Varicella in Pediatric Renal Transplant Recipients

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Varicella

in Pediatric

Renal

Transplant

Recipients

Ruth Lynfield, MD5; John T. Herrin, MBBS, FRACP*; and

Robert H. Rubin, M14

ABSTRACT. As of November 1991, 8of 83 children who had received renal transplants at Massachusetts General Hospital since January 1979 required admission for

pH-mary variceila. All 8 had cutaneous manifestations of

disease, and 4 had evidence of visceral disease. Three of these 8 children received varicella zoster immune glob-ulin (VZIG) after exposure to varicella in the remaining

children, exposure was not revealed until symptoms were present. All 8 children were treated with high-dose

intravenous acydovir. Two children died of

complica-lions of varicella infecfion, induding 1 child who

re-celved VZIG on the day of exposure to varicella. Neither VZIG prophylaxis nor treatment with intravenous

acy-dovir offers complete protection against severe varicella

infection to immunosuppressed children who have re

celved organ transplants. A high priority should be given to the evaluation of alternative treatments, such as

vac-cination to the varicella virus, which could be

adminis-tered to susceptible transplant candidates, preferably

prior to transplantation. Pediatrics 199290:216-220;

var-icella, pediatric renal transplant.

ABBREVIATIONS. VZIG, varicella zoster immune globulin; AST,

aspartate aminotransferase; LDH, lactate dehydrogenase; po, by mouth; gd, every day; IV, intravenous.

Varicella is a disease of childhood, with

approxi-mately 90% of all cases occurring in children 1 to 14

years of age.”2 The varicella virus is endemic in most

communities, and it is seasonally epidemic. The virus

is highly communicable, with a secondary attack rate

close to 90% in susceptible children.3 In the normal

child, varicella is most often a benign disease; in the

immunocompromised child, however, varicella may

disseminate to visceral tissues, causing severe

morbid-ity and even death.9 Children who receive organ

transplants are particularly vulnerable to severe

var-icella infection, as they receive lifelong

immunosup-pressive therapy. Varicella zoster immune globulin

(VZIG) may ameliorate disease if given early after

viral exposure’#{176}; unfortunately, it may fail to prevent

serious disease.5 Similarly, although acyclovir may

reduce the severity of disease and may shorten the

phase of vesicle formation,”2 its protection is

incom-plete, esedally in patients with established visceral

disease.’ Here we review all known cases of primary

varicella among children who received renal

trans-From the C’S Service and Department of Medicine, Massachusetts

General Hospital, Boston.

Received for publication Aug 16, 1991; accepted Jan 15, 1992.

Reprint requests to (R.L) Infectious Disease Unit, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129.

plants at Massachusetts General Hospital between

January 1979 and November 1991 (Table).

CASE REPORTS

Patient 1, a 10-year-old boy, was readmitted 8 years after his first cadaveric renal transplant and 5 years after his second cadav-eric transplant. He was thought to have chronic rejection of this

kidney and maintained a serum creatinine level of 2.7 mg/dL. He was exposed to varicella during the course of an admission for an orthopaedic procedure and received VZIG (375 U) on the day of exposure. Seven days later, he noted abdominal pain followed by nausea and vomiting. Two days after the onset of abdominal pain, a diffuse maculopapular rash developed on his upper shoulders, arms, and back. The following day he was tachypneic (respiratory rate of 40 to 48 breaths per minute). The rash had extended to the buttocks and to the forehead and was noted to be pruritic. Labo-ratory studies disclosed the following values: serum amylase, 189 U/L; aspartate aminotransferase (AST), 990 U/L; lactate dehydro-genase (LDH), 1230 U/L; alkaline phosphatase, 21 U/L. White blood cell count was 10.4 x i0/mrn (81% polymorphonuclear leukocytes, 2% band forms, 7% lymphocytes, 1% monocytes), hematocrit was 27.7%, and platelet count was 326 X 103/mm3. A radiograph of the abdomen was negative, and an ultrasonogram

