The role of antihistamines in upper respiratory tract infections

The role of antihistamines in upper respiratory tract infections Robert C. Welliver, MD Buffalo, N.Y. Antihistamines are commonly administered for URI, but their efficacy cannot be easily demonstrated. Three placebo-controlled, double-blind studies identified either a slight or no beneficial effect of oral (chlorpheniramine and terfenadine) and nasal (diphenhydramine) antihistamines on mild and moderately ill patients with One reason for this lack of effect is that unlike other mediators (e.g., kinins, albumin, and neutrophils) that have been found to correlate with symptoms of URI, histamine is not present in increased concentrations in persons with Viruses can induce histamine release from basophils during subsequent exposure to antigens. Some studies have shown that this mechanism is mediated by interferon. Histamine release independent of antigen challenge has not been demonstrated. Some infected persons manifest the production of virusspecific IgE antibodies; this is most common in the nasopharyngeal secretions of patients with wheezing. Histamine and LTC4 have been noted in higher concentrations in these patients than in patients infected without wheezing. This subpopulation of virusspecific IgE responders may be candidates for antihistamine therapy. Antihistamines are commonly used to treat URIs. This article explores the effectiveness of antihistamines in It also reviews studies designed to determine which mediators are important in causing the symptoms of Finally, it describes the formation of virus-specific IgE and the release of such chemical mediators into the airway at the time of viral infection. STUDIES OF THE EFFECTS OF ANTIHISTAMINES IN URI Several meticulously designed trials have evaluated the effect of antihistamines in Crutcher and From the Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, and the Division of Infectious Diseases, The Children's Hospital, Buffalo, N.Y. Reprint requests: Robert C. Welliver, MD, Division of Infectious Diseases, Children's Hospital, 219 Bryant St., Buffalo, NY 14222. 1/0/23311 Abbreviations used URI: Upper respiratory tract infections TAME: Tosyl-L-arginine methyl ester PGD2: Prostaglandin Dz RSV: Respiratory syncytial virus LTC4: Leukotriene C4 Kantner I studied 106 persons who were ill for less than 48 hours with symptoms of a These subjects received either chlorpheniramine, 4 mg four times daily, or a placebo. For the first 48 hours after enrollment in the study, they were confined at the study site. The patients were examined three times a day during the period of confinement and kept illness logs both while confined and for up to 7 days after the onset of the illness. Severity of illness was determined by measuring each of five symptoms and four signs on a 4-point scale. Inclusion criteria were symptom scores ->6 and sign scores ->5; patients with lower scores (i.e., those with milder forms of illness) were excluded from this study. At the end of each day, a global assessment of patient illness and side effects was recorded. The results slightly favored antihistamine therapy in Cumulative illness scores, which were calculated by adding up the illness scores on each day, were lower in the chlorpheniramine group (p < 0.005); cumulative sign scores fell just short of statistical significance (p = 0.052). Global assessments favored the treatment group by day 2 of the study and continued to favor the treatment group through day 7. Side effects were reported with equal frequency in both placebo and antihistamine groups. However, the beneficial effects averaged between 0.5 to 1.0 illness point per day, which indicated that the clinical benefit was minimal in those receiving the antihistamine. In another study, 2 the effects of antihistamines administered either orally or by nasal spray were evaluated in persons experimentally inoculated with rhinovirus type 39. This study involved 23 adults who were seronegative for rhinovirus at the time of experimental infection. Twenty-four hours after inoculation, they were given chlorpheniramine (4 mg four times daily), diphenhydramine nasal spray (adminis- 633

634 Welliver J. ALLERGY CLIN. IMMUNOL, OCTOBER 1990 TABLE I. Mediators in antigen-induced rhinitis Mediator Early response Late response Histamine Increased Increased TAME esterase Increased Increased Kinins Increased PGD2 Increased No change Data from Naclerio RM, Proud D, Togias, AG, et al. N Engl J Med 1985 ;3 t 3:65-70, by permission of the New England Journal of Medicine. TABLE I!. Correlation of mediator concentration with illness scores in experimental rhinovirus URI Substance in Correlation secretions coefficient Probability Kinins 0.549 <0.01 TAME-esterase activity 0.563 <0.005 Neutrophils 0.605 <0.005 Albumin 0.674 <0.001 Histamine - 0.041 NS Data from Naclerio RM, Proud D, Lichtettstein LM, et al. J Infect Dis 1988;157:133-42, University of Chicago, publisher. tered two