- Email: [email protected]
Natural history of frequent recurrences of herpes simplex labialis
Natural history of frequent recurrences of herpes simplex labialis Larry E. Davis, MD, FACP,* Jack C. Redman, MD,** Leroy C. McLaren, PhD,*** Albuquerque, NM, UNIVERSITY
OF NEW
MEXICO
SCHOOL
Betty J. Skipper, PhD,**
and
OF MEDIClNE
We prospectively studied all herpes simplex labialis (HSL) episodes in a group of 84 (age, 6 to 7 1 years) persons who previously had frequent recurrences of HSL to determine whether their recurrences of HSL were different from those of the general population. The mean ~?rstandard error for number of HSL outbreaks for 6 months was 2.7 + 0.3. Age, gender, or season did not influence the recurrence rate. The mean time to vesicle healing of 214 outbreaks was 6.4 f 0.2 days. Again, age or gender did not influence healing time. An episode of HSL did not elicit a refractory period to the next attack of HSL. Furthermore, the severity of the previous HSL lesion did not influence the interval to next recurrence or the location of the next lesion. In 47%, the next recurrence of HSL crossed the midline of the face, and in 45%~, it moved from one lip to the other. The high recurrence frequency and multiple facial locations of HSL lesions seen in these persons differed from the general population, who report infrequent lesions of HSL at the same facial location. (ORAL SURC ORAL MED ORAL PATHOL 1988;66:558-61)
A
t least 100 million American adults are infected with the herpes simplex virus.’ From 20% to 40% of adults have infrequent recurrent HSL, but in 2% it is a serious problem. =x3Whereas much is known about the virology of individual HSL lesions,4s5less is known about the frequency and characteristics of recurrences of HSL.5 In particular, there is little information about the nature of recurrences of HSL in persons who have frequent recurrences of HSL. Are these persons at the upper end of a normal spectrum of recurrent HSL or are they different from the normal population? We had the opportunity to perform a two-part study of a population of healthy persons with frequent recurrences of HSL. First, we determined, in a double-blind, placebocontrolled study, whether intradermal gamma globulin had efficacy in preventing recurrences of HSL. Gamma globulin was tested because an anecdotal report suggested it to be beneficial in preventing
*Neurology Service, Veterans Administration Medical Center, and the Departments of Neurology and Microbiology, University of New Mexico School of Medicine, Albuquerque, N.M. **Department of Family, Community Medicine, and Emergency Medicine, University of New Mexico School of Medicine. ***Department of Microbiology, University of New Mexico School of Medicine.
558
recurrences of HSL.6 In our double-blind study, we found that gamma globulin was not different from placebo.’ Second, we prospectively evaluated the characteristics of each person’s recurrences of HSL including facial location, severity, interval between recurrences, and possible interactions of one HSL lesion on the next HSL episode. Since no differences were found between the two treatment groups, data from both groups were pooled for the natural history analysis of frequent recurrences of HSL. MATERIALS
AND METHODS
One hundred healthy persons who reported at least eight recurrences of HSL in the preceding 2 years volunteered. Before entry into the study, all persons were examined during a recurrence of HSL for the presence of typical HSL lesions by a physician experienced in diagnosing HSL. Patients with atypical or doubtful lesions were excluded. Informed consent was obtained after the nature of the study was explained. Personswere asked to carefully document on a questionnaire each recurrence of HSL for the next 6 months, including a comparison of the severity of each outbreak of HSL with the severity of their average outbreak of HSL. Enrollment in this study occurred over a period of 3 years. The results were statistically analyzed by chi square and analysis
Recurrent herpes simplex labialis
Volume 66 Number 5
0
1
2
3
4
5
6
7
0
9
IO
11
559
12
Number of HSL Recurrences / 6 Months Fig.
Table
1.
Recurrences
of herpes
simplex labialis during the 6month study period.
