Manifestations and outcome of extra-pulmonary tuberculosis: impact of human immunodeficiency virus co-infection.

SETTING: Metropolitan New Orleans. OBJECTIVE: To determine the impact of human immunodeficiency virus (HIV) co-infection on the manifestations and outcome of extra-pulmonary tuberculosis (EPTB). DESIGN: Retrospective analysis of 136 patients diagnosed with EPTB between 1 January 1993 to 31 December 2001. Characteristics of EPTB were compared by HIV serostatus. RESULTS: Of those tested for HIV (n = 87), 42.5% were seropositive. Except for a higher frequency of disseminated TB among co-infected persons, the manifestations, laboratory diagnostic yield and outcome of EPTB were similar between HIV-infected and non-infected persons. The overall fatality rate was 20%; HIV-infected patients had a three-fold higher mortality compared to non-infected persons. In multivariate logistic regression analysis, factors associated with death were: HIV-seropositive (adjusted odds ratio [aOR] 5.2, 95% CI 1.1-24.65) compared to HIV-seronegative, disseminated and meningeal compared to lymphatic disease (aOR 16.87, 95% CI 12.31-123.34), and lack of TB treatment compared to receipt of TB treatment (aOR 29.23, 95% CI 14.47-191.23). CONCLUSION: Manifestations of EPTB were non-specific and did not differ between HIV-infected and non-infected persons. Severe disease, lack of TB treatment and HIV co-infection were associated withdeath. Approaches are needed to reduce EPTB morbidity and mortality, especially among HIV-infected persons.

HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.

Long-term outcome of inpatients with tuberculosis assigned to outpatient therapy at a local clinic in New Orleans.

BACKGROUND: To characterize the New Orleans tuberculosis (TB) patient population and determine what factors might influence outcome, we followed inpatients with active disease at a large, public hospital who then received outpatient treatment at a public clinic. METHODS: A total of 61 patients were enrolled from January 1, 1993 through July 1994 and followed until no patients were actively receiving treatment. Demographic and psychosocial data were collected and associated with the number of months of treatment received and final outcome. RESULTS: Of the 61 patients, 26 (43%) completed treatment, 15 (25%) were lost to follow-up, 11 (18%) died, and 9 (14%) were referred out of the area during treatment. Among those lost to follow-up, 60% received only one month of treatment. Homelessness was the only factor significantly related to whether or not a patient completed outpatient therapy (p = .02) with almost 60% of all homeless patients becoming lost to follow-up. Assignment to directly observed therapy (DOT) did not significantly raise compliance rates. HIV status did not significantly alter the duration of treatment, but these patients had a mortality rate 3 times that of the other patients. CONCLUSIONS: Efforts to improve TB control should focus on increasing compliance, particularly among the homeless. Although expansion of DOT is essential, raising therapy completion rates to acceptable levels may require additional social services, financial incentives and enforceable legal remedies for noncompliance. More rigorous treatment guidelines are needed to assure consistent management of patients who receive interrupted treatment.

Aspergillus flavus mycetoma and epidural abscess successfully treated with itraconazole.

Aspergillus spp. rarely cause mycetomata. We report a patient with diabetes and nephrotic syndrome with Aspergillus flavus mycetoma of the back, with the development of an epidural abscess, diskitis and vertebral osteomyelitis. The patient was successfully treated with decompressive laminectomy and a 14-month itraconazole regimen. Serial serum itraconazole levels and quantitative Aspergillus antigen levels were performed. This is the second reported and first extrapedal case of mycetoma caused by A. flavus.

Clinical manifestations and implications of coinfection with Mycobacterium kansasii and human immunodeficiency virus type 1.

We conducted a retrospective study to further elucidate the clinical presentations and prognosis of disease due to Mycobacterium kansasii in patients infected with human immunodeficiency virus (HIV). Forty-nine HIV-infected patients first had M. kansasii isolated at a mean CD4 cell count of 62/mm3 and at a mean interval of 17 months after the diagnosis of AIDS. Seventeen of the 49 patients had disseminated disease caused by M. kansasii. Twenty-nine patients had a positive acid-fast smear of sputum, and 35 were known to be cigarette smokers. At the time of initial isolation of M. kansasii, 13 patients had other concurrent pulmonary isolates and 15 had another mycobacterial species concurrently isolated (the Mycobacterium avium complex in 13 instances). Patients who received antimycobacterial treatment survived longer than those who did not. Only one of the 49 patients was definitively determined to be colonized with M. kansasii without disease; therefore, it appears that pulmonary isolates of M. kansasii in HIV-infected patients are almost always associated with disease. The increase in rates of M. kansasii disease among HIV-infected patients has paralleled the rise of AIDS in Louisiana. So far, this state has recorded more coinfections with M. kansasii and HIV than any other.

Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus.

Zidovudine is metabolized to an inactive 5'-glucuronide and has a short plasma half-life requiring frequent dosing. The present study in six patients without symptoms who were infected with human immunodeficiency virus was undertaken to determine if coadministration of valproic acid which, like zidovudine, is metabolized by glucuronidation, would alter zidovudine disposition. Under steady-state conditions for both drugs, the plasma area under the curve for zidovudine increased twofold with a corresponding decline in its oral clearance when given with valproic acid. The mean 5'-glucuronide/zidovudine urinary excretion ratio was reduced by more than 50%, and the amount of unconjugated zidovudine recovered in urine increased by more than twofold. There was no significant increase in the plasma half-life of zidovudine. The effects of valproic acid on zidovudine glucuronidation were related to plasma valproic acid concentrations. Valproic acid inhibits glucuronidation of zidovudine and increases its oral bioavailability.

Treatment of cytomegalovirus retinitis with intravitreal injection of liposome encapsulated ganciclovir in a patient with AIDS.

To study its safety and efficacy in treating cytomegalovirus (CMV) retinitis, an AIDS patient received an intravitreal injection of liposome encapsulated ganciclovir in the right eye. The left eye served as a control, receiving intravitreal free ganciclovir. The right eye showed no retinal haemorrhages or detachment; however, vision declined initially, stabilising later. Weekly examination showed neither progression of the CMV retinitis nor new lesions in the right eye. The left eye showed reactivation of old CMV retinitis. Liposome encapsulated ganciclovir reduced the number of intravitreal injections, stabilising CMV retinitis, and warrants further study.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

Rapid and sensitive assay for fluconazole which uses gas chromatography with electron capture detection.

Fluconazole, an orally active antifungal agent, has been shown to be clinically beneficial for maintenance therapy of cryptococcal meningitis. A sensitive gas-liquid chromatographic assay with electron capture detection, which required only a single extraction step and precluded any pretreatment of the chromatographic column, was developed for fluconazole. The assay was linear from 0.1 to 20 micrograms/ml, with a correlation coefficient of 0.999. The intraassay and interassay coefficients of variation were less than 9%. The measured values on average were within 8% of the target values. The extraction recoveries ranged from 87 to 106%. Steady-state plasma fluconazole levels (mean +/- standard deviation) in three AIDS patients with cryptococcal meningitis receiving 200 mg of fluconazole per day ranged from 8.95 +/- 1.32 to 11.41 +/- 0.63 micrograms/ml and were within the expected range for this dosing rate, on the basis of previous studies. The ratio of fluconazole concentration in cerebrospinal fluid to fluconazole concentration in plasma in one patient receiving 400 mg/day was 0.73 at steady state and was consistent with published reports.

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single-dose and steady-state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus-seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half-life (t1/2) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long-term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10- to 14-fold higher than the corresponding single-dose concentrations. The terminal t1/2 (washout) after 16 weeks greatly exceeded the t1/2 observed after a single oral dose (151 versus 29.6 hours). Ribavirin-induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

Neurologic aspects of North American zoonoses.

Neurologic dysfunction is a frequent presentation or complication of zoonotic infections. The differential diagnosis is broad and will include nonzoonotic diseases as well. Patterns of neurologic findings, systemic signs of infection, and epidemiologic risk factors are useful in the approach to diagnosis and initial empiric treatment of the patient with suspected zoonotic infection. Associations between these patterns and specific organisms are emphasized by means of tables and algorithms.

Protection of zidovudine-induced toxicity against murine erythroid progenitor cells by vitamin E.

The ability of vitamin E (alpha-tocopherol) to stimulate erythroid progenitor cells was investigated in an attempt to identify ways to ameliorate zidovudine (azidothymidine, AZT)-induced anemia. In vitro, alpha-tocopherol acid succinate (ATS), upon incubation with murine bone marrow cells at concentrations of up to 4 micrograms/ml, caused a dose-dependent increase in erythroid colony-forming unit (CFU-E)-derived colonies. This increase was equivalent to the effect demonstrated by 50 mU of recombinant human erythropoietin (rhEpo) or 200 U of recombinant interleukin 3 (rIL-3). For in vivo studies, anemia was produced in CD-1 male mice by administering AZT in drinking water (1.5 mg/ml). Treatment with vitamin E (50 mg/kg body weight) or Epo (0.4 U per mouse) was initiated 24 h later and continued for five consecutive days. Seventh day bone marrow cells from femurs were assayed for CFU-E-derived colonies. Both vitamin E and Epo significantly increased the number of CFU-E-derived colonies by 75% and 86% of control, respectively, indicating that these agents were approximately similar in protecting the bone marrow from AZT-induced toxicity.

