Journal of Medical Virology 37:113-115 (1992)

Low Antibody Avidity in Elderly Chickenpox Patients Barry D. Schoub, Nigel K. Blackburn, Sylvia Johnson, Jo M. McAnerney, and Bennie Miller National Institute for Virology, Department of Virology, University of the Witwatersrand, South Africa and Rietfontein Hospital, Johannesburg, South Africa

A small outbreak of chickenpox confirmed serologically in 3 elderly patients from a geriatric

mary from reactivation of VZV infection [Kangro e t al., 1991; Blackburn et al., 19911.

home is described. Disease was probably due t o exogenous reinfection, yet nevertheless the avidity of specific antibodies measured by the urea denaturation test was even lower than in primary chickenpox controls, which themselves were, as expected, significantly lower than zoster controls. In elderly individuals susceptibility t o reinfection with varicella-zoster virus (VZV) with clinical manifestation such as chickenpox may well be associated with the decay of specific humoral immunity detectable by antibodies of particularly low avidity, in contrast t o reactivation of latent VZV presenting clinically as zoster, which is related to deficiencies in specific cellular immunity. 0 1992 Wiley-Liss, Inc.

MATERIALS AND METHODS Description of Outbreak A 66-year-old female resident of a geriatric home, who had developed pyrexia 5 days earlier, was admitted to Rietfontein Hospital, Johannesburg with a disseminated vesicular rash clinically typical of chickenpox. A few days later a 76-year-old male resident and a 63year-old male staff member of the same home were admitted to Rietfontein Hospital with clinically typical chickenpox. There was no history of contact and no further cases of chickenpox or zoster. All 3 patients had mild disease but were treated with acyclovir, and all made uneventful recoveries.

KEY WORDS varicella-zoster virus, VZV, humoral immunity, cellular immunity

INTRODUCTION Chickenpox, the clinical expression of primary infection with varicella-zoster virus (VZV), is essentially a disease of childhood, with over 90% of cases presenting in individuals under 15 years of age [Centers for Disease Control, 19841 and seropositivity rates in adulthood varying from 90% [Schoub et al., 19851 to over 95% [Trlifajova et al., 19893. In contrast, zoster, the clinical manifestation of reactivation of VZV, is rare in childhood and is at least 4 times less common below the age of 50 a s in the ninth decade of life [Miller, 19801. Chickenpox is thus not unexpectedly rare in the elderly. In 1979 Rahman 119791 described a n outbreak of VZV infection in a geriatric hospital in the United Kingdom where 2 of 4 patients presented with zoster and 2 with chickenpox. A decade later Demisse and Ayres 119891 recorded a cluster of 3 elderly patients admitted to a geriatric ward with clinical diagnoses of chickenpox. We describe a small outbreak of chickenpox in 3 elderly patients, 2 of them residents and l a n employee of a geriatric home. Sera from these patients were examined by the urea denaturation test to distinguish pri0 1992 WILEY-LISS, INC.

Laboratory Investigations Unfortunately virus detection or isolation was not carried out in any of the 3 patients and laboratory diagnosis of VZV infection was confirmed by serology. Clotted blood from all 3 patients was taken within a day of admission and examined for VZV-specific IgM and IgG antibodies using a commercial ELISA test (Mecconti GmbH D-6380, Bad Hamburg). Serological results were expressed as a n ELISA ratio (ER): ER=

OD reading of test ODof cutoff



Avidity Test Specific VZV IgG antibodies in the 3 patients were examined for avidity by the urea denaturation test, together with stored sera from 9 chickenpox patients, ranging in age from 7-32 years (median = 26) and 11 zoster patients varying in age from 18-74 (median age = 32), who served a s chickenpox and varicella controls, respectively. The urea denaturation test was performed as described previously for cytomegalovirus antibodies LBlackburn et al., 19911. Briefly, patients’ serum was added to wells coated with VZV antigen. After a speci-

Accepted for publication November 21,1991. Address reprint requests to Prof. B.D. Schoub, National Institute for Virology, Private Bag X4, Sandringham 2131, South Africa.

Schoub et al.

114 5

TABLE I. Avidity Index Values of Chickenpox, Zoster, and Elderly Chickenpox Patients Patient categorya C Z EC

No.

tested 9

Avidity indices (AI) Very low Low High Mean 50% A1 1 0 3

6

aC = chickenpox controls; 2 =

2 11 0 zoster controls; EC

chickenpox patients.

