How is fever beneficial

In fact, the index case had taken an antipyretic for a fever, highlighting the potential for these medications to make the disease more difficult to detect. Third and most important, there is real concern about patient morbidity and mortality due to abrogation of host defenses, which remain inadequately understood. The protective value of fever may be slight but crucial for individual patients.

In a pandemic involving millions, even a modest protective effect can affect large numbers of patients. As we have recently learned, timing is everything when introducing control measures in a pandemic.

Early interventions have a disproportionate effect on exponential growth and outcomes. Early initiation of host defenses in individuals is similarly important. At the early part of the pathogen growth curve, the benefit of control measures may not be apparent to the observer and the costs may seem excessive.

By slowing the spread of infection, the increasingly and overwhelmingly rapid spread is avoided, potentially ending the epidemic or at least gaining valuable time to develop sophisticated defenses and vaccines. Likewise for flattening the curve in newly infected individuals. Defenses like fever that are deployed early have the potential to favorably alter the trajectory of infection, providing time until adaptive immune defenses e. In these patients, early-stage immune defenses may have been inadequate to control the infection [ 36 ], resulting in later defenses that can be harmful themselves [ 77 , 78 ].

Similarly, fever and the acute phase response may prevent late sequelae of infection. We have discussed the benefits and costs of allowing fever to occur Fig. Several decades of intensive care experience have shown that many aggressive interventions aimed at restoring homeostasis do not improve outcomes [ 80 , 81 ]. Reduced intensity of treatment has produced equivalent or better patient outcomes in a variety of clinical settings, including mechanically ventilated patients receiving lower than normal tidal volumes [ 82 ], avoiding supplemental oxygen in patients with acute myocardial infarctions [ 83 ], less aggressive nutritional supplementation in patients receiving intensive care [ 84 ], and abandoning early goal-directed therapy in sepsis [ 85 ].

Similarly, aggressive measures to normalize body temperature, compared to usual care, have not improved outcomes in febrile patients [ 63 ]. Even usual care, the typical treatment of fever with NSAIDs and acetaminophen, is not evidence-based, raising questions for infection outcomes that could be answered by new research. Whether to raise temperatures therapeutically is another unanswered question. People with infections have recurring concerns and seek medical guidance for fever, and also for aches and pains, depression, fatigue, and reduced appetite.

We note the curious situation that biomedical science can promptly determine the exact genotype of infectious agents through advances in molecular biology, but we are still in the dark regarding our most ancient evolved responses to infection. Since there is no currently accepted understanding of how the numerous seemingly harmful components of the acute phase response function together in defense, this should be a long-term research priority. More urgently, this pandemic is an opportunity to undertake a randomized controlled study on the effect of antipyretics on COVID outcomes.

Until that time, medical decision making should be guided by the precautionary principle to take reasonable steps to reduce risk to patients [ 88 ]. Practitioners should consider the likely protective role of fever, weighed against the need to treat pain and discomfort. Especially with COVID, in which we are almost exclusively relying on intrinsic host immune defenses to resolve the infection, we propose erring on the side of not intervening with anti-pathogen defenses like fever.

In the absence of evidence definitively showing their harm in specific situations, it would be prudent in a life-threatening infection to take advantage of all of our evolved defenses.

In addition to the local inflammatory response to infection, the systemic defensive responses to infection are known as the acute phase response [ 13 , 89 ]. Besides fever, other components include mobilization of leukocytes; production of a variety of protective proteins acute phase proteins ; reduced blood levels of iron, zinc, and manganese; reduced erythrocyte production beyond simple iron deficiency ; reduced appetite anorexia ; breakdown of muscle protein and fat cachexia or hypercatabolism ; and the uncomfortable, motivation-sapping sickness symptoms and behaviors we associate with infection, including lethargy, depression and aches.

Because these responses are initiated by the host, not by the pathogen, and because they are evolutionarily conserved—appearing in all vertebrates and many invertebrates [ 32 , 33 ]—the acute phase response is considered an adaptive non-specific response to infection.

While some components of the acute phase response are generally accepted to be beneficial, other acute phase responses—lassitude, anorexia and cachexia—can seem more harmful than beneficial and their function has been debated [ 16 , 18 , 90—92 ]. Each of the components of the acute phase response involves either self-harm or the expenditure of limited resources. This includes manufacturing acute phase proteins and supporting an increased metabolic rate.

The most widely-cited explanation for these elements of the acute phase response was proposed by Hart [ 16 ] and extended by Straub et al. This hypothesis centers around the need to conserve resources and to reallocate energy resources towards supporting an effective immune defense.

