I~P P. PHOPHYSIOLDGY

ELSEVIER Pathophysiology 2 (1995) 55-59

A comparison of core and skin temperature among normal and febrile children with cerebral malaria, uncomplicated malaria, and measles

F. Esamai a , * S. Jivaji b, p. Forsberg c, D.H. Lewis d, G.M. Anabwani a

a Department of Child Health and Paediatrics, Faculty of Health Sciences, Moi University, P.O. Box 4606, Eldoret, Kenya b Department of Human Pathology, Faculty of Health Sciences, Moi University, P.O. Box 4606, Eldoret, Kenya

c Department oflnfectious Diseases, Faculty of Health Sciences, Link6ping University, S-581 85 Linkb'ping, Sweden d Clinical Research Centre, Faculty of Health Sciences, Linkb'ping University, S-581 85 Lmk6ping, Sweden

Received 18 October 1994; accepted 20 October 1994

Abstract

Forty-four children were studied to compare the pathogenesis of fever in cerebral malaria, uncomplicated malaria and measles at the Eldoret District Hospital (EDH). A control group of normal children was used. The three patient groups were studied for three consecutive days measuring skin and core temperature three-times a day using the Liquid Crystal Device (LCD) thermometer. A statistical analysis of the results within and between the groups was carried out for core and skin temperature over the study period. No statistical differences were found between the groups for either the skin or the core temperature, but a significant statistical difference was demonstrated between the core and the skin temperature for all of the groups for each of the three days, No statistical difference was found when the differences between the core and skin temperature were compared between cerebral malaria and uncomplicated malaria. The possible roles of fever in morbidity and mortality are discussed, with special reference to cerebral malaria.

Keywords: Cerebral malaria; Fever; Core temperature; Skin temperature; Microcirculation; Infants

1. Introduct ion

The microcirculation may be affected in cerebral malaria involving both cerebral and peripheral blood vessels. Other malaria-like febrile diseases affect mainly the peripheral microvessels [1-3]. The normal human tempera ture is considered to be between 36.4°C and 37.4°C, which is known as the thermostatic set point and temperatures higher than 37.4°C are considered to be fever [4]. Fever is usually a result of the pyrogen driving the thermostatic set point to a higher level causing a disparity between the existing temperature and that dictated by the set point. The pyrogens raise body temperature by increasing heat production and fever therefore causes a hypermetabolic state. With a I°C rise in temperature, metabolism is increased by 10-13% [4]. Fever contributes to morbidity and mortal- ity especially in children and more so in cerebral

* Corresponding author. Fax: +254-321-33041.

0928-4680/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0 9 2 8 - 4 6 8 0 ( 9 4 ) 0 0 0 3 4 - 4

malaria, due to febrile convulsions and increased metabolic rate. Reports indicate that tumour necrosis factor (TNF) may be a significant contributor to the development of fever in cerebral malaria patients and therefore ant i-TNF therapy may be useful in its man- agement [5-11].

Fever is a common feature of many tropical diseases and the difference between the core and skin tempera- ture may be an indicator of the microcirculation in an individual [12-14]. It is therefore logical to assume that in patients with cerebral malaria this difference may well be significant, in view of the pathophysiology of the disease. Studies on the haemodynamics and mi- crovascular changes of patients with cerebral malaria suggest that there may be differences between such patients as compared to normals or patients with un- complicated malaria or other diseases, such as measles [14-22]. The difference between the core and skin temperature is usually considered a measure of the microcirculation and the findings of this study may give an insight into this and permit, in addition, an analysis

56 F. Esamai et al. / Pathophysiology 2 (1995) 55-59

of the differences between the various disease states studied. Thus, even if the difference between core and skin temperature may be the same irrespective of the disease state, the temperature difference between core and skin would be useful if it is different in different diseases. Such differences could then be used as a diagnostic criterion of the specific disease entity as well as in differentiating febrile conditions. This would be useful in the developing countries, where modern diag- nostic facilities are scarce and infectious diseases are prevalent. A review of the literature shows that no similar studies have been done and therefore the re- sults of this study may be useful as a baseline.

