Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents.

The known effects of highly active antiretroviral therapy (HAART) on opportunistic infections (OIs) range from immune restoration disease to remission of specific OIs. In the present study, Mycobacterium avium complex infection recurred in 3 patients receiving antimycobacterial therapy and HAART. At the time of the initial M. avium infection, the mean CD4 cell count was 22.3 cells/mm3, and the HIV viral load was 181,133 copies/mL. Relapse occurred a mean of 14. 3 months after the first episode; the mean follow-up CD4 cell count was 89/mm3 (mean elevation of 66 cells/mm3), and the HIV viral load was <400 copies/mL in each patient. M. avium was isolated from blood (1 patient), blood and lymph node (1), and small-bowel tissue (1). M. avium infection may recur as a generalized or focal disease in those who are receiving antimycobacterial agents but whose HAART-associated CD4 cell recovery, although significant, is not optimal.

Granulocyte-macrophage colony-stimulating factor upregulates reduced 5-lipoxygenase metabolism in peripheral blood monocytes and neutrophils in acquired immunodeficiency syndrome.

Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway, which play a role in host defense, and are synthesized by both monocytes (peripheral blood monocyte [PBM]) and neutrophils (PMN). Because 5-LO metabolism is reduced in alveolar macrophages and PMN from acquired immunodeficiency syndrome (AIDS) subjects, we investigated the synthesis of LT by PBM and PMN from these subjects. There was a reduction (74.2% +/- 8.8% of control) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infected compared with normal subjects. Expression of 5-LO (51.2% +/- 8.8% of control), and 5-LO activating protein (FLAP) (48.5% +/- 8.0% of control) was reduced in parallel. We hypothesized that this reduction in LT synthetic capacity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We treated 10 AIDS subjects with GM-CSF for 5 days. PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO and FLAP expression. PMN leukotriene B(4) (LTB(4)) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phospholipase A(2) expression. In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced 5-LO metabolism. GM-CSF therapy reversed this defect in both PBM and PMN. In view of the role of LT in antimicrobial function, cytokine administration in AIDS may play a role as adjunct therapy for infections.

HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications.

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.

To characterize the clinical features of human immunodeficiency virus (HIV)-associated fever of unknown origin (FUO) in the United States, we performed a retrospective analysis of cases that fulfilled specific criteria (published by Durack and Street in 1991) at two medical centers in the United States between 1992 and 1997. Seventy cases met criteria for HIV-associated FUO; the mean CD4 cell count was 58/mm3, and the mean duration of fever was 42 days. A cause of FUO was found in 56 of the 70 cases; 43 were of a single etiology, and in 13 cases multiple conditions were established. The most common diagnoses were disseminated Mycobacterium avium infection (DMAC; 31%), Pneumocystis carinii pneumonia (13%), cytomegalovirus infection (11%), disseminated histoplasmosis (7%), and lymphoma (7%). In this United States series, FUO occurs most often in the late stage of HIV infection, individual cases often have multiple etiologies, and DMAC is the most common diagnosis.

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0+/-1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2+/-9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 microgram daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans. Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy.

Spinal cord infection: myelitis and abscess formation.

PURPOSE: Our purpose was to describe the MR findings and evolution of spinal cord abscess and to define those MR features that allow differentiation of cord infection from other intramedullary abnormalities. METHODS: We retrospectively reviewed the MR studies of all patients in whom intramedullary spinal cord abscess was proved either by blood or cerebrospinal fluid culture or by serologic examination at our institution between January 1988 and January 1996. The study group included four adults and two children, 7 to 74 years old (mean age, 38 years). RESULTS: Initial MR studies showed intramedullary high signal on T2-weighted sequences with poorly defined marginal enhancement on T1-weighted images. On follow-up contrast-enhanced T1-weighted studies, the lesions had well-defined enhancing margins with central low signal intensity. After the initiation of therapy, T2 signal abnormalities decreased markedly and contrast-enhanced studies showed ring enhancement. These T1 findings resolved with treatment over serial studies in four patients. The organisms identified were Streptococcus milleria, S pyogenes, atypical mycobacteria, Mycobacterium tuberculosis, and Schistosoma mansoni (both children). CONCLUSION: A characteristic sequence of imaging findings aids in the differentiation of cord infection from other intramedullary lesions.

Trimethoprim/sulfamethoxazole incremental dose regimen in human immunodeficiency virus-infected persons.

