Quality of life measurement in paediatric and adolescent populations with HIV: a review of the literature.

PURPOSE: To review the quality and utility of currently available self-report generic quality of life (QOL) and health-related quality of life (HRQOL) measures for use with children and adolescents with human immunodeficiency virus and/or acquired immunodeficiency syndrome (HIV/AIDS). METHODS: Literature searches were conducted to identify QOL and HRQOL measures developed for, adapted for, or otherwise used with paediatric and adolescent populations with HIV/AIDS. The quality of measures (i.e. item generation techniques, instrument properties including reliability, validity and responsiveness) were compared and critically evaluated. RESULTS: Nineteen QOL/HRQOL measures were identified. Item content was generated from the respondent (adult) population in only eight (42%) measures. Seventeen (90%) measures reported internal reliability in the accepted range between 0.70 and 0.90 and four (21%) reported reproducibility statistics in this range. Although validity was reported for 19 (100%) measures, only six (32%) showed evidence for three or more properties, with construct validity being the most commonly reported aspect. The authors of eight (42%) measures reported evidence for responsiveness. CONCLUSIONS: While almost all measures reviewed demonstrated adequate psychometric properties, only one-third demonstrated all aspects of validity, and less than half demonstrated responsiveness. None included paediatric or adolescent populations with HIV/AIDS in their development, neglecting to obtain input from target respondents in item generation to determine what health-related and daily functioning factors are of importance to them. Despite noted limitations, the AUQUEI or the SWED-QUAL appear the best currently available generic measure, and the MQOL-HIV the preferred disease-specific measure, at least for use with older adolescents/young adults.

A feverlike response inhibits expression of delayed-type hypersensitivity in rats.

To determine the effect of fever on cell-mediated immunity, the preoptic area of male rats was cooled after either a sensitizing or a challenge injection of keyhole-limpet hemocyanin, and the delayed-type hypersensitivity inflammatory response was measured. Cooling the preoptic area for 5 days, starting shortly after the sensitizing injection of antigen, did not speed up the development of the capacity to respond to a challenge injection of antigen nor did it influence the magnitude of the resulting inflammatory response. In sensitized animals, however, cooling the preoptic area for 24 h, starting shortly after the challenge injection of antigen, raised core temperature to an average of 40 degrees C and decreased the magnitude of the inflammatory response by 25%, whereas heating the preoptic area caused a fall in core temperature to an average of 35 degrees C and increased the response by about 25%. There was, in fact, a moderate negative correlation (r = 0.85) between core temperature and the size of the inflammation. Furthermore, the inhibitory effect of cooling the preoptic area could be blocked neither by adrenalectomy nor by diazepam (0.5 mg/kg body wt), a drug that suppresses most endocrine responses to stress. It is therefore suggested that the expression of delayed-type hypersensitivity is inhibited at elevated body temperatures and that fever may thus weaken the defenses of the host against infection.

Diazepam inhibits stimulating effect of cooling preoptic area on antibody production.

To clarify the mechanism of the stimulating effect of fever on the primary antibody response, rats were immunized with sheep erythrocytes, and a fever-like response was induced by cooling the preoptic area for five days. Diazepam, 0.5 mg/kg, given daily during the cooling time, did not affect the normal antibody response of the control animals nor did it prevent the rise in body temperature elicited by cooling the preoptic area but it did, nevertheless, strongly reduce the stimulating effect of this procedure on antibody production. A smaller reduction of this effect was also seen in adrenalectomized rats in which a physiological and stable plasma level of corticosterone was maintained. Because diazepam suppresses some sympathetic and endocrine responses to stress, these data suggest that the effect of cooling the preoptic area on the primary antibody response, and, by inference, that of fever, is to a large extent mediated by the adrenal and other stress response or responses to the cold stimulus. The results do not, however, exclude the possibility of an additional, direct effect of the elevated body temperature on immunocompetent cells.

Mechanism of action of physical antipyresis in the rat.

To study the mechanism of action of physical antipyresis, core temperature was measured in two groups of rats in which heat loss was increased by cold exposure and by cooling an inferior cava heat exchanger, respectively, both before and after infection with Salmonella enteritidis. Cold exposure did not influence core temperature. On the other hand, cooling the heat exchanger caused a fall in core temperature of approximately 0.7 degree C, to 37 degrees C in normothermia and to 38.5 degrees C 24 h after the infection. These lower core temperatures were then regulated against any further increase in heat loss until the thermoregulatory metabolic capacity of the animals was exhausted and a hypothermia developed. It is concluded that in infectious fever the threshold temperature of shivering increases as much as core temperature. Furthermore it is suggested that physical antipyresis, such as sponging with tepid water, induces a moderate but regulated fall in temperature to about the threshold of shivering and that its efficacy may increase with ambient temperature.

Long-term cold adaptation in the rat.