This study was therefore carried out with the objec- tive of exploring the difference between the core and skin temperature in four study groups, namely the differences were compared within and between groups on three consecutive days at eight-hourly intervals. Of interest was the question as to whether core and skin temperature have any predictive value for the disease states studied.

2. Material and methods

This cross-sectional study was carried out in the Eldoret District Hospital (EDH), Kenya, over a seven- month period, from February to September 1993, which falls within the rainy season during which malaria is prevalent in this area. The age and sex of these chil- dren are shown in Table 1.

All children in the study were examined by the principal investigator (FE) before admission into the study and daily for the three days of the study period in the Paediatric Wards of EDH. Normal children were examined once on follow-up at the Paediatric Out-Pa- tient Clinic (POPC) of EDH and only those that were certified to be well and fully recovered were included. A peripheral blood smear was examined in all these children and those positive for malaria parasites were excluded. In addition, a haemoglobin estimation was carried out and those with levels less than 100 g / l were excluded.

Children were diagnosed to be suffering from cere- bral malaria when they presented with the following symptoms: presence of asexual forms of Plasmodium

Table 1 Patient material

Category Total Male/ Age in months

number Female Mean Median (Range)

Normal 14 9/5 21.9 15 (7-96) Cerebral malaria 7 5/2 41.7 36 (11-132) Malaria 14 5/9 22.6 18 (4-42) Measles 9 7 /2 36.6 12 (5-96)

Table 2 Normal children (n = 14) temperature mean 5: S.D.

Day Core temperature Skin temperature morning morning

1 36.4 ± 0.50 34.2 5:0.43 a

a p < 0.001.

falciparum malaria parasites in the peripheral blood smear and by the Quantitative Buffy Coat (QBC) method, fever, drowsiness or unarousable coma and convulsions; no clinical or laboratory evidence of meningitis.

Children were considered to be suffering from un- complicated malaria if they presented with fever, pres- ence of the asexual forms of the P. falciparum malaria parasites in the peripheral blood smear in both the thick and thin smears and by the QBC method. In addition, their haemoglobin had to be > 50 g / l , and the patients should have no features consistent with severe or cerebral malaria and should not be in shock.

Children were considered to be suffering from measles if they presented with fever, coryza, conjunc- tivitis, cough and the typical maculopapular rash. A peripheral blood smear was examined in all these cases to exclude malaria and those with positive smears were excluded from the study.

The temperatures were measured three times a day (viz. 9.00 a.m, 15.00 p.m. and 19.00 p.m., respectively) for all study patients, except for the normal children in whom it was recorded once because they were re- cruited in the outpatient clinic after which they re- turned home.

The temperature was measured using the Liquid Crystal Device (LCD) strip thermometer for all the patients in this study. Both core and skin temperature were recorded simultaneously using two thermometers in all of the patients for the three days. The core temperature was recorded by placing the child on its side with the LCD thermometer between the skin of the child and the blanket or mattress. The thermome- ter was placed in the area between the axilla and the costal margin and was read after 10 min. The skin temperature was measured by placing and pressing the LCD thermometer on the skin over the calf muscles and the temperature was read after 10 rain. The par- ents or guardians gave an informed written consent before their children were entered into the study.

All the data were recorded in a predesigned data form for each patient at the end of the third day except for the normal cases in whom the data was recorded on the same day.

The data were analysed using a two-way analysis of variance (ANOVA) first to compare the results of the different groups. Significance was determined using Student's t-test. A level of P < 0.05 was considered

F. Esamai et al. / Pathophysiology 2 (1995) 55-59 57

statistically significant. The data are presented as mean _+ S.D.

3. Results

A total of 44 children aged between 6 months and twelve years were studied. There were four groups.

3.1. Normal children

Table 2 shows the temperature data gathered on the normal children. There was a highly significant statisti- cal difference between the core and skin temperature taken once in the morning (P < 0.001).

Table 3 shows the temperature readings for morn- ing, afternoon and evening on all 3 days for all three disease groups.

3.2. Core vs. skin temperature

When the core and skin temperatures were com- pared between the study groups for days 1, 2 and 3, and between morning, afternoon and evening for the three days, there was a highly statistically significant difference between the two temperatures in all of the pairs ( P < 0.001).

3. 4. Skin temperature

There was no statistical difference in the skin tem- perature readings between days 1, 2 and 3 for morning, afternoon and evening in any of the groups.

