The impact of omalizumab on paid and unpaid work productivity among severe Japanese cedar pollinosis (JCP) patients.

AIMS: Japanese cedar pollinosis (JCP) is a form of seasonal allergic rhinitis that affects 38.8% of the Japanese population. Particularly severe and most severe symptoms among JCP patients can lead to impairments of paid work productivity and unpaid work activities. Indeed, the current standard of care (SoC) is not always able to relieve these symptoms. Omalizumab, a novel JCP treatment recently approved in Japan, provides an effective add-on therapy to the SoC. This study estimates the effect of omalizumab on paid and unpaid work activities (i.e. its social impact) in patients with severe and most severe JCP symptoms in Japan. METHODS: The impact of omalizumab was estimated through a one-year static cohort model using the Work Productivity and Activity Impairment Allergy Specific (WPAI-AS) questionnaire derived from a clinical trial on omalizumab enrolling patients with severe and most severe JCP symptoms, which had been conducted in Japan. This effect was quantified using Japanese official statistics on employment and time use. The human capital approach and the proxy good approach were employed to monetize paid and unpaid work activities, respectively. A sensitivity analysis was implemented to account for modeling structural uncertainties. RESULTS: Our results show that the use of omalizumab might reduce the paid and unpaid work productivity losses due to severe and most severe JCP by nearly one-third. In the severe symptom period of three weeks, 36.6 million hours of lost paid and unpaid work hours could be avoided, which sums up to a monetized productivity loss of 728.3 million USD. CONCLUSIONS: Omalizumab could provide substantial benefits in terms of paid and unpaid work activities in patients with severe and most severe JCP. Our results also highlight the importance of considering unpaid work in estimating productivity costs due to poor health.

N-acetylcysteine does not affect the lymphocyte proliferation and natural killer cell activity responses to exercise.

This study evaluated whether N-acetylcysteine (NAC) attenuates the reduced lymphocyte proliferation and natural killer (NK) cell activity responses to exercise in humans. Fourteen oarsmen were double-blind randomized to either NAC (6 g daily for 3 days) or placebo groups. During 6-min "all-out" ergometer rowing, the concentration of lymphocytes in the peripheral blood increased, with no significant difference between NAC and placebo as reflected in lymphocyte subsets: CD4(+), CD8(+), CD16(+), and CD19(+) cells. The phytohemagglutinin-stimulated lymphocyte proliferation decreased from 9,112 +/- 2,865 to 5,851 +/- 1,588 cpm (P < 0.05), but it was not affected by NAC. During exercise, the NK cell activity was elevated from 17 +/- 3 to 38 +/- 4% and it decreased to 7 +/- 1% below the resting value 2 h into recovery. Yet, when evaluated as lytic units per CD16(+) cell, the NK cell activity decreased during and after exercise without a significant effect of NAC. We conclude that NAC does not attenuate the reduction in lymphocyte proliferation and NK cell activity associated with intense exercise.

Immunological effects of a hyperinsulinaemic euglycaemic insulin clamp in healthy males.

