Morning Report (My Second) Steve Anisman July 18, 2002
The Case 74 yo F with large L sided CVA 2 years PTA which had left her unable to meaningfully communicate, and with R sided paralysis. Hx includes a-fib, G-tube for inability to swallow, MRSA 1 year ago. 3 days PTA, she fell out of her wheelchair and “hasn’t been right since.” On day of admission, family called EMT because Pt was oliguric, and unresponsive in bed with blankets on. Family was concerned that Pt may have had another stroke. EMT’s arrive to find Pt as described, with temp 107.6OF.
The Case She was transferred to ED, intubated, placed under cooling mist, fans, and given IF fluids. Hospital course remarkable for acute renal failure with eventual resolution, predicted CK curve, and ultimate return to baseline. Remaining issues are focused on disposition, as there is some reluctance to place her back with family secondary to concerns of neglect, and her Hx of MRSA make placement difficult.
Hyperthermia Whoops… Instead, let’s talk about
Fever Definition: Above normal temperature, with set point modification. Normal Temperature: 6:00 < 37.2oC (98.9oF) 16:00 < 37.7oC (99.9oF) We’re assuming oral readings here, which are expected to be ______________ rectal or tympanic (both “core”) readings. 0.6o (1.0o) below The reason for the discrepancy is evaporative heat loss from mouth breathing, particularly in patients with respiratory disease (and tachypnea).
Temperature variation Typically, temperature varies about 0.5oC throughout the day. In fever, this range can double – diurnal variation remains, but at a higher level. Women’s basal temperature drops by ~0.6oC during the two weeks prior to ovulation – increased temp at ovulation persists until the end of menses. Seasons, pregnancy, digestion all can change set point but not in a reliable way.
Fever vs. other hotnesses Set point is maintained by the thermoregulatory center in the anterior hypothalamus, and is fixed in early childhood. Control is maintained by increasing heat production in muscle and liver or increasing heat loss through skin and lungs. In fever, the set point becomes elevated. Hyperthermia has nothing to do with metabolic control – the body is simply loaded with heat above its ability to dissipate it. Diurnal variation is not seen with hyperthermia, and antipyretics are ineffectual. Hyperpyrexia is fever > 41.5oC, typically as a result of CNS hemorrhage, but occasionally with severe infections.
Why do I feel so… …“feverish?” The set point is raised (more details soon), and in order to raise the body temperature to the new level, vasomotor neurons cause vasoconstriction. Vasoconstriction shunts blood to the internal organs, decreasing heat loss from the skin, making extremities feel cold. Shivering is initiated to increase heat production from muscles, and the liver kicks in a few extra joules. Still, we feel cold. Silly humans then crawl under a heavy blanket on the couch and turn up the heat in the warmest room in the house. The body temperature eventually fluctuates around the new set point just as it did around the old one.
But how? Pyrogens. Anything that causes fever is a pyrogen. Exogenous pyrogens are typically microbes or their toxins, such as gram negative lipopolysaccaride endotoxin and the gram positive toxic shock syndrome toxin (Staph species). Toxins from Staph & Strep also act as “superantigens” – they act not only as exogenous pyrogens, but they also bind with MHC II (major histocompatibility complex 2) and T cells to cause the release of endogenous pyrogens.
Ahh, endogenous pyrogens. IL-1, IL-6, TNF (tumor necrosis factor), CNTF (ciliary neurotropic factor), and interferon-alpha all will cause the hypothalamus to upregulate the set point. The final common pathway seems to be IL-6, as absence of the IL-6 gene prevents animals from developing fever from bacterial infection. Any of these factors, injected into healthy subjects in miniscule doses, will cause fever in the absence of actual infection.
The hypothalamus, again These factors are released into the bloodstream by monocytes, macrophages, endothelial cells, and other cells in response to infection, and they collect in areas surrounding the thermoregulatory centers of the hypothalamus called OVLT (organ vasculosum lamina terminalis), where prostaglandin E2 (PGE2) is synthesized. There are 4 receptors for PGE2 in the brain – one of them is the thermoregulator and raises the set point in response to PGE2, using elevated cAMP as the cellular messenger.
…and even the brain The brain responds to many direct viral insults by releasing IL-1, IL-6, INF, and CNTF – these seem to bypass the PGE2 pathway and are able to raise the hypothalamic set point all by themselves. The brain also seems to respond to various other insults in the same way, which explains why intracranial hemorrhage also is often associated with fever. PGE2 is also synthesized and circulated in the periphery in response to pyrogenic cytokines – this causes arthrlagia and myalgia.
Stop the madness! If you can block PGE2, you can prevent fever. The rate limiting step in PGE2 production is the release of arachidonic acid from cell membranes – the arachidonic acid is then used as a substrate for cyclooxygenase, which itself is a substrate for PGE2. ASA inhibits cyclooxygenase directly. Acetominophen is oxidized in the brain by cytochrome p450 and its metabolite inhibits cyclooxygenase (but it is less effective in the periphery because the metabolite does not appear there). Corticosteroids inhibit cyclooxygenase and also block mRNA transciption of the pyrogenic cytokines.
The call from Gail “Dr. Anisman sorry to call so late Mrs. Rodriguez is a 4A patient you’re covering she’s here for DKA but her sugars have been fine she has a fever of 102 I woke her up to check it and she’s sleeping again I’ll give her a few Tylenol, OK?” MY RESPONSE: “Umm… Who is this?”
Your response: “It depends.” Fever can be our friend... or …fever can be our enemy.
