Philip A. Mackowiak

Drug Fever: A Critical Appraisal of Conventional Concepts: An Analysis of 51 Episodes in Two Dallas Hospitals and 97 Episodes Reported in the English Literature

Because no systematic analysis of drug fever has been done, there has been no means for testing the validity of published characterizations of this clinical entity. We reviewed the clinical characteristics of 51 episodes of drug fever in 45 patients hospitalized at two Dallas hospitals between 1959 and 1986, and 97 episodes reported in the English literature between 1966 and 1986. Unlike characterizations found in textbooks and review articles, we found relative bradycardia in a minority of cases reviewed; little risk associated with rechallenge unless underlying cardiovascular disease was present; no characteristic fever pattern; a highly variable lag time between the initiation of the offending agent and the onset of fever; an infrequent association with either rash or eosinophilia; and no apparent association of drug fever with systemic lupus erythematosus, atopy, female sex, or advanced age.

Concepts of Fever: Recent Advances and Lingering Dogma

Fever has been a preoccupation of clinicians since medicines beginning. One might therefore expect that basic concepts relating to this physiological response would be well delineated and that such concepts would be widely known. In fact, only in the past several decades has the febrile response been subjected to scientific scrutiny. As a result of recent scientific investigation, modern concepts have evolved from a perception of fever as nothing more than a rise in core temperature to one in which fever is recognized as a complex physiological response characterized by a cytokine-mediated rise in temperature, as well as by generation of acute-phase reactants and activation of a panoply of physiological, endocrinologic, and immunologic systems. The average clinician appears to have little more than a regrettably rudimentary knowledge of these modern concepts of fever. This symposium summary considers many such concepts that have immediate relevance to the practice of medicine.

