Aspergillus flavipes group osteomyelitis.

Lumbar vertebral osteomyelitis caused by Aspergillus Flavipes group organisms developed in a nonchronically immunosuppressed patient. Diagnosis was confirmed morphologically and culturally from both closed needle biopsy of the vertebrae and subsequent lumbar laminectomy. The patient was treated with 3 g of amphotericin B with apparent eradication of the organism.

Measles immunity after revaccination: results in children vaccinated before 10 months of age.

Measles immunity was studied in children in a private pediatric practice who had been revaccinated because they had received their primary measles vaccination before 1 year of age. Antibody was measured in 72 of these children who had received the first injection of live measles virus vaccine at less than 10 months of age, and the second at greater than 1 year of age. Of the 72 children, 29 (40%) had no detectable antibody and the geometric mean titer for the group was approximately 1:4. Of the children with low antibody titers, 15 were given a third injection of measles vaccine and five (33%) still did not respond. Cell-mediated immunity as indicated by lymphocyte transformation to measles antigen was measured in 11 of the children. Five (45%) had responses to measles antigen, but the responses did not correlate with the presence or absence of antibody. This study confirms the observation that revaccination is unsuccessful in many children who received measles vaccine in the first year of life, and shows that even a third injection of vaccine may fail to produce a significant antibody response.

Failure of ketoconazole in an immunosuppressed patient with pulmonary blastomycosis.

A renal transplant recipient presented with pulmonary blastomycosis. Because of recent data suggesting a role for ketoconazole in the treatment of blastomycosis and concern for preserving her functioning renal transplant, she was started on therapy with ketoconazole, 400 mg daily. After four months of continuous therapy, she developed skin and laryngeal involvement requiring emergency tracheostomy; subsequent therapy with amphotericin B resulted in resolution of her disease. This is an example of life-threatening progression of blastomycosis in an immunosuppressed patient during ketoconazole therapy.

The measurement of serum 5-fluorocytosine levels in the presence of miconazole.

Miconazole is effective against a wide variety of fungi, and may be of value when used in combination with 5-fluorocytosine in the treatment of life-threatening mycotic infections. Because the hematologic toxicity of 5-fluorocytosine is related to high serum levels, the effects of miconazole on the standard disc diffusion assay for 5-fluorocytosine were studied. When standards were made in either undiluted or 10% pooled human serum, no difference in zone size between 5-fluorocytosine alone and the combination of 5-fluorocytosine and miconazole was found. It is concluded that, in this assay system, miconazole does not affect the disc diffusion test for serum 5-fluorocytosine levels.

Sex steroid regulation of autoimmunity.

The immune response of males and females is not identical but instead has been shown to be dimorphic in its nature, with females generally demonstrating a greater overall response than males. This dimorphism extends to both the humoral and cell mediated systems and appears to be mechanistically based on the differences in type and concentration of sex steroids in males vs females. Furthermore, growth hormone and prolactin secretions which are different in males and females may also be partly responsible for the observed dimorphism. Because autoimmune disease results from a pathological perturbation of normal immune function, it follows that expression of these diseases will also demonstrate a dimorphic pattern. Examples of this autoimmune dimorphism include (but are not limited to) lupus, rheumatoid arthritis and multiple sclerosis with the two former more prevalent in females than males and the latter more severe during pregnancy. To explain autoimmune dimorphism it therefore becomes necessary firstly to describe the cellular and hormonal interactions found in normal immune regulation and thereafter extrapolate these to autoimmune phenomena.

Anabolic steroid effects on immune function: differences between analogues.