The purpose of this study was to determine the in-vivo and in-vitro effects of insulin, at physiological and supraphysiological concentrations, on the human immune system. Ten healthy young men went through a sequential two-step hyperinsulinaemic euglycaemic clamp. Plasma insulin concentrations were increased from baseline (9.0 microU/ml) to 49.1 microU/ml after 1 h of insulin infusion (step I) and to 1281 microU/ml (step II) after 2 h of infusion. As control experiments infusions of isotonic saline were performed. The unstimulated natural killer (NK) cell activity among blood mononuclear cells (BMNC) increased in response to supraphysiological plasma insulin levels (baseline versus step II: 20.6 +/- 11.3 versus 27.8 +/- 14.4%). The percentages of the D16+ NK cells did not change, indicating an enhanced cytotoxic capability per individual NK cell. Insulin also slightly increased the activity of NK cells in vitro. A decline at step II in the concentrations of monocytes (0.29 +/- 0.09 versus 0.12 +/- 0.03 x 10(9)/L), lymphocytes (1.57 +/- 0.46 versus 1.22 +/- 0.25 x 10(9)/L), and CD16+(24.2 +/- 17.5 versus 16.7 +/- 11.2 x 10(7)/L), CD14+ (20.9 +/- 10.8 versus 8.6 +/- 3.9 x 10(7)/L), HLA-DR+ (37.2 +/- 22.1 versus 19.2 +/- 10.7 x 10(7)/L) and CD45RO+ (91.6 +/- 33.4 versus 61.7 +/- 6.4 x 10(7)/L) cells as well as in the percentages of CD14+ cells (11.2 +/- 4.7 versus 6.4 +/- 2.3%) and CD14+/HLA-DR+ monocytes (9.7 +/- 3.9 versus 4.8 +/- 2.8%) were observed. No changes were found at step I. Hyperinsulinaemia did not change the percentages of the CD3+, CD4+, CD8+, CD19+, CD56+, CD11a+, CD45RO+ and CD45RA+ cells, the numbers of circulating immunoglobulin (Ig)G-, IgA- and IgM- secreting cells, or the proliferative responses of BMNC to phytohaemagglutinin, purified derivative of tuberculin or interleukin (IL)-2. Hyperinsulinaemia did not change the in-vitro sensibility to insulin. In conclusion, supraphysiological insulin levels increased the activity of the individual NK cells, but decreased the numbers of NK cells, lymphocytes and activated monocytes. The findings are presumably of minor clinical relevance but may indicate an insulin-induced immune activation.

Somatostatin attenuates the hyperthermia induced increase in neutrophil concentration.

This study was designed to test the hypothesis that the immune changes seen during in vivo whole body hyperthermia are mediated by elevations in the plasma concentrations of either catecholamines, growth hormone or beta-endorphins. Eight healthy volunteers were immersed in a hot water bath (WI; water temperature 39.5 degrees C) for 2 h during which their rectal temperature rose to 39.5 degrees C. In a single blind, randomized, cross-over study the stress hormone effects were blocked one at a time by administration of propranolol, somatostatin or naloxone; the results were compared to those obtained during saline infusion (control). Blood samples were collected before, at the end of 2 h of WI (body temperature 39.5 degrees C), and 2 h later. Hormone blockade did not abolish the hyperthermia-induced recruitment of natural killer (NK) cells to the blood, and no influence was observed on the percentages or concentrations of any other subpopulations of blood mononuclear cells, except that the number of cluster designation (CD)3+ cells slightly increased after hyperthermia only in the propranolol experiment. Furthermore, the NK cell activity, both unstimulated and interferon-alpha or interleukin-2 stimulated, did not differ from the control situation. It is of interest, however, that somatostatin partly abolished the hyperthermia induced increase in the neutrophil number. Based on these data and previous results showing that growth hormone infusion increases the concentration of neutrophils in the blood, it is suggested that growth hormone is at least partly responsible for hyperthermia induced neutrocytosis.

Influence of minor increases in plasma catecholamines on natural killer cell activity.

This study was designed to test the hypothesis that the modulations of the human immune system in relation to in vivo whole body hyperthermia may be ascribed to elevations in the plasma epinephrine and norepinephrine concentrations. In a single-blind, controlled, cross-over study, 8 healthy volunteers were selectively infused norepinephrine and epinephrine, respectively, for 1 h, in order to obtain twofold increases in the plasma concentrations of these hormones, thereby mimicking the increases seen during in vivo whole body hyperthermia. Epinephrine infusion increased baseline, interleukin-2 and interferon-alpha stimulated natural killer cell activity, and the percentage and concentration of cluster designation (CD)16+ cells, whereas the neutrophil and lymphocyte count or the CD3+, CD4+, CD8+, CD19+ and CD14+ cell subtypes were not influenced. Norepinephrine infusion did not cause any changes in these variables. It is concluded that epinephrine, but not norepinephrine, may be responsible for the hyperthermia-induced effects on natural killer cells.