BACKGROUND: The mechanism of tolerance to incremental doses of trimethoprim-sulfamethoxazole given to human immunodeficiency virus-infected persons who have had a prior intolerance to this agent has not been studied. OBJECTIVE: We prospectively evaluated a regimen of incremental doses of oral trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected persons who had a prior trimethoprim-sulfamethoxazole-induced fever and nonexfoliative skin rash to investigate the mechanism by which it permits tolerance. METHODS: Oral trimethoprim (0.00004 mg)/sulfamethoxazole (0.00002 mg) was given to 22 human immunodeficiency virus-infected persons on day 1 and gradually increased over eight days to 1 double strength (DS) tablet/day in an outpatient setting. At study entry, skin tests and IgG antibodies to sulfa were performed; the latter was repeated at study week 4. RESULTS: Nineteen patients tolerated trimethoprim/sulfamethoxazole at the completion of the 8-day protocol (86% effective). Moderate toxicities occurred in eight persons during the desensitization protocol; five of these were able to continue trimethoprim/sulfamethoxazole with adjunctive prednisone. Skin tests to sulfa antigen were negative in all persons. Eleven patients at study entry had antibodies to sulfamethoxazole; IgG antibodies appeared at week 4 in 8 of the 11 patients who initially had no antibody detected. CONCLUSIONS: The mechanism of tolerance to the incremental doses of trimethoprim/sulfamethoxazole given to previously intolerant human immunodeficiency virus-infected persons is not due to desensitization and remains undetermined.

Cytokines enhance neutrophils from human immunodeficiency virus-negative donors and AIDS patients to inhibit the growth of Mycobacterium avium in vitro.

Mycobacterium avium is one of the most prevalent opportunistic infections in AIDS patients, and neither prophylaxis nor treatment against M. avium is effective. To evaluate host defense mechanisms against mycobacterial infections, studies investigated whether neutrophils from AIDS patients could inhibit the growth of M. avium in vitro and what cytokines enhance neutrophil function against M. avium. Peripheral blood neutrophils from human immunodeficiency virus-negative and AIDS patients were incubated with media, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-8, or macrophage-inhibitory proteins and infected with M. avium, and the inhibition of bacterial growth was determined. G-CSF (1000 U/mL) and GM-CSF (2000 U/mL) stimulated neutrophils from AIDS patients to significantly inhibit M. avium growth. These results demonstrate that neutrophils from AIDS patients can respond to exogenously supplied G-CSF or GM-CSF by inhibiting the growth of M. avium.

5-Lipoxygenase metabolism in alveolar macrophages from subjects infected with the human immunodeficiency virus.

Pulmonary infection represents a major source of morbidity and mortality in AIDS. One important component of pulmonary host defense is the elaboration by resident alveolar macrophages (AM) of proinflammatory leukotrienes (LT) and other 5-lipoxygenase (5-LO) metabolites of arachidonic acid (AA). In this study, we compared the 5-LO metabolic capacity of AM isolated from normal controls with two groups of HIV-infected subjects: (1) patients with low CD4 counts undergoing diagnostic evaluation for pulmonary indications, and (2) volunteers without pulmonary complaints stratified into normal (> 500) and low (< 200) CD4 count groups. Compared with AM from control subjects, AM from HIV-infected subjects with normal and low CD4 counts demonstrated a marked reduction in LT synthesis. This reduced metabolic capacity could not be attributed to in vivo activation because there was no increase in lavage fluid LTB4 levels. However, there was a reduction (approximately twofold) in 5-LO protein expression in both the normal and the low CD4 subsets. 5-LO-activating protein (FLAP) expression was unchanged in cells from the normal CD4 HIV group, but was decreased threefold in the two groups with low CD4 counts. These observations indicate that there is a graded defect in the 5-LO metabolic capacity of AM from HIV-infected subjects, with decreased expression of only 5-LO in the normal CD4 group, and decreased expression of both 5-LO and FLAP in the low CD4 group. This defect would be expected to compound the immunosuppression seen in these subjects.

Interleukin-12 enhances antigen-specific proliferation of peripheral blood mononuclear cells from HIV-positive and negative donors in response to Mycobacterium avium.