As an untoward effect of chronic anabolic steroid use, immunologic alterations may be induced. To evaluate this possibility five commercially available steroids with various types of structural differences were studied in male Sprague-Dawley rats. Animals were divided into five groups and treated with testosterone (Group 1), testosterone propionate (Group 2), testolactone (Group 3), oxandrolone (Group 4), and stanozolol (Group 5). Androgenic anabolic steroids were administered daily, subcutaneously dissolved in oil, at a dose of 1.1 mg/kg. Immune alterations were assessed by skin-test responses to phytohemagglutinin. After five days of treatment (1.1 mg/kg/day) a significant immuno-suppression was observed with all groups. However, by day 10, groups 3, 4, and 5 showed an immuno-stimulation. Using oxandrolone as the model stimulant, serum testosterone levels were significantly suppressed, while castration abolished the stimulatory effect. These observations indicate that immune alterations do occur with anabolic steroids which are immuno-suppressive when the steroid nucleus is intact and immuno-stimulatory with nuclear alterations. It appears that these changes are associated with altered gonadal testosterone release.

Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275.

BACKGROUND: Active nutrition therapy and the anabolic steroid oxandrolone (OX), in selected patients with severe alcoholic hepatitis, significantly improved liver status and survival. We report here on the changes in their nutritional parameters. METHODS: Protein energy malnutrition (PEM) was evaluated and expressed as percent of low normal in 271 patients initially, at 1 month and at 3 months. Active therapy consisted of OX plus a high caloric food supplement vs a matching placebo and a low calorie supplement. RESULTS: PEM was present in every patient; mean PEM score 60% of low normal. Most of the parameters improved significantly from baseline on standard care; the largest improvement seen in visceral proteins, the smallest in fat stores (skinfold thickness). Total PEM score significantly correlated with 6 month mortality (p = .0012). Using logistic regression analysis, creatinine height index, hand grip strength and total peripheral blood lymphocytes were the best risk factors for survival. When CD lymphocyte subsets replaced total lymphocyte counts in the equation, CD8 levels became a significant risk factor (p = .004). Active treatment produced significant risk factor (p = .004). Active treatment produced significant improvements in those parameters related to total body and muscle mass (ie, mid arm muscle area, p = .02; creatinine height index, p = .03; percent ideal body weight, p = .04). CONCLUSION: Deterioration in nutritional parameters is a significant risk factor for survival in severe patients with alcoholic hepatitis. This deterioration is reversible with standard hospital care. Active therapy further improves creatinine height index, mid arm muscle area and total lymphocyte counts. Hence, these later parameters appear to be the best indicators for follow-up assessments.

Case report: invasive pulmonary aspergillosis in a nonimmunosuppressed patient.

A patient with no known underlying immunosuppressive disorder who developed invasive pulmonary aspergillosis is described. A review of the English literature revealed ten other presumably nonimmunosuppressed patients with invasive aspergillosis. All had evidence of necrotizing pneumonitis with frequent cavity formation. Nine of the 11 patients died without the diagnosis of aspergillosis having been entertained. Invasive pulmonary aspergillosis does occur in the nonimmunosuppressed host and should be considered when an etiologic agent is not readily identified in a patient with rapidly progressive diffuse necrotizing pneumonitis.

Biphasic in vivo immune function after low- versus high-dose alcohol consumption.

A series of experiments was performed to assess the alterations in immune status in vivo that are associated with differences in the amount and duration of ethanol intake. Using a nonspecific delayed cutaneous hypersensitivity-like response to the intradermal injection of phytohemagglutinin, the area of induration (skin test response) was significantly enhanced (p = 0.008) after low-dose ethanol (0.5 g/kg) administered daily by gastric gavage for 5 days. High-dose ethanol (6.0 g/kg) significantly diminished this response (p = 0.03). Using an experimental model of Mycobacterium bovis hepatitis, the host immune response was also altered in a biphasic manner after chronic, 28-day ethanol consumption. With this model 0.43 +/- 0.03 g/kg/day (mean +/- SEM) of ethanol (low dose) was associated with a 40% improvement in the removal of the organisms from liver tissue (p = 0.002). High dose (12.1 +/- 0.5 g/kg/day) impaired removal, resulting in a 55% increase in the number of viable organisms (p = 0.001). The levels of three cytokines, MIF, TNF-alpha, and IL-2, known to be involved in the modulation of the host response to mycobacterial infections, were measured in sera after the infection. The serum levels of these cytokines in response to infection did not correlate with this biphasic response to different alcohol dose levels.