1. To determine whether long-term cold exposure induces insulative adaptation in the rat, two groups of eight adult animals each were exposed to 4 and 25 degrees C, respectively, for 18 months. 2. At any ambient temperature between -5 and 30 degrees C, the cold adapted animals had a higher rate of oxygen uptake, and higher unfurred skin temperatures than the controls. 3. At ambient temperatures below thermoneutrality, whole body thermal resistance increased continuously in both groups of animals. 4. It is concluded that long-term exposure does not induce insulative adaptation, and that thermal resistance is not maximal at the lower critical temperature.

The effect of a fever-like response on the secondary antibody response of the rat.

Since fever appears to modulate the primary humoral immune response, a fever-like response was induced in 18 rats by cooling their preoptic areas during the first five days after re-immunization with sheep erythrocytes. The titre of antibodies in these rats was the same as that in 17 control animals, indicating that the febrile response does not influence the magnitude of the secondary antibody response. It is suggested that only those fevers evolving in the early phase of a primary, natural infection may modulate the magnitude of the humoral immune response to the pathogen.

Autonomic thermoregulation after separation of the preoptic area from the hypothalamus in rats.

To clarify the role of the hypothalamic preoptic area in autonomic thermoregulation, the preoptic area (POA) of rats was disconnected from the rest of the brain-stem by bilateral microknife cuts which spared or included the medial forebrain bundle. The animals' metabolic responses to exogenous norepinephrine (0.5 mg/kg, im) were then measured at ambient temperatures of 25 degrees and 15 degrees C. Oxygen uptake and colonic and tail skin temperatures were also measured at ambient temperatures of 34 degrees, 25 degrees, and 15 degrees C. Finally, the febrile response to a challenge with live Salmonella enteritidis was studied. Except for a slightly higher oxygen uptake at all ambient temperatures in the rats in which the medial forebrain bundle was cut, no differences were found in any of the variables studied between the POA-disconnected and the sham-operated animals. We conclude, therefore, that the POA is not essential for the integration of autonomic thermoregulatory responses in the rat.

Fever in mammals: is it beneficial?

Fever appears to protect ectotherms against infectious disease perhaps because it increases their aerobic metabolic capacity, which is temperature-dependent. Mammals, however, have a high aerobic capacity and normally regulate a high body temperature. Thus, the further increase in temperature induced by interleukin-1 may be dangerous, and the resulting increase in aerobic capacity may not be necessary for an effective defense. In fact, recent evidence suggests that although the neuroendocrine cold defense responses that are stimulated in fever enhance the defenses of the host, the increase in temperature harms these defenses. Data, however, are scarce and equivocal, and the function of fever in mammals is still uncertain.

The effect of intraseptally applied vasopressin on thermoregulation in the rat.

The thermoregulatory effects of intraseptal injection of arginine vasopressin were studied in eight rats in which a thermode and a bilateral cannula had been chronically implanted into the preoptic area and lateral septa, respectively. Intraseptal injection of vasopressin completely suppressed the increase in heat production and body temperature elicited by cooling the preoptic area, but did not appear to affect vasomotor tone. Vasopressin also inhibited heat production in a cold environment, and thus induced a marked drop in core temperature; skin temperature did not, however, fall as much as core temperature suggesting that some vasodilatation occurred. At an ambient temperature in the upper range of thermoneutrality vasopressin had no effect on the thermoregulatory variables studied. It is concluded that vasopressin does not reduce the normal set point temperature and that its main effect is to inhibit thermoregulatory heat production. This effect may explain its antipyretic action.

The effect of hypothalamic temperature on the immune response in the rat.

To clarify the role of febrile temperatures on the immune system, rats were immunized with sheep erythrocytes and their core temperature was then changed by continuously cooling or heating the preoptic area for five days. Core temperatures of up to 2 degrees C above or below normal were associated with a high titre of antibodies against sheep erythrocytes, whereas larger displacements of core temperature, as well as normal temperature, were associated with a low titre. These results are at variance with the idea that the production of antibodies is proportional to body temperature. It is suggested that the immunostimulation elicited by heating and cooling the preoptic area, and by inference that the immunostimulation associated with fever, could be due to factors other than the change in body temperature.

Adaptive changes in cats after long-term exposure to various temperatures.

Two groups of cats were exposed to 5 and 30 degrees C, respectively for 24 mo in climatic chambers under artificial illumination. Then the ambient temperatures were reversed for both groups for another 36 mo. The group adapted to cold for 36 mo showed an increase in fur growth (+35%), an increase in resting metabolism (+20%), and a shift in threshold of the cold-induced metabolic response to 8 degrees C lower ambient temperatures. Norepinephrine (0.4 mg . kg-1) elicited nonshivering thermogenesis (+37%) in the cold-adapted animals but was ineffective in the warm-adapted ones. Fur insulation at thermoneutrality was 55% higher in the cold-adapted cats. During acute exposure to -5 degrees C, tissue insulation decreased in both groups; fur insulation increased by 34% in the warm-adapted cats but remained nearly constant in the cold-adapted animals. At all ambient temperatures cold-adapted cats had higher (+0.4 degrees C) rectal temperatures. Body weight was not significantly different in both groups, although the cats living in the cold had a 45% higher metabolism. This was compensated by an increased food consumption.

