In vitro selection of miltefosine resistance in promastigotes of Leishmania donovani from Nepal: genomic and metabolomic characterization.

In this study, we followed the genomic, lipidomic and metabolomic changes associated with the selection of miltefosine (MIL) resistance in two clinically derived Leishmania donovani strains with different inherent resistance to antimonial drugs (antimony sensitive strain Sb-S; and antimony resistant Sb-R). MIL-R was easily induced in both strains using the promastigote-stage, but a significant increase in MIL-R in the intracellular amastigote compared to the corresponding wild-type did not occur until promastigotes had adapted to 12.2 µM MIL. A variety of common and strain-specific genetic changes were discovered in MIL-adapted parasites, including deletions at the LdMT transporter gene, single-base mutations and changes in somy. The most obvious lipid changes in MIL-R promastigotes occurred to phosphatidylcholines and lysophosphatidylcholines and results indicate that the Kennedy pathway is involved in MIL resistance. The inherent Sb resistance of the parasite had an impact on the changes that occurred in MIL-R parasites, with more genetic changes occurring in Sb-R compared with Sb-S parasites. Initial interpretation of the changes identified in this study does not support synergies with Sb-R in the mechanisms of MIL resistance, though this requires an enhanced understanding of the parasite's biochemical pathways and how they are genetically regulated to be verified fully.

Autoimmunity in chronic urticaria and urticarial vasculitis.

In contrast to acute urticaria, etiology cannot be identified in most cases of chronic urticaria. Recent evidence suggests that a subset of patients with chronic urticaria may have an autoimmune basis for their condition. The demonstration of antithyroid autoantibodies in some patients with chronic idiopathic urticaria (CIU) provides support for an association. However, the discovery of a positive skin test response to intradermal injection of autologous serum in as many as 60% of patients with CIU led to the identification of autoantibodies to IgE and the alpha-chain of the high-affinity IgE receptor, Fc epsilon RI alpha. Additional studies have demonstrated that some of these autoantibodies are capable of releasing histamine from donor basophils and mast cells. This article reviews the literature that addresses a possible autoimmune etiology in a subset of patients with CIU. Urticarial vasculitis is differentiated from chronic urticaria based on clinical features and biopsy findings of leukocytoclastic vasculitis. Most cases of urticarial vasculitis are secondary to an underlying systemic disease. The presence of autoantibodies has also been demonstrated in a subset of patients with primary urticarial vasculitis. This article briefly reviews some of this data.

Anaphylaxis: diagnosis and treatment.

Anaphylaxis is a clinical syndrome and is caused by many different agents. Acute therapy is epinephrine. Chronic therapy depends on the agent causing the anaphylaxis, but usually consists of avoidance of the agent only. Individuals who suffer from this problem should be issued epinephrine and wear or carry medical alert bracelets.

Hymenoptera hypersensitivity in an imported fire ant endemic area.

BACKGROUND: Imported fire ants are a common cause of insect venom hypersensitivity in the Southeastern United States. OBJECTIVE: The purpose of this study was to determine the most frequent insect cause for evaluation in a Hymenoptera hypersensitivity clinic in an area endemic for the imported fire ants. METHODS: This was a retrospective study reviewing all patients seen in a venom clinic at a large teaching hospital. RESULTS: Of the 703 patients evaluated, between 1985 and 1995, 515 (73%) had reactions consistent with systemic anaphylaxis for which a determination of specific IgE was appropriate. Of the 703 patients seen, 315 (45%) had a positive history and skin test positivity and were offered specific immunotherapy. This was 61% of those individuals skin tested. Of the total patients seen, imported fire ants were responsible for 42% of the visits to the clinic and accounted for 59% of the total immunotherapy that was begun in this endemic area. CONCLUSION: In areas endemic for the imported fire ants, the most frequent cause of Hymenoptera hypersensitivity is the imported fire ant.

Aeroallergen-specific IgE changes in individuals with rapid human immunodeficiency virus disease progression.

BACKGROUND: Progression of human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS) is associated with elevated total IgE; however, previous cross-sectional studies have differed in their assessment of concurrent changes in allergic disease prevalence. OBJECTIVE: Assessment of changes in aeroallergen-specific IgE during progression from early to late HIV disease. METHODS: Total IgE, aeroallergen-specific IgE (rye grass, ragweed, Alternaria, dust mite, and cat), IFN-gamma, IL-4, and soluble CD23 (sCD23) were measured in a longitudinal study of 20 subject who had progressed from early-HIV infection (mean CD4 lymphocyte count of 650/mm3) to AIDS (mean CD4 lymphocyte count of 40/mm3) over an average of 4 years. RESULTS: Prevalence of positive aeroallergen specific-IgE assays in early HIV disease (T1 subjects with 13 positives) decreased with progression to late disease (five subjects with nine positive, P = .057), while total IgE increased from a median of 69 to 116 IU/mL. IFN-gamma and IL-4 were unchanged, while sCD23 decreased from a median of 72 to 9 U/mL (P = .0005) with disease progression in the full cohort. In contrast to other subjects, the subgroup of individuals with total IgE > 150 IU/mL in both early and late HIV disease demonstrated an increased frequency of aeroallergen-specific IgE. CONCLUSIONS: The elevation of total IgE associated with rapid HIV-1 disease progression was unexplained by concurrent changes in aeroallergen-specific IgE, IL-4, IFN-gamma, or sCD23. Overall, aeroallergen-specific IgE expression was less prevalent with HIV-1 progression, except in those individuals with elevated total IgE both before and after progression to AIDS.