Effects of elevated plasma noradrenaline concentration on the immune system in humans.

This study was designed to test the hypothesis that elevated plasma noradrenaline concentrations contribute to the exercise-induced modulation of the activity and percentage of the natural killer (NK) cells, and the leucocyte concentration. In a single blind, controlled, cross-over study, eight healthy men had noradrenaline infused for 1 h and achieved plasma noradrenaline concentrations comparable (20-fold increment) to those previously observed in cycle ergometer exercise (75% of maximal oxygen uptake for 1 h). The noradrenaline infusion increased the unstimulated, the interleukin-2 and interferon-alpha stimulated NK cell activity, and the percentage of CD16+ cells. The natural lytic activity per CD16+ cell however, did not change. The concentration of neutrophils, lymphocytes and CD16+ cells increased during the infusion. The neutrophil concentration remained elevated 2 h after infusion, at which time the lymphocyte count was back to normal. These results are comparable with the effects in the exercise model, and it is suggested that the augmented plasma noradrenaline concentrations, seen during extreme exercise, may participate in the exercise-induced immune changes.

The response on glucoregulatory hormones of in vivo whole body hyperthermia.

This study was designed to examine the effects of in vivo hyperthermia on the circulating concentrations of a number of glucoregulatory hormones potentially involved in immunomodulation. Eight healthy male volunteers were immersed for 2 h in a hot water bath (water temperature 39.5 degrees C) (WI) during which period their rectal temperature rose to 39.5 degrees C. In a control study the subjects were immersed in thermoneutral water (water temperature 34.5 degrees C). Blood samples were collected before, at body temperature 38 degrees C (42.5 (30-52), median and range), minutes of hot WI, 39 degrees C (72.5 (58-97) minutes of hot WI), and 39.5 degrees C (at the end of 2 h of hot WI), as well as 1 and 2 h after cessation of 2 h of hot WI. In the control experiment blood samples were collected at identical time points. The growth hormone concentrations were elevated already at 38 degrees C to 24.2 (3.9-55.0) mU/l and peaked at 39 degrees C to 48.4 (20.8-81.5) mU/l compared to 0.3 (0.3-9.0) mU/l at baseline; at 39.5 degrees C the concentration declined to 31.6 (13.0-48.0) mU/l and further to 7.4 (0.8-17.3) mU/l 1 h after ending hot WI. The beta-endorphin levels were augmented at 39 degrees C and 39.5 degrees, to 8.0 (3.4-27.8) pmol/l and 8.1 (3.1-44.6) pmol/l, respectively, from 2.2 (0.7-5.6) pmol/l baseline. Glucagon levels raised from 23.0 (12.0-32.0) pmol/l to 32.0 (24.0-52.0) pmol/l at 39 degrees C, and to 38.5 (26.0-57.0) pmol/l at 39.0 degrees C. Insulin levels remained unchanged. Plasma glucose increased from 4.75 (4.2-7.6) mmol/l to 5.20 (4.6-5.6) mmol/l alone after 90 min of WI (temperature 39-39.5 degrees C). It is concluded that in vivo whole body WI hyperthermia increases the circulating levels of several essential glucoregulatory hormones.

Immune changes during whole body hot water immersion: the role of growth hormone.

NASA: Studies examined the role of growth hormone, catecholamines, and beta-endorphins in changes in natural killer cell activity, subtypes of blood mononuclear cells, and leukocyte concentration in response to hot water immersion in humans. The response of leukocytes and neutrophils to 2 hours of hot water immersion and simultaneous administration of propranolol, somatostatin, naloxone, or isotonic saline are reported.^ieng

Exercise-induced immunomodulation--possible roles of neuroendocrine and metabolic factors.