Fever: Blessing or Curse? A Unifying Hypothesis

Lear: But yet thou art my flesh, my blood, my daughter; Or rather disease thats in my flesh, Which I must needs call mine, thou art a boil, A plague-sore, an embossed carbuncle, In my corrupted blood. Shakespeare King Lear. 2.6 The teleologic significance of the febrile response has recently generated considerable controversy. Substantial data indicate both potentiating and inhibitory effects of the response on resistance to infection, and no unifying hypothesis has been offered to explain such apparently contradictory observations. As a result, confusion exists concerning appropriate clinical situations (if any) in which fever or its mediators should be suppressed. Beneficial Effects Data illustrating fevers beneficial effects come from several sources. Studies of the phylogeny of fever have shown that the response is widespread within the animal kingdom [1]. With few exceptions, reptiles, amphibians, and fish, as well as several invertebrate species, have been shown to manifest fever in response to challenge with microorganisms or other known pyrogens. This fact has been viewed by some as the strongest evidence that fever is an adaptive response, based on the argument that the metabolically expensive increase in body temperature that accompanies the febrile response would not have evolved and been so faithfully preserved within the animal kingdom unless fever had some net benefit to the host. Further evidence of fevers beneficial nature can be found in many investigations showing that various animals have enhanced resistance to infection with increases in body temperature within the physiologic range [1]. Of these, several reported by Kluger and associates [1, 2] deserve particular attention because of the quality of the experimental fever model. The model involves infection of the reptile Dipsosaurus dorsalis with Aeromonas hydrophila, one of the animals natural pathogens. In their initial work with the model, Kluger and associates established that D. dorsalis responds to infection by increasing its thermal set point in a fashion remarkably similar to that of the febrile response of mammals. Unlike mammals, however, D. dorsalis, a poikilotherm, raises its body temperature in response to infection by behavioral means and can do so only if placed in an environment having an appropriate thermal gradient. By manipulating the models thermal gradient, Kluger and colleagues showed a direct correlation between body temperature and survival after infecting the lizards with A. hydrophila. They also showed that suppression of the febrile response of infected reptiles with sodium salicylate results in a substantial increase in mortality [3]. Covert and Reynolds [4] duplicated these findings in an experimental model involving goldfish. In mammalian experimental models, increasing body temperature by artificial means has been reported to enhance resistance of mice to herpes simplex virus [5], poliovirus [6], Coxsackie B virus [7], rabies virus [8], and Cryptococcus neoformans [9] but to decrease resistance to Streptococcus pneumoniae [10]. Increased resistance of rabbits to S. pneumoniae [11] and C. neoformans [12], of dogs to herpes virus [13], of piglets to gastroenteritis virus [14], and of ferrets to influenza virus [15] has also been observed after induction of artificial fever. Unfortunately, because raising the body temperature by artificial means does not duplicate the physiologic alterations that occur during fever in homeotherms (and, indeed, entails several opposite physiologic responses [16]), data obtained using mammalian experimental models have been less convincing than those obtained using reptiles or fish. Like the animal data, clinical data include evidence of both beneficial effects of fever and adverse effects of antipyretics on the outcome of infections. In a retrospective analysis of 218 patients with gram-negative bacteremia, Bryant and colleagues [17] reported a positive correlation between maximum temperature on the day of bacteremia and survival. A similar relation has been observed in an analysis of 184 cases of polymicrobial sepsis using log linear models [18]. When Weinstein and colleagues [19] examined factors influencing the prognosis of spontaneous bacterial peritonitis, they identified an association between a temperature of greater than 38 C and increased survival. It has been reported that children with chickenpox who are treated with acetaminophen have a longer time to total crusting of lesions than controls who receive placebo [20]. Stanley and colleagues [21] have reported that adults infected with rhinovirus have more nasal viral shedding when they receive aspirin than when given placebo. Further, Graham and colleagues [22] have reported a trend toward longer duration of rhinovirus shedding in association with antipyretic therapy and have shown that use of aspirin or acetaminophen is associated with suppression of the serum-neutralizing antibody response and with increased nasal symptoms and signs. These data, like those reviewed above, can be interpreted in several ways and do not prove a causal relation between fever and improved prognosis during infection. Nevertheless, they are consistent with such a relation, and when considered in concert with the phylogeny of the febrile response and the animal data outlined above, the data leave little doubt that, at least in some situations, fever is an adaptive response. Whereas the foregoing investigators examined the relation between the elevation of core temperature and the outcome of infection, others have considered the endogenous mediators of the febrile response. In such studies, all five of the major pyrogenic cytokines (that is, interleukin-1, tumor necrosis factor, interleukin-6, interferon, and interleukin-2) have been shown to have immune-potentiating capabilities that might theoretically enhance resistance to infection [23]. In vitro and in vivo investigations of these cytokines have provided evidence of a protective effect of interferon, tumor necrosis factor, or interleukin-1 against plasmodia species [24-26], Toxoplasma gondii [27], Leishmania major [28], Trypanosoma cruzi [29], and Cryptosporidium species [30]. In studies of Plasmodium berghei, Mellouk and colleagues [24] showed that interferon inhibits development of intrahepatic sporozoites by stimulating host cells to produce L-arginine-derived nitrogen oxides that are toxic to the intracellular parasite. Others have shown a similar phenomenon in macrophages stimulated by tumor necrosis factor in combination with interferon [28]. Several recent reports have also shown that pyrogenic cytokines enhance resistance to viral [31-33] and bacterial infections [34, 35]. Although the previous data make a convincing case for a beneficial effect of fever and its mediators on the outcome of infection, this benefit appears to be limited. Treatment of normal and granulocytopenic animals with interleukin-1 has been shown to prevent death in some gram-positive and gram-negative bacterial infections [35]. However, interleukin-1 is effective only if administered an appreciable time (for example, 24 hours) before initiation of infections having rapidly fatal courses. In less acute infections, interleukin-1 administration can be delayed until shortly after the infectious challenge. Such observations suggest that those physiologic alterations of fever that enhance resistance to infection might be clinically effective only against localized infections and the early stages of systemic infections when these infections are of only mild to moderate severity. It is of interest, in this regard, that the protection against A. hydrophila by fever in the lizard has been attributed to enhanced influx of inflammatory cells into the local site of inoculation of the gram-negative bacterium, thereby preventing its dissemination [36]. Adverse Effects The febrile responses potential for harm is reflected in a recent flurry of reports suggesting that interleukin-1, tumor necrosis factor, interleukin-6, and interferon mediate the physiologic abnormalities of certain infections. Although proof of an adverse effect of fever on the clinical outcome of these infections has yet to be established, the implication is that if pyrogenic cytokines contribute to the pathophysiologic burden of infections, both the mediators themselves and the febrile response are potentially deleterious. The most persuasive evidence in this regard originates from studies of gram-negative bacterial sepsis [37]. It has long been suspected that bacterial lipopolysaccharides play a pivotal role in the syndrome. Purified lipopolysaccharide induces a spectrum of physiologic abnormalities that are similar to those occurring in patients with gram-negative bacterial sepsis. In experimental animals, challenge with lipopolysaccharide causes tumor necrosis factor and interleukin-1 to be released into the bloodstream coincident with the appearance of signs of sepsis [38]. Interleukin-1, alone or in combination with other cytokines, induces many of the same physiologic abnormalities (for example, fever, hypoglycemia, shock, and death) seen after administration of purified lipopolysaccharide [39]. In a murine experimental model for septic shock, interferon administered before or as long as 4 hours after lipopolysaccharide challenge increases mortality, whereas pretreatment with anti-interferon antibody significantly reduces mortality [40]. In several recent investigations, the adverse effects of gram-negative bacterial sepsis or lipopolysaccharide injections or both have been attenuated by pretreating experimental animals with interleukin-1 antagonists [41, 42] and monoclonal antibodies directed against tumor necrosis factor [43, 44] and interleukin-6 [45]. Further, animals rendered tolerant to tumor necrosis factor by repeated injections of recombinant tumor necrosis factor are protected against the hypotension, hypothermia, and lethality of gr

Infections in hairy cell leukemia: Clinical evidence of a pronounced defect in cell-mediated immunity

