Prophylaxis of varicella in high-risk children: Dose-response effect of zoster immune globulin

368

March 1981 TheJournalofPEDIATRICS

Prophylaxis of varicella in high-risk children: Dose-response effect of zoster immune globulin Immunodeficient patients who were presumed to be susceptible received zoster immune globulin prophylaxis after exposure to varicella. The highest clinical attack rate (35.9%) was seen in household contacts," the lowest attack rate (0%) was observed in children exposed at school Among household contacts, 48 of 100 patients who received high titer ZIG (reciprocal complement fixation titer >_ 2,560) developed fourfold rises in serum CF antibody between pre- and 48-hour post-treatment specimens, compared to only one of 34 patients treated with lower titer ZIG lots (P < 0.001). Patients who developed fourfold antibody rises were significantly less likely to contract clinical varicella (P < 0.01). Patients who received high titer ZIG also had significantly lower risks of death (P= 0.025) and complications (P = 0.006). Among ZIG-treated patients who contracted clinical varicella, 80% developed mild disease (< 100 pox), and the median incubation period was prolonged Immunodeficient children exposed to varicella benefit from ZIG prophylaxis and higher titer ZIG is of greatest benefit.

W a l t e r A. O r e n s t e i n , M.D.,* David L. H e y m a n n ,

M.D.,

R o b e r t J. Ellis, Ph.D., R o b e r t L. Rosenberg, M . D . , J a m e s N a k a n o ,

Ph.D.,

Neal A. H a l s e y , M.D., A t l a n t a , Ga., G a r y D. Overturf, M . D . , L o s A n g e l e s , Calif., G r e g o r y F. H a y d e n , M . D . , and J o h n J. W i t t e , M . D . , A t l a n t a , Ga.

CHICKENPOX may be associated with severe illness in children whose immune systems are compromised. 1~ Initially, attempts at passive prophylaxis of varicella in immunodeficient patients were made with commercially available immune serum globulin. In immunodeficient children exposed to chickenpox, administration of ISG sometimes led to a decreased number of skin lesions, but not a decreased rate of clinical attacks or complication rates? In healthy children, doses of as high as 0.6 ml per pound result in modification of the illness without affecting secondary clinical attack rates in families.' The lack of success of ISG in the prophylaxis of varicella in immunodeficient children led to trials of other agents that would passively transfer effective antibody. In

From the Center for Disease Control, Bureau of State Services and Bureau of Laboratories, and Los Angeles County-University of Southern California Medical Center. *Reprint address: Immunization Division, BSS, Centerfor Disease Control, Atlanta, GA 30333.

Vol. 98, No. 3, pp. 368-373

1969, Brunell and associates~ were able to prevent clinical varicella in normal siblings of ill patients by using zoster immune globulin prepared from patients convalescing from herpes zoster. Further studies showed that children Abbreviations used CF: complement fixation CNS: central nervous system FAMA: fluorescent antibody to membrane antigen GMT: geometric mean titer HT: high titer ISG: immune serum globulin LT: low titer ZIG: zoster immune globulin ZIP: zoster immune plasma CDC: Center for Disease Control V-Z: varicella-zoster AC: anticomplementary having compromised immune systems who received Z I G within 72 hours following exposure to varicella-zoster virus tended to have low clinical attack rates, mild illnesses, and low complication rates. 6-9 Similarly, low