of the abdomen revealed mild ascites. Medications at this time

were prednisone, 10 mg by mouth (po) every day (qd), and aza-thioprine, 75 mg po qd (the patient’s weight was 30 kg). Azathio-prine was discontinued. On the following day he had a temperature of 38.4#{176}Cand rigors. The exanthem now had a vesicular compo-nent, and a Tzanck smear revealed multinucleated giant cells. Intravenous (N) acycbovir was started at a reduced dose of 105 mg every 8 hours (because of the development of oliguric renal failure); broad-spectrum antibiotics were begun and he was transferred to the intensive care unit. He deteriorated rapidly with progressive

tachypnea (respiratory rate of 50 to 60 breaths per minute), wors-ening liver function tests (AST level rose to 5160 U/L), and prolon-gation of the prothrombin and partial thromboplastin times. Ten and one half hours after transfer, he became unresponsive. He died shortly thereafter. Postmortem examination revealed evidence of disseminated varicella, with multiple hemorrhages in the liver and in the gastrointestinal mucosa, and with pulmonary microthrombi and congestion. Varicella zoster virus was isolated from a buffy coat culture and from a vesicular aspirate done on the day prior to death.

Patient 2, a 17-year-old boy, began to have back pain 7 days after receiving a living-related renal transplant. He returned to the hospital 2 days after the onset of back pain with adiffuse vesicular rash over his trunk, face, and thighs. In retrospect, it was deter-mined that he had been exposed to varicella 2 weeks prior to transplant. He was started on a regimen of N acyclovir, 1000 mg every 8 hours. Laboratory tests were remarkable for an AST value of 340 U/L and an LDH value of 1220 U/L. Serum creatinine level was 1 mg/dL. White blood cell count was 13.8 X 103/mm3 (66% polymorphonuclearleukocytes, 9% band forms, 19% lymphocytes, 2% monocytes). Medications at this time were prednisone, 30 mg 0 twice a day, and azathioprine, 100 mg po qd (weight 74 kg). Within 26 hours of admission, hypotension and disseminated

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Post-Hospital* Patient Weight, kg Time After Transplant Immuno-suppressive Regimen

VZIG? Year of

Varicella and Presenting

Treatment Alteration in Regimen

Outcome

Symptoms

I 30 8 y after

cadav-eric transplant no. 1, 5 y after cadavenc transplant

no. 2

Prod: 10 mg qd Aza: 75 mg qd

On the day of exposure 1987: abdomi-nal pain, nausea, vom-iting for 4 d, rash for 2 d

Acycbovir, 2doses Aza discon-tinued Disseminated infection leading to death

2 74 7 d after

living-related trans-plant

Prod: 30 mg bid Aza: 100 mg qd

No 1985: back pain

for 2 d, then vesicular rash

Acydovir

for 3 d

Aza discon-tinued Disseminated infection leading to death

3 41 4

y

after

cadav-eric trans-plant, 1 y after living-related

transplant

Prod: 7.5 mg qd Aza: 75 mg qd CyA: 150 mg qd

4 d after exposure

1990: abdomi-nab pain, back pain, vesides for 2 d

Acydovir for 14 d

Aza decreased to 25 mg qd; CyA decreased to 75 mg qd

Increase in LFTs and amylase, recovered; graft

rejec-tion 2 wk

later

4 47 11 y after

living-related tram-plant

Pred: 25 mg qod Aza: 100 mg qd

No 1991: vesicular

rash and ab-dominal pain for 12 h

Acycbovir for 14 d

Aza discon-tinued Increase in LFTs, re-covered 5 6 7 22 31 47

1 y after

living-related traits-plant

6 wk after living-related

transplant 3 y after

Prod: 9 mg qd

Aza: 50 mg qd CyA: 150 mg qd

Prod: 12.5 mg qd CyA: 200 mg qd

Prod: 15 mg qod

Aza: 100 mg qd

No

On the day of exposure

No

1988: cough for 3 d, then flank pain and vesicles 1990: vesicles

on abdomen and trunk for

2 d 1989: back pain

for 3 d, fever for 2 d, rash for 1 d

Acydovir for 7 d

. Acycbovir

for 7 d

Acycbovir

for 4 d None

None

Recovered; graft

rejec-tion 1 wk later Uneventful

recovery

Uneventful

recovery

8 24 5 y after

Prod: 5 mg qd Aza: 25 mg qd

No 1991: vesicular

rash for 7 h

Acyclovir for 7 d

None Recovered;

mild rejec-tion 1 wk later

cydosporine A; qd, every day; bid, twice a day; qod, every other day; VZIG, TABLE. Presentation and Clinical Course of Pediatric Renal Transplant Recipients With Varicella Infection at Massachusetts General

