Pediatric Fever – Myth 4/10: Do we need to treat all fevers?

Myth #4: All fevers need to be treated with fever reducing medicine 

What are the benefits of fever? What literature supports the treatment of fever in pediatric patients? This is part 4 of a 10-part series where I will busting what I consider to be the top 10 myths involving pediatric fever. 

Lwoff A, 1959¹

• This is a super old study from 1959, when poliovirus was still a thing. They looked at poliovirus and viral yield at different temperatures. What they found, is that as temperature increases, the viral yield of polio  significantly decreases, especially around 40° C.

Small, 1986²

This 1986 study looked at effects of body temp on the growth of pneumococcal meningitis in rabbits. Specifically, they assessed the doubling time of pneumococcal meningitis. In this study, they took some bacteria and spread in on a soy broth petri dish and a little more on a petri dish with rabbit CSF. They controlled the temperatures in the range of normal body temperature as well as at the level of a typical fever using incubation for the petri dish samples. They also directly inoculated rabbits with the bacteria and controlled their body temperatures using ambient air temperature and an antipyretic. What they observed is pretty cool. There was no growth in the petri dish studies at temperatures of 41° Cand higher. In rabbits whose fever was not suppressed, the mean bacterial doubling time was 2.76 +/- 1.43 h and those with a blunted febrile response from Urethane, there was a significantly faster mean bacterial growth rate (doubling time = 1.10 +/- 0.27 h; P less than 0.02). When the antipyretic effect of urethane was counteracted by raising the ambient temperature, animals also showed a marked reduction in pneumococcal growth rates.Thus, body temperature appears to be a critical determinant of pneumococcal growth rates in experimental meningitis. 

Bernheim, 1976³

Here is a 1976 study of fever on lizards that were injected with the bacteria Aeromonas hydrophilia. They took 12 lizards and injected them with bacteria and gave them all sodium salicylate, a fever reducing medication like Aspirin. 5 of the lizards developed a fever and all 5 of them survived. 7 of the lizards did not develop fever and all 7 of them died within in 3 days

Osaewa E, Muschel LH, 1964⁴

This 1964 study looked at Serum resistance of certain Gram-Negative bacteria in rabbits. They used Paracolobacterium ballerup, which is thought to be completely insusceptible to the bactericidal action of the Antibody-Complement system and found that these bacteria become extremely sensitive to the immune system at temperatures > 37° Cin both pre and post-immunized rabbits. They also found that the sensitivity to Penicillin increased as fever increased. 

Nahas GG, et al., 1971⁵

This 1971 study looking at effects of pH and Temperature on leukocyte motility. It showed that the rate of human PMN mobility was markedly enhanced by temperatures between 32 and 42° C. On a side note in this study, there was not much effect from pH 6.5 and 7.5 and there was a rapid inhibition of motility at a pH > 7.6.

Austin TW, Truant G,. 1978⁶

This 1978 study assessed neutrophil function in the setting of fever vs antipyretic use. They used Boyden chambers with PMNs and S. aureus and looked at effects at normal body temperatures in the setting of fever with and without antipyretics including salicylates, acetaminophen and phenacetin. Investigators found that bacterial killing was increased at temps > 40° C(after 2hours, the inverse was true). However, the kicker is that when antipyretics were used with temps above 40° C, bactericidal activity and neutrophil migration were significantly suppressed. It is important to note that neutrophil viability was not affected in any arms of this study and neutrophil activity was similar at 37 and 40° C. 

Sugimura T, et al., 1994⁷

Here is a 1994 study from Japan of 208 outpatient children aged 6 months – 15 years with fever from a bacterial upper respiratory source. They assessed the rate of pneumonia development in the setting antipyretic use and found that patients who developed pneumonia had similar level of fever. However, the group that developed fulminant pneumonia received more daily doses of Tylenol (2.5 vs roughly 1.5). 

El-Radhi AS., et al., 1992⁸

This 1992 study looked at 102 children with Salmonella gastroenteritis and evaluated the duration of salmonella excretion (in weeks) based on the height of fever. They showed that fever was associated with a much more rapid excretion rate with complete excretion of salmonella within 10 days in children who produced fevers above 40° Cand as long as 2 months in those whose fevers were controlled. 

Graham NM., et al., 1990⁹ 

Here is a study from 1990 that took 60 people that either really love science, or really needed money and sprayed rhinovirus up their noses. 56 got infected with the common cold producing virus. There were 4 arms of this study; Aspirin, Acetaminophen, Ibuprofen and a Placebo. What they found was that in the Aspirin and Tylenol group, serum antibody levels were decreased, and length of symptoms increased. Also, viral shedding was the same in all groups. 