Host response to mycobacterial infection in the alcoholic rat: male and female dimorphism.

Increased susceptibility to tuberculosis occurs in the alcoholic. One explanation for the altered susceptibility is a change in T-lymphocyte modulation. To evaluate this, 24 male and 24 female Sprague-Dawley rats were treated with either a Lieber-type liquid ethanol diet (LED) or an isocaloric control (LCD). After 2 weeks, half the subjects were infected with BCG (10(8) colony-forming units) and sacrificed after 42 days. Splenic helper (CD4) and suppressor/cytoxic (CD8) cells were quantitated by flow cytometry. By three-way analysis of variance, splenic cellularity was significantly increased by infection (p < 0.0001) but suppressed by LED (p = 0.0002). There was a marginal sexual difference (p = 0.065) with females exhibiting a 35% lower response while on alcohol. Examining lymphocyte subsets, the most significant changes were observed after infection (BCG) and alcohol treatment (LED). CD4 levels were diminished by LED (p = 0.0002) but markedly increased by infection (p < 0.0001), producing a highly significant interaction that affected both absolute number (p < 0.0001) and relative percent present (p = 0.0078). CD8 was influenced only by infection (p < 0.0001). This resulted in a infection-related increase in the CD4/CD8 ratio which was lower with LED (p = 0.0032). Splenic T-lymphocytes, predominately CD4, are involved in the host response to BCG hepatitis and are adversely influenced by LED, which may contribute to increased susceptibility.

Cytokine response to BCG infection in alcohol-fed mice.

Alcoholics have increased susceptibility to infections including tuberculosis. Chronic alcohol treatment impairs host response to bovine mycobacterium infection from BCG. This study assesses the role of four cytokines (TNFalpha, IFNgamma, IL-4, and IL-10) in this impaired response. Twenty male C57BL/6 mice were pair-fed on the Lieber DiCarli control (LCD) or ethanol (LED) diets for 28 days. The LED treated subjects ate ad lib and consumed a mean of 13 g/kg/d of ethanol. After 14 days, based on body weight, subjects were randomly divided into four treatment groups of five each. Ten infected with 2x10(6) colony-forming units (CFU) of BCG by tail-vein. On day 28, the mice were sacrificed. Liver was cultured to determine the mycobacteria CFU/g tissue. Spleens were assayed for the levels of TNFalpha, IFNgamma, IL-4, and IL-10 mRNA relative to mRNA levels for a housekeeping gene using a quantitative reverse transcriptase PCR. Without BCG infection, only the mRNA for IFNgamma was increased by LED treatment, 51% (p = 0.0001). BCG infection significantly increased TNFalpha, IFNgamma, and IL-10 mRNA (p<0.0001). IL-4 mRNA decreased (p = 0.0006). Chronic LED plus BCG infection further increased TNFalpha (p = 0.002) and IFN-gamma (p = 0.04); IL-10 was unchanged, whereas IL-4 was marginally further decreased (p = 0.06). CFU/liver increased with LED (mean +/- SD, 72+/-33x10(5) vs. 39+/-17x10(5); p = 0.004). A significant direct correlation was observed between CFU and TNFalpha, r = 0.70, p = 0.03. In conclusion, BCG infection increases TNFalpha, IFNgamma, & IL-10 and decreases IL-4. CFU numbers correlate with mRNA for TNFalpha, and LED inhibits host containment of BCG infection as measured by liver CFU. This study could not identify cytokine alterations in either Th1- or Th2-type immune responses that might contribute to the impaired host response to the BCG infection.

A four-year review of patients with hepatitis C antibody in Department of Veterans Affairs facilities.

