrhea in AIDS.

Dissociated nystagmus as a common sign of ocular motor disorders in HIV-infected patients.

In order to determine if ocular motor disturbances due to brainstem and cerebellar dysfunction provide a frequent and early marker for HIV infection of the brain, neurological examination was performed in 133 HIV-infected persons who were consecutively admitted to our hospital. In 22 patients (17%) we found no other reason for cerebellar or pontomesencephalic signs than HIV encephalopathy. Ocular motor disorders accounted for the most frequent signs of cerebellar and pontomesencephalic dysfunction. Ocular motor disorders mainly consisted of dissociated nystagmus (n = 12), gaze-evoked nystagmus (n = 10) and impaired smooth pursuit (n = 6). Cerebellar ataxic gait and dysmetria were present in 3 patients. Since dissociated nystagmus was the primary ocular motor disorder, we assume that the medial longitudinal fasciculus may be a predilected circumscribed area for HIV infection of the brain. We suppose that cerebellar and pontomesencephalic disorders may be an early marker for HIV encephalopathy because they were the only neurological signs found in 12 patients.

Serum neopterin levels as predictor of AIDS.

The reliability of laboratory parameters for the prediction of impending manifestation of AIDS in HIV-1 infected patients was investigated. Over a mean observation period of approximately 1 year (5 to 33 months) 56 patients were studied. Eleven patients progressed to AIDS (group 1) and 45 remained free of AIDS-defining disease (group 2). Eight candidate-predictor variables were measured on each patient at the beginning of the observation period: neopterin, hemoglobin, lymphocytes, CD4 counts, CD8 counts, platelets, gammaglobulins, and erythrocyte sedimentation rate. In a linear discrimination analysis, a stepwise entry of these parameters into the discriminant function was effected according to which variable added most to the separation into groups 1 and 2. Neopterin proved to be most discriminating with no improvement of separation when adding further variables. Thus, a final allocation rule was computed using neopterin alone. This rule assigns neopterin levels above 21.9 nmol/l to group 1 and levels below to group 2. We conclude, tentatively, that in HIV-infected patients neopterin levels of 22 nmol/l and over may indicate the manifestation of AIDS in the year to come.

[The place of 67Ga scintigraphy in the primary diagnosis and follow-up evaluation of opportunistic pneumonia in patients with AIDS]. / Stellenwert der 67Ga-Szintigraphie in der Primärdiagnostik und Verlaufsbeurteilung opportunistischer Pneumonien bei Patienten mit AIDS.

Opportunistic pneumonias are a life-threatening complication in patients with AIDS. Early diagnosis and therapy is necessary to improve prognosis. This study was designed to assess the value of 67Ga scintigraphy in the primary detection and follow-up of these special pneumonias. 67Ga scintigraphy was performed in 40 patients: 10 normal controls and 30 HIV-positive patients with AIDS or AIDS-related complex (ARC). 67Ga scan results were compared with current chest radiographs and the results of pathogen detection. The evaluation of positive scans was based on a quantification of the pulmonary uptake, expressed as a pulmonary/soft-tissue uptake ratio. Only 8/30 patients had a normal scan, 22/30 showed diffuse (13/22) or focal (9/22) increases of pulmonary uptake. In 7/8 patients with normal scans the chest radiograph was negative as well. The one patient with negative scan but positive chest radiograph had pulmonary Kaposi's sarcoma. In 11/22 patients the 67Ga scan and chest radiograph were positive simultaneously. In the other 11/22 patients with positive scans chest radiographs were initially negative but showed pathology in 5 cases within 1-2 weeks. The reason for positive scans in most cases was an opportunistic lung infection; other forms of pneumonia were only observed in two cases. The defined uptake ratio demonstrated to be a highly sensitive parameter for monitoring pneumonia and the effects of therapy in follow-up studies. In conclusion, quantitative 67Ga scintigraphy proved to be a reliable and highly sensitive method for primary detection and follow-up of opportunistic pneumonias in patients with AIDS.