Doran TF., et al., 1989¹⁰

This is one of my favorite studies in this section. A 1989 study of 72 children with chickenpox age 1-12 years of age. Investigators wanted to see how fever control with Tylenol vs Placebo differed. They looked at symptoms such as itching, activity and appetite and found no significant difference between Tylenol and doing absolutely nothing at all. However, and here is where it gets good; they found that the time to total scabbing of lesions (you know, the time when the child is no longer infectious) was over 24 hours longer in the group who took Tylenol. Placebo wins!

Williams LK., et al., 2004¹¹

This is the last study in this section, but it’s an interesting one. It is a 2004 study of 855 Suburban Detroiters. Investigators set out to determine if fevers by age 1 led to allergic sensitization at ages 6 or 7. Remember, the hygiene hypothesis? The “Hygiene Hypothesis” is a theory suggesting that a young child’s environment can be “too clean” to effectively stimulate or challenge the child’s immune system and suggests that the lack of immune system challenges as a child results in many people developing immune-related health problems such as asthma. Well, what they found is that the more frequent fevers occurred before age 1, the LESSlikely kids were to have Atopy by symptoms or serologic testing at ages 6-7. Each episode of fever before age 1 was associated with reduced odds for allergic sensitization. 

So, when do we need to treat fevers?

Surprisingly, few studies have been performed to determine if the benefits of antipyretic use outweigh its risks.¹²There are 2 general assumptions on the argument to treat a fever. First, fever is uncomfortable. Secondly, fever suppression will reduce this discomfort.¹³We tend to treat fevers in children to decrease pain and prevent excessive lethargy. Kids feel better, are more likely to eat and drink and avoid dehydration. Mostly, it helps with the parent’s anxiety of the fever if it is treated. 

The only clinical condition with abundant evidence to support aggressive antipyretic treatment is in acute brain injury.^14-16Antipyretic therapy has not been shown to decrease the recurrence of febrile seizure.¹⁷

As clinicians, we tend to feel justified in the treatment of fevers in situations where there is a decrease in energy supply and an increase in metabolic rate.¹⁸This is seen in burn patients, those with cardiovascular and pulmonary diseases, prolonged febrile illnesses and in postoperative patients. We are more aggressive in treating patients who are hypoxic, such as in bronchiolitis, because fever may increase oxygen requirements and worsen the disease. These metabolic demands include an increase in sympathetic tone, oxygen consumption and respiratory rate.¹⁹ They peak during the chill phase and are largely due to shivering.²⁰ Unfortunately, experimental evidence of the benefit to controlling fever in these situations is lacking.²¹

In one in a randomized controlled trial of adult ICU patients in septic shock, fever reduction via cooling has documented benefit leading to a reduction in vasopressor use and mortality.²²One observational study has shown a reduced in-hospital mortality and time to death with the use of antipyretics in the adult ICU.²³ However, this literature was observational in nature and likely represents the effect of indication bias as patients were adjusted based on multiple potential confounders including suspected infection of lesser illness and severity. 

Let’s summarize the evidence…

• There is quite a bit of literature supporting the befits of fever. 
• Fevers activate the body’s immune system and are helpful in fighting infection
• We typically treat fever to decrease pain and excessive lethargy. Kids feel better, are more likely to eat and drink and not get dehydrated. Mostly, it helps with the parent’s anxiety if the fever if it is treated. 
• It is recommended to treat fevers in situations where there is a decrease in energy supply and an increase in metabolic rate. This is seen in burn patients, those with cardiovascular and pulmonary diseases, prolonged febrile illnesses and in postoperative patients
• We are more aggressive in treating patients who are hypoxic, such as in bronchiolitis because fever may increase oxygen requirements and worsen the disease. 
• Children are usually pretty symptomatic with fevers greater than 40° C, so we are usually pretty aggressive with treatment at this point. 

So, for our fourth myth questioning if all fevers need to be treated with an antipyretic….i would consider this BUSTED.

References

1. Lwoff, A. (1959). Factors influencing the evolution of viral diseases at the cellular level and in the organism. Bacteriol Rev, 23(3):109-124. PMID: 14419105
2. Small PM, et al. (1986). Influence of body temperature on bacterial growth ratees in experimental pneumococcal meningitis in rabbits. Infect Immun. 52(2):484-7. 
3. Bernheim HA, Kluger MJ. (1976). Fever: effect of drug-induced antipyresis on survival. Science, 193(4249):237-9.
4. Osaewa E, Muschel LH,. (1964). Studies relating to the serum resistance of certain gram negative bacteria. J Exp Med, 119:41-51. PMCID: PMC2137802
5. Nahas GG, et al., (1971). Direct Measurement of Leukocyte Motility: Effects of pH and Temperature. Proc Soc Biol Med. 138(1):350-2. PMID: 5125534
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11. Williams LK., et al. (2004). The relationship between early fever and allergic sensitization at age 6 to 7 years. J Allergy Clin Immunol, 113(2):291-6. PMID: 14767444
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