Practice parameters for the diagnosis and management of immunodeficiency. The Clinical and Laboratory Immunology Committee of the American Academy of Allergy, Asthma, and Immunology (CLIC-AAAAI)

In this brief review, only the most useful immunologic tests available for defining host defects that lead to susceptibility to infection have been emphasized. It should be pointed out that those evaluations and tests ordered by the physician will rule out the vast majority of the currently recognized defects. Finally, it is important that any patients identified as abnormal by these screening tests be characterized as fully as possible in centers specializing in these diseases before therapy is initiated, since what may appear to be a simple diagnosis on the surface may be an indicator of more complex underlying problems.

In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.

The natural history of exposure to the imported fire ant (Solenopsis invicta).

BACKGROUND: Imported fire ants (IFA) are a common cause of insect venom hypersensitivity in the southeastern United States. The purpose of this study was to determine the sting attack rate and development of specific IgE in an unsensitized population. METHODS: Study participants consisted of 137 medical students with limited exposure to IFA-endemic areas who were temporarily training in San Antonio, Tex. Subjects were surveyed for prior IFA exposure with a questionnaire, and IFA-specific IgE was evaluated with RAST and intradermal skin testing. Evaluations were performed on arrival and reported at departure from the endemic area 3 weeks later. RESULTS: One hundred seven subjects completed the study. Field stings were reported in 55 subjects, resulting in a sting attack rate of 51%. In these 55 subjects 53 (96%) reported a pustule or a small local reaction at the sting site, one (2%) reported an isolated large local reaction, and none reported a systemic reaction. At the 3-week follow-up skin test and RAST conversions occurred in seven subjects (13%) and in one subject (1.8%), respectively. CONCLUSIONS: Even brief exposures to IFA-endemic areas result in significant sting rates and concurrent rapid development of IFA-specific IgE in 16% of stung subjects.

Multivariate models for predicting progression to AIDS and survival in human immunodeficiency virus-infected persons.

Nine hundred thirty persons enrolled in the US Air Force Human Immunodeficiency Virus (HIV) Natural History Study were evaluated with a standard battery of 30 potential surrogate markers of disease progression. A risk score for predicting progression to AIDS was then calculated for each patient in the cohort by using the four highest-ranking variables from multivariate analysis: percentage of CD4 CD29 cells, anergy status, age, and hemoglobin. For predicting survival, beta 2-microglobulin replaced age in the Cox model. Stratification according to the risk score demonstrated that rates of progression to AIDS and survival were significantly different between risk groups (P < .0001). The novel combination of these markers results in extremely accurate risk scores, which may serve as the basis for the development of true surrogate markers of disease progression.

Allergy to beta-lactams: a survey of current practices.

Many issues related to the diagnosis and management of beta-lactam drug allergy still await definitive recommendations. To determine how practicing allergists deal with some of these dilemmas, a questionnaire was mailed to 3500 physician members and fellows of the American Academy of Allergy and Immunology. It was also sent to each of the allergy training program directors in the United States to determine what is currently taught to fellows in training. Benzylpenicilloyl-polylysine (Pre-Pen) and fresh penicillin G are used for skin testing by more than 86% of both respondent groups, whereas minor determinant mixtures are used by only 40%. Epicutaneous followed by intradermal injection was the skin test technique used by 86% of these allergists. More than 90% said they would skin test in cases of reaction history of urticaria, whereas only 1.5% would test in cases of family history of penicillin allergy. Practicing allergists and program directors differed slightly when queried about cephalosporin cross-reactivity. Program directors were more cautious in their use of cephalosporins with patients allergic to penicillin. Program directors were also more likely to repeat skin testing before future penicillin courses than were practicing allergists. Clearly, some individual approaches to the diagnosis and management of beta-lactam allergy are practiced. Development of practice guidelines by our professional organizations may be useful.

Imported fire ants: the ants from hell!