I. Effect of gender and age on frequency of herpes simplex labialis Group
Total Females Males <29 years 30-54 years >.5S years
Mean HSL frequency before study (per 6 months) 3.5 3.4 3.7 4.3 3.6 2.5
+ k 2 2 i r
0.3* 0.3 1.0 0.5 0.6 0.1
Mean HSL frequency during study (per 6 months)
(82)? (63) (19) (20) (39) (23)
2.7 2.7 2.7 2.0 3.4 2.2
k 2 -t j: 2 +
0.3* 0.3 0.6 0.3 0.5 0.3
(84) (65) (19) (21) (39) (24)
Mean HSL duration during study (days) 6.5 6.6 6.3 7.5 6.2 6.1
-t 0.3* t 0.4 +_ 0.6 zt 1.0 Z!I 0.4 rf: 0.5
(72) (54) (18) (16) (35) (21)
‘Numbers represent mean + SE. t( ) is number in sample. Ten persons did not have any episodes of HSL during the study and two failed to give accurate dates of HSL outbreaks or exact number of outbreaks in preceding 2 years.
of variance. The entry HSL lesion was not included in this statistical analysis. RESULTS
Eighty-four of the 100 persons returned the completed questionnaire and were included in this analysis. Two hundred fourteen attacks of HSL were analyzed. The mean + standard error of recurrences of HSL per 6 months was 2.7 & 0.3 (Fig. 1). Neither gender nor age influenced the rate of recurrence of HSL (Table I). The mean duration & standard error of HSL lesion was 6.5 -t 0.3 days. Again, neither
gender nor age influenced the time to healing (Table I). Recurrent lesions of HSL occurred in the following lip areas: right upper, 26%; right lower, 19%; left upper, 23%; left lower, 22%; and nose, 10%. Vesicles appeared more commonly on the upper lip, but the difference was not significant. We found no significant differences in localization of HSL lesions when data were analyzed by gender or age (data not shown). The site of the next recurrent lesion of HSL seldom was in the same facial quadrant. In 45% of 138 recurrent lesions with accurate reported location, the next HSL lesion moved from one lip to the
560
Davis et al.
Table
II. Effect of a herpes simplex labialis lesion on interval to and severity of next lesion _____-
Oral ‘November
Severity of initial lesion*
Sample size
Mean duration of initial lesions (days)
Less severe than usual Usual severity More severe than usual
78 57 16
5.0 7.1 9.0
Median interval to next lesion (days1 20 17 25
Severity of next HSL lesion**
Surf 1988
(% I
Less severul--~--‘-~~------~~-Usual ~ More sew-c than usual ) severit} than usual -64 41 31
31 41 38
5 12 25
*Subjects rated each outbreak of HSL with respect to severity of their typical or average HSL lesion. **There is a statistically significant association between the severity of the initial lesion and the severity of the next lesion (p < 0.05).
other. In 47% of 88 recurrent lesions in which the side of the previous lesion was reported, the next lesion crossedthe midline to appear on the contralatera1 side. Season did not influence the frequency of recurrence: winter (December to February), 1.4 lesions/ person; spring (March to May), 1.5; summer (June to August), 1.2; and fall (September to November), 1.4 (not significant). When analyzed for separate age strata, the season also did not influence the recurrence rates. The severity of the previous HSL lesion influenced the severity of the next lesion, but not the location of the next lesion or the interval to the next lesion (Table II). No refractory period to the next outbreak of HSL was found. During the next 4 weeks after the entry HSL lesion, five persons had the next outbreak in week 1, six in week 2, sevenin week 3, and nine in week 4. DISCUSSION
In this study, we found several differences between our group with frequent recurrences of HSL and the general population. Personsin our group reported an average of 3.5 episodesof HSL per 6 months over the 2 years before the start of the study. During the study, they had an average of 2.7 episodes of HSL per 6 months. Although the episodes were not verified by viral culture, our rate of recurrence was similar to the recurrence rate reported in three other studies of persons with frequent recurrences of HSL.8,9xloHowever, the recurrence rate was markedly higher than the 0.2 to 1 episode of HSL per 6 months reported for the general population.“,‘* It appears that persons who have frequent recurrences of HSL continue to have recurrences of HSL at a higher rate than the general population. If they were part of the general population, but just at the upper end of the normal curve of recurrences of HSL, one might have expected this group to have returned to the mean during the study. We found that an outbreak of HSL did not