Acute muscular exercise induces an increased neutrophil count concomitant with recruitment of natural killer (NK), B and T cells to the blood as reflected by an elevation in the total lymphocyte count. Meanwhile, following intense exercise of long duration the lymphocyte count declines, non-MHC-restricted cytotoxicity is suppressed, but the neutrophil concentration increases. In relation to eccentric exercise involving muscle damage, the plasma concentrations of interleukin-1, interleukin-6 and the tumor necrosis factor are elevated. In this review we will propose a model based on the possible roles that stress hormones play a mediating the exercise- related immunological changes: adrenaline and to a lesser degree noradrenaline are responsible for the immediate effects of exercise on lymphocyte subpopulations and cytotoxic activities. The increase in catecholamines and growth hormone mediate the acute effects of exercise on neutrophils, whereas cortisol may be responsible for maintaining lymphopenia and neutrocytosis after exercise of long duration. Lastly, the role of beta-endorphin is less clear, but the cytokine response is closely related to muscle damage and stress hormones do not seem to be directly involved in the elevated cytokine level. Other possible mechanisms of exercise-induced immunomodulation may include the so-called glutamine hypothesis, which is based on the fact that skeletal muscle is an important source of glutamine production and that lymphocytes are dependent on glutamine for optimal growth. Furthermore, physiological changes during exercise, e.g. increased body temperature and decreased oxygen saturation may also in theory contribute to the exercise-induced immunological changes.

Lymphocyte, NK and LAK cell responses to maximal exercise.

To evaluate if exhaustion after maximal exercise suppresses the immune system; ten healthy male oarsmen (maximal oxygen uptake, 5.7 +/- 0.2 l.min-1; mean and SE) performed a six minute "all-out" bout on a rowing ergometer (394 +/- 12 watt). Rowing increased the blood leucocyte count as reflected in the concentrations of lymphocytes, monocytes, and neutrophils. Two hours after rowing the leucocyte and neutrophil numbers remained elevated, while the lymphocyte count decreased below the prevalue. The concentrations of cluster designation CD3+ (pan T), CD4+ (T subset), CD8+ (T subset), CD19+ (B cells), and CD16+ natural killer (NK) cells increased during rowing with the elevation in CD16+ cells being sevenfold. Only the concentration of CD3+ and CD8+ cells decreased below prevalues two hours after exercise. The lymphokine activated killer (LAK) cell activity of blood mononuclear cells (BMNC), and the NK cell activity of BMNC (%lysis per fixed number of BMNC), either unstimulated or stimulated with interleukin-2, interferon-alfa or indomethacin, also increased in response to rowing, and returned to the prevalues after two hours. In contrast, the BMNC proliferative responses did not change significantly. The evaluation of NK and LAK cell activities, and the proliferative responses of BMNC suggest that six minute maximal exercise does not suppress the immune response during recovery, even when a large muscle mass is involved.

Pentoxifylline therapy in HIV seropositive subjects with elevated TNF.

Tumor necrosis factor-alpha (TNF-alpha) is thought to induce cachexia in subjects infected with human immunodeficiency virus (HIV), and it has been suggested that HIV-seropositive patients would benefit from treatment with pentoxifylline, a known suppressor of TNF-alpha production. The purpose of the present study was to examine how pentoxifylline at a dose of 800 mg thrice daily would influence the cellular immune system in HIV-seropositive persons with elevated TNF-alpha. Six HIV-seropositive subjects with elevated amounts of TNF-alpha in plasma at least at two occasions were included in an open, controlled, randomized, cross-over study consisting of a 6 week treatment period and a 6 week control period. Blood samples were collected before and at the end of each period. Pentoxifylline treatment did not influence the concentration of plasma-TNF-alpha, subpopulations of blood mononuclear cells, the proliferative responses nor the natural killer (NK), and lymphokine activated killer (LAK) cell activities. Furthermore, pentoxifylline treatment did not influence the weight, temperature, well being, or tiredness of the subjects. However, the patients frequently reported gastrointestinal side effects. In vitro, however, pentoxifylline at suprapharmacological concentrations inhibited the blood mononuclear cell (BMNC) proliferative responses, NK, and LAK cell activities.