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clinical attack and complication rates have been seen in patients who received infusions of zoster immune plasma, also collected from patients convalescing from herpes zoster# 10., In addition to the apparent benefits for prevention or modification of clinical varicella, ZIG has been shown to increase the proportion which will be subclinical infections. Using fluorescent antibody to membrane antigen titers to determine asymptomatic seroconversion in ZIGtreated household exposures, Gershon et al 8 found that 33% of ZIG recipients infected with varicella did not develop clinical illness. This is well above the estimated incidence of subclinical infection of 4% in normal children.4, Since 1972, the Center for Disease Control in Atlanta has coordinated a nationwide program for distributing and evaluating ZIG. This report describes the experience after the administration of ZIG to 533 children during the period November 6, 1974, to November 1, 1976. METHODS ZIG preparation. ZIG was prepared at CDC from plasma collected by plasmapheresis approximately seven to 28 days after onset of rash in patients with herpes zoster. The plasma was fractionated using the Cohn cold ethanol method. 1: Samples of plasma from each plasmapheresis were tested by complement fixation test performed at CDC using antigen prepared from V-Z virus grown in human embryonic fibroblasts. ~"8 Seven lots of ZIG were prepared, each using 80 to 140 units of convalescent plasma (approximately 250 ml/unit). Five units of plasma from patients convalescing from chickenpox were used in three of the lots. The total weight of plasma in each lot varied between 20.0 and 22.5 kg. Five of the seven lots were prepared from units of plasma calculated to have an approximate reciprocal CF geometric mean titer of 160; the final reciprocal CF antibody titers of these high titer ZIG lots were 2560 or 5120. Two lots were made from plasma units with reciprocal CF GMT of 40. Both of these two lots yielded low titer ZIG with reciprocal CF titer of 1280 (LT1 and LT~). ZIG administration. Both LT~ and HT ZIG were distributed in vials containing 1.25 ml with recommended dosage of one vial for each 10 kg of body weight or fraction thereof. For example, a 12 kg child and a 20 kg child would each have received 2 vials or 2.5 ml. The LT2 lol-of ZIG was administered in twice the dosage to increase the quantity of antibody. The LT1 lot of ZIG and one lot of HT ZIG were distributed simultaneously in a double-blind randomized fashion. The subsequent five lots were administered in consecutive order as produced.

Prophylaxis of varicella in high-risk children

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Table I. Criteria for release of zoster immune globulin for varicella prophylaxis A. Underlying illness or condition (any one) 1. Leukemia or lymphoma 2. Congenital or acquired immunodeficiency 3. Immunosuppressive medication 4. Newborn infant of mother with varicella B. Type of exposure to varicella or zoster patient (any one) 1. Household contact 2. Playmate contact (> 1 hour play indoors) 3. Hospital contact (in adjacent beds or same 2-4 bed room) 4. School contact (adjacent desks in same classroom or same carpool) 5. Newborn contact (newborn whose mother developed varicella less than 5 days prior to delivery) C. Negative or unknown history of prior disease D. Less than 15 years of age* E. Request made within 72 hours of exposuret *In rare instances,persons 15 to 19 years of age were treated. tWithin 72 hours of birth for newborncontacts. Requests for ZIG by physicians were made to one of 20 national consultants who evaluated the requests. If the patient met the study criteria (Table I), ZIG was dispatched immediately. Physicians of all ZIG-treated patients were asked to return clinical follow-up forms four weeks after treatment, or two weeks after illness if it occurred. Serum collections. Serum samples were requested from all ZIG recipients immediately prior to treatment ($1), 48 hours following ZIG administration ($2), and four weeks following ZIG administration or two weeks following clinical infection ($3). In patients who were exposed to a household contact, a fourth serum sample was requested three months after ZIG administration ($4). All serum samples were analyzed at CDC by the complement fixation test. Patient analysis and definition of varieella susceptible ZIG recipients. Clinical attack rates were determined for all ZIG recipients. Additionally, a group of children determined to be susceptible to varicella at the time of ZIG receipt were selected for further analysis. This latter group of children was selected on the following criteria: (1) Potential susceptibility as indicated by pretreatment CF titer of < 1:4, and (2) if varicella developed, it occurred between ten and 35 days after the identified exposure. Infants developing varicella less than ten days after birth were also included in this group, since the major indication for ZIG in neonates was the prevention of severe congenital varicella. TM A subgroup of presumed varicella-susceptible patients, household contacts, was chosen for more extensive analyses since they represented the most uniformly and intensely exposed group and at highest risk for acquired varicella. Children without

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The Journal of Pediatrics March 1981

Table II. Overall clinical attack rate, by exposure status, for ZIG-treated selected contacts* November 6, 1974November 1, 1976 Type of exposure

