Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive serologic result for Lyme disease. A cost-effectiveness analysis.

PURPOSE: To examine the cost-effectiveness of empirical, parenteral antibiotic treatment of patients with chronic fatigue and myalgia and a positive serologic result for Lyme disease who lack classic manifestations. DATA SOURCES: Peer-reviewed journals, opinion of experts in the field, and published epidemiologic reports. STUDY SELECTION: Consensus by authors on articles that indicated methods for patient selection; on criteria used for diagnosis; on immunologic methods used for classifying patients; on the dose and duration of therapy; and on criteria by which responses to therapy were ascertained. DATA EXTRACTION: In a cost-effectiveness model, the costs and benefits of empirical parenteral therapy for patients seropositive for Lyme disease were compared with a strategy in which only patients having classical symptoms of Lyme disease were treated. DATA SYNTHESIS: In areas endemic for Lyme disease, the incidence of false-positive serologic results in patients with nonspecific myalgia or fatigue exceeds by four to one the incidence of true-positive results in patients with nonclassical infections. Treatment of the former group of patients costs $86,221 for each true-positive patient treated. The empirical strategy causes 29 cases of drug toxicity for every case in the more conservative strategy. If patients were willing to pay $3485 to eliminate anxiety about not treating possible true Lyme disease, the empirical strategy would break even. CONCLUSION: For most patients with a positive Lyme antibody titer whose only symptoms are nonspecific myalgia or fatigue the risks and costs of empirical parenteral antibiotic therapy exceed the benefits. Only when the value of patient anxiety about leaving a positive test untreated exceeds the cost of such therapy is the empirical treatment cost-effective.

Is it Lyme disease? How to interpret results of laboratory testing.

Although laboratory testing is likely to have a greater role in diagnosis and monitoring of treatment of Lyme disease in the future, at present physicians must rely on a combination of history taking, clinical manifestations, and laboratory results. Unwarranted antibiotic therapy is to be avoided. Asymptomatic persons with positive serologic results who live in an endemic area present a challenge, and borderline serologic results in patients with manifestations of late Lyme disease are also troubling. All relevant clinical information must be considered before treatment is undertaken, until more specific and sensitive tests are available.

Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease.

OBJECTIVE: To compare lymphocyte proliferative responses to Borrelia burgdorferi in healthy controls and patients with Lyme disease. PATIENTS: Twelve patients fulfilling case-definition criteria for Lyme disease. Twelve healthy volunteers and two newborns served as controls. MEASUREMENTS: Antibodies to B. burgdorferi were measured by enzyme-linked immunosorbent assay (ELISA). Proliferation of peripheral blood lymphocytes cultured for 5 days with B. burgdorferi, recall antigens, or pokeweed mitogen was measured by radioactive thymidine uptake. RESULTS: Lymphocytes from 11 patients with Lyme disease, 8 healthy seronegative controls, and two newborns showed elevated responses when stimulated with B. burgdorferi. When a patient and a control were studied on the same day, the patient's lymphocyte response to B. burgdorferi exceeded the control's in only 5 of 12 cases. Lymphocytes from both patients and controls responded to B. burgdorferi isolates from three different sources. CONCLUSIONS: Heightened lymphocyte responses to B. burgdorferi are found in patients with Lyme disease but elevated responses also frequently occur in healthy controls. At present, the interpretation of a positive lymphocyte response to B. burgdorferi would be difficult in ambiguous clinical situations.

Suboptimal levels of hydrogen peroxide scavengers in synovial fluid: in vitro augmentation with slow acting antirheumatic drugs.

Phagocyte released reactive oxygen species are inflammatory mediators contributing to articular damage and potentially modulating local immune responses. We studied the protection afforded by synovial fluid (SF) against an important reactive oxygen species intermediate, hydrogen peroxide, quantitating SF-H2O2 scavenger levels and testing their functional capacity. Mean H2O2 scavenger levels in noninflammatory SF were low -3.9 mumol H2O2/ml-and similar to those found in plasma. Higher levels were found in inflammatory SF (24.6 mumol H2O2/ml), but still far below those found in whole blood (1,145.2 mumol H2O2/ml). SF with higher scavenger levels protected lymphocytes from H2O2 mediated damage and reversed lymphocyte suppression mediated by activated polymorphonuclear leukocytes. SF-H2O2 scavengers could be augmented by addition of certain blood cell subtypes, known enzymatic and chemical scavengers and also by several slow acting antirheumatic drugs. Our results indicate that the adaptive response of inflamed SF to reactive oxygen species is suboptimal. However it also appears that SF antioxidant levels could be augmented by certain slow acting antirheumatic drugs if sufficient tissue levels were obtained.