3.5. Malaria vs. cerebral malaria

There was no statistical difference between these two groups in all the three day readings for morning, afternoon and evening with regard to both the core and skin temperature.

3. 6. Measles, malaria and cerebral malaria

When the temperature readings for both core and skin in all the three groups were compared for morn- ing, afternoon and evening in the three days horizon- tally for each day, there was no statistically significant difference.

The results tabulated indicate that there was a ten- dency to higher temperature readings on day 1 among cerebral malaria patients than the other groups, but the differences were not statistically significant. Simi- larly there appears to be a sharper drop in temperature on day 2 from the day 1 readings in the cerebral malaria group than in the other groups, but this is not statistically significant.

3.3. Core temperature 4. Discussion

There was no statistical difference in the core tem- perature readings between days 1, 2 and 3 for morning, afternoon and evening in any of the groups.

Temperature measurement is an important clinical parameter in medical practice with the main objective of recording the presence or absence of fever in pa-

'Fable 3

Cerebral malaria, uncomplicated malaria and measles mean ± S.D.

Day Core temperature Skin temperature

morning afternoon evening morning afternoon evening

Cerebral malaria (n = 7) 1 38.6 ± 1.13 38.3 ± 0.76 38.3 ± 0.76 2 37.4 ± 1.27 37.1 ± 1.07 d 36.9 ± 0.69 c,e

3 36.6 ± 0.79 e 36.7 ± 0.49 e 36.7 ± 0.49 e

Uncomplicated malaria (n = 14) 1 38.0 ± 0.84 38.1 ± 0.63 37.9 ± 0.74 2 37.2 _+ 0.70 e 37.1 ± 0.83 e 36.8 ± 0.58 c,f

3 36.8 ± 0.58 d,f 36.8 ± 0.43 f 36.6 ± 0.50 f

Measles (n = 9) 1 38.0 ± 0.56 37.9 ± 0.74 38.1 ± 0.53

2 37.2 ± 1.39 37.1 ± 1.27 37.0 ± 1.00 d 3 36.4 ± 0.88 f'g 36.7 + 0.50 d 36.3 ± 0.71 f

35.0 ___ 1.41 a 35.3 ± 1.60 a 35.3 _+ 1.60 a 34.9 + 1.57 b 34.4 _+ 0.79 b 34.9 ± 1.57 a 34.3 ± 0.49 b 34.1 _+ 0.38 b 34.3 _+ 0.49 b

35.1 ± 1.14b 35.0 + 1.08 b 34.8 ± 0.80 b 34.6 ± 0.76 b 34.6 ± 0.76 b 34.5 ± 0.76 b 34.1 ± 0.36 b,d 34.2 ± 0.43 b,d 34.3 ± 0.47 b

35.2 ± 1.09 b 34.8 ± 0.67 b 35.2 ± 1.20 b

34.3 _+ 0.71 b,d 34.4 ± 0.73 b 34.2 ± 0.44 b 34.2 ± 0.44 b,d 34.2 ± 0.44 b,d 34.2 ± 0.44 b

a p < 0.01 compared to core temperature measured at the same time. b p < 0.001 compared to core temperature measured at the same time. c p < 0.05 compared to morning core temperature. d p < 0.05 compared to Day 1, e p < 0.01 compared to Day 1.

f P < 0.001 compared to Day 1.

g P < 0.05 compared to Day 2.

58 F. Esamai et al. / Pathophysiology 2 (1995) 55-59

tients all over the world. Fever is usually considered to be present when the temperature is above 37.4°C Tem- perature can be measured using the glass or the LCD thermometer with comparable precision [23].

The gradient between core and skin temperature is thought to increase when patients are exposed to con- ditions of rapid heat loss that may occur in febrile patients such as those with cerebral malaria [4]. This has not been observed in this study in which the temperature gradient between skin and core is statisti- cally significant within all the groups - - including the reference group of normal children - - and with no significant differences between the groups. This may be explained by the fact that heat loss in these cases may not have been as rapid as expected [4]. These findings also show that the core and skin temperature are not dependent on the underlying disease; neither does the core and skin temperature gradient change as the patient recovers.