produce any refractory period to the next attack of HSL. Six percent of the subjects had their next attack within 1 week and 13% within 2 weeks of the entry HSL episode. Furthermore, increased severity of the previous HLS lesion, as reported by the subject, did not affect the interval to the next recurrence of HSL, affect the location of the next lesion, or reduce the severity of the next lesion. In fact, an HSL lesion that was “more severe than usual” significantly increased the likelihood that the next recurrent lesion would also be “more severe than usual.” These clinical observations have not been previously reported and suggest that large HSL lesions do not induce greater cellular or humoral immune responsesthat result in lengthening the time to next recurrence, lessening the severity of the next attack, or directing the location of the next lesion. This is consistent with another study that found the rate of occurrence of HSL lesions was not related to the magnitude of the serum herpes simplex virus antibody titer.13 The site of the next HSL lesion and the interval between attacks were found to vary markedly for any one person. In 47%, the next lesion crossedthe facial midline, and in 45%, it moved from one lip to the other. These findings and another study” suggest that the small number of persons with frequent recurrences of HSL differ biologically from members of the general population who report infrequent episodes of HSL, usually at the same facial site.3,‘4 Our findings also suggest that persons who have frequent recurrences may harbor herpes simplex virus that is latent in several different locations within both trigeminal ganglia. Virus reactivated within neurons in the different ganglion locations would then travel down different dendritic pathways to produce vesicles in different facial locations. It is interesting to speculate that these persons might harbor different herpes simplex virus strains within their trigeminal ganglia that could exacerbate at different times. This speculation is supported by the observation that whereas most trigeminal ganglia
Recurrent herpes simplex labialis
Volume 66 Number 5
harbor only one strain of herpes simplex virus,15 occasionally more than one strain has been isolated.16 This study was supported by the Research Veterans Administration Medical Center.
Service,
REFERENCES I. Nahmias AJ, Josey WE, Naib ZM, Lute CF, Duffy A. Antibodies to Herpesvirus hominis types 1 and 2 in humans. Am J Epidemiol 1970:91:539-46. 2. Ship II; Miller MF, Ram C. A retrospective study of recurrent herpes labialis (RHL) in a professional population, 1958-197 I. ORAL SURG ORAL MED ORAL PATHOL 1977; 44:723-30. 3. Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. ORAL SURG ORAL MED ORAL PATHOL 1976;41:498-507. 4. Spruance SL, Overall JC, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis. N Engl J Med 1977;297:69-75. 5. Corey L, Spear PG. Infections with herpes simplex viruses. N Engl J Med 1986;314:749-57. 6. Redman JC. lntradermal gamma globulin for herpetic diseases (letter). Postgrad Med 1984;75:60-4. I. Redman JC, Davis LE, McLaren LC, Skipper BJ. Intraderma1 gamma globulin for herpes labialis? Results of a doubleblind study. Postgrad Med 1986;79:315-8. 8. Aiuti F, Sirianni MC, Paganelli R, Stella A, Turbessi G, Fiorilli M. A placebo-controlled trial of thymic hormone treatment of recurrent herpes simplex labialis infection in immunodeficient hosts. Int J Clin Pharmacol Ther Toxicol 1983;21:81-6.
561
9. Milman N, Scheibel J, Jessen 0. Lysine prophylaxis in recurrent herpes simplex labialis: A double-blind, controlled crossover study. Acta Dermatovener (Stockholm) 1980; 60:85-7. 10. Bader C, Crumpacker CS, Schnipper LE, et al. The natural history of recurrent facial-oral infection with herpes simplex virus. J Infect Dis 1978;138:897-905. 11. Spoor HJ. The course and management of recurrent herpes. Cutis 1979;24:309-3, 335-6. 12. Lafferty WE, Coombs RW, Benedetti J, Critchlow C, Corey L. Recurrences after oral and genital herpes simplex virus infection. N Engl J Med 1987;316: 1444-9. 13. Higgins PG. Recurrent herpes simplex virus infections. Br J Dermatol 1974;91:11 l-3. 14. Douglas RG, Cough RB. A prospective study of chronic herpes simplex virus infection and recurrent herpes labialis in humans. Journal of Immunology 1970;104:289-95. 15. Lonsdale DM, Brown SM, Subak-Sharpe JH, et al. The polypeptide and DNA restriction enzyme profiles of spontaneous isolates of herpes simplex virus type 1 from explants of human trigeminal, superior cervical, and vagus ganglia. J Gen Virol 1979;43:151-71. 16. Lewis ME, Leung WC, Jeffrey VM, Warren KG. Detection of multiple strains of latent herpes simplex virus type 1 within individual human hosts. J Viral 1984:52:300-5. Reprint requests to: Larry E. Davis, M.D Neurology Service VA Medical Center 2100 Ridgecrest SE Albuquerque, NM 87108