The effect of whole body heat exposure and of cooling the hypothalamus on antibody titre in the rat.

In rats implanted with chronic hypothalamic thermodes and immunized with sheep erythrocytes, body temperature was increased, 4 h per day for 2 weeks, either by exposing the animals to external heat or by cooling the preoptic area. The titre of antibodies against sheep erythrocytes was nearly tripled by preoptic cooling but was drastically decreased by heat exposure. These opposing effects of active and passive increases in body temperature indicate that factors other than the change in body temperature must also have played a significant role in modifying the humoral immune response.

Fever and survival in the rat. The effect of enhancing fever.

To study the effect of fever on infectious disease in a mammal, rats, partially restrained by an antirotatory device and with chronically implanted preoptic thermodes, were injected with Salmonella enteritidis and, in some of them, the hypothalamus was then continuously cooled to enhance the febrile response. All animals developed a fever that peaked 2 days after the infection, reaching 40.9 +/- 0.2 (SD) degrees C in the nine hypothalamic cooled and only 39.8 +/- 0.4 degrees C in the 13 control animals (P less than 0.001). All the hypothalamic cooled animals died within 8 days of infection, whereas only 23% of the controls had died after 28 days of infection (P = 0.0006). When the hypothalamus was continuously cooled in five uninfected animals, rectal temperature increased to 40.9 +/- 0.3 degrees C but 24 h later it had decreased to 39.6 +/- 0.3 (P less than 0.025). This decrease in body temperature suggests that the hypothalamic thermosensors had partially lost their effectiveness. It is concluded that cooling the hypothalamus increases the mortality rate in rats infected with S. enteritidis and that this effect could be mediated by the high body temperature or by the concomitant metabolic and endocrine responses thus induced.

The central control of shivering and non-shivering thermogenesis in the rat.

1. To test whether the preoptic area controls only non-shivering and the spinal cord only shivering thermogenesis, ten rats were chronically implanted with a preoptic and a spinal cord thermode each. The following were then studied: (a) the effect of propranolol (8 mg/kg.hr) on the metabolic response to cooling the preoptic area, and the spinal cord, (b) the effect of exogenous noradrenaline (0.5 mg/kg) on the metabolic response to cooling the preoptic area, and the spinal cord, and (c) the effect of warming the preoptic area on the metabolic response to cooling the spinal cord, and vice versa. 2. Administration of propranolol inhibited the metabolic response to cooling each of the thermosensitive areas, but the response to cooling the preoptic area was more strongly inhibited than that to cooling the spinal cord. 3. Administration of exogenous noradrenaline did not prevent the metabolic response to cooling either the preoptic area or the spinal cord. 4. Warming the spinal cord completely inhibited the metabolic response to cooling the preoptic area, and warming the preoptic area fully inhibited the metabolic response to cooling the spinal cord. 5. It is concluded that exogenous noradrenaline underestimates the capacity for non-shivering thermogenesis, and that both thermosensitive areas can control both forms of thermogenesis, but that the preoptic area threshold of non-shivering thermogenesis is probably lower than that of shivering, while the spinal cord threshold of shivering is probably lower than that of non-shivering thermogenesis.

Autonomic thermoregulation after intermittent cooling of the spinal cord and cold exposure in the rat.

1. O2 consumption, rectal and several skin temperatures were studied, at various ambient temperatures, in unanaesthetized rats that had been thermally stressed for an average of 290 h either by prolonged and intermittent cooling of the spinal cord or by prolonged and intermittent exposure to an ambient temperature which induced the same increase in O2 consumption as did the thermal stimulation of the spinal cord. 2. At all the test ambient temperatures, both groups of thermally stressed animals maintained a metabolic level higher than that of the controls. In the animals previously exposed to cold the extent by which the metabolic rate was greater than that of the control animals was independent of ambient temperature; in those previously subjected to cooling of the spinal cord, however, it increased as the ambient temperature was lowered. Rectal and average skin temperatures were essentially unaffected by the treatments. 3. It is concluded that prolonged and intermittent cooling of the spinal cord increases the gain of the temperature control system, whereas prolonged and intermittent cold exposure has no effect on it, and that these forms of thermal stimulation are therefore not equivalent.

The control of shivering and non-shivering thermogenesis in the rat.

1. The effect of intraperitoneal administration of propranolol (4, 8 and 12 mg/kg) on colonic temperature was studied in twelve rats during exposure to ambient temperatures of 30, 15 and 5 degrees C. 2. At 30 degrees C, propranolol had no effect on colonic temperature; at 15 and 5 degrees C, however, 4 mg propanolol/kg induced a fall in colonic temperature of about 0-8 degrees C, whereas 8 and 12 mg propanolol/kg induced a fall of about 1-5-2-0 degrees C. 3. Assuming that the temperature regulations system of the rat has a proportional controller and that the effect of propranolol was due to the blockade of non-shivering thermogenesis, the results are interpreted as showing that shivering is activated only when heat loss exceeds the capacity for non-shivering thermogenesis.