We compared infection rates in 12 patients with hairy cell leukemia (a malignant neoplasm for which the cell of origin remains controversial) with rates in 15 patients with chronic lymphocytic leukemia (a known B-lymphocyte neoplasm) recently treated at four Dallas hospitals. We found a significantly higher over-all rate of infections in the patients with hairy cell leukemia (P = 0.004 BY Gehans variation on the generalized Wilcoxon test). This increased rate was primarily due to a significantly higher rate of infections normally controlled by the cell-mediated immune system (P = 0.005). Despite these findings, five of six patients with hairy cell leukemia who were skin-tested exhibited intact delayed type hypersensitivity, and each of the three patients examined serologically produced antibodies normally in response to recent infections. A review of the case records of 173 previously described patients with hairy cell leukemia, demonstrated a similar predilection of patients with this disease for infections normally controlled by cell-mediated immunity. In this regard, they were similar to previously described patients with Hodgkins disease. Both over-all infection rates and rates of fatal infection were highest in patients with hairy cell leukemia who received chemotherapy as their sole form of treatment and lowest in those who underwent splenectomy as their only form of antitumor therapy.

Brief history of antipyretic therapy.

Both external cooling and pharmacotherapy have been used to treat fever since time immemorial. In the past century such treatments have proliferated at an astonishing rate. The COX-2 inhibitors are the most recent additions to the antipyretic pharmacopoeia. Additional research is needed to determine whether they represent an important new chapter in antipyretic therapys long history or, for that matter, if the benefits of any currently available treatment for fever outweigh its cost.

The relationship between age and fever magnitude.

Background: Infections are an important cause of morbidity and mortality in older people; however, they are often difficult to diagnose because the signs and symptoms of infection in older people are frequently atypical. Fever, one of the most important signs of infection, is a case in point. Preliminary evidence suggests that the febrile response in older persons is blunted, leading to the clinical maxim, “the older, the colder.” The objective of this study was to assess the effect of age on the febrile response to moderate‐to‐severe pneumonia in hospitalized patients adjusted for the effect of anatomic site at which the temperature was measured. Methods: This is a retrospective cohort study of 320 hospitalized patients with moderate‐to‐severe pneumonia. The study was designed to assess the effect of age on the febrile response to moderate‐to‐severe pneumonia in hospitalized patients, adjusting for the effect of the anatomic location of the temperature measurement. The highest temperature of each day and the anatomic sites at which temperatures were taken (axillary, oral, rectal, or other) on days 1 and 2 of infection and at hospital discharge. Baseline demographic information, including age, were obtained for each patient. Results: There were 320 patients (median age, 64 years; range, 18–97 years). Using a linear regression model, significant inverse correlations were found between age and the temperature for patients on the first and second days of hospitalization (P<0.001). For each decade increase in age, the average temperature on the first 3 days of infection was lower by 0.15°C. Temperature at discharge, a surrogate for baseline temperature, also decreased at an equal rate with age. Conclusion: In this study, the febrile response to infections was reduced with increasing age and baseline temperatures were generally lower in older patients.

Recycling Metchnikoff: probiotics, the intestinal microbiome and the quest for long life

Over a century ago, Elie Metchnikoff theorized that health could be enhanced and senility delayed by manipulating the intestinal microbiome with host-friendly bacteria found in yogurt. His theory flourished for a time, then drifted to the fringe of medical practice before re-emerging in the mid-1990s as a concept worthy of mainstream medical attention. Metchnikoff also predicted the existence of bacterial translocation and anticipated theories linking chronic inflammation with the pathogenesis of atherosclerosis and other disorders of the aged.

Physiological Rationale for Suppression of Fever

Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the other is that suppression of fever will reduce, if not eliminate, the noxious effects of fever. At present, neither assumption has been validated experimentally.

Teichoic Acid Antibodies in Chronic Staphylococcal Osteomyelitis

Gel-diffusion and the enzyme-linked immunosorbent assay (ELISA) were used to quantify and to identify the immunoglobulin class of teichoic acid antibodies in patients with chronic staphylococcal osteomyelitis and a wide variety of other infections. Teichoic acid antibodies were identified by gel-diffusion in 14 of 23 patients with staphylococcal endocarditis, six of 30 with staphylococcal bacteremia without endocarditis, four of 35 with staphylococcal skeletal infections, and one of 45 with nonstaphylococcal infections. None of the 20 patients with chronic staphylococcal osteomyelitis had positive gel-diffusion assays, even though many had had their infections for several years. The ELISA method was more sensitive than gel-diffusion in measuring teichoic acid antibodies, but was also much less specific. Teichoic acid antibodies were detected predominantly in the IgG fraction of serum. Our findings suggest that the presence and degree of antigenemia are more important than the duration of the staphylococcal infection in stimulating production of teichoic acid antibodies.

Diagnostic Implications and Clinical Consequences of Antipyretic Therapy

It has been suggested that the response to antipyretic therapy might differentiate between fevers due to serious illness and fevers caused by less severe disorders; that neoplastic fevers are more responsive to nonsteroidal anti-inflammatory drugs than are infectious fevers; that the metabolic costs of fever can exceeds its clinical benefits; that antipyretic therapy can prevent or reverse febrile seizures in children and fever-associated mental dysfunction in frail elderly patients. This article examines the data on which these assertions are based.