"Best-of-breed" vs. monolithic solutions. Roundtable discussion.

The debate is hotter now than it was when we alluded to it in our June issue's "round table." CIOs and IS directors still wonder about the strategic advantages of single-vendor solutions vs. the best-of-breed approach. In June we noted that this dynamic has driven system acquisitions for several years. Since then we have witnessed what amounts to a feeding frenzy. We asked a few experts to discuss their perceptions of the controversy. Their comments follow.

Cytokine production ex vivo: effect of raised body temperature.

This study was designed to examine the effects of hyperthermia in humans on the production of interleukin (IL)-1 alpha, IL-1 beta, tumour necrosis factor (TNF)beta and interferon (IFN)gamma, determined in supernatants from in vitro lipopolysaccharide or phytohemagglutinin stimulated blood mononuclear cells (BMNC), including the effect of indomethacin in the assays on these cytokines. Eight healthy volunteers were immersed into a hot water bath (water temperature 39.5 degrees C) for 2 h, during which their rectal temperature rose to 39.5 degrees C. On a later day they served as their own controls, being immersed into thermoneutral water (34.5 degrees C) for 2 h. Blood samples were collected before, at body temperatures of 38, 39 and 39.5 degrees C, and 2 h after water immersion and at corresponding time points in the control experiment. Hyperthermia did not influence the production of cytokines from stimulated BMNC. Indomethacin in the assays significantly enhanced the ex vivo production of TNF beta at hyperthermic and thermoneutral conditions; this indomethacin enhanced production of TNF beta declined from pre-value in the hyperthermia experiment compared to the control experiment. Furthermore, indomethacin augmented the production of IFN gamma from stimulated BMNC both in the hyperthermic and the control experiments; the indomethacin effect was, however, not different at the two conditions. It is suggested that hyperthermia alters the sensitivity of BMNC to prostaglandins.

Natural killer cell response to exercise in humans: effect of hypoxia and epidural anesthesia.

For the response of immunologically competent blood cells to exercise, the importance of afferent nerve impulses was evaluated. On separate days, seven males cycled in a recumbent position approximately 60% of maximal O2 uptake with and without sensory nerve blockade by lumbar epidural anesthesia. Blood samples were collected after 60 min of rest, 20 min of exercise, and 120 min postexercise. Subsequently, on each day, the subjects were exposed to 11.5% O2-88.5% N2 for 10 min. This was followed by 20 min of hypoxic exercise at the same work rate, and a final blood sample was obtained. The concentrations of lymphocytes expressing the cluster designation (CD) cell-surface antigens CD3, CD4, CD8, and CD14 became elevated during exercise, and these responses were enhanced by hypoxia (P < or = 0.01). The most pronounced changes were within the concentrations of CD16+ and CD56+ natural killer cells, which increased twofold during normoxic and fivefold during hypoxic exercise (P < or = 0.01). Sensory nerve blockade decreased the number of CD3+ and CD4+ cells and increased the percentage of CD16+ cells, independent of exercise and hypoxia (P < or = 0.05). Sensory nerve blockade caused minor enhancement in the increase of unstimulated natural killer cell activity during exercise (P = 0.07) and enhanced the interferon-alpha-stimulated activity at normoxia (P < or = 0.05), whereas no effect was detected at hypoxia. The results demonstrate that the responses of immunological competent cells to normoxic and hypoxic exercise are not abolished by blockade of nerve impulses from active muscle.

The immune system during exposure to extreme physiologic conditions.

It is not clear how the immune system is modulated in response to physical stress (e.g. trauma, surgery, burn and sepsis). In order to better understand the stress-induced immune changes, effects of isolated stressors are evaluated. Human experiments include hypoxia, head-up tilt, hyperthermina and exercise, which influence all lymphocyte subtypes and especially so the natural killer (NK) cells. In essence, the immune response is enhanced even by light physical stress, but suppressed after prolonged, intense stress.