times daily), or an appropriate placebo. These persons were also sequestered for several days. During this time, illness Symptoms were monitored three times a day, and the number Of facial tissues used for nose blowing were counted. Nasal patency was monitored by an airflow measuring device on the third day after the onset of illness. Inoculated persons shed virus for 70% to 80% of the patient days, regardless of the form of therapy they received, which indicated no antiviral effect of the antihistamine preparations. The number of persons who developed symptoms of URI was slightly lower in the antihistamine group, as were nasal symptom scores. However, none of these differences was of great magnitude, and none was statistically significant. Nasal patency improved for approximately 2 hours after each inhalation of diphenhydramine nasal spray compared with placebo spray, but this improvement was not maintained beyond this interval. This study exhibited some benefit of the use of antihistamines in URI, but it was limited by the small number of patients studied as well as by the mild nature of the illnesses present in the study participants. Even with comparatively high doses of antihistamine reaching the nasal mucosa by way of the diphenhydramine spray, large differences in illnesses were not observed. A third study 3 evaluated the effectiveness of terfenadine in adults with recent onset of symptoms of Symptoms resolved at about the same rate in patients receiving terfenadine as in placebo recipients. This study exhibited a strong placebo effect in the management of URI; 48% of placebo recipients said they would use the same study medication again for treating cold symptoms. INFLAMMATORY MEDIATORS IN URI The levels of various inflammatory mediators have been measured during early and late allergic responses to nasal challenge with pollen antigen in sensitive patients/as shown in Table I, histamine, TAME esterase, kinins, and PGD2 are increased after early responses; histamine and TAME esterase are also increased after late responses. Kinins show a borderline increase after late responses, but PGD2 shows no change from baseline over the same period. Naclerio et al. 5 studied these same mediators in experimental rhinovirus Persons with symptoms of infection showed increases in levels of kinins, TAME-esterase activity, and albumin, as well as in the number of neutrophils in nasal secretions. Asymptomatic but infected individuals and uninfected individuals did not develop similar increases. The total number of reported symptoms correlated significantly with the total measured concentrations of kinins, albumin, TAME-esterase activity, and neutrophils, with albumin and neutrophil concentrations correlating most strongly. Illness scores tended to rise before kinin or albumin levels began to increase. Kinin concentrations showeda marked diurnal variation, whereas respiratory symptoms remained relatively constant. More importantly, histamine concentrations did not increase in any subject group and did not correlate with symptom scores (Table II). Therefore on the basis of these data, antihistamines would not be expected to have an important effect on the course of illness during VIRUS-BASOPHIL INTERACTIONS Several investigations into whether viruses are capable of inducing histamine release by direct interaction with basophils have been completed. ~-s The first of these studies 6 found that incubation of a variety of viruses with leukocyte preparations enhanced the ability of basophils to release histamine when subsequently challenged with either ragweed antigen E or anti-ige. The same authors presented considerable evidence to indicate that interferon was responsible for the enhanced histamine release. In another study 7 incubation of leukocyte prepara-

VOLUME 86 Antihistamines in URI 635 NUMBER 4, PART 2 tions with influenza A virus enhanced subsequent histamine release on challenge with ragweed antigen E or a calcium ionophore. Incubation of leukocyte suspensions with interferon enhanced histamine release to ragweed antigen E but not to the ionophore, suggesting the existence of both interferon-dependent and interferon-independent mechanisms that enhance histamine release. In a third study, 8 viruses such as influenza and rhinovirus type 13, which are potent inducers of interferon, were shown to be capable of inducing enhanced histamine release. However, this was also true of viruses such as RSV and rhinovirus type 1, which are incapable of inducing significant production of interferon. Thus there appear to be several mechanisms by which viruses may enhance histamine release during subsequent exposure to allergens. However, none of the studies demonstrated histamine release during direct incubation of viruses with basophils. This research was carried out in nonallergic persons; the outcome might be different in persons with atopic dispositions or in those with high titers of [ge antibody directed against specific viruses. VIRUS-SPECIFIC IgE RESPONSES Studies of infants with RSV and parainfluenza virus infections have demonstrated the production of virusspecific IgE antibody at the time of infection with these agents. 