S Abbreviations: Prod, prednisone; Aza, azathioprine; CyA,

varicella zoster immune globulin; LFT, liver function test.

mortem examination revealed evidence of severe varicella infection, with disseminated intravascular coagulation, pulmonary and gas-trointestinal hemorrhages, and hepatic necrosis.

Patient 3, a 9-year-old girl, was readmitted 4 years after a cadaveric renal transplant and 1 year after a living-related renal transplant. Following this transplant her serum creatinine concen-tration stabilized at 2 to 2.5 mg/dL She received VZIG (500 U) 4 days after exposure to varicella. Fourteen days later, scalp vesides developed, followed by abdominal and back pain. Two days later, she was admitted to the hospital with ageneralized vesicular rash. Medications at the time of admission were prednisone, 7.5 mg po qd; azathiopnne, 75 mg po qd; and cyclosporine, 150 mg po qd (weight 41 kg). Laboratory findings at the time of admission revealed a white blood cell count of 11.1 X 10/mm (90% poly-morphonudear leukocytes, 5% lymphocytes, 5% monocytes), an amylase level of 213 U/L, and an AST value of 232 U/L. A chest radiograph was unremarkable. She received 1200 mg of N acycbo-vir over the first 24 hours, then 400 mg N qd, in view of renal insufficiency (serum creatinine concentration ranged from 2.4 to 4.2 mg/dL). Her azathioprine dose was decreased to 25 mg po qd (until day 1 1, when it was adjusted to 25 mg alternating with 50

mg every other day), and her cyclosporine dose was decreased to

75 mg po qd; her prednisone dose was maintained at 7.5 mg po qd. Over the initial days in the hospital, her AST level rose to a peak of 1539 U/L. She received a 14-day course of acydovir, and the disease resolved. Two weeks after recovery, a significant

epi-sode of rejection occurred, requiring intensified immunosuppres-sion. Varicella did not recur in association with antirejection thor-apy.

Patient 4, a 13-year-old boy, was readmitted 11 years after a living-related renal transplant. His varicella exposure was not iden-rifled. He had a 12-hour history of progressive abdominal pain associated with a vesicular rash over his face and trunk. On admission he had vesides on his face and trunk, and left upper-quadrant tenderness. Serum creatinine concentration was 1.6 mg/ dL, and white blood cell count was 6.3 x 103/mm3 (74% polymor-phonudear leukocytes, 20% lymphocytes, 4% monocytes). A chest radiograph was dear. Medications were prednisone, 25 mg every other day, and azathioprine, 100 mg qd (weight 47 kg). Azathio-prine was discontinued and N acydovir was started at 500 mg every 8 hours. The interVal was changed to every 12 hours, every 16hours, and then every 12 hours to adjust for renal insufficiency. Liver function tests shortly after admission revealed an AST value of 549 U/L and an LDH value of 1394 UIL. On the third hospital day AST value peaked at 2005 U/L, and LDH at 3214 U/L. Azathioprine was resumed on the sixth hospital day at adose of 50 mg and then increased to 75 mg on the seventh hospital day. He was treated with N acydovir for 14 days, and the disease resolved.