Resources are conserved by restricting less essential activities and not foraging for food. Another hypothesis is that replicating pathogens can be especially vulnerable to many of the harmful components of the acute phase response, so that the harm involved is directed more to pathogens than to the host [ 18 , 49 ].

In this view, reduced appetite is a nutritional strategy that disproportionately starves pathogens of energy and micronutrients. A recently proposed additional hypothesis views sickness behavior as an evolved defense that primarily benefits close relatives. Many potential pathogens can survive and function over a wide range of temperatures cooler than their optimum. Temperatures that are slightly higher than the optimum can damage proteins including enzyme function , membrane lipids, and RNA and disrupt DNA synthesis in the cells of both hosts and pathogens [ 20 , 95 , 96 ].

However, one of the concerns about the efficacy of fever in harming pathogens is that febrile temperature i. So how can the heat of fever be expected to harm or even kill most host-adapted pathogens [ 95 ]?

And furthermore, why should we expect that the heat will harm the pathogens including virally infected cells more than the host [ 18 ]? The temperature to which pathogens at the infected site are actually exposed is currently unknown [ 18 , 98 ]. However, it is almost certainly higher than that of the blood entering the infected site since heat is generated at inflammatory foci.

It has been proposed that one source of this heat is from the macrophages in these inflamed plaques that have upregulated levels of mitochondrial uncoupling protein 2, which generates heat rather than ATP [ ]. Neutrophils activated to undergo the respiratory burst as with phagocytosis generate substantial heat [ — ], as expected from the oxidative reactions that produce reactive oxygen species.

LeGrand and Day [ 18 ] proposed that since growth and replication are universally sensitive to disruption by stressors of any kind, replicating pathogens and infected cells generating pathogens localized at the infected site would tend to be more vulnerable to heat stress than non-replicating host cells stromal cells or infiltrating effector immune cells. Immune cells recruited to the site of infection e.

Therefore, it is not surprising that the optimal functional temperature of activated leukocytes is higher than normal core body temperature. In this view, fever provides a crucial temperature boost to locally warmed tissues at infected sites, elevating the temperature to the level that damages pathogens. Additionally, the systemic febrile temperature may impair replication of pathogens that have spread.

This is analogous to iron deprivation as a host defense during infection: systemically iron is mildly restricted, but locally at the infected site it is much more restricted, and limited even further within phagolysosomes [ 18 ]. All immune defenses involve important costs and benefits.

The benefits of the acute phase response typically outweigh its costs, because fever and other nonspecific stressors exploit the vulnerabilities of rapidly dividing pathogens [ 49 ]. As a result, costs are preferentially imposed on pathogens instead of healthy host cells. Some pathogens have counteradaptations that protect against acute phase response stresses, but these impose trade-offs themselves for pathogens. Microbe-derived heat shock proteins, for instance, impair pathogen replication and trigger additional immune responses from the host [ 37 ].

LeGrand and Alcock [ 49 ] identified a number of conditions where immune brinksmanship may be a losing strategy for an infected host. One example is having insufficient metabolic, nutritional or physiologic reserves needed to survive the stress.

Having comorbidities, such as heart failure or impaired lung function, also reduce the potential payoff. Other threats to the host, such as having co-infection with another pathogen or a recent previous infection, also decrease the odds of success. Other costs specific to fever include harming tissues with rapid growth, such as during spermatogenesis in the testes [ ] and embryonic and fetal development [ ]. Additionally, some specialized pathogens may be relatively resistant to stresses imposed by the host.

Old age is a risk factor for respiratory failure and death in COVID, and in some of these cases, the costs of the immune response may exceed its benefits [ ]. Proximate explanations include attenuated immune responses in the aged immunosenescence [ ] or excessive innate immune activation inflammaging [ ].

We note that impaired infection control may impose additional immune costs, taking the patient to the brink with potentially lethal self-harm.

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A new study in mice shows that it helps immune cells more quickly reach and attack harmful germs. His team studied how immune cells travel from a blood vessel to the site of an infection.

A fever gives the cells a superpower that speeds up that trip, his team found. Millions of T cells flow through the blood on the lookout for harmful bacteria and viruses. Most of the time, they flow along in a quiet, monitoring mode. But as soon as they detect potential danger, they kick into high gear. Now they head for the nearest lymph node. Hundreds of these small, bean-shaped glands are scattered throughout our bodies. Their job is to trap disease-causing microbes near the site of an infection.

That helps the T cells home in to attack the invaders and clear them out. You may have felt swollen lymph nodes in your neck, under your jaw or behind your ears.

The immune system is similar in people and mice. One is alpha-4 integrin INT-eh-grin. The other is known as heat shock protein 90, or Hsp As body temps climb, T cells make more Hsp90 molecules. This makes them sticky. Fever and immunity. In:Psychoneuroimmunology, vol.

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