OBJECTIVE: To determine if the addition of recombinant (r) human interleukin (IL)-12 enhances in vitro proliferative responses to Mycobacterium avium of peripheral blood mononuclear cells (PBMC) from HIV-positive donors with CD4 cell counts < 100 x 10(6)/l. DESIGN AND METHODS: PBMC proliferative responses to virulent and avirulent serovars of M. avium in the presence and absence of exogenously added IL-12 were determined in 24 HIV-positive and 11 HIV-negative donors by 3H-thymidine uptake assay. Changes in CD4 and CD8 cell populations after IL-12 treatment and M. avium stimulation were analyzed by FACS. RESULTS: IL-12 significantly enhanced proliferation of PBMC to both virulent and avirulent M. avium from all 24 HIV-positive donors (P = 0.0001) although the magnitude varied for each donor. In contrast, addition of IL-12 to PBMC from HIV-negative donors only increased the proliferative responses to the virulent M. avium serovar 4 (P = 0.0044). PBMC from HIV-positive donors in the presence of IL-12 responded better to the avirulent serovar of M. avium than the virulent serovar 4. Proliferative responses of HIV-positive donors to M. avium alone, however, were significantly less (P = 0.0013) than that of HIV-negative donors. Increased proliferative responses of HIV-positive donors were independent of CD4 counts. No significant changes in the ratio of CD4+ to CD8+ T cells occurred in either HIV-positive or negative donors under any culture conditions. CONCLUSION: In vitro proliferative responses of PBMC from HIV-positive donors to M. avium were significantly enhanced by the addition of human rIL-12, which was not dependent on their CD4 cell counts. The use of IL-12 as an enhancer of cell-mediated immunity in AIDS patients against M. avium infections deserves further study.

Transmission of human immunodeficiency virus infection presumed to have occurred via female homosexual contact.

We describe a 24-year-old woman infected with the human immunodeficiency virus (HIV) whose sole risk behavior was prior sexual contact with an HIV-infected woman. Our patient's clinical course suggests that viral transmission occurred during the beginning of their sexual relationship. Our case, combined with those previously reported, provides evidence that female homosexual activity can be a risk behavior for acquisition of HIV infection. Seroprevalence studies, however, have not provided evidence for transmission of HIV by this behavior. These studies, combined with the sparse number of individual case reports, suggest that female homosexual activity is an inefficient mechanism of HIV transmission.

Pharmacokinetics and bioavailability of fluconazole in patients with AIDS.

Fluconazole pharmacokinetics were evaluated for 10 volunteers with AIDS who had no clinical evidence of gastroenteritis. Single 100-mg intravenous (i.v.) and oral (p.o.) doses were administered in a randomized, crossover design. i.v. doses were delivered by a constant-rate infusion over 30 min. Serum fluconazole concentrations were measured by gas-liquid chromatography. The i.v. and p.o. studies were modelled simultaneously by iterative two-stage analysis, which provided individual parameter estimates and a population pharmacokinetic model. Median areas under the concentration-time curves for i.v. and p.o. studies did not differ (90.6 and 99.3 micrograms/ml.h, respectively). Consistent with this finding, the median fractional bioavailability was 1.1 (range, 0.45 to 1.3), comparable to those in healthy subjects. Serum pharmacokinetics in these AIDS patients were generally similar to published data for healthy volunteers. However, following p.o. dosing, we observed a slightly delayed and highly variable time to maximum concentration in serum (median, 2 h; range, 15 min to 8 h). Data were well described by a linear, two-compartment pharmacokinetic model with first-order absorption and elimination. Repeated-measures analysis of variance found no significant differences among any of the pharmacokinetic parameters between i.v. and p.o. studies. On the basis of our findings, we suggest no change in dosage of p.o. fluconazole in patients with AIDS who show no clinical signs of enteropathy.

Chorioamnionitis caused by Capnocytophaga: case report and review.

We report a case of pathologically demonstrated chorioamnionitis due to Capnocytophaga species. The mother had high fever and marked uterine tenderness, and the infant had poor Apgar scores, fever, and pulmonary infiltrates. Both recovered after receiving specific antibiotics. Pathological examination of the placenta revealed acute chorioamnionitis, subchorionitis, and vasculitis of the umbilical vein. The dramatic clinical and pathological features of this case are compared with those of the nine previously reported cases of infection due to Capnocytophaga species occurring in pregnancy.

Fever of unknown origin: review of 86 patients treated in community hospitals.

This study describes the clinical features of fever of unknown origin (FUO) in 86 patients in a community setting from 1984 to 1990. Infectious diseases remain the most common category of illnesses causing FUO; in this study, infectious diseases including recently described diseases--such as AIDS (three cases) and Lyme disease (one case)--caused FUO in 28 patients. Although percutaneous computed tomography-guided procedures were useful for obtaining diagnostic specimens (15 cases), a noninvasive approach established the diagnosis in many instances (37 cases). In all but nine cases, diagnostic testing was guided by abnormalities detected during the physical examination or routine laboratory tests.