No. treated

No. ill

Attack rate %

Household Playmate Hospital School Newbornt Unknown

142 110 52 32 16 1

51 8 4 0 5 0

35.9 7.3 7.7 0.0 31.3 0.0

Total

353

68

19.3

*Selected patients: (1) CF Titer of $1 < 4; (2) Incubation period for illness--> 10 days and ---<35 days; (3) ZIG requested within 72 hours of exposure; (4) Clinicalfollow-upis known. tCases with incubationperiod < 10 days also included. clinical follow-up, without pretreatment serum samples, or those with serum which was anticomplementary in the CF test, were not included in the final tabulation. Complement fixation test. The CF test employed was described by Palmer and Casey 13 with varicella CF antigen prepared according to the method of Martin and Palmer. 17 Anticomplementary activity was removed or reduced by a carbon dioxide (dry ice) treatment, and high AC activity, often found in zoster immune globulin samples, was removed or reduced either by carbon dioxide treatment or by kaolin treatment consisting of five cycles of shaking and settling. TM RESULTS Patients. Five hundred and thirty-three children meeting the criteria in Table I were treated with ZIG between November 6, 1974, and November 1, 1976. Children exposed to household contacts accounted for 198 (37.1%) of the 533 patients, followed by those exposed to playmates (29.6%), hospital contacts (17.6%), and school contacts (8.1%). Newborn infants accounted for 6.8% of patients. The type of exposure for four patients was unknown. Clinical follow-up was obtained on 452 (84.8%) patients. Of these 452 patients, 90 developed clinical varicella, an overall clinical attack rate of 19.9%. Of the 452 children on whom follow-up was obtained, 99 were eliminated from analysis because pretreatment serum specimens were inadequate, pretreatment CF titers were _> 1:4, or onset of varicella rash occurred < 10 or > 35 days after the reported exposure. This left 353 children, presumed to be susceptible to varicella, on whom uniform data were available for analysis. For these 353 patients, clinical attack rates for varicella ranged from 0% among those with exposure at school to 35.9% among those with exposure in the household (Table II).

Attack rate among household contacts. Of 353 presumed varicella susceptible patients, 142 (40%) were exposed in the household; they ranged in age from 4 months to 19 years, with a mean age of 5.4 years. There were no significant differences in age distribution by lot of ZIG administered. Leukemia and lymphoma were the most common underlying illnesses (73.2%), followed by patients taking immunosuppressive medication (10.6%), other types of neoplasia (9.2%), primary immune deficiency disease (2.8%), and acquired disorders of the immune system, such as systemic lupus erythematosus (2.8%). The underlying illness was not known for two patients. The proportion of patients in each underlying disease category did not vary from lot to lot. There were no significant differences in the mean dose administered for the six lots distributed in doses of 1 vial (1.25 ml) per 10 kg of body weight or fractions thereof. The mean doses for these lots varied from 0.149 to 0.166 rnl/kg. Only the doses distributed in double the usual volume from the LT2 lot were significantly higher than in the other lots. The attack rate of clinical varicella in patients treated with either LT1 or LT2 Z I G was not significantly different from those treated with HT Z I G (Table III). Patients who developed fourfold or greater rises in C F antibody between pre ($1) and 48-hour post ($2) treatment serum specimens were protected from clinical varicella. $2 serum specimens were available from 134 of the 142 susceptible household exposures. The clinical attack rate was 22.4% among 49 patients who developed a fourfold or greater rise in CF antibody between $1 and $2 serum specimens, compared to 44.7% among 85 patients who failed to develop a fourfold increase (P < 0.01, chi square). A higher proportion of HT Z I G recipients had a fourfold rise in CF titer between S~ and S~ serum specimens than was true for LT~ and LT~ Z I G recipients (Table III). Patients treated with LT~ Z I G were significantly less likely to develop antibody rises compared to patients treated with HT Z I G (P < 0.001 chi square). Almost all of the fourfold rises (45/49) were from < 2 to 4. Severity of illness in ZIG recipients. Of the 51 susceptible household contacts who became ill, 13 (25%) had one to ten pox, 28 (55%) had 11 to 100, and 10 (20%) had more than 100. The severity of clinical illness as determined by the number of pox did not vary significantly according to antibody titer of the administered ZIG. Six patients developed complications of varicella; four had received LT~ Z I G and two, HT ZIG. Of the latter two patients, one developed pneumonia and central nervous system complications, and the second CNS varicella. The

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Prophylaxis o f varicella in high-risk children

37I

Table III. Clinical attack rates and --> 4 fold antibody rise S1-S~ in recipients of Z I G of differing CF titer Clinical attack rate