Inhibition of human T lymphocyte E rosette formation by neutrophils and hydrogen peroxide. Differential sensitivity between helper and suppressor T lymphocytes.

Co-incubation of human mononuclear cells with small numbers of autologous polymorphonuclear leukocytes resulted in a ratio-dependent inhibition of T lymphocyte rosette formation with sheep erythrocytes (SRBC). Inhibition by polymorphonuclear leukocytes was reversed with catalase, implicating H2O2 or associated products as the suppressive agent(s). Exposing T lymphocytes directly to micromolar concentrations of H2O2 also inhibited subsequent rosette formation. Inhibition was dose-dependent between 40 and 320 microM H2O2 and was not due to cytotoxicity at those H2O2 concentrations. Kinetic studies demonstrated that after exposing T lymphocytes to H2O2 a proportion of cells appeared to be relatively resistant in that they retained their ability to form E rosettes. T cell phenotype analysis of these cells showed that, in contrast to untreated T cells, H2O2-treated T rosette-forming cells were almost exclusively of the helper/inducer phenotype. Analysis with the monoclonal antibody 4B4 revealed that H2O2-resistant T rosette-forming cells contained significantly fewer 4B4-positive cells than predicted for the T helper population, indicating that H2O2-resistant T cells might be a subset of helper/inducer T lymphocytes. The interaction between H2O2 and T cells was rapid but did not lead to loss of Leu-5b binding sites. Preliminary functional analysis indicates that interleukin 2 production and phytohemagglutinin-induced proliferation by the relatively H2O2-resistant T cells is similar to untreated T cells. In contrast, H2O2-treated T cells which lost their ability to form E rosettes produced undetectable levels of interleukin 2 and proliferated poorly in response to phytohemagglutinin. Finally, mononuclear cells pretreated with H2O2 and subsequently stimulated with mitogens demonstrated a preferential expansion of the T helper population with concomitant loss of T suppressors. Our results show that, although neutrophil-released H2O2 inhibits effective interactions between SRBC and T lymphocyte sheep erythrocyte receptors, there appears to be a population of T helper cells which is relatively resistant to H2O2 both in terms of SRBC rosette formation and response to mitogens. These data suggest that at sites of inflammation phagocyte-released H2O2 could exert immunoregulatory effects on T cells by altering T cell subset survival and allowing the function of a particular lymphocyte population to predominate.

Suppression of human lymphocyte proliferation by activated neutrophils or H2O2: surviving cells have an altered T helper/T suppressor ratio and an increased resistance to secondary oxidant exposure.

Either activated neutrophils (PMNs) or nanomole amounts of reagent hydrogen peroxide (H2O2) were found to cause catalase-reversible suppression of concanavalin A (Con A)-stimulated human lymphocyte proliferation. Suppression required PMN activation and occurred with PMN/lymphocyte ratios found in peripheral blood. Inhibition by reagent H2O2 occurred with 10-40 nmol H2O2/1 X 10(6) lymphocytes, a noncytolethal amount which is produced readily by PMA-activated PMNs. Lymphoblasts recovered from suppressed cultures were two- to fourfold less sensitive than control lymphoblasts to a second exposure to H2O2. These relatively H2O2-resistant lymphoblasts also scavenge H2O2 at higher rates than do control lymphoblasts. Progeny lymphocytes from suppressed cultures contain an unusually high percentage of T helper cells with a concomitant decrease in T suppressors. These studies demonstrate a potential immunoregulatory role for phagocyte-released oxidants, especially H2O2, and suggest a possible additional mechanism to explain the excess of T helpers observed in situations of chronic inflammation.

Anti-beta 2-microglobulin antibodies in systemic lupus erythematosus and ankylosing spondylitis: effects on in vitro lymphocyte function.

Antibodies to beta 2-microglobulin (anti-beta 2-mu) were isolated from sera of 6 patients with systemic lupus erythematosus (SLE) and 6 patients with ankylosing spondylitis (AS) by affinity chromatography on beta 2-mu-Sepharose. Specificity of the purified anti-beta 2-mu antibodies was demonstrated by immunofluorescent reactivity with cell surface beta 2-mu and by reactivity with purified beta 2-mu in ELISA. Anti-beta 2-mu from both SLE and AS patients inhibited Concanavalin A and phyto hemagglutinin induced proliferation of normal human peripheral blood lymphocytes (PBL) in a concentration dependent manner. High concentrations of anti-beta 2-mu inhibited pokeweed mitogen (PWM) induced PBL proliferation whereas lower concentrations enhanced the PWM response. Anti-beta 2-mu also inhibited E-rosette formation. The inhibition and enhancement of mitogen induced PBL proliferation and the inhibition of E-rosette formation were reversed when the antibodies were preincubated with purified beta 2-mu.