Comparison of methods for HIV isolation from monocytes and lymphocytes of seropositive asymptomatic hemophiliacs and homosexuals.

1. Since monocyte-macrophages have been recognized as HIV targets in addition to CD4+ T-lymphocytes, we have evaluated HIV infection of purified peripheral blood mononuclear cell fractions obtained from 10 seropositive asymptomatic hemophiliacs and compared it with that of 10 asymptomatic homosexual patients. 2. HIV was isolated more frequently from the lymphocytes than the monocytes of both groups of patients. 3. HIV preferentially replicated in phytohemagglutinin-stimulated lymphocytes compared with growth factor-treated monocytes. Monocytes did not preferentially harbour HIV in either group.

Cryptococcus neoformans pulmonary infection in HIV-1-infected patients.

Cryptococcus neoformans (Cn) is a frequent pathogen in patients infected with the human immunodeficiency virus (HIV-1). We review the initial presentation and clinical course of 18 HIV-1-infected (HIV+) patients with a Cn pulmonary infection. Simultaneous positive cerebrospinal fluid (CSF) cultures were found in 10 (63%) of 16 examined. The most frequent presenting symptoms were fever (87%) and pulmonary complaints (60%). Although the most common chest radiographic finding was bilateral diffuse interstitial infiltrates, nodules and cavitary lesions were also seen. Nine (50%) of the 18 patients died within 6 weeks of diagnosis. Of six patients with an isolated Cn pulmonary infection, five have subsequently died. Three of these five patients did not receive maintenance therapy and had confirmed or probable relapse. Patients initially presenting with an isolated Cn pulmonary infection may later show disseminated disease, suggesting that such patients should receive both acute and maintenance therapy.

Aspergillus keratitis with intraocular invasion.

A healthy 48-year-old man developed Aspergillus keratitis following mild corneal trauma. Intensive medical therapy, initially empirical, then guided by in vitro sensitivity testing, as well as attempts at surgical excision of the infection, were ultimately unsuccessful. The poor therapeutic response may have been due to fungal penetration of the deep corneal stromal before treatment was initiated. The clinical and histologic features of A keratitis are described and related to fungal keratitis in general. The strengths and limitations of laboratory diagnostic aids are discussed. Fungal keratitis may follow a disarmingly mild early clinical course, but requires prompt, aggressive therapy if serious complications are to be avoided.

Invasive external otitis. Report of 21 cases and review of the literature.

We report 21 cases of invasive external otitis and review 130 cases from the English literature. Invasive external otitis is the term that most appropriately describes the locally invasive Pseudomonas infections that begins in the external ear canal, breaches the epithelial barrier and results in signs of local subcutaneous tissue invasion. Nineteen patients were diabetic. FIfteen of these 19 had preexistent, long-standing diabetes (average 15.8 years) and 10 had microvascular disease. Studies of the skin of the temporal bone in two patients provided evidence of diabetic microangiopathy of the dermal capillaries. Pseudomonas aeruginosa was isolated from the involved area in all cases. All patients without neurologic deficits survived, compared with six of nine with deficits of the central nervous system. All 13 patients in whom initial therapy was successful received a combination of an aminoglycoside and a semisynthetic penicillin, whereas all six episodes of recurrent disease occurred when only one antibiotic was used. The overall mortality was 15 percent (three of 20 in whom the long-term outcome is known). We propose that diabetic microangiopathy of the skin of the temporal bone results in poor local perfusion and creates an environment well suited for invasion by Pseudomonas aeruginosa. There is a good correlation between the extent of disease clinically and prognosis. Effective treatment requires early diagnosis and combination therapy with an aminoglycoside and a semisynthetic penicillin.

Alternaria sinusitis.

Alternaria is a fungus of the class Deuteromycetes and the family Dematiaceae. Fungi of this genus have generally been regarded as nonpathogenic and as contaminants when isolated from clinical specimens. Hypersensitivity to Alternaria spores, however, has long been recognized as a cause of allergic pulmonary disease. More recently, the organism has also been demonstrated to have potential for opportunistic invasion of immunosuppressed and debilitated patients. Presented is a case in which this organism was repeatedly isolated from naso-oral tissue specimens from an otherwise healthy patient. The organism was seen in biopsies from a granulomatous hyperplastic destructive disease of the maxilla and soft tissues of the face which extended to the ethmoid sinus and fistulized through the hard palate. The clinical course, pathophysiology and therapeutic approach are discussed. The management of this disease requires a multidisciplinary approach involving the otolaryngologist, infectious disease specialist and pathologist.