Patient 5, a 7-year-old boy, was readmitted 1 year after a living-related renal transplant. Two weeks after exposure to varicella, a dry cough developed. He sought care 3 days later, when flank pain and a vesicular rash developed. Medications at the time of admis-sion were prednisone, 9 mg po qd; azathioprine, 50 mg po qd; and cydosporine, 150 mg po qd (weight 22 kg). White blood cell count

was 12.9 x 103/mm3 (70% polymorphonudear leukocytes, 12%

band forms, 13% lymphocytes, 5% monocytes), and serum creati-nine level was 1.9 mg/dL. He had a dear chest radiograph. No

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change was made in his immunosuppressive regimen. He received 280 mg of N acydovir on the first hospital day followed by 200 mg N every 12 hours for five doses. The dose was modified for changes in renal function, and he received 100 mg every 12 hours

thereafter. He recovered uneventfully after 7 days of treatment.

One week later, a severe rejection episode led to the loss of his renal allograft.

Patient 6, a 13-year-old boy, was readmitted 6 weeks after a living-related renal transplant. On the day of exposure to varicella he received VZIG (500 U). Two weeks later, he noted a veside on his lower abdomen. Over the next 2 days he noted several more

vesicles on his abdomen and trunk and sought medical care. Laboratory fmdings at the time of admission were normal, indud-ing a serum creatinine level of 0.7 mgJdL White blood cell count was 4.4 X 103/mm3 (60% polymorphonudear leukocytes, 32% lymphocytes, 8% monocytes). Medications at the time of admission were prednisone, 12.5 mg qd, and cydosporine, 200 mg qd (weight 31 kg). His medications were not altered. He received a 7-day course of N acydovir (310 mg N every 8 hours) and had an unremarkable course.

Patient 7, a 10-year-old boy, was readmitted 3 years after a living-related renal transplant. His varicella exposure was not iden-tified. He was admitted after 3 days of lower back pain followed by fever and a generalized maculopapular exanthem with vesicular

components. White blood cell count shortly after admission was 5.5 X 103/mm3 (51% polymorphonuclear leukocytes, 39%

lympho-cytes, 9% monocytes), and serum creatinine level was 1.2 mg/dL. Medications at the time of admission induded prednisone, 15 mg every other day, and azathioprine, 100 mg qd (weight 47 kg). He was treated with N acydovir, 450 mg N every 8hours, for 4 days. No change was made in his immunosuppressive regimen. He did well, with resolution of back pain and skin lesions.

Patient 8, a 7-year-old boy, was readmitted 5 years after a living-related renal transplant. In retrospect, it was determined that sev-oral children in his class had been infected with varicella. At the time of admission he had vesides on his chest and back and a 7-hour history of rash. Laboratory findings at the time of admission

were normal, induding a serum creatinine level of 0.5 mg/dL.

White blood cell count was 6.7 X iO/mm (86% polymorphonu-dear leukocytes, 13% lymphocytes, 1% monocytes). Medications at the time of admission were prednisone, 5 mg qd, and azathio-prine, 25 mg qd (weight 24 kg). His medications were not altered. He received a 7-day course of N acyclovir (450 mg N every 8 hours) and had an unremarkable course. One week later, he had a mild episode of rejection which responded to an increase in steroid therapy.

DISCUSSION

Varicella zoster virus may disseminate widely in

the immunocompromised host, leading to

pneumo-nitis, encephalitis, hepatitis, pancreatitis, and

dissem-inated intravascular coagulation.9”3”4 Abdominal

pain may precede the development of rash.6 Severe

morbidity and even death may be seen in organ

transplant recipients, despite the use of

immunopro-phylaxis and antiviral therapy. In a study of 67

pe-diatric liver transplant recipients, McGregor et a1’

found that 14 children contracted varicella. Eight of

the 14 received zoster immune globulin, and 13 of

the 14 were treated with IV acyclovir. Despite this, 2

children died, including 1 who received acyclovir and

another who received both immunoprophylaxis and

acyclovir. In an earlier study of pediatric renal

trans-plant recipients, Feidhoff et al9 noted that 19 of 160

patients subsequently contracted varicella. Eight of

19 had severe complications, and 1 child died. Five

of the 19 received zoster immune plasma or globulin

after exposure. Nonetheless, severe varicella

devel-o_ in 2 of these children, including the child who

died. Our experience has been even more

discourag-ing. Of our 8 patients with varicella, 4 had evidence

of visceral disease and 2 of these died. One of the

children who died and another who had severe

dis-ease received VZIG after exposure. All patients were

treated with IV acyclovir, although treatment was

begun after the onset of disseminated disease in the

2 patients who died.