Suppression of human lymphocyte responses in chronic renal failure mediated by adherent cells: analysis in serum-free media.

Concanavalin A (Con A)-induced proliferative responses by mononuclear leukocytes (MNCs) from patients with chronic renal failure (CRF) who were undergoing maintenance hemodialysis were studied with serum-free media to analyze leukocyte function independent of either uremic or normal serum factors. When we increased the number of cultured MNCs by 2.5- to fivefold over that normally used in microcultures and reduced the mitogen concentration, Con A induced proliferative responses 10- to 1000-fold higher than those in unstimulated cultures. In 12 of 15 patients with CRF observed, Con A-induced MNC responses were significantly depressed as compared with those in age- and sex-matched controls. Responses in 10 of these 12 patients with CRF improved significantly immediately after dialysis, but the improvement was only temporary. With MNCs from patients with CRF before dialysis, removal of adherent cells significantly improved their responses to Con A. Similar increases with adherent cell depletion were not found either in cultures of control MNCs or in patient MNCs after dialysis. Indomethacin, a cyclooxygenase inhibitor, added to unseparated MNCs from patients before dialysis, significantly increased responses in 13 of 15 patients. This effect of indomethacin was found less frequently in MNC cultures from normal persons or from patients with CRF after dialysis. Nonadherent lymphocytes from patients with CRF were not abnormally sensitive to inhibition by exogenously added prostaglandin E2. We conclude that MNCs from most patients with CRF have depressed reactivity when cultured without serum and that responses improve temporarily after dialysis. Adherent cells are largely responsible for inhibiting lymphocyte responses, and monocyte-released cyclooxygenase products appear to mediate much of this suppression.

In vitro production and scavenging of hydrogen peroxide by D-penicillamine. Relationship to copper availability.

The capacity of D-penicillamine (DP) to produce or scavenge hydrogen peroxide was investigated. DP added to copper produced H2O2. Greater production was observed with copper sulfate than with copper bound to ceruloplasmin. In contrast, DP in the absence of copper scavenged H2O2, as measured in a direct assay. Furthermore, DP or D-cysteine alone reversed H2O2-mediated inhibition of concanavalin A-stimulated mononuclear cell proliferation. These opposing immunomodulating properties of DP may be relevant to its toxic or therapeutic actions in rheumatoid arthritis.

Suppression of human lymphocyte mitogenesis mediated by phagocyte-released reactive oxygen species: comparative activities in normals and in chronic granulomatous disease.

Human blood monocytes and neutrophils stimulated in vitro with phorbol myristate acetate, N-formyl-L-methionyl-L-leucyl-L-phenylalanine, activated zymosan, or heat aggregated gamma-globulin were found to suppress lymphocyte mitogenic responses. In activated phagocyte-lymphocyte cocultures, both blast transformation and [3H]-thymidine incorporation were reduced while numbers of dead cells were increased, thus suggesting a cytolethal suppressive mechanism. Suppression was prevented by catalase but not by other oxygen radical scavengers nor by cyclooxygenase inhibitors, thus implicating H2O2 as the suppressive mediator. Activated monocytes and neutrophils but not lymphocytes released measurable quantities of H2O2 into cell supernatants. However, transfer of an inhibitory effect with these supernatants was not routinely achieved. Finally, as opposed to normals, lymphocyte blastogenesis in chronic granulomatous disease patients was not inhibited by their activated phagocytes. However, catalase -reversible suppression could be restored in cocultures of normal phagocytes and patient lymphocytes. In conclusion, these studies demonstrate a potentially important mechanism whereby activated phagocytes may alter lymphocyte reactivity.

Specificity of allogeneic cell recognition by human lymphocytes in vitro.

Human lymphocytes proliferate in vitro in response to foreign histocompatibility antigens that are present on allogeneic lymphocytes. Within a population of immunocompetent lymphocytes there are specific subpopulations that respond to allogeneic cells from different individuals. A means of selectively eliminating such subpopulations is suggested.

Specificity of antigen recognition by human lymphocytes in vitro.

Delayed hypersensitivity reactions in vivo are exquisitely specific, in terms of both a lack of response after induction of tolerance and a response after sensitization. These studies in vitro demonstrate that this specificity, at least at the level of antigen recognition, is probably derived from different populations of cells, each responding to different antigens.