Antibody rise

Lot

Reciprocal ZIG CF titer

Total number

Number ill

% 1ll

Total numberer

No. 4-fold rises

% with rise

Low titer lot 1 Low titer lot 2* High titer lots High titer lots

1,280 1,280 2,560 5,120

23 14 85 20

9 7 30 5

39 50 35 25

21 13 80 20

0 1 37 11

0 8 46 55

*Given in twicethe volumeof the other lots (i.e. 2.5 ml/10 kg). tExcludes eight patients for whom S~ specimenswere unavailable.

complications in LTI Z I G recipients included pneumonia (2), CNS complications (1), and both pneumonia and CNS complications (1). Two of these four patients died from varicella. One death occurred in a 7-year-old boy with a history of congenital renal hypoplasia who had received a kidney transplant from his mother. He had been maintained on immunosuppressive medication during the incubation period and then developed varicella pneumonia. The other death occurred in a 13-year-old boy with reticulum cell sarcoma who was maintained on vincristine, prednisone, and radiotherapy throughout his incubation period. He developed varicella complicated by pneumonia, encephalitis, and hepatitis. Patients treated with LT1 Z I G had a significantly higher risk of complications (P = 0.006, Fisher exact test) and death (P = 0.025, Fisher exact test) when compared to HT Z I G recipients. Incubation period and subclinical varicella in ZIG recipients. In persons who developed clinical varicella, there was no correlation between titer and quantity of Z I G administered and length of the incubation period. The median incubation period between reported exposure and onset ofvaricella rash was 18 days. A single peak was present between 12 and 26 days. Five cases had incubation periods between 29 and 35 days. One of these five had a documented second exposure to varicella 14 days prior to onset of rash. A fourfold rise in CF antibody titer between either pre ($1) and three months post (S,) treatment serum specimens or between 48 hour (S~) and two-week post illness or four-week post (S~) treatment specimens was considered confirmatory laboratory evidence of V-Z infection. Such evidence was obtained in 27 of the 45 (60.0%) ill patients for whom adequate specimens were available. Ten of the 78 (12.8%) well children with adequate serum specimens also had fourfold rises in CF antibgdy, an overall subclinical infection rate of 8.1% (10/123). The rate did not vary with quantity of antibody administered. The overall proportion of laboratory a n d / o r clinically confirmed

varicella infections which were subclinical was 18.2% (10/55). Since the CF test confirmed only 60% of the cases of clinical varicella, if a similar sensitivity applied to subclinical infection, the true subclinical infection rate may be higher. DISCUSSION Initially it was hoped that ZIG efficacy could be evaluated in a prospective double-blind placebo controlled study; however, the apparent benefits of ZIG in both normal and immunodeficient patients precluded such a study: Thus, after nine years of studying ZIG, there is no definitive proof that it is effective in preventing or modifying varicella in patients whose immune systems are compromised, since no well-matched, untreated control group is available to compare to treated patients. Nonetheless, the available data permit some conclusions. The attack rate of clinical varicella among household exposures was 36%. A similar clinical attack rate has been observed in patients treated with ZIP?' 1,,. ,, The expected clinical varicella attack rate is unknown, although reported secondary attack rates of clinical varicella in normal children following household exposures have varied from 61 to 89%." 2o However, normal children may have more intense exposure and hence a higher attack rate than immunodeficient children, since parents of the latter children may be more alert to prevent contact once varicella is recognized in the household. Meyers and Witte, 9 in a prospective evaluation of patients who did not receive ZIG, either because it was unavailable or because the patient had been exposed more than 72 hours preceding the request, found that only seven of 14 (50%) immunodeficient patients contracted varicella; Geiser et al ~ found in a retrospective chart review that 14 of 14 household contacts developed clinical varicella. Although neither of these groups is strictly comparable to our own, the group reported by Meyers and Witte is probably most similar because it was composed of patients for whom ZIG was requested.

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Orenstein et al.