Hepatitis C virus [HCV] has recently been recognized as an emerging pathogen of surprising proportions. The clinical liver illness associated with HCV infection can be minimal or none, but in a notable number of persons it can ultimately cause debilitating chronic liver disease, fibrosis, cirrhosis, and hepatic failure, and it is likely related to an increased incidence of hepatocellular carcinoma. From 1991 to 1994, an annual electronic census was sent to 168 Veterans Health Administration facilities requesting serologic data on HCV in patients seen in Department of Veterans Affairs facilities. Response rate to the mandatory survey was 100%. In 1991, 6,612 individual patients were reported as positive for HCV antibody in the Department of Veterans Affairs system. This increased yearly from 1992 to 1994 with 8,365, 14,097, and finally 18,854 persons, respectively. This represents an increase of more than 285% during the 4-year period. Increases in HCV antibody for the same period were seen in all major regions of the United States and in the specified large metropolitan areas. In the New York area and in coastal California, this trend of new case identification may have plateaued during 1993 and 1994. Overall, total patients seen nationally in the Veterans Health Administration increased by only 4.87% during the same period, 1991 to 1994. Thus, the increase in persons positive for HCV antibody is not based on work load alone. The impact of HCV disease on patient well-being and health care costs cannot be overestimated.

A six-year epidemiologic review of pneumonia in Department of Veterans Affairs facilities.

OBJECTIVE: Pneumonia and acute lower respiratory infections are a major problem in the United States and worldwide. As one of the largest health care organizations in the United States, the Department of Veterans Affairs is an ideal location for an epidemiologic review of pneumonia over an extended period of time. METHODS: Data for this study were retrieved from the Department of Veterans Affairs Austin Automation Center, the central repository for patient data in the Veterans Health Administration (VHA). In addition, specific data regarding penicillin-resistant Streptococcus pneumoniae in VHA facilities were obtained from an annual electronic nationwide census. RESULTS: The case rate of pneumonias as a discharge diagnosis increased during the 6-year period. For the diagnosis group of bronchopneumonia and pneumonia with organism unspecified, the largest subset examined, total numbers and rates for this specific diagnosis increased during the study period. When fiscal year (FY)91 and FY96 were compared, rates increased for three diagnoses: overall pneumonia, pneumonia in infectious diseases classified elsewhere, and pneumococcal pneumonia. Decreases in rates occurred between FY91 and FY96 for pneumonia caused by other specified organisms and other bacterial pneumonia. The total number of discharges from VHA facilities decreased during the 6-year period. CONCLUSIONS: The numbers of episodes of bronchopneumonia and pneumonia with organism unspecified, the largest pneumonia subset, increased during the 6-year period to greater than 27,000 cases. As the number of total discharges from the VHA decreased, the combination of increasing actual numbers and decreasing discharges yielded increased rates for overall pneumonia and certain subsets. These data should be useful in developing aggressive preventive strategies.

Nosocomial and nursing home-acquired pneumonia. Recent therapeutic advances.

In recent years, new broad-spectrum antibiotics have become available for the treatment of complex pneumonia. Used with care, these agents may allow effective monotherapy of difficult-to-treat pulmonary infections, with the added benefit of decreased toxicity in comparison with the more traditional multiple-drug combinations. The newer antibiotics are relatively expensive, but cost of their use can be justified by their reduced toxicity (in comparison with some antibiotic combinations) and by the avoidance of additional laboratory fees for routine drug monitoring. It is hoped that the major benefits that can accrue with proper use of the newer agents will not be outweighed by problems resulting from their indiscriminate use, such as increased bacterial resistance and exorbitant healthcare costs.

Amphotericin B and 5-fluorocytosine: in vitro effects on lymphocyte function.