Treating early in the course of infection is

impor-tant. Balfour’3 found that if acyclovir was

adminis-tered to immunocompromised children within 2 days

of the appearance of rash, visceral disease did not

develop, although complications and even death

oc-curred when it was administered after the fifth day

of rash. Acyclovir should be administered

intrave-nously in transplant patients with evidence of primary

varicella, as the oral bioavailabffity is poor,’5 and the

varicella zoster virus is relatively resistant to this drug

(in vitro studies suggest that this virus is twofold to

eightfold less susceptible than herpes simplex’6).

Dos-age should be adjusted in the presence of renal

in-sufficiency.

Although varicella zoster virus has not been as well

studied as other herpesviruses (particularly cytomeg-alovirus and Epstein-Barr virus’720) in the organ

transplant recipient, it is reasonable to assume that

similar host defense mechanisms and pathogenic

fac-tors may be involved. Virus-specific cytotoxic T cells

are thought to play a crucial role in host defense

against these viruses.2’ T lymphocytes are inhibited

by cyclosporine and, to a lesser extent, by

azathio-prine.22’23 Thus, it is predictable that in the presence

of active, replicating varicella virus, the dose and

duration of cyclosporine and/or azathioprine therapy

may be a major determinant of clinical outcome.

McGregor et al7 found that high-dose cyclosporine

therapy (15 to 26 mg/kg per day) was associated with

greater morbidity and mortality from varicella than

low-dose therapy (7i to 13.7 mg/kg per day) in

pediatric liver transplant recipients. Feldhoff et al9

found an increased incidence of severe varicella in

children who continued to receive azathioprine

ther-apy for 3 or more days after the onset of viral ifiness.

In contrast, maintenance therapy with prednisone (up

to 0.5 mg/kg per day) did not appear to be associated

with an increased severity of varicella in these

pa-tients.7’9 Although severe and even fatal infections

have been described in children receiving steroids for

other conditions, many of these patients were

receiv-ing high-dose therapy.227 Therefore, modification of

immunosuppressive therapy-especially

discontinu-ing #{224}zathioprine and adjusting high-dose

cyclospor-ine during the acute ifiness-may reduce the

inci-dence of severe infection. However, these

modifica-tions may fail to affect the course of rapidly

progressive disease. It is likely that the intensity of

immunosuppression prior to infection is at least as

important as the intensity of immunosuppression

after infection in determining clinical outcome. The

high level of immunosuppression in patient 2 at the

onset of his infection presumably accounted for the

severity of his infection. The severity of infection in

patient 1 is less clear, and it may be related to the

cumulative effect of years of immunosuppressive

therapy that included daily prednisone.

Prevention of clinical disease would be preferable

(4)

disease may occur despite the use of

immunoprophy-laxis. Of our 48 pediatric patients who received

trans-plants since 1985, 6 children have had varicella, 2

despite the administration of VZIG. Among these 48

patients, VZIG was given to 9 who had a single

exposure, and in 1 of these disease subsequently

developed. VZIG was administered to 3 others

mul-tiple times for multiple exposures, and severe disease

developed in 1 of these (patient 3). One alternative,

despite its poor bioavailability, might be high-dose

oral acyclovir in addition to, or instead of, VZIG

prophylaxis. However, the disadvantage of both

VZIG and oral acyclovir is that a seronegative child

is likely to encounter the varicella virus on multiple occasions as he or she returns to a normal life

follow-ing organ transplantation. In addition, these

treat-ments are cumbersome (administration of VZIG

re-quires a prompt visit to a physician’s office or a

hospital) and expensive. Lastly, exposures may be

unknown to the child or his or her parents (patients

4 and 7), or recognized only in retrospect (patients 2,

5, and 8). A more lasting strategy is badly needed.

Active immunization may provide a solution.