The mechanisms of fever development are thought to be the same irrespective of the underlying disease state. However, it is thought that the fever in malaria, especially cerebral malaria, is a result of an enhanced TNF activity [5-10]. It is also thought that fever in- hibits parasite growth, while TNF has other anti-para- site effects; both would be beneficial to the patient. These observations corroborate studies that show the fever-reducing activity of anti-TNF therapeutic agents [11]. Anti-TNF reduces fever compared to placebo and higher therapeutic doses are more effective [5].

However, most studies indicate that the higher the TNF levels the more severe the p. falciparum malaria and that higher TNF levels correlate with high mortal- ity [11,24]. TNF exacerbates the sequestration of para- sites in the cerebral blood vessels by upgrading adhe- sion molecules i.e ICAM-1, that mediate the binding of p. falciparum to the vascular endothelium [25,26]. The high levels of TNF in areas of dense sequestration may stimulate endothelial release of nitric oxide that may raise intracranial pressure and disturb neuronal con- duction [25,26].

These observations on fever and its management are important with regard to cerebral malaria, because mortality is estimated to be about 15-30%, irrespective of antimalarial sensitivity of the parasite. This means that parasitaemia per se is not the sole reason for this mortality. It is not known what contribution fever has in this regard, since it is responsible for a significant proportion of febrile convulsions, hyperpyrexia and hypermetabolic state, but it must be considerable [27].

It is therefore imperative to utilise all the available methods of fever management in febrile children in addition to the specific and supportive measures for the underlying disease. Such methods would include tepid sponging, antipyretics and anticonvulsants when needed.

Shock which is a common feature of algid malaria and in severe haemolysis that follows heavy para- sitaemia is not a common manifestation of cerebral malaria [27,28] except in cases of hyperpyrexia. This means that fever may contribute to the morbidity of cerebral malaria. However, fever has not been found to have any influence on the mechanism of rosette forma- tion that is a feature of cerebral malaria through which cytoadherence occurs leading to the pathological changes seen in these cases [29].

When one considers atmospheric or room tempera- ture and body temperature, one would expect the morning or evening differences between core and skin temperature to be significantly higher than the after- noon differences, especially in the tropics where this study was carried out. This is because the afternoons are usually warmer than either the mornings or evenings in the tropics at most times and the skin in the exposed areas of the body are in direct contact with the room or atmospheric temperatures. However, this study does not show this, which confirms the estab- lished mechanisms of body temperature regulation [4].

We have not found studies that compare core and skin temperature in the available scientific literature and therefore a comparative analysis of our findings is not possible. The results of this study indicate a signifi- cance in the difference between core and skin temper- ature for all groups but not between groups. This is important for the tropical countries where infectious diseases are common and it would have been more so if there were significant differences between the groups, as these could serve as a criterion in diagnosis.

5. Conclusions

No significant difference between uncomplicated malaria and cerebral malaria exists when comparing the difference between core and skin temperature. This means that the temperature gradient cannot be utilised as a diagnostic tool for predicting the clinical course of malaria in children.

Significant statistical difference exists between core and skin temperature in normal and febrile children, which means that there is a pattern through which the body adjusts in response to changes in body tempera- ture and which is independent of the disease state.

6. Recommendations

Further study should be carried out in an attempt to establish whether there exists a difference between core and skin temperature in children that survive and those that eventually die of cerebral malaria.

F. Esamai et al. /Pathophysiology 2 (1995) 55-50 59

Further research should be carried out, for example, on the use of anti-TNF agents for fever reduction in cerebral malaria in view of the possible role fever plays in morbidity and mortality in this condition. Of interest here also is the use of immunoglobulins in the treat- ment of cerebral malaria [30].

Aggressive and precise management of fever should be undertaken in febrile children in an attempt to minimise morbidity and mortality that may be related to it.

Acknowledgements

The original results reported in this communication were supported in part by grants-in-aid from SIDA and from the Faculty of Health Sciences, Link6pings Uni- versity. The authors thank Patrick Chweya for techni- cal assistance and the nursing staff of the Paediatric Wards. Professor Terence Ryan, Department of Der- matology, Slade Hospital, Oxford, U.K. is thanked for the gift of the LCD thermometers.

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