9ll As shown in Table III, virus-specific IgE is found infrequently in persons who develop URIs or pneumonia without wheezing at the time of infection with these agents. In contrast, most patients who develop wheezing at the time of infection with either of these agents develop virus-specific IgE responses in their nasopharyngeal secretions. Histamine and LTC4 have also been demonstrated to be present in the respiratory secretions of persons with RSV infection.9, 12 Histamine is measurable in low concentrations in a few persons with URI alone at the time of RSV infection, but with greater frequency and in higher concentrations in those patients with wheezing at the time of RSV infection (Table IV). LTC4 is also recovered significantly more often and in greater concentrations in persons with wheezing than in nonwheezing, infected persons. Because no samples were obtained before RSV infection in these persons, it is not known how much of an increase in histamine or LTC4 occurred from baseline. In other unpublished data from our laboratories, concentrations of histamine and leukotrienes have usually not been detectable in persons who have no symptoms and are uninfected. TABLE III. Frequency of detection of RSV or parainfluenza virus-specific IgE antibody in nasopharyngeal secretions after infection Frequency of detection of virus-specific IgE No. positive/no, tested (%) Time after onset of illness (d) Cause of Form of infection illness 0-7 14-35 RSV URI 0/9 (0) 0/4 (0) Pneumonia 0/9 (0) 1/7 (14) Wheezing 24/53 (45) 23/35 (66) PIV URI 1/10 (10) 3/10 (30) Wheezing 8/12 (67) 6/8 (75) Data from Welliver RC, Wong DT, Sun M, Middleton E Jr, Vaughan RS, Ogra PL. N Engl J Med 1981;305:841-6, and Welliver RC, Wong DT, Sun M, McCarthy N. Am J Dis Child 1986;140:34-40, copyright 1986, American Medical Association. ['IV, Parainfluenza virus. TABLE IV. Release of inflammatory cell mediators during viral infection Form of illness Histamine* LTC4t No. positive/no. No. positive/no, tested (%); mean tested (%); mean concentration concentration Non-RSV URI 3/15 (20); 0.4 -- RSV URI 1/2 (50); 1.1 7/21 (33); 224 RSV bronchiolitis 27/37 (73); 2.8 29/43 (67); 1271 Data from Welliver RC, Wong DT, Sun M, Middleton E Jr, Vaughan RS, Ogra PL. N Engl J Med 1981;305:841-6; and Volovitz B, Welliver RC, DeCastro G, Krystofik DA, Ogra PL. Pediatr Res 1988;24:504-47. *Histamine concentration in ng/ml of fluid recovered. tltc4 concentration in pg/0.1 ml of fluid recovered. ANTIHISTAMINES IN THE PREVENTION OF OTITIS MEDIA AFTER URI Otitis media is a relatively common complication of URI in children. Although usually not serious, it is temporarily painful. In addition, it may exert long-term adverse effects on hearing or the development of language skills in patients with persistent ear infections. If antihistamines or decongestantantihistamine combinations could maintain the patency of the eustachian tubes, they could be beneficial in the prevention of the development of otitis media in children with

636 Welliver J. ALLERGY CLIN. IMMUNOL. OCTOBER 1990 In one study, 13 475 episodes of URI occurred in 104 preschool children older than 9 months of age. At the onset of upper respiratory tract symptoms, the children received either a placebo or a decongestant-antihistamine compound containing brompheniramine. Fifteen (6.4%) of 234 colds treated with placebo and 14 (5.8%) of 241 colds treated with the decongestant-antihistamine compound were followed by otitis media, which indicates that antihistamines are not effective in the prevention of ear infections after Whether an atopic disposition predisposes a child to the development of otitis media remains controversial.~4. ~5 In any case, the administration of oral decongestant-antihistamine compounds to children with middle ear effusions has not been shown to be beneficial, whether all patients with serous effusions or only those patients with a history of allergy were evaluated. 16 CONCLUSION In summary, several studies suggest a beneficial effect for antihistamines in URI, and at least an equal number show no beneficial effects. Even in the studies with positive results, the effects are comparatively minor and probably not of much clinical benefit. Sedative effects were not observed, thus allowing for the possibility that higher doses of antihistamines might produce more apparent benefit. However, the fact that persons with URI do not seem to have increased concentrations of histamine in comparison with uninfected persons suggests little expected benefit from the use of antihistamines in this population. Certain subsets of persons develop virus-specific IgE in nasopharyngeal secretions and release mediators when they develop These are predominantly patients who have wheezing at the time of infection. It is not clear that the same changes occur in persons who have only UR/at the time of infection. Nevertheless, a prospective evaluation of atopic individuals at the time of URI for the development of virusspecific IgE and mediator re/ease might identify a subset of persons who would be candidates for antihistamine therapy. Finally, on the basis of current data, there does not seem to be a role for antihistamines in the prevention of otitis media in persons with REFERENCES 1. Crutcher JE, Kantner TR. The effectiveness of antihistamines in the common cold. I Clin Pharrnacol 1981;21:9-15. 