The incidence of clinical varicella was lower in patients in whom there was a fourfold or greater CF antibody rise demonstrated between pre- and 48-hour post-treatment specimens. These antibody rises correlated with the quantity of antibody administered, suggesting that the administration of large quantities of antibody can lower the clinical attack rate. Z I G recipients with clinical varicella usually had fewer skin lesions (80% with < 100 pox) than would be expected in healthy children/Further, children who developed complications or died were significantly more likely to have been treated with a low titer lot of ZIG. These data are similar to those o f Gershon et a l l ' who found that children who failed to demonstrate passively acquired antibody following Z I G administration were more like to develop varicella complications. The failure of most patients treated with the LT~ lot of ZIG in double the usual dose to show significant increases in CF antibody between the $1 and $2 serum specimens might be explained by a lower quantity of antibody administered from this lot. The LT2 lot was prepared from plasma with a CF GMT fourfold lower than the GMT of HT plasma. Thus the difference in final antibody titers between the LT~ and HT lots may have been slightly, though undetectably, greater than the twofold difference measured. Doubling the dose of the LT~ lot may not have yielded a quantity of antibody equivalent to HT lots. The incubation period for normal children who contract chickenpox following household exposure averages 14 to 15 days, most cases occurring within 17 days following exposure." 4. ~o Our findings indicate that ZIG treatment may prolong the interval between exposure and onset of rash in those who subsequently manifest clinical illness, and provide further evidence that administration of ZIG leads to modification of the natural illness. Our data also confirm previous reports documenting prolonged incubation periods in ZIG-treated and ZIP-treated patients.S, ~o All patients were presumed to be immunodeficient and almost all patients with malignancy were receiving chemotherapy at the time Z I G was requested. However, no attempt was made to correlate complications with the severity of underlying immune deficiency by using lymphocyte counts or other measures of immune function. Thus, it is possible that a higher incidence of complications occurred in patients treated from the LT1 lot because they were more severely immunodeficient than those treated with HT lots; however, this seems unlikely. A low subclinical infection rate for varicella is expected in normal children, based on a study by Ross' in which only 4% of household contacts did not develop illness after multiple exposures. Subclinical illness rates based on CF titer determinations have never been estimated, either

The Journal o f Pediatrics March 1981

in immunodeficient or normal patients. The subclinical infection rate may be as high as 33% following Z I G administration when infection is documented with F A M A titers. 8 The rate of subclinical irafections in Z I G treated patients (8.1%) in this study is slightly higher than that in Ross' study (4%), but lower than those studies employing F A M A titers. The F A M A titer is generally regarded to be a more sensitive indicator of immunity to varicella than the CF test. ~' ~ Unfortunately, F A M A results in this study were not reproducible and were excluded from analyses. The CF titers were reproducible in our laboratory and therefore utilized to titer sera. In this study, an attempt was made to ensure that uniform data were available on all patients and to eliminate subjects who were probably immune (i.e., patients with CF titers of _> 4). Many children with C F titers of < 4 may actually be immune, because the C F test is not a sensitive indicator of immunity. If there were a significant number of such children, this could have prevented us from observing a statistically significant difference in clinical attack rate according to antibody titer of administered ZIG. Despite the limitations of the CF test, it has been useful in demonstrating a lower attack rate in those who developed significant titers after Z I G administration, and an apparent dose-response relationship between quantity of antibody administered and development of significant CF antibody titers. Immunodeficient patients exposed to varicella benefit from ZIG administration. Further, there is a doseresponse relationship, with higher titer Z I G offering the greatest benefits. The authors gratefully acknowledge the participation of the following ZIG consultants: J. Lyle Conrad; M.D., Atlanta; A. W. Karchmer, M.D., Martin S. Hirsch, M.D., and John F. Modlin, M.D., Boston; Anne A. Gershon, M.D., New York; Richard G. Judelsohn, M.D., Buffalo; Richard Hong, M.D., and Sheldon Horowitz, M.D., Madison; Brian Lauer, M.D., C. Henry Kempe, M.D., and Kenneth Mclntosh, M.D., Denver; Moses Grossman, M.D., and Delmer Pascoe, M.D., San Francisco; Joel D. Meyers, M.D., Seattle. The authors also acknowledge the contributions by Mrs. Peggy Stoudenmire, who coordinated the collection of data, Donna Miller, who performed the CF tests, and William K. Harrell, Ph.D., and James Green, who coordinated production of ZIG. We are especially thankful to Stephen Preblud, M.D., and Alan Hinman, M.D., for their help with this manuscript. REFERENCES

1. Gordon JE: Chickenpox: An epidemiolegical review, Am J Med Sci 244:132, 1962. 2. Feldman S, Hughes WT, and Daniel CB: Varicella in children with cancer: seventy-seven cases, Pediatrics 56:388, 1975.

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