Diagnostic benefit to fever? Obviously, fever is an indicator that there is something wrong, usually infectious in nature. Our usual response to fevers > 101.5o is to examine for something focal and send appropriate cultures (or simply send pan cultures and CXR if between 01:00 and 06:30). Some diseases have characteristic fever curves. For example, typhoid fever and disseminated TB have reversal of diurnal highs and lows (daily high ~ 06:00, daily low ~ 16:00). P. vivax and P. ovale have fever spikes q 48 h (P. falciparum’s cycle = 48 hrs; temp doesn’t always correlate). P. malariae has fever spikes q 72 h.
Diagnostic benefit to fever? An entity called “cyclic neutropenia” is characterized by pharyngitis, aphthous stomatitis, and rare bacterial systemic infections. If it isn’t treated, it can result in chronic gingivitis with tooth loss &/or perforation of abdominal viscus. Fevers last 3 days, and recur every 18-24 days. Every degree farenheit should correlate with 10 beats per minute. With 99o and 80 as “normal,” 104o should have pulse of 140. Relative bradycardia (temperature-pulse dissociation) can be seen in M. pneumoniae pneumonia, typhoid fever, blackwater fever (P. falciparum with hemolysis) brucellosis, leptospirosis, some drug-induced fevers, and factitious fever.
Diagnostic benefit to fever? Sustained fever (one that ignores the diurnal rhythm of which we’ve become so fond) can be seen in central nervous system injury, pneumococcal pneumonia, or psittacosis. Remittant fever (one with a baseline fever, interspersed with daily spikes above that baseline) can be seen in bacterial endocarditis, brucellosis, or malignancy. A fever that spikes sharply twice a day is seen in gonococcal endocarditis (but not in gonococcemia alone). Other than malaria, causes of relapsing infection include Spirillum minus (rat bite) infection, Streptobacillus moniliformis infection (“Haverhill fever”), chronic meningococcemia, and 10-15% of Hodgkin’s disease.
Is fever our enemy? Peripheral PGE2 is a potent immunosuppressant. Patients don’t like feeling feverish. Metabolic demands of fever (particularly during the shivering phase) are high, and particularly in patients with cardiac or pulmonary disease and high metabolic load, reducing O2 demand (by as much as 20% in critically ill patients if paralysis is also used!) seems like a good idea. Fever reduction in experimental patients (innoculated with sandfly fever) led to amelioration of fever-induced losses in mental work performance.
Is fever our enemy? If bacterial toxins act as pyrogens (which they do), it seems like poor teleologic strategy unless fever offered a survival advantage for these bacteria. The fever often seen post-MI has no survival benefit (Pt’s with fever do no better than those without), and this is likely to be a case where the increased metabolic load is dangerous. Most important to us, however, is the fact that Gail doesn’t like fever.
Is fever our friend? Higher temperatures impair the replication of many microorganisms. They lead to the release of acute phase reactants by the liver, some of which bind divalent cations – which are needed for the replication of many microorganisms. They lead to anorexia, which reduces available glucose, and metabolism is shifted towards proteolysis and lipolysis. Somnolence is induced, leading to decreased energy demand. Higher temperatures seem to help leukocytes in identifying and attacking antigenic tumor cells. It seems that it would be unwise evolutionary strategy for every higher animal to develop and maintain a febrile response if there were no benefit.
Is fever our friend? Animals innoculated with bacteria show a survival rates directly related to febrile response. The febrile animals had lower bacterial load in tissue, had more frequent sterile blood cultures, and greater accumulation of leukocytes at the site of innoculation than animals without fever. The degree of fever had no effect, however. Low temperatures (sub-physiologic) are correlated with poor immunologic response. Studies have demonstrated reduced bacterial killing directly related to reductions in temperature, that lymphocytes are more sluggish at low temperatures, and that patients cooled intraoperatively are more likely to develop infection.
Is fever our friend? IL-1 not only acts as a pyrogen, but also as a lymphocyte activator, a trigger for the release of endorphins, a trigger for the release of ACTH, and a direct stimulator of the adrenal gland to release corticosteroid. PMN’s display higher chemotactic and phagocytic activity at 40oC than at 37oC (but were ineffectual at 42oC or higher). PMN motility improves progressively as temp increases from 37 to 42. The improved effectiveness of PMN’s at higher temperatures does not seem to be true for Staph species.
Is fever our friend? T-lymphocyte mediated toxicity is enhanced when sensitization to antigens occurs at higher temperatures. Subsequent antibody levels are higher. LIF (leukocyte migration inhibition factor) is produced in greater quantities by monocytes at greater temperatures, keeping cells at the site of infection. Lymphocyte-produced IFN (interferon), which can activate monocytes and NK (natural killer) cells, and which is an indicator for effective antigen recognition, works 4-16 times better at higher temperatures. Monocytes proliferate at a greater rate and function more effectively at 38.5-40oC than at 37o – not only that, but they were more resistant to damage by viruses.
Is fever just an acquaintance? The benefits in recognition and activation are not maintained for B cells and for NK cells at higher temperatures – in fact, these cells work less well during fever. Fortunately, they are not essential in the initial phase of most infections, and the loss seems to be outweighed by the benefit to T cells and PMN’s. Additionally, the suppression of NK cells during active infection may help limit collateral damage to viable tissue in the region of infection.
Take home points • Fever is our friend – it helps us diagnose. • Fever is our friend – it helps us fight infection. • Fever is our friend – it makes life harder for bugs. • Be nice to your friends. • If you have to treat, use acetominophen.