I

12

3

Elderly chickenpox patients

0

Chickenpox controls Zoster controls

4

34.0% 66.1%

1 0

10.4% = elderly

3 L

0

n

5

2

fied time the wells were rinsed with a n 8 M solution of urea and soaked in this solution for 3 minutes to remove low-affinity antibodies. The wells were rinsed once in the standard rinse solution and the method continued as for a routine VZV IgG test. The absorbance readings of the standard test were compared to the readings obtained after the urea denaturation procedure, giving a n avidity index. The avidity index was expressed as a percentage calculated a s follows 10

index

the absorbance reading after urea wash = absorbance reading without urea wash

T

T

20

30

40

60

Avidity Index

'O0.

Statistical Analysis Statistical analyses were carried out by Fischer's exact test.

RESULTS Infection with VZV was confirmed serologically in all 3 elderly varicella patients with ER IgM values of 2.13, 3.39, and 1.13, and IgG ER values of 3.05, 3.08, and 2.98, respectively. The avidity tests were repeated in triplicate for the elderly chickenpox patients, and the mean AIs for each of the patients were 12.6%, 8.8%, and 9.9%) respectively. The mean A1 for all 3 of the elderly varicella patients was 10.4%. The avidity tests were done in duplicate for each of the chickenpox and the zoster control sera, and the means of each of the 2 values calculated. The AIs of the chickenpox controls ranged from 12.3 to 53.9% (mean = 34.02961, while those of the zoster controls ranged from 46.9 to 100% (mean = 66.1%).The A1 values were divided into high (>50%), low (20-50%), and very low ( ~ 2 0 % )All . 3 of the elderly chickenpox patients fell into the very low category, while 1of the 9 chickenpox and none of the 12 zoster controls were in this category (P = 0.00197). In the low category there were 6 of 9 chickenpox controls but only 1 of 12 zoster controls (P = 0.008978), while in the high category were found 11 of 12 zoster controls but only 2 of 9 chickenpox controls (P = 0.002167). The distribution of A1 values amongst the 3 groups of patients are shown in Table I and Fig. 1.

DISCUSSION The pathogenesis of reactivation of VZV following primary chickenpox has not as yet been established. Antibodies levels (including VZV-specific IgA) are

60

70

90

100

(%I

Fig. 1. Distribution of avidity indices amongst elderly chickenpox patients, chickenpox controls, and zoster controls.

maintained at normal or sometimes even raised levels in elderly and immunocompromised individuals [Miller, 1980; Gershon and Steinberg, 1981; Burke et al., 1982; Berger et al., 1981; Levy et al., 19831. However, diminished cellular immune function manifesting as reduced in-vivo skin test and in-vitro lymphoproliferative responses to VZV antigen have been demonstrated in the aged and are presumed to be related to increased incidence of zoster in elderly and immunocompromised individuals [Miller, 1980; Gershon and Steinberg, 1981; Burke et al., 1982; Berger e t al., 1981I. Immune protection from primary infection is, however, mediated by antibodies a s evidenced by the efficacy of passive immunization with specific anti-VZV immunoglobulin to exposed neonates [Miller et al., 19891 and adults [Centers for Disease Control, 19841. Exogenous reinfection does occur, although in the majority of cases it is subclinical and only detected serologically LGershon et al., 19841. Clinical reinfection is rare but has been documented following immunization and infection, despite the presence of specific antibody demonstrated by the fluorescent antibody to membrane antigen (FAMA) test, which is a n indication of immunity [Gershon et al., 19841. Respiratory transmission and establishment of infection in previously infected individuals is thought to be the mechanism for the occurrence of clusters or so-called outbreaks of zoster, although it has yet to be explained how this speculated subclinical infection could cause reactivation [Palmer et al., 1985; Editorial, 19851. The avidity of IgG antibodies to specific antigens, as measured by their resistance to denaturation by 8 M