2. Gaffey JM, Gwaltney JM, Sastre A, Dressier WE, Sorrentino JV, Hayden FG. Intranasally and orally administered antihis- tamine treatment of experimental rhinovirus colds. Am Rev Respir Dis 1987;136:556-60. 3. Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness of oral terfenadine in natural colds: evidence against histamine as a mediator of common cold symptoms. Pediatr Infect Dis J 1988;7:223-8. 4. Naclerio RM, Proud D, Togias AG, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 1985; 313:65-70. 5. Naclerio RM, Proud D, Lichtenstein LM, et al. Kinins are generated during experimental rhinovirus colds. J Infect Dis 1988; 157:133-42. 6. Ida S, Hooks JJ, Siraganian P, Notkins AL. Enhancement of IgE-mediated histamine release from human basophils by viruses: role of interferon. J Exp Med 1977;145:892-906. 7. Busse WW, Swenson CA, Borden EC, Treuhaft MW, Dick EC. Effect of influenza A virus on leukocyte histamine release. J ALLERGY CLIN IMMUNOL 1983;71:482-8. 8. Chonmaitree T, Lett-Brown MA, Tsong Y, Goldman AS, Baron S. Role of interferon in leukocyte histamine release caused by common respiratory viruses. J Infect Dis 1988; 157:127-32. 9. Welliver RC, Wong DT, Sun M, Middleton E Jr, Vaughan RS, Ogra PL. The development of respiratory syncytial virusspecific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med 1981;305:841-6. 10. Bui RHD, Molinaro GA, Kettering JD, Heiner De, Imagawa DT, St. Geme JW Jr. Virus-specific IgE and IgG4 antibodies in serum of children infected with respiratory syncytial vires. J Pediatr 1987;110:87-90. 11. Welliver RC, Wong DT, Sun M, McCarthy N. Parainfluenza virus bronchiolitis: epidemiology and pathogenesis. Am J Dis Child 1986;140:34-40. 12. Volovitz B, Welliver RC, DeCastro G, Krystofik DA, Ogra PL. The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res 1988;24:504-7. 13. RandallJE, Hendley JO. A decongestant-antihistaminemixture in the prevention of otitis media in children with colds. Pediatrics 1979;63:483-5. 14. Draper WL. Secretory otitis media. Laryngoscope 1967;78: 636-41. 15. Virolainen E, Puhakka H, Aantaa E, Tuohimaa P, Ruuskanen O, Meurman OH. Prevalence of secretory otitis media in 7 to 8 year old children. Ann Otol Rhinol Laryngol 1980;89(suppl): 7-10. 16. Cantekin EI, Mandell EM, Bluestone CD, et al. Lack of efficacy of a decongestant-antihistamine combination for otitis media with effusion ("secretory" otitis media) in children. N Engl J Med 1983;308:297-301. DISCUSSION Question. Many patients with allergic rhinitis report that they seem to have colds that last for a long time. One interpretation of their comments is that what they are experiencing are really not colds but allergies. Another interpretation is that maybe they do get colds more often, perhaps because their mucosa is more susceptible. With that background, are patients with allergic rhinitis especially vulnerable to the development of colds? Dr. Welliver. They do not seem to get more frequent

VOLUME 86 Antihistamines in URI 637 NUMBER 4, PART 2 colds, at least not in the pediatric populations that have been studied. The frequency of colds seems to be the same, particularly the frequency of documentable colds, in which in addition to the presence of symptoms, you can recover a virus. Question. In the study you described on the prevention of otitis media, do you know how many of the patients were allergic? Dr. Welliver. No, I do not think that was investigated in that study. Other investigators have looked at the incidence of otitis media in children with high IgE and low IgE concentrations, and it did not seem to be different; neither did the number of colds or the number of lower respiratory tract illnesses not associated with wheezing. The frequency of wheezing was definitely skewed toward groups with high IgE titers. Question. You discussed the production of anti-ige antibodies in response to RSV infection. Has anyone done those types of studies on rhinovirus to see if that viral antigen is capable of eliciting an IgE antibody? Dr. Welliver. The advantage of conducting this research with RSV is that there is essentially one serotype. Studies on rhinovirus are more complicated, and we have not done them yet, because so many serotypes exist. It would be necessary to know each person's infecting serotype before we could look at his or her response.