A live, attenuated varicella vaccine was developed

in Japan in the early 19705.28 Takahashi29

adminis-tered the vaccine to 171 children with nephrotic

syn-drome, 106 of whom were receiving steroid therapy.

Serological response was detected in almost all, and

no serious clinical reactions were observed. Broyer

and Boudailliez3#{176} vaccinated seronegative uremic

chil-then at least 2 months prior to renal transplantation.

Twenty of 23 seronegative children who received the

Oka strain vaccine seroconverted, although antibody

titers were low. Antibody titers rose in 4 of 5 children

after revaccination. Titers also rose in 41 of 47 uremic

children who had positive serological responses prior

to vaccination. Among patients who received vaccine,

there were five cases of mild varicella. Further studies

assessing time of vaccination, number of doses, side

effects, and safety should be undertaken in children

who are transplant candidates. These studies should

include the efficacy of vaccine in protecting patients

who demonstrate seroconversion with vaccine, since

superinfection of seropositive individuals (from

infec-tion with wild-type virus) has been described.3’

The direct effects of primary varicella in these renal

transplant patients is obvious. What is of further

concern is that herpesvirus infection can have indirect

effects as well. There is increasing evidence that the

closely related cytomegalovirus can induce allograft injury3235 in patients undergoing renal, cardiac, liver,

and lung transplants. The mechanisms postulated to

account for this effect include molecular mimicry and

the elaboration of cytokines in response to the

sys-temic viral infection. The finding in this series of three

patients with allograft dysfunction in association with

varicella infection raises the possibility of varicella

zoster virus also causing this effect-all the more

reason for developing an effective preventive strategy

for this problem.

In conclusion, our experience has indicated a high

morbidity and mortality rate among pediatric renal

transplant recipients who are infected with primary

varicella. Susceptible children should be given VZIG

upon exposure to the virus and admitted for IV

acy-clovir therapy at the first sign of infection. Modifica-tion of immunosuppressive therapy, especially

dis-continuation of azathioprine and adjustment of

high-dose cyclosporine during the acute illness, may reduce

the severity of illness. However, progression to severe

disease and death can still occur even if these

meas-ures are taken. In addition, the clinician must be alert

to the possibility of subsequent graft dysfunction. A

high priority should be given to the evaluation of the

efficacy of varicella vaccine in seronegative children

with end-stage renal or hepatic disease prior to and

following organ transplantation.

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ABSTRACT

CDC. International Task Force for Disease Eradication. JAMA. 1992;267:1053.

The International Task Force for Disease Eradication (ITFDE) was formed in 1988

to systematically evaluate the potential for global eradicability of candidate diseases,

identify specific bathers to their eradication that might be surmounted, and promote

eradication efforts. In its first meetings in 1989 the ITFDE determined that two of

eight diseases examined were eradicable (polio and dracunculiasis) and three others

were. candidates for elimination of transmission or clinical symptoms. This report

summarizes the results of the third and fourth meetings in 1990 and 1991 in which

the eradicability of seven other diseases were evaluated. These were mumps, rubella,

hepatitis

B, neonatal tetanus, diphtheria, pertussis, and yellow fever. Mumps and

rubella are probably eradicable, and eradication is economically feasible because of

MMR vaccine availability. Hepatitis B transmission can be eliminated over decades

by universal vaccination. Neonatal tetanus is completely preventable but cannot be

eradicated. Diphtheria might eventually be eradicable. Pertussis is not eradicable

but better control could be obtained by vaccine improvement and more thorough

study of the disease’s epidemiology in developing countries. Yellow fever is not

eradicable

but

better vaccine use could eliminate yellow fever in urban areas. The

ITFDE also endorsed programs to use mass chemotherapy with broad-spectrum

anthelminthics to reduce the burden of disease caused by schistosomiasis, ascariasis,

hookworm

disease,

and

trichuriasis.

The

1991 World Health Assembly adopted a

resolution to eradicate dracunculiasis by the end of 1995 and leprosy elimination

by the year 2000.

Submitted by Karen Olness, MD

(6)

1992;90;216

Pediatrics

Ruth Lynfield, John T. Herrin and Robert H. Rubin