The effects of amphotericin B, 5-fluorocytosine, and the combination of both drugs on lymphocyte function in vitro were investigated. Amphotericin B, alone or in combination with 5-fluorocytosine, significantly suppressed both spontaneous lymphocyte transformation and the response of lymphocytes to stimulation with streptokinase-streptodornase. 5-Fluorocytosine had no effect on spontaneous or antigen-induced transformation. Lymphocyte responses to the mitogens phytohemagglutinin and concanavalin A were not changed by exposure to amphotericin B, 5-fluorocytosine, or the combination of both drugs. T-lymphocyte receptors for sheep erythrocytes and B-lymphocyte surface immunoglobulin and receptors for complement were not changed by treatment with amphotericin B or 5-fluorocytosine.

Amphotericin B and 5-fluorocytosine: effects on cell-mediated immunity.

Although single-dose amphotericin B therapy appears to be immunostimulatory in mice, no data are available regarding the effects of chronic anti-fungal drug therapy on the immune system. We studied the effects on the guinea-pig cellular immune system of 4 weeks of treatment with amphotericin B, 5-fluorocytosine, or the combination of both drugs. The in vitro lymphocyte response to phytohaemagglutinin and the specific antigen, picryl human serum albumin (picHSA), were not affected by anti-fungal drug treatment. At 1.5 weeks of therapy with amphotericin B, skin test reactivity to picHSA was significantly reduced but returned toward normal by the end of 3.5 weeks of drug therapy. Macrophage migration inhibitory factor production by guinea-pig peripheral blood lymphocytes was significantly reduced after 4 weeks of amphotericin B therapy. No immunostimulatory properties could be ascribed to amphotericin B. 5-fluorocytosine had no effect on cellular immunity.

Determination of serum 5-fluorocytosine concentrations in the presence of ketoconazole.

Because in-vitro antifungal synergism has been shown between the imidazoles and 5-fluorocytosine, we have evaluated the accuracy of a standard disc diffusion assay for serum 5-fluorocytosine levels in the presence of ketoconazole. In the usual clinical concentrations, ketoconazole does not interfere with the determination of serum 5-fluorocytosine levels by this standard test.

Polymicrobial bacteremia.

Of 26,961 blood cultures taken during an 18-month period at the Cincinnati General Hospital, 1,715 (6%) were positive. Ninety-four patients had blood cultures containing more than one organism. Although aerobic and anaerobic streptococci were the most frequently isolated bacteria, a variety of microorganisms, including Staphylococcus aureus and the Klebsiella-Enterobacter-Serratia group, was isolated in different combinations depending on the underlying disease. Neurological illness, malignant neoplasms, burns, and decubitus ulcers were among the most common underlying conditions found. The overall mortality was 54%, but only 58% of these deaths were specifically related to an episode of polymicrobial bacteremia. Patient survival was significantly related to appropriate antimicrobial therapy.

Alteration of in vitro human lymphocyte function by ethanol, acetaldehyde and acetate.

Infection is a major cause of morbidity and mortality in chronic alcoholics and may be attributable to altered lymphocyte function. To evaluate this possibility, the effects of physiologic concentrations of ethanol (ETH) and its metabolites, acetaldehyde (ACH) and acetate (ACT), were studied using in vitro mononuclear cell cultures prepared from normal human donors. ETH depressed DNA synthesis induced by both phytohemagglutinin-M(PHA) and Concanavalin A (Con A). ACH significantly impaired Con A and PHA stimulated lymphocyte DNA synthesis. Con A and PHA induced blastogenesis was also significantly reduced by the in vitro addition of ACT. Spontaneous lymphocyte transformation in these three-day cultures was not affected by ethanol but was decreased by the addition of high dose acetate and acetaldehyde. Lymphocyte response to candida and trichophyton antigens was significantly depressed by ETH and its metabolites. Monocyte depletion by adherence had no effect on these results. Treatment of lymphocytes with ETH, ACH or ACT did not change T cell binding of sheep erythrocytes or B cell expression of surface immunoglobulin or receptor sites for complement. It is concluded that both ethanol and its metabolites in physiologic concentrations significantly inhibited lymphocyte function without altering surface markers.