OF NEW
MEXICO
SCHOOL
Betty J. Skipper, PhD,**
and
OF MEDIClNE
We prospectively studied all herpes simplex labialis (HSL) episodes in a group of 84 (age, 6 to 7 1 years) persons who previously had frequent recurrences of HSL to determine whether their recurrences of HSL were different from those of the general population. The mean ~?rstandard error for number of HSL outbreaks for 6 months was 2.7 + 0.3. Age, gender, or season did not influence the recurrence rate. The mean time to vesicle healing of 214 outbreaks was 6.4 f 0.2 days. Again, age or gender did not influence healing time. An episode of HSL did not elicit a refractory period to the next attack of HSL. Furthermore, the severity of the previous HSL lesion did not influence the interval to next recurrence or the location of the next lesion. In 47%, the next recurrence of HSL crossed the midline of the face, and in 45%~, it moved from one lip to the other. The high recurrence frequency and multiple facial locations of HSL lesions seen in these persons differed from the general population, who report infrequent lesions of HSL at the same facial location. (ORAL SURC ORAL MED ORAL PATHOL 1988;66:558-61)
A
t least 100 million American adults are infected with the herpes simplex virus.’ From 20% to 40% of adults have infrequent recurrent HSL, but in 2% it is a serious problem. =x3Whereas much is known about the virology of individual HSL lesions,4s5less is known about the frequency and characteristics of recurrences of HSL.5 In particular, there is little information about the nature of recurrences of HSL in persons who have frequent recurrences of HSL. Are these persons at the upper end of a normal spectrum of recurrent HSL or are they different from the normal population? We had the opportunity to perform a two-part study of a population of healthy persons with frequent recurrences of HSL. First, we determined, in a double-blind, placebocontrolled study, whether intradermal gamma globulin had efficacy in preventing recurrences of HSL. Gamma globulin was tested because an anecdotal report suggested it to be beneficial in preventing
*Neurology Service, Veterans Administration Medical Center, and the Departments of Neurology and Microbiology, University of New Mexico School of Medicine, Albuquerque, N.M. **Department of Family, Community Medicine, and Emergency Medicine, University of New Mexico School of Medicine. ***Department of Microbiology, University of New Mexico School of Medicine.
558
recurrences of HSL.6 In our double-blind study, we found that gamma globulin was not different from placebo.’ Second, we prospectively evaluated the characteristics of each person’s recurrences of HSL including facial location, severity, interval between recurrences, and possible interactions of one HSL lesion on the next HSL episode. Since no differences were found between the two treatment groups, data from both groups were pooled for the natural history analysis of frequent recurrences of HSL. MATERIALS
AND METHODS
One hundred healthy persons who reported at least eight recurrences of HSL in the preceding 2 years volunteered. Before entry into the study, all persons were examined during a recurrence of HSL for the presence of typical HSL lesions by a physician experienced in diagnosing HSL. Patients with atypical or doubtful lesions were excluded. Informed consent was obtained after the nature of the study was explained. Personswere asked to carefully document on a questionnaire each recurrence of HSL for the next 6 months, including a comparison of the severity of each outbreak of HSL with the severity of their average outbreak of HSL. Enrollment in this study occurred over a period of 3 years. The results were statistically analyzed by chi square and analysis
Recurrent herpes simplex labialis
Volume 66 Number 5
0
1
2
3
4
5
6
7
0
9
IO
11
559
12
Number of HSL Recurrences / 6 Months Fig.
Table
1.
Recurrences
of herpes
simplex labialis during the 6month study period.