Chickenpox in the Elderly urea, is low in the early stages of primary chickenpox infection but increases markedly in convalescence and is high in recurrent infections and reactivation [Kangro et al., 19911.However, the increase in avidity of IgG antibodies cannot be directly correlated with IgG subclasses, which do not reliably relate to primary infection or reactivation or reinfection with viruses, such as VZV and rubella [Echevarria et al., 1990; Thomas and Morgan-Capner, 19881. I t is also not clear which antibodies directed against specific proteins of the virus are responsible for neutralization, although there is some evidence that antibodies to the major glycoprotein, gpIII, may be protective [Dubey et al., 19881. Antibodies to the major glycoproteins of the virus have been shown to have higher avidity than, for example, those against internal proteins, such as the p32ip36 nucleoproteins [Kangro e t al., 19911. Loss ofhigh-avidity antibodies may thus be related to loss of protective humoral immunity. It should, however, be noted that antibodies to one of the most important of the protective glycoproteins, gpIII, are almost undetectable by the ELISA test [Grose and Litwin, 19881. In the 3 elderly chickenpox patients described above, i t has not been possible to establish definitively whether the clinical illness was due to primary exogenous infection, zoster reactivation with dissemination resembling chickenpox, or exogenous reinfection. As primary exogenous infection is very rare in elderly individuals, i t would be extremely unlikely to occur in a cluster of 3 persons of advanced age. Disseminated zoster is characteristically a severe disease with a high mortality, often associated with immunosuppression. All 3 patients presented with relatively mild, uncomplicated disease, which is consistent with exogenous reinfection [Gershon et al., 19841. It is postulated that during VZV epidemics virus circulates freely through the respiratory tracts of immune as well as nonimmune individuals. Clinical manifestations of infection in individuals who have previously been exposed to the virus would then be related to a number of host factors, including the immune status. Zoster, the reactivation of endogenous infection of neural cells, may occur in individuals with specific cellular immune deficits but adequate humoral immunity to the virus. Exogenous reinfection manifesting as chickenpox could occur in individuals whose humoral immunity may be inadequate as manifested by a drop in the avidity of specific antibodies. This return to relative susceptibility to exogenous infection may occur in elderly individuals as a result of the decay of humoral

115

immunity with the aging process, and a drop in protective antibodies, which may be detected by the presence of very low avidity antibodies.

REFERENCES Berger R, Florent G, Just M (1981): Decrease of the lymphoproliferative response to varicella-zoster virus antigen in the aged. Infection and Immunity 32:24-27. Blackburn NK, Besselaar TG, Schoub BD, OConnell KF (1991):Differentiation of primary cytomegalovirus infection from reactivation using the urea denaturation test for measuring antibody avidity. Journal of Medical Virology 335-9. Burke BL, Steele RW, Beard OW, Wood JS, Cain TD, Marmer MS (1982):Immune responses to varicella-zoster in the aged. Archives of Internal Medicine 142:291-293. Centers for Disease Control (1984): Varicella-zoster immune globulin for the prevention of chickenpox. Annals of Internal Medicine 100:859-865. Demisse A (1989):Chickenpox in the elderly. British Journal of Clinical Practice 43:422-424. Dubey L, Steinberg SP, LaRussa P, Oh P, Gershon AA (1988):Western blot analysis of antibody to varicella-zoster virus. Journal of Infectious Diseases 157:882-888. Echevarria JM, Tellez A, Martinez-Martin P (1990): Subclass distribution of the serum and intrathecal IgG antibody response in varicella-zoster virus infections. Journal of Infectious Diseases 162:621-626. Editorial (1985):Outbreaks of shingles. Lancet 21105-1106. Gershon AA, Steinberg SP, Gelb L (1984): Clinical reinfection with varicella-zoster virus. Journal of Infectious Diseases 149:137-142. Gershon AA, Steinberg SP (1981): Antibody responses to varicellazoster and the role of antibody in host defense. American Journal of the Medical Sciences 28212-17. Grose C, Litwin V (1988): Immunology of the varicella-zoster virus glycoprotein. Journal of Infectious Diseases 157:877-881. Kangro HO, Manzoor S,Harper DR (1991):Antibody avidity following varicella-zoster virus infections. Journal of Medical Virology 33:lOO-105. Levy E, Mosovitz B, Friedman M, Sarov I(1983): Detection of varicella-zoster virus-specific IgA antibodies in varicella and zoster patients and in healthy adults of various ages by solid-phase radioimmunoassay. Intervirology 20:123-128. Miller E, Cradock-Watson JE, Ridehalgh MK (1989):Outcome in newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 2:371373. Miller AE (1980): Selective decline in cellular immune response to varicella-zoster in the elderly. Neurology 30:582-587. Palmer SR, Caul EO, Donald DE, Kwantes W, Tillet H (19851: An outbreak of shingles? Lancet 2:110E-1110. Rahman M (1979): Outbreak of chickenpox and herpes zoster in a geriatric hospital. British Journal of Clinical Practice 33:291-293. Schoub BD, Johnson S,McAnerney JM (1985):Prevalence of antibodies to varicella zoster virus in healthy adults. South African Medical Journal 67:929-931. Thomas HIJ, Morgan-Capner P (1988):Specific IgG subclass antibody in rubella virus infections. Epidemiology and Infection 100:443454. Trlifajova J , Svandova E, Pokorny J , Pokorny J (1989): A laboratory study of age-related varicella incidence and prevalence in the Czech Socialist Republic. Acta Virologica 33:183-187.

Low antibody avidity in elderly chickenpox patients.

A small outbreak of chickenpox confirmed serologically in 3 elderly patients from a geriatric home is described. Disease was probably due to exogenous...
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