Discrete gastrointestinal mass lesions caused by cytomegalovirus in patients with AIDS: report of three cases and review.

We report the detailed clinical features of discrete mass lesions of the gastrointestinal tract caused by cytomegalovirus in three patients who had the acquired immunodeficiency virus syndrome. The disease occurred in the fundus of the stomach in one patient and in the cecum in the other two persons. The symptoms as well as radiographic and endoscopic findings in each case are described and are shown to be indistinguishable from those resulting from a neoplasm. The diagnosis was established by the presence of inflammation with cytomegalovirus-like inclusions and confirmed by immunoperoxidase staining. Cytomegalovirus infection should be considered, along with Kaposi's sarcoma and lymphoma, as a cause of focal mass lesions of the alimentary tract in persons infected with HIV.

Catheter infection caused by Methylobacterium in immunocompromised hosts: report of three cases and review of the literature.

Three cases of catheter infection due to Methylobacterium extorquens are reported. Each patient had a history of acute leukemia and was immunocompromised; two had undergone bone marrow transplantation, and the third was receiving consolidation chemotherapy. All three patients survived after removal of the central venous catheter and antibiotic treatment. The clinical features of these cases are compared with those of the 12 previously reported cases of infection due to Methylobacterium species.

Verapamil impairs human neutrophil chemotaxis by a non-calcium-mediated mechanism.

The in vitro effect of pharmacologic concentrations (10(-8) to 10(-6) mol/L) of verapamil on human neutrophil migration and response to chemotactic signals was examined. Human neutrophils were preincubated (15 minutes) in verapamil and then assayed for chemotactic response to formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) (10(-8) mol/L). Cell viability was not affected by verapamil treatment. Verapamil-treated cells displayed 40% to 50% reductions in directed migration at all concentrations (P less than 0.02). Activated random migration (chemokinesis) was also impaired by verapamil treatment, but random locomotion was not affected except at a high concentration (10(-6) mol/L). This pharmacologic action of verapamil was not rapidly reversible by washing cells free of drug, but it was necessary that cells be exposed to drug before the chemotactic signal. In addition to f-Met-Leu-Phe, chemotactic response to activated human serum was also reduced for neutrophils. Several experiments were conducted to determine whether verapamil affected neutrophils as a calcium antagonist. Calcium antagonist binding-site assays using radiolabeled dihydropyridines provided no evidence for the presence of calcium channels in neutrophil membranes. Also, 45Ca2+ uptake assays demonstrated increased uptake of 45Ca2+ by f-Met-Leu-Phe-stimulated neutrophils, but no effect on uptake by verapamil exposures (10(-6) mol/L). Finally, the cytosolic calcium-chelating dye, quin 2 acetomethoxy ester (quin 2), was used as a fluorescent indicator to measure cytosolic Ca2+ concentrations, [Ca2+]i, in neutrophils. Verapamil exposures over a wide concentration range (10(-6) to 10(-4) mol/L) did not affect resting [Ca2+]i or [Ca2+]i transients after f-Met-Leu-Phe (10(-8) mol/L) stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of drugs that block calcium channels on the microbicidal function of human neutrophils.

The central role of calcium ions in cell physiology prompted us to examine the hypothesis that pharmacological concentrations of calcium channel-blocking drugs might affect human neutrophil (PMN) functions. The capacity of PMNs suspended in verapamil hydrochloride for killing Pseudomonas aeruginosa during two hour incubations was significantly impaired (P less than .05). Several observations suggested that this drug effect was the result of altered calcium metabolism: exposure to verapamil decreased the uptake of 45Ca++ by PMNs subsequently exposed to the calcium ionophore A23187; verapamil did not impair PMN function in the absence of extracellular calcium; and the addition of A23187 concomitantly with (but not following) verapamil prevented PMN dysfunction. In addition, nifedipine, a structurally dissimilar calcium channel-blocking drug, also impaired the bactericidal activity of PMNs against Pseudomonas aeruginosa (P less than .02). Further studies revealed that treatment with verapamil did not affect PMN phagocytosis, but significantly impaired the PMN respiratory burst (as shown by superoxide anion generation assay; P less than .05). We conclude that PMNs exposed to pharmacological concentrations of calcium channel-blocking drugs exhibit a reduced capacity to kill bacteria.