I. Effect of gender and age on frequency of herpes simplex labialis Group
Total Females Males <29 years 30-54 years >.5S years
Mean HSL frequency before study (per 6 months) 3.5 3.4 3.7 4.3 3.6 2.5
+ k 2 2 i r
0.3* 0.3 1.0 0.5 0.6 0.1
Mean HSL frequency during study (per 6 months)
(82)? (63) (19) (20) (39) (23)
2.7 2.7 2.7 2.0 3.4 2.2
k 2 -t j: 2 +
0.3* 0.3 0.6 0.3 0.5 0.3
(84) (65) (19) (21) (39) (24)
Mean HSL duration during study (days) 6.5 6.6 6.3 7.5 6.2 6.1
-t 0.3* t 0.4 +_ 0.6 zt 1.0 Z!I 0.4 rf: 0.5
(72) (54) (18) (16) (35) (21)
‘Numbers represent mean + SE. t( ) is number in sample. Ten persons did not have any episodes of HSL during the study and two failed to give accurate dates of HSL outbreaks or exact number of outbreaks in preceding 2 years.
of variance. The entry HSL lesion was not included in this statistical analysis. RESULTS
Eighty-four of the 100 persons returned the completed questionnaire and were included in this analysis. Two hundred fourteen attacks of HSL were analyzed. The mean + standard error of recurrences of HSL per 6 months was 2.7 & 0.3 (Fig. 1). Neither gender nor age influenced the rate of recurrence of HSL (Table I). The mean duration & standard error of HSL lesion was 6.5 -t 0.3 days. Again, neither
gender nor age influenced the time to healing (Table I). Recurrent lesions of HSL occurred in the following lip areas: right upper, 26%; right lower, 19%; left upper, 23%; left lower, 22%; and nose, 10%. Vesicles appeared more commonly on the upper lip, but the difference was not significant. We found no significant differences in localization of HSL lesions when data were analyzed by gender or age (data not shown). The site of the next recurrent lesion of HSL seldom was in the same facial quadrant. In 45% of 138 recurrent lesions with accurate reported location, the next HSL lesion moved from one lip to the
560
Davis et al.
Table
II. Effect of a herpes simplex labialis lesion on interval to and severity of next lesion _____-
Oral ‘November
Severity of initial lesion*
Sample size
Mean duration of initial lesions (days)
Less severe than usual Usual severity More severe than usual
78 57 16
5.0 7.1 9.0
Median interval to next lesion (days1 20 17 25
Severity of next HSL lesion**
Surf 1988
(% I
Less severul--~--‘-~~------~~-Usual ~ More sew-c than usual ) severit} than usual -64 41 31
31 41 38
5 12 25
*Subjects rated each outbreak of HSL with respect to severity of their typical or average HSL lesion. **There is a statistically significant association between the severity of the initial lesion and the severity of the next lesion (p < 0.05).
other. In 47% of 88 recurrent lesions in which the side of the previous lesion was reported, the next lesion crossedthe midline to appear on the contralatera1 side. Season did not influence the frequency of recurrence: winter (December to February), 1.4 lesions/ person; spring (March to May), 1.5; summer (June to August), 1.2; and fall (September to November), 1.4 (not significant). When analyzed for separate age strata, the season also did not influence the recurrence rates. The severity of the previous HSL lesion influenced the severity of the next lesion, but not the location of the next lesion or the interval to the next lesion (Table II). No refractory period to the next outbreak of HSL was found. During the next 4 weeks after the entry HSL lesion, five persons had the next outbreak in week 1, six in week 2, sevenin week 3, and nine in week 4. DISCUSSION
In this study, we found several differences between our group with frequent recurrences of HSL and the general population. Personsin our group reported an average of 3.5 episodesof HSL per 6 months over the 2 years before the start of the study. During the study, they had an average of 2.7 episodes of HSL per 6 months. Although the episodes were not verified by viral culture, our rate of recurrence was similar to the recurrence rate reported in three other studies of persons with frequent recurrences of HSL.8,9xloHowever, the recurrence rate was markedly higher than the 0.2 to 1 episode of HSL per 6 months reported for the general population.“,‘* It appears that persons who have frequent recurrences of HSL continue to have recurrences of HSL at a higher rate than the general population. If they were part of the general population, but just at the upper end of the normal curve of recurrences of HSL, one might have expected this group to have returned to the mean during the study. We found that an outbreak of HSL did not
produce any refractory period to the next attack of HSL. Six percent of the subjects had their next attack within 1 week and 13% within 2 weeks of the entry HSL episode. Furthermore, increased severity of the previous HLS lesion, as reported by the subject, did not affect the interval to the next recurrence of HSL, affect the location of the next lesion, or reduce the severity of the next lesion. In fact, an HSL lesion that was “more severe than usual” significantly increased the likelihood that the next recurrent lesion would also be “more severe than usual.” These clinical observations have not been previously reported and suggest that large HSL lesions do not induce greater cellular or humoral immune responsesthat result in lengthening the time to next recurrence, lessening the severity of the next attack, or directing the location of the next lesion. This is consistent with another study that found the rate of occurrence of HSL lesions was not related to the magnitude of the serum herpes simplex virus antibody titer.13 The site of the next HSL lesion and the interval between attacks were found to vary markedly for any one person. In 47%, the next lesion crossedthe facial midline, and in 45%, it moved from one lip to the other. These findings and another study” suggest that the small number of persons with frequent recurrences of HSL differ biologically from members of the general population who report infrequent episodes of HSL, usually at the same facial site.3,‘4 Our findings also suggest that persons who have frequent recurrences may harbor herpes simplex virus that is latent in several different locations within both trigeminal ganglia. Virus reactivated within neurons in the different ganglion locations would then travel down different dendritic pathways to produce vesicles in different facial locations. It is interesting to speculate that these persons might harbor different herpes simplex virus strains within their trigeminal ganglia that could exacerbate at different times. This speculation is supported by the observation that whereas most trigeminal ganglia
Recurrent herpes simplex labialis
Volume 66 Number 5
harbor only one strain of herpes simplex virus,15 occasionally more than one strain has been isolated.16 This study was supported by the Research Veterans Administration Medical Center.
Service,
REFERENCES I. Nahmias AJ, Josey WE, Naib ZM, Lute CF, Duffy A. Antibodies to Herpesvirus hominis types 1 and 2 in humans. Am J Epidemiol 1970:91:539-46. 2. Ship II; Miller MF, Ram C. A retrospective study of recurrent herpes labialis (RHL) in a professional population, 1958-197 I. ORAL SURG ORAL MED ORAL PATHOL 1977; 44:723-30. 3. Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. ORAL SURG ORAL MED ORAL PATHOL 1976;41:498-507. 4. Spruance SL, Overall JC, Kern ER, Krueger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis. N Engl J Med 1977;297:69-75. 5. Corey L, Spear PG. Infections with herpes simplex viruses. N Engl J Med 1986;314:749-57. 6. Redman JC. lntradermal gamma globulin for herpetic diseases (letter). Postgrad Med 1984;75:60-4. I. Redman JC, Davis LE, McLaren LC, Skipper BJ. Intraderma1 gamma globulin for herpes labialis? Results of a doubleblind study. Postgrad Med 1986;79:315-8. 8. Aiuti F, Sirianni MC, Paganelli R, Stella A, Turbessi G, Fiorilli M. A placebo-controlled trial of thymic hormone treatment of recurrent herpes simplex labialis infection in immunodeficient hosts. Int J Clin Pharmacol Ther Toxicol 1983;21:81-6.
561
9. Milman N, Scheibel J, Jessen 0. Lysine prophylaxis in recurrent herpes simplex labialis: A double-blind, controlled crossover study. Acta Dermatovener (Stockholm) 1980; 60:85-7. 10. Bader C, Crumpacker CS, Schnipper LE, et al. The natural history of recurrent facial-oral infection with herpes simplex virus. J Infect Dis 1978;138:897-905. 11. Spoor HJ. The course and management of recurrent herpes. Cutis 1979;24:309-3, 335-6. 12. Lafferty WE, Coombs RW, Benedetti J, Critchlow C, Corey L. Recurrences after oral and genital herpes simplex virus infection. N Engl J Med 1987;316: 1444-9. 13. Higgins PG. Recurrent herpes simplex virus infections. Br J Dermatol 1974;91:11 l-3. 14. Douglas RG, Cough RB. A prospective study of chronic herpes simplex virus infection and recurrent herpes labialis in humans. Journal of Immunology 1970;104:289-95. 15. Lonsdale DM, Brown SM, Subak-Sharpe JH, et al. The polypeptide and DNA restriction enzyme profiles of spontaneous isolates of herpes simplex virus type 1 from explants of human trigeminal, superior cervical, and vagus ganglia. J Gen Virol 1979;43:151-71. 16. Lewis ME, Leung WC, Jeffrey VM, Warren KG. Detection of multiple strains of latent herpes simplex virus type 1 within individual human hosts. J Viral 1984:52:300-5. Reprint requests to: Larry E. Davis, M.D Neurology Service VA Medical Center 2100 Ridgecrest SE Albuquerque, NM 87108