Influence of elevated body temperature on circulating immunoglobulin-secreting cells.

This work was designed to investigate the effect of in vivo hyperthermia in man on circulating immunoglobulin-secreting cells. Eight healthy male volunteers were immersed into a hot waterbath (WI) (water temperature 39.5 degrees C) for 2 h, whereby their body temperature rose to 39.5 degrees C. On another occasion they served as their own controls, being immersed into thermoneutral water (water temperature 34.5 degrees C) for 2 h. Blood samples were drawn before immersion, at body temperatures of 38, 39 and 39.5 degrees C, as well as 2 h after WI when their body temperatures were normalized. In the control experiments, blood samples were drawn at identical time points. A significant increase in the number of IgM-secreting cells per fixed number of blood mononuclear cells (BMNC) occurred 2 h after WI, whereas the number of IgA-secreting cells per fixed number of BMNC did not change. When the possible redistribution of BMNC was taken into account, the concentrations of IgM- and IgA-secreting cells (per ml blood) increased non-significantly during WI.

Modulation of the counts and functions of neutrophils and monocytes under in vivo hyperthermia conditions.

The present work was designed to examine the effect of in vivo hyperthermia on the cell number and functions of polymorphonuclear leucocytes (PMN) and monocytes in human beings. Eight healthy volunteers were immersed into a waterbath (WI) (water temperature 39.5 degrees C) for 2 h, whereby their rectal temperature rose to 39.5 degrees C. On a later day they served as their own controls, being immersed into thermoneutral water (34.5 degrees C) for 2 h. Blood samples were collected before immersion, at body temperatures of 38, 39 and 39.5 degrees C as well as 2 h after water immersion. The neutrophil count was significantly increased at 39.5 degrees C, as well as 2 h after hot WI, compared with control. The monocyte count was significantly augmented at 38 and 39 degrees C and 2 h after hyperthermic load. The FMLP-induced chemiluminescence response, for a given number of PMN, was significantly reduced 2 h after hot WI. The total amount (per litre of blood) of superoxide production by PMN stimulated with opsonized zymosan (OZ) was significantly augmented at 39 and 39.5 degrees C and 2 h after WI. In vivo hyperthermia did not affect the function of monocytes, but when correlated to the changes in the concentrations of monocytes (response per litre blood) a significant increase in the phorbol myristate acetate (PMA)- and OZ-enhanced superoxide production occurred at 38 and 39 degrees C, as well as 2 h after termination of hot WI. Furthermore the OZ-enhanced monocyte chemiluminescence response per litre of blood was significantly enhanced 2 h after hot WI.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that the effect of bicycle exercise on blood mononuclear cell proliferative responses and subsets is mediated by epinephrine.

The present study was designed to test the hypothesis that the exercise-induced changes in blood mononuclear cell (BMNC) subsets, BMNC proliferative responses and lymphokine activated killer (LAK) cell activity are mediated by increased epinephrine concentrations. Healthy male volunteers 1) exercised on a bicycle ergometer (75% of VO2max, 1 h) and 2) on another day were given epinephrine as an intravenous infusion to obtain plasma epinephrine concentrations comparable with those seen during exercise. Blood samples were collected in the basal state, during the last minutes of exercise or epinephrine infusion and 2 h later. During both perturbations the %CD3+ and %CD4+ T cells declined and the %CD16+ NK cells increased. Two h afterwards the CD14+ monocytes increased, while no changes were observed in %CD8+ T cells or %CD20+ B cells. The phytohemagglutinin (PHA) response declined during both epinephrine infusion and exercise experiments. The changes in interleukin-2 (IL-2) effect on proliferation and cytotoxic activity (LAK cell activity) were more pronounced in exercise experiments than during epinephrine. Exercise and epinephrine caused increase in concentrations of lymphocytes and neutrophils, but the changes were more pronounced in exercise experiments. The results indicate that, in response to physical exercise, the rise in plasma epinephrine may contribute to the changes in cellular immunity.