Imported fire ants may certainly be considered the ANTS FROM HELL! This review focuses on both the interesting entomology of fire ants and the important medical characteristics of fire ant stings. They sting and they kill; they destroy; they mate in mid-air; and we may not be able to stop them. However, although they inject extremely potent venom, individuals can prevent secondary infections by leaving the so-called pustules alone and not opening them. Individuals who suffer systemic reactions may receive adequate treatment with the whole body extract immunotherapy.

Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients.

OBJECTIVE: To evaluate the prognostic significance of cutaneous delayed-type hypersensitivity (DTH) skin testing in persons infected with HIV. DESIGN: Cohort study. SETTING: United States Air Force (USAF) Medical Center. PATIENTS: Consecutive sample of 889 HIV-infected USAF personnel or dependents undergoing their first staging evaluation from 1985 through August 1990 in the USAF HIV Natural History Study. MEASUREMENTS: All patients were evaluated with DTH skin testing including purified protein derivative and four control skin test antigens: mumps, candida, tetanus toxoid, and trichophyton. In addition, all patients underwent CD4+ T-cell surface marker determinations. The relation between DTH skin test response at first evaluation and progression to Walter Reed stage 6 (presence of an AIDS-defining opportunistic infection) was evaluated using Kaplan-Meier survival analysis. RESULTS: Patients with more than 400 CD4+ T cells/mm3 are more likely than those having fewer than 400 CD4+ T cells per mm3 to respond to at least one (94% compared with 67%, P < 0.001) or at least two (86% compared with 45%, P < 0.001) DTH skin tests. Mean CD4 counts are lower for anergic compared with nonanergic patients and for patients responding to a single control skin test compared with those responding to two or more skin tests (P < 0.05). The DTH skin test response at first evaluation was also found to predict progression to AIDS; the relative risk at 5 years of follow-up was 2.5 (95% CI, 1.2 to 5.2) for anergy compared with a single positive skin test and 3.0 (CI, 1.4 to 6.2) for a single compared with two or more skin test responses. The DTH skin test response at first evaluation was a predictor of progression (P < 0.001) when controlling for initial CD4 count and Walter Reed stage in a Cox proportional hazards regression analysis. CONCLUSIONS: The DTH skin test response, a functional measure of cellular immunity, is an independent predictor of progression to AIDS in persons with HIV.

Imported fire ant immunotherapy: effectiveness of whole body extracts.

The purpose of this study was to determine if whole body extract (WBE) immunotherapy for imported fire ant (IFA) hypersensitivity is effective. This evaluation was carried out by retrospectively interviewing 76 patients with a history of generalized allergic reactions to IFA stings and positive skin tests to IFA-WBE. The study groups consisted of 65 patients on immunotherapy and 11 similar patients who were not treated for various reasons. In addition, an IFA sting challenge was performed in 30 volunteers of the 65 patients on immunotherapy. The retrospective review showed that of the 65 patients on immunotherapy there had been 112 subsequent field-sting episodes in 47 patients. Only one sting episode in this group (2.1%) produced an anaphylactic reaction. Six of the 11 patients not on immunotherapy have had subsequent field re-sting episodes, and each has had a systemic reaction. Repeat skin testing on 31 of the 65 patients in the immunotherapy group showed persistent positive responses in five (16%), but each was at a lower dilution than initially. Responses of the other 26 of the 31 patients who had skin testing had become negative. The four untreated patients who were available for skin testing continued to have positive responses at comparable dilutions on skin testing. Sting challenges carried out on 30 volunteers from the 65 patients (all from the 31 who had repeat skin tests) on immunotherapy resulted in only local reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-DR4-associated nonresponsiveness to mountain-cedar allergen.

We did human lymphocyte antigen (HLA)-DR and DQ typing on 37 subjects with mountain-cedar (MC) pollinosis as defined by history and a positive skin test. Of these 37 subjects, 31 were subdivided into 18 subjects with a single positive skin test (SPST) and 13 subjects with multiple positive skin tests (MPSTs). We also typed 51 subjects without MC sensitivity or atopy as defined by history and negative skin tests to a battery of aeroallergens. We also typed 116 subjects in whom MC sensitivity had not been determined. Total IgE, Mc-specific immunoglobulin E (sIgE), and MC-sIgE binding bands by immunoblot were also determined on the subjects with SPSTs and MPSTs. No significant differences were found between the subjects with SPSTs and MPSTs for HLA type, total IgE, MC sIgE, or bands bound by MC sIgE by immunoblot. There was a strong negative relationship between HLA-DR4 and subjects with MC pollinosis; chi-square, 14.857; p = 0.0096; and odds ratio, 0.139. These findings suggest that there is no difference in genetic immunoregulation between subjects with SPSTs and MPSTs but that the presence of the DR4 gene product is associated with a decreased risk of an